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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'.
|
Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.
1 CASE REPORT
A 28‐year‐old female, with her third pregnancy (one completed to term and one spontaneous abortion with unknown cause) at 39 weeks of gestational age and with a history of CPVT type 1 (pathological mutation c.506G > A in the ryanodine receptor [RYR2] gene) (Hsueh, Weng, & Chen, 2006), underwent secondary prevention single‐chamber, single‐coil Boston Scientific Energen implantable cardioverter defibrillator (ICD) placement after she had a sudden cardiac arrest at 23 years of age. The cardiac arrest occurred while the patient was driving, and she was found to be in ventricular tachyarrhythmia by the police. At that point, etiology of the arrest had not been determined and genetic testing had not been performed due to cost limitations.
Of note, the patient's first pregnancy and vaginal delivery occurred prior to her episode of sudden cardiac arrest. These events were uncomplicated and resulted in a child who had sudden cardiac death at 2 years of age (previously asymptomatic); autopsy did not show any abnormalities and DNA testing diagnosed CPVT due to a RyR2 mutation. This eventually led to the genetic evaluation and diagnosis in our patient.
Our patient presented at 23 weeks of gestational age for a fetal cardiology evaluation. She was asymptomatic, except for occasional lower extremities edema. Her cardiovascular examination was normal. She was taking metoprolol 25 mg daily and flecainide 50 mg twice daily before, and it was continued throughout the entire pregnancy. Her ICD was programmed with VVI pacing at 35 bpm, with a ventricular tachycardia (VT) monitor zone at 190 bpm and only one therapy zone of a ventricular fibrillation (VF) zone at 240bpm (anti‐tachycardia pacing [ATP] only during charge, then shock). Her fetal echocardiography was normal. During follow‐up, interrogation of ICD showed no history of ATP or shock therapy delivered. It also demonstrated 3 episodes of non‐sustained VT (NSVT) (9–18 s at rates of 217–254 bpm) in the first trimester. Episodes of NSVT became more frequent (about once a week from 29 to 33 WGA) and she remained asymptomatic during these events. ICD settings and medications doses were kept unchanged throughout the pregnancy. Given the episodes of NSVT, the metoprolol was increased to 25 mg twice daily.
A multidisciplinary meeting, attended by maternal fetal medicine, cardiology (general, fetal, and electrophysiology), anesthesiology, intensive care (cardiovascular [CVICU] and neonatal [NICU]), and social work, was held to discuss the case. It was agreed to have a route and timing of delivery based on the usual indications, with follow‐up by maternal fetal medicine every 2 weeks until 36 WGA, then weekly thereafter. Serial ultrasound assessment to monitor fetal growth and a repeated fetal echocardiogram was scheduled at 30 WGA.
For labor and delivery, the plan was arranged as follows: Care team huddle to ensure all team members were in agreement with the management plan.
Collect cord blood sample for genetic testing for CPVT (RyR2).
Newborn to be monitored in the NICU for risk of arrhythmia and hypoglycemia. Mother opted for breastfeeding to provide beta‐blockade to the newborn, understanding this may be suboptimal.
Early epidural anesthesia and prophylactic dexmedetomidine were recommended for sympathetic suppression.
Continuous cardiovascular monitoring.
Avoidance of sympathomimetics (i.e., terbutaline, epinephrine, and methergine) for the usual labor indications; phenylephrine was the recommended vasopressor if needed.
Electrolytes goal: magnesium >2 mg/dl, ionized calcium >4.5 mg/dl, and potassium >3.5 mg/dl. This was to prevent confounding causes of ventricular ectopy.
Esmolol infusion to be initiated depending on the last dose of metoprolol and ectopic burden.
Flecainide to be continued as scheduled and additional doses could be considered for increased ectopic burden.
ICD lower ventricular pacing rate adjustment to improve rate regulation (pacing at higher rates).
If surgical delivery, ICD shock setting should be turned off to avoid possible inappropriate therapy delivery secondary to cauterizer. If so, external defibrillator pads should be placed.
Maintain open communication with the patient throughout labor to promote the least possible stressful environment.
Two CVICU nurses to provide collaborative care during labor and delivery.
She was admitted at 39 weeks of gestational age for induction of labor. Her ICD interrogation showed two episodes of NSVT in the week prior to admission. During labor, an epidural with bupivacaine was placed, sympathomimetic medication was avoided, and infusions of dexmedetomidine at 0.1 mcg/kg/min and esmolol at 50 mcg/kg/min were started. Given increased polymorphic PVC burden (bigeminy), esmolol was up‐titrated to 150 mcg/kg/min and the ventricular pacing rate was increased to 100 bpm resulting in suppression of ectopy (Figure 1). She delivered a 2608 g female without complications. Esmolol and dexmedetomidine infusions were gradually weaned off within the next 12 hr after metoprolol was restarted. Ventricular pacing was set to baseline configurations 24 hr postpartum. Neonate was observed in the NICU for 48 hr without symptoms. Genetic testing from cord blood was obtained, and results were negative for the maternal mutation.
Figure 1 PVC burden. a, Premature ventricular contractions (PVC) with trigeminy pattern. b, Histogram with decreasing PVC burden after increasing esmolol dose
2 DISCUSSION
Catecholaminergic polymorphic ventricular tachycardia is a rare inherited rhythm disorder with an estimated prevalence of about 0.1 per 1,000 people. It could be associated with autosomal dominant transmission (RyR2 gene mutation, CPVT 1) or autosomal recessive transmission (CASQ2 gene mutation, CPVT 2) (Priori, Wilde, & Horie, 2013). This channelopathy is caused by a mutation that provokes excessive intramyocardial calcium release in the setting of a catecholamine surge, and presents with ventricular tachycardia/fibrillation during exercise or emotional stress that can variably manifest from palpitations to sudden death. Pregnancy induces several hormonal, physiologic, and autonomic changes, including increased cardiovascular response to circulating catecholamines (Barron, Mujais, Zinaman, Bravo, & Lindheimer, 1986), and the peripartum is a stage that carries a significant amount of emotional and physical stress.
There is very limited literature regarding the management of patients with CPVT during the peripartum period. Our literature search found only four case reports describing their experience with labor and delivery in patients with polymorphic VT (Ahmed & Phillips, 2016; Burrows, Fox, Biblo, & Roth, 2013; Friday, Moak, Fries, & Iqbal, 2015; Gogle & Kemp, 2018). Given that this is a rare clinical scenario, and there are a lack of guidelines for its management, approaches have varied within all cases reported, including a clinical dilemma about the need to treat or not to treat an asymptomatic patient (Kotschet, Hunter, Kroushev, & Wallace, 2017).
Although there are conflicting data about the amount of catecholaminergic surge in vaginal versus cesarean delivery, research has shown that maternal levels of catecholamines are higher during vaginal delivery compared with cesarean section (Irestedt, Lagercrantz, Hjemdahl, Hagnevik, & Belfrage, 1982); however, the combined pregnancy and postpartum arrhythmic risk in CPVT patients may not be elevated compared with the nonpregnant period (Cheung, Lieve, & Roston, 2019; Roston, van der Werf, & Cheung, 2020). It is known that epidural anesthesia during labor reduces maternal catecholamine levels, probably by eliminating the psychological and physical stress associated with painful uterine contractions (Shnider et al., 1983), reason why our management included early application of this therapy.
Our case presented with a previous history of uncomplicated vaginal delivery that occurred before her cardiac arrest. Although not hemodynamically significant, there was an increase in the frequency of NSVT toward the end of the pregnancy and this was more noticeable during the labor, despite early epidural anesthesia and sympathetic suppression. This increment in her ectopic burden improved after beta‐blockade increase and adjustment of the ventricular pacing rate.
3 CONCLUSION
Defining a clear multidisciplinary plan, including anticipated escalation of care for possible complications, helped provide an effective approach to treat this unusual situation on a rare condition and created a level of familiarity among the care providers that certainly contributed to deliver a safer and less stressful experience for both, patient and providers.
CONFLICT OF INTEREST
The authors declare that there are no relevant or material financial interests that relate to disclose.
AUTHOR CONTRIBUTION
All authors participated in writing and editing the manuscript.
ETHICS
The Institutional Review Board of the University of Minnesota waived the need for ethics approval and the need to obtain consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this non‐interventional study.
|
ESMOLOL HYDROCHLORIDE, FLECAINIDE ACETATE, METOPROLOL
|
DrugsGivenReaction
|
CC BY
|
32978983
| 16,659,519
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Live birth'.
|
Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.
1 CASE REPORT
A 28‐year‐old female, with her third pregnancy (one completed to term and one spontaneous abortion with unknown cause) at 39 weeks of gestational age and with a history of CPVT type 1 (pathological mutation c.506G > A in the ryanodine receptor [RYR2] gene) (Hsueh, Weng, & Chen, 2006), underwent secondary prevention single‐chamber, single‐coil Boston Scientific Energen implantable cardioverter defibrillator (ICD) placement after she had a sudden cardiac arrest at 23 years of age. The cardiac arrest occurred while the patient was driving, and she was found to be in ventricular tachyarrhythmia by the police. At that point, etiology of the arrest had not been determined and genetic testing had not been performed due to cost limitations.
Of note, the patient's first pregnancy and vaginal delivery occurred prior to her episode of sudden cardiac arrest. These events were uncomplicated and resulted in a child who had sudden cardiac death at 2 years of age (previously asymptomatic); autopsy did not show any abnormalities and DNA testing diagnosed CPVT due to a RyR2 mutation. This eventually led to the genetic evaluation and diagnosis in our patient.
Our patient presented at 23 weeks of gestational age for a fetal cardiology evaluation. She was asymptomatic, except for occasional lower extremities edema. Her cardiovascular examination was normal. She was taking metoprolol 25 mg daily and flecainide 50 mg twice daily before, and it was continued throughout the entire pregnancy. Her ICD was programmed with VVI pacing at 35 bpm, with a ventricular tachycardia (VT) monitor zone at 190 bpm and only one therapy zone of a ventricular fibrillation (VF) zone at 240bpm (anti‐tachycardia pacing [ATP] only during charge, then shock). Her fetal echocardiography was normal. During follow‐up, interrogation of ICD showed no history of ATP or shock therapy delivered. It also demonstrated 3 episodes of non‐sustained VT (NSVT) (9–18 s at rates of 217–254 bpm) in the first trimester. Episodes of NSVT became more frequent (about once a week from 29 to 33 WGA) and she remained asymptomatic during these events. ICD settings and medications doses were kept unchanged throughout the pregnancy. Given the episodes of NSVT, the metoprolol was increased to 25 mg twice daily.
A multidisciplinary meeting, attended by maternal fetal medicine, cardiology (general, fetal, and electrophysiology), anesthesiology, intensive care (cardiovascular [CVICU] and neonatal [NICU]), and social work, was held to discuss the case. It was agreed to have a route and timing of delivery based on the usual indications, with follow‐up by maternal fetal medicine every 2 weeks until 36 WGA, then weekly thereafter. Serial ultrasound assessment to monitor fetal growth and a repeated fetal echocardiogram was scheduled at 30 WGA.
For labor and delivery, the plan was arranged as follows: Care team huddle to ensure all team members were in agreement with the management plan.
Collect cord blood sample for genetic testing for CPVT (RyR2).
Newborn to be monitored in the NICU for risk of arrhythmia and hypoglycemia. Mother opted for breastfeeding to provide beta‐blockade to the newborn, understanding this may be suboptimal.
Early epidural anesthesia and prophylactic dexmedetomidine were recommended for sympathetic suppression.
Continuous cardiovascular monitoring.
Avoidance of sympathomimetics (i.e., terbutaline, epinephrine, and methergine) for the usual labor indications; phenylephrine was the recommended vasopressor if needed.
Electrolytes goal: magnesium >2 mg/dl, ionized calcium >4.5 mg/dl, and potassium >3.5 mg/dl. This was to prevent confounding causes of ventricular ectopy.
Esmolol infusion to be initiated depending on the last dose of metoprolol and ectopic burden.
Flecainide to be continued as scheduled and additional doses could be considered for increased ectopic burden.
ICD lower ventricular pacing rate adjustment to improve rate regulation (pacing at higher rates).
If surgical delivery, ICD shock setting should be turned off to avoid possible inappropriate therapy delivery secondary to cauterizer. If so, external defibrillator pads should be placed.
Maintain open communication with the patient throughout labor to promote the least possible stressful environment.
Two CVICU nurses to provide collaborative care during labor and delivery.
She was admitted at 39 weeks of gestational age for induction of labor. Her ICD interrogation showed two episodes of NSVT in the week prior to admission. During labor, an epidural with bupivacaine was placed, sympathomimetic medication was avoided, and infusions of dexmedetomidine at 0.1 mcg/kg/min and esmolol at 50 mcg/kg/min were started. Given increased polymorphic PVC burden (bigeminy), esmolol was up‐titrated to 150 mcg/kg/min and the ventricular pacing rate was increased to 100 bpm resulting in suppression of ectopy (Figure 1). She delivered a 2608 g female without complications. Esmolol and dexmedetomidine infusions were gradually weaned off within the next 12 hr after metoprolol was restarted. Ventricular pacing was set to baseline configurations 24 hr postpartum. Neonate was observed in the NICU for 48 hr without symptoms. Genetic testing from cord blood was obtained, and results were negative for the maternal mutation.
Figure 1 PVC burden. a, Premature ventricular contractions (PVC) with trigeminy pattern. b, Histogram with decreasing PVC burden after increasing esmolol dose
2 DISCUSSION
Catecholaminergic polymorphic ventricular tachycardia is a rare inherited rhythm disorder with an estimated prevalence of about 0.1 per 1,000 people. It could be associated with autosomal dominant transmission (RyR2 gene mutation, CPVT 1) or autosomal recessive transmission (CASQ2 gene mutation, CPVT 2) (Priori, Wilde, & Horie, 2013). This channelopathy is caused by a mutation that provokes excessive intramyocardial calcium release in the setting of a catecholamine surge, and presents with ventricular tachycardia/fibrillation during exercise or emotional stress that can variably manifest from palpitations to sudden death. Pregnancy induces several hormonal, physiologic, and autonomic changes, including increased cardiovascular response to circulating catecholamines (Barron, Mujais, Zinaman, Bravo, & Lindheimer, 1986), and the peripartum is a stage that carries a significant amount of emotional and physical stress.
There is very limited literature regarding the management of patients with CPVT during the peripartum period. Our literature search found only four case reports describing their experience with labor and delivery in patients with polymorphic VT (Ahmed & Phillips, 2016; Burrows, Fox, Biblo, & Roth, 2013; Friday, Moak, Fries, & Iqbal, 2015; Gogle & Kemp, 2018). Given that this is a rare clinical scenario, and there are a lack of guidelines for its management, approaches have varied within all cases reported, including a clinical dilemma about the need to treat or not to treat an asymptomatic patient (Kotschet, Hunter, Kroushev, & Wallace, 2017).
Although there are conflicting data about the amount of catecholaminergic surge in vaginal versus cesarean delivery, research has shown that maternal levels of catecholamines are higher during vaginal delivery compared with cesarean section (Irestedt, Lagercrantz, Hjemdahl, Hagnevik, & Belfrage, 1982); however, the combined pregnancy and postpartum arrhythmic risk in CPVT patients may not be elevated compared with the nonpregnant period (Cheung, Lieve, & Roston, 2019; Roston, van der Werf, & Cheung, 2020). It is known that epidural anesthesia during labor reduces maternal catecholamine levels, probably by eliminating the psychological and physical stress associated with painful uterine contractions (Shnider et al., 1983), reason why our management included early application of this therapy.
Our case presented with a previous history of uncomplicated vaginal delivery that occurred before her cardiac arrest. Although not hemodynamically significant, there was an increase in the frequency of NSVT toward the end of the pregnancy and this was more noticeable during the labor, despite early epidural anesthesia and sympathetic suppression. This increment in her ectopic burden improved after beta‐blockade increase and adjustment of the ventricular pacing rate.
3 CONCLUSION
Defining a clear multidisciplinary plan, including anticipated escalation of care for possible complications, helped provide an effective approach to treat this unusual situation on a rare condition and created a level of familiarity among the care providers that certainly contributed to deliver a safer and less stressful experience for both, patient and providers.
CONFLICT OF INTEREST
The authors declare that there are no relevant or material financial interests that relate to disclose.
AUTHOR CONTRIBUTION
All authors participated in writing and editing the manuscript.
ETHICS
The Institutional Review Board of the University of Minnesota waived the need for ethics approval and the need to obtain consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this non‐interventional study.
|
ESMOLOL HYDROCHLORIDE, FLECAINIDE ACETATE, METOPROLOL
|
DrugsGivenReaction
|
CC BY
|
32978983
| 16,659,519
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'.
|
Peripartum management of a patient with catecholaminergic polymorphic ventricular tachycardia.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal cardiac channelopathy characterized by episodes of ventricular tachycardia (VT) during exercise or in stressful situations. As the peripartum period creates a stressful environment, we describe our approach of this rare condition in a very common situation, child birth.
1 CASE REPORT
A 28‐year‐old female, with her third pregnancy (one completed to term and one spontaneous abortion with unknown cause) at 39 weeks of gestational age and with a history of CPVT type 1 (pathological mutation c.506G > A in the ryanodine receptor [RYR2] gene) (Hsueh, Weng, & Chen, 2006), underwent secondary prevention single‐chamber, single‐coil Boston Scientific Energen implantable cardioverter defibrillator (ICD) placement after she had a sudden cardiac arrest at 23 years of age. The cardiac arrest occurred while the patient was driving, and she was found to be in ventricular tachyarrhythmia by the police. At that point, etiology of the arrest had not been determined and genetic testing had not been performed due to cost limitations.
Of note, the patient's first pregnancy and vaginal delivery occurred prior to her episode of sudden cardiac arrest. These events were uncomplicated and resulted in a child who had sudden cardiac death at 2 years of age (previously asymptomatic); autopsy did not show any abnormalities and DNA testing diagnosed CPVT due to a RyR2 mutation. This eventually led to the genetic evaluation and diagnosis in our patient.
Our patient presented at 23 weeks of gestational age for a fetal cardiology evaluation. She was asymptomatic, except for occasional lower extremities edema. Her cardiovascular examination was normal. She was taking metoprolol 25 mg daily and flecainide 50 mg twice daily before, and it was continued throughout the entire pregnancy. Her ICD was programmed with VVI pacing at 35 bpm, with a ventricular tachycardia (VT) monitor zone at 190 bpm and only one therapy zone of a ventricular fibrillation (VF) zone at 240bpm (anti‐tachycardia pacing [ATP] only during charge, then shock). Her fetal echocardiography was normal. During follow‐up, interrogation of ICD showed no history of ATP or shock therapy delivered. It also demonstrated 3 episodes of non‐sustained VT (NSVT) (9–18 s at rates of 217–254 bpm) in the first trimester. Episodes of NSVT became more frequent (about once a week from 29 to 33 WGA) and she remained asymptomatic during these events. ICD settings and medications doses were kept unchanged throughout the pregnancy. Given the episodes of NSVT, the metoprolol was increased to 25 mg twice daily.
A multidisciplinary meeting, attended by maternal fetal medicine, cardiology (general, fetal, and electrophysiology), anesthesiology, intensive care (cardiovascular [CVICU] and neonatal [NICU]), and social work, was held to discuss the case. It was agreed to have a route and timing of delivery based on the usual indications, with follow‐up by maternal fetal medicine every 2 weeks until 36 WGA, then weekly thereafter. Serial ultrasound assessment to monitor fetal growth and a repeated fetal echocardiogram was scheduled at 30 WGA.
For labor and delivery, the plan was arranged as follows: Care team huddle to ensure all team members were in agreement with the management plan.
Collect cord blood sample for genetic testing for CPVT (RyR2).
Newborn to be monitored in the NICU for risk of arrhythmia and hypoglycemia. Mother opted for breastfeeding to provide beta‐blockade to the newborn, understanding this may be suboptimal.
Early epidural anesthesia and prophylactic dexmedetomidine were recommended for sympathetic suppression.
Continuous cardiovascular monitoring.
Avoidance of sympathomimetics (i.e., terbutaline, epinephrine, and methergine) for the usual labor indications; phenylephrine was the recommended vasopressor if needed.
Electrolytes goal: magnesium >2 mg/dl, ionized calcium >4.5 mg/dl, and potassium >3.5 mg/dl. This was to prevent confounding causes of ventricular ectopy.
Esmolol infusion to be initiated depending on the last dose of metoprolol and ectopic burden.
Flecainide to be continued as scheduled and additional doses could be considered for increased ectopic burden.
ICD lower ventricular pacing rate adjustment to improve rate regulation (pacing at higher rates).
If surgical delivery, ICD shock setting should be turned off to avoid possible inappropriate therapy delivery secondary to cauterizer. If so, external defibrillator pads should be placed.
Maintain open communication with the patient throughout labor to promote the least possible stressful environment.
Two CVICU nurses to provide collaborative care during labor and delivery.
She was admitted at 39 weeks of gestational age for induction of labor. Her ICD interrogation showed two episodes of NSVT in the week prior to admission. During labor, an epidural with bupivacaine was placed, sympathomimetic medication was avoided, and infusions of dexmedetomidine at 0.1 mcg/kg/min and esmolol at 50 mcg/kg/min were started. Given increased polymorphic PVC burden (bigeminy), esmolol was up‐titrated to 150 mcg/kg/min and the ventricular pacing rate was increased to 100 bpm resulting in suppression of ectopy (Figure 1). She delivered a 2608 g female without complications. Esmolol and dexmedetomidine infusions were gradually weaned off within the next 12 hr after metoprolol was restarted. Ventricular pacing was set to baseline configurations 24 hr postpartum. Neonate was observed in the NICU for 48 hr without symptoms. Genetic testing from cord blood was obtained, and results were negative for the maternal mutation.
Figure 1 PVC burden. a, Premature ventricular contractions (PVC) with trigeminy pattern. b, Histogram with decreasing PVC burden after increasing esmolol dose
2 DISCUSSION
Catecholaminergic polymorphic ventricular tachycardia is a rare inherited rhythm disorder with an estimated prevalence of about 0.1 per 1,000 people. It could be associated with autosomal dominant transmission (RyR2 gene mutation, CPVT 1) or autosomal recessive transmission (CASQ2 gene mutation, CPVT 2) (Priori, Wilde, & Horie, 2013). This channelopathy is caused by a mutation that provokes excessive intramyocardial calcium release in the setting of a catecholamine surge, and presents with ventricular tachycardia/fibrillation during exercise or emotional stress that can variably manifest from palpitations to sudden death. Pregnancy induces several hormonal, physiologic, and autonomic changes, including increased cardiovascular response to circulating catecholamines (Barron, Mujais, Zinaman, Bravo, & Lindheimer, 1986), and the peripartum is a stage that carries a significant amount of emotional and physical stress.
There is very limited literature regarding the management of patients with CPVT during the peripartum period. Our literature search found only four case reports describing their experience with labor and delivery in patients with polymorphic VT (Ahmed & Phillips, 2016; Burrows, Fox, Biblo, & Roth, 2013; Friday, Moak, Fries, & Iqbal, 2015; Gogle & Kemp, 2018). Given that this is a rare clinical scenario, and there are a lack of guidelines for its management, approaches have varied within all cases reported, including a clinical dilemma about the need to treat or not to treat an asymptomatic patient (Kotschet, Hunter, Kroushev, & Wallace, 2017).
Although there are conflicting data about the amount of catecholaminergic surge in vaginal versus cesarean delivery, research has shown that maternal levels of catecholamines are higher during vaginal delivery compared with cesarean section (Irestedt, Lagercrantz, Hjemdahl, Hagnevik, & Belfrage, 1982); however, the combined pregnancy and postpartum arrhythmic risk in CPVT patients may not be elevated compared with the nonpregnant period (Cheung, Lieve, & Roston, 2019; Roston, van der Werf, & Cheung, 2020). It is known that epidural anesthesia during labor reduces maternal catecholamine levels, probably by eliminating the psychological and physical stress associated with painful uterine contractions (Shnider et al., 1983), reason why our management included early application of this therapy.
Our case presented with a previous history of uncomplicated vaginal delivery that occurred before her cardiac arrest. Although not hemodynamically significant, there was an increase in the frequency of NSVT toward the end of the pregnancy and this was more noticeable during the labor, despite early epidural anesthesia and sympathetic suppression. This increment in her ectopic burden improved after beta‐blockade increase and adjustment of the ventricular pacing rate.
3 CONCLUSION
Defining a clear multidisciplinary plan, including anticipated escalation of care for possible complications, helped provide an effective approach to treat this unusual situation on a rare condition and created a level of familiarity among the care providers that certainly contributed to deliver a safer and less stressful experience for both, patient and providers.
CONFLICT OF INTEREST
The authors declare that there are no relevant or material financial interests that relate to disclose.
AUTHOR CONTRIBUTION
All authors participated in writing and editing the manuscript.
ETHICS
The Institutional Review Board of the University of Minnesota waived the need for ethics approval and the need to obtain consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this non‐interventional study.
|
ESMOLOL HYDROCHLORIDE, FLECAINIDE ACETATE, METOPROLOL
|
DrugsGivenReaction
|
CC BY
|
32978983
| 16,659,519
|
2021-03
|
What was the administration route of drug 'PALBOCICLIB'?
|
Safety of palbociclib concurrent with palliative pelvic radiotherapy: discussion of a case of increased toxicity and brief review of literature.
Several cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are indicated in the treatment of metastatic hormone receptor-positive (HR)/ human epidermal growth factor receptor 2 (HER2) negative breast cancer which includes palbociclib, ribociclib and abemaciclib. Pelvic radiation therapy (RT) is often indicated for symptomatic or progressive bone metastasis. There are limited data on concurrent use of CDK4/6 inhibitors with pelvic RT with few retrospective studies in the literature involving a small number of patients. The major side effects of these agents include haematological toxicities, while non-haematological toxicities are less severe. There are concerns for an increased possibility of synergistic toxicity with concurrent use of CDK4/6 inhibitors with pelvic RT. Here we describe an instance of acute grade 3 gastrointestinal toxicity and discuss the relevant literature. A 77-year-old lady treated with palliative conventional RT 30 Gy/ 10 fractions concurrently with palbociclib to left hemipelvis and proximal femur, developed severe pancolitis starting 5 days from last RT. She needed inpatient care for 3 weeks and recovered with mesalamine and supportive care. We also postulate a few strategies that can be adopted in patients receiving palliative RT in such a scenario. The agents should be stopped 1 week before, during and for a time (1 week minimally) after RT. A shorter course of 5 fractions (and ablative RT as indicated) can be considered to minimise treatment gaps. Highly conformal techniques (intensity-modulated radiotherapy/ volumetric-modulated arc therapy) can significantly reduce bowel dose and should be considered in patients with pre-existing GI comorbidities or prior GI toxicity with these agents.
Introduction
Palbociclib, taken in conjunction with an antiestrogen agent, is indicated for the treatment of hormone receptor‐positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer and was approved by the Food and Drug Administration (FDA) on an accelerated basis in 2015.
1
,
2
,
3
Palbociclib is a selective inhibitor of cyclin‐dependent kinases 4/6 (CDK4/6) controlling the G1/S checkpoint of the cell cycle. In patients with HR + breast cancer, oestrogen signalling works coupled with cyclin D‐CDK4/6‐INK4‐Rb pathways.
4
Thus the use of CDK4/6 inhibitors along with endocrinal therapy, can lead to more efficient blockade of cell division and overcome resistance to hormonal therapy alone. The standard regimen is oral administration once daily for 3 weeks, followed by 1 week off, in a 28‐day cycle. The most common grade 3 or 4 adverse event when used along with letrozole
2
or fulvestrant
1
is neutropenia (50% to 65%), although febrile neutropenia is rare. Minor toxicities include fatigue, nausea, arthralgias and anaemia. Although median progression‐free survival (PFS) in the 1st line setting is approximately 24 months, almost double the PFS with hormonal therapy alone, drug resistance and progressive disease eventually occur.
2
,
5
Radiation therapy (RT) plays an integral role in the palliation of metastatic breast cancer, and there is emerging evidence of a positive impact of ablative RT on survival for patients with oligometastatic disease.
6
,
7
Bones, particularly the spine and pelvis, are the most frequent site of metastatic disease in HR + HER2‐ breast cancer. Patients with newly diagnosed metastatic disease are frequently started on systemic therapy with palbociclib plus either an aromatase inhibitor or fulvestrant, and concurrently referred for palliative RT to symptomatic sites of disease. It is also not uncommon for patients who have had a fairly long duration of disease response or stability from endocrine therapy plus palbociclib, but develop progressive disease at one or two bone sites, to be referred for palliative RT to that site while the systemic therapy is left unchanged with the goal of delaying the switch to chemotherapy. With pelvic bones and sacrum accounting for approximately 35% active bone marrow in adults
8
and the radiation field to these areas including a significant amount of bowel,
9
,
10
,
11
there may be concerns of synergistic haematological as well gastrointestinal (GI) toxicity when RT is delivered concurrently with palbociclib. Being a relatively newer drug introduced in clinical practice within the last 5 years, we have limited data regarding the safety of combining RT with palbociclib.
12
,
13
,
14
,
15
,
16
,
17
We present an instance of accelerated GI toxicity in a patient receiving palliative RT to pelvis concurrently with palbociclib and letrozole and subsequently discuss the related literature. Consent for the use of de‐identified patient information was obtained as per institutional policy (Sunnybrook Health Sciences Centre).
Case Discussion
A 77‐year‐old lady was diagnosed initially with left‐sided HR+/HER2‐ breast cancer, for which she had undergone mastectomy and axillary lymph node dissection revealing a 3.5 cm invasive ductal carcinoma, grade 2, with six lymph nodes involved with macrometastasis out of 10 dissected. She was treated with adjuvant chemotherapy (5‐fluorouracil, epirubicin, cyclophosphamide and docetaxel). She received adjuvant radiotherapy to the left chest wall and ipsilateral regional nodal volumes (axilla, supraclavicular fossa, internal mammary chain) 50 Gy in 25 fractions according to standard institutional practice. She continued endocrine therapy with exemestane for 6 years until she had a recurrence involving the subcutaneous left chest wall and multiple bones (spine, pelvis) associated with mild intermittent pain. She was switched to tamoxifen, which resulted in good pain relief and disease control. After 3 years, she developed clinically asymptomatic progression of disease in her bones and chest wall. She was started on palbociclib (100 mg orally, 3 weeks on, 1 week off) and letrozole (2.5 mg daily). She tolerated the regimen well without major toxicities (mild arthralgia during the initial few months) and did not require any dose modification. After 30 months, she complained of increasing left hip pain. The bone scan was unchanged from previous imaging, but computed tomography (CT) of chest, abdomen, pelvis demonstrated oligoprogression with an increase in size of a prior metastasis in the left ilium, and a new area involving the left femoral head (Fig. 1). There was no evidence of visceral metastases. She was referred to the radiation oncology clinic. She described mechanical pain of moderate‐intensity related to the iliac metastasis that was not relieved by regular use of analgesics. She denied any limitation in her activities of daily living. Her comorbidities included hypertension, hyperlipidaemia and type 2 diabetes mellitus (well controlled on oral medications).
Figure 1 Bone scintigraphy (A) and computed tomography coronal view (B) showing the site of metastatic disease in bone involving left ilium and left femur (represented with arrows).
She was presented with the options of either stereotactic body radiotherapy (SBRT) or conventionally fractionated radiotherapy (CRT), and the pros and cons of both techniques were discussed with her. She preferred CRT and received 30 Gy in 10 fractions over 2 weeks using parallel opposed portals to the left hemipelvis and proximal femur. The maximum dose delivered to bowel bag and rectum was 30.98 Gy and 32.18 Gy, respectively (RT isodose and dose volume histogram shown in Fig. 2). It was decided to include intervening areas of disease involving the left pelvis along with the target areas of progressive disease. She continued her palbociclib‐letrozole during RT, as she had tolerated it very well previously. Five days following completion of RT, she presented to the emergency with acute onset bloody diarrhoea and severe abdominal cramping without any fever. She was managed in the inpatient setting, and investigations turned out negative for any infective aetiology. CT abdomen showed generalised thickening of the colon predominantly affecting the rectum, sigmoid and descending colon suggestive of pancolitis (Fig. 3). Colonoscopy demonstrated fragile mucosa extending 20 cm from the anal verge, and biopsy showed inflammatory changes. The patient was treated with mesalamine in tapering dose (10 mg daily for 1 week, 2.5 mg daily 1 week) and supportive care. Her symptoms had sufficiently improved 3 weeks after admission to enable discharge and she reported significant improvement of her left hip pain. Palbociclib was held during the entire course of inpatient care and for the subsequent 3 weeks. Letrozole was switched to exemestane. Last follow‐up (4 months post‐RT), she remained free of gastrointestinal symptoms but complained of recurrence of pain in her left hip. Exemestane will be discontinued and replaced with fulvestrant.
Figure 2 The isodose curves for the radiation plan on the planning computed tomography axial view (A). The dose volume histograms for bowel bag, rectum and urinary bladder are shown in Figure B.
Figure 3 Figure A is the computed tomography axial view done at 5 days after completion of radiation (during admission) showing colitis represented as thickening of mucosa most apparent in the descending colon and rectosigmoid junction (arrows). Figure B shows the repeat computed tomography at 3 weeks from radiation completion with a resolution of the mucosal thickening.
Discussion
We have recently witnessed a paradigm shift in the systemic therapy of cancer with the introduction of newer targeted agents, immunotherapies, cell cycle inhibitors and antiangiogenic therapies. The biological behaviour and clinical consequences of these agents, when used along with RT, need to be better understood, as there are concerns of possible increased toxicity from interactions.
18
,
19
The CDK4/6 inhibitors currently approved for use in HR + HER2‐ metastatic breast cancer include palbociclib, ribociclib and abemaciclib, and their clinical indications are likely to expand in the coming years.
20
Patients with HR + metastatic breast cancer usually have protracted survival, particularly when the disease is confined to bone only, in which case the median survival can extend to five years or longer.
21
,
22
Therefore, a significant proportion of patients may require RT to the bony pelvis while they are on treatment with CDK4/6 inhibitors. It is crucial to establish safe and effective protocols for combining RT with new targeted drugs, to avoid escalating toxicities and minimise interruption of systemic therapy.
There are few reports available related to the use of CDK4/6 inhibitors concurrent with palliative RT, and those reports involve a limited number of patients. Chowdhury et al. described 16 patients receiving RT to various metastatic sites within 2 weeks of use of palbociclib.
15
The most common indication was bone metastases in 11 patients (including 4 pelvic RT), brain metastasis in 4 patients and mediastinal RT in 1 patient. The authors reported excellent tolerance with only grade 2 haematological toxicities in 2 patients, all other toxicities (cutaneous, neurologic and GI) were grade 1 only. Another series by Ippolito et al. reported the use of palbociclib and ribociclib concurrently with RT in 13 and 3 patients (total 24 courses of treatment), respectively, including RT to the pelvis in 6.
16
Grade 3 or higher toxicity was haematological (neutropenia) in 5 patients (sites treated‐humerus, lumbar spine, chest wall, femur neck, scapula), with 60% of them experiencing neutropenia during the previous cycles of palbociclib/ ribociclib. No GI toxicity was observed in any patients from 6 courses of treatment to pelvis and 4 to the abdomen (spine). In a recent series by Beddok et al., palbociclib was used in 30 patients, and the most common toxicities reported were radiation dermatitis and neutropenia.
17
Nine patients received palbociclib concurrently with loco‐regional RT and palbociclib was discontinued in two patients due to toxicity (grade 3 dermatitis and febrile neutropenia in 1 patient, grade 2 dysphagia in 1 patient).
In contrast, like the patient described in our report, Kawamoto et al. observed severe acute enterocolitis in a patient treated with palliative RT (30 Gy/10 fractions for iliac and sacral metastases) concurrently with palbociclib‐fulvestrant.
13
However, unlike the present case, the patient had previously experienced grade 1 diarrhoea on palbociclib. The patient recovered from the acute RT toxicity in 3 weeks with supportive care. We have briefly summarised the different studies describing the association of use of RT with CDK4/6 inhibitors in Table 1.
Table 1 Studies reporting use of CDK4/6 inhibitors along with radiotherapy in breast cancer.
Study Patients CDK4/6 inhibitors used Radiation sites Radiation dose Radiation techniques Toxicity profile
Hans et al.
12
5 Palbociclib
Vertebra (2)
Sacroiliac (1)
Scapula‐humerus (1)
Liver (1)
Bone metastasis (20 Gy/5 fractions)
Liver‐60 Gy/10
Liver‐radiosurgery
Grade 3 neutropenia (2)
Grade 3 anaemia (1)
Grade 3 thrombocytopenia (2)
Grade 2 mucositis (1)
Grade 1 mucositis (1)
Kawamoto et al.
13
1 Palbociclib Pelvis 30 Gy/10 Conformal
Grade 1 diarrhoea (during RT)
Grade 3 colitis (resolved with supportive care)
Meattini et al.
14
5 Ribociclib
Femur (2)
Hip (1)
Lumbar vertebra (1)
Cervical‐thoracic vertebra (1)
20 Gy/5 (4)
30 Gy/5 (1, femur neck)
3DCRT (4)
VMAT (1)
Grade 3‐4 neutropenia (1)
Grade 3‐4 diarrhoea/ vomiting (1, RT to hip)
Chowdhary et al.
15
16 Palbociclib
Vertebra (9)
Pelvic bone (2)
Hip (2)
Shoulder (1)
Femur/ Knee (2)
Ribs (1)
Calvarium (1)
Brain (4)
Mediastinum (1)
Bone SBRT: 18 Gy/1; 30 Gy/3
Bone 3DCRT:30 Gy/10; 35 Gy/14; 37.5 Gy/15
Brain WBRT: 30 Gy/10: 35 Gy/14
Mediastinum: 36 Gy/18
Bones: 3DCRT‐15, SBRT‐2, IMRT‐1)
Brain: WBRT‐3, Cavity SRS‐1
Mediastinum: IMRT
Grade 2 haematological toxicity (2)
No grade 3‐4 haematological toxicity
No grade 2‐4 cutaneous, neurological, gastrointestinal toxicity
Ippolito et al.
16
16
Palbociclib (13)
Ribociclib (3)
Thorax non‐spine (8)
Pelvis non‐spine (6)
Thoracic vertebra (4)
Abdominal vertebra (4)
Skin (1)
IMN (1)
Median dose for palliative RT 30 Gy, range 8‐36 Gy)
5 patients with oligometastasis/ recurrence (sternum, spine, humerus, skin, IMN): median dose 50 Gy (range, 39.6‐60 Gy)
3DCRT (19)
VMAT (3)
IMRT (2)
Grade 3‐4 neutropenia (5)
No grade 2‐4 anaemia, thrombocytopenia
Grade 2 dermatitis (1, RT for skin)
No other grade 2‐4 non‐haematological toxicity
Beddok et al.
17
30 Palbociclib
LR (9)
Bone (24)
Brain (2)
LRRT‐50 Gy/25 (7)
50.4 Gy with SIB of 64.4 Gy in 28 (2)
Metastatic sites
20 Gy/5 (13)
30 Gy/10 (10)
8 Gy/1 (3)
SRS‐18 Gy/1 (1)
LRRT‐IMRT
3DCRT‐majority of RT to metastatic sites
SRS for brain
Grade 2 or higher toxicities were seen in 13 patients (neutropenia in 9, dermatitis in 2, dysphagia in 1, pain in 1)
Palbociclib was discontinued in 2 patients receiving LRRT
Current study 1 Palbociclib Pelvis 30 Gy/10 2‐field opposing portals Grade 3 colitis (resolved with supportive care)
CDK4/6 inhibitor: cyclin‐dependent kinase 4/6 inhibitor; RT: radiation; 3DCRT: 3‐dimensional conformal radiotherapy; VMAT: volumetric‐modulated arc therapy; SBRT: stereotactic body radiotherapy; WBRT: whole brain radiotherapy; SRS‐stereotactic radiosurgery; IMRT: intensity‐modulated radiation therapy; IMN: internal mammary node. LR: loco‐regional.
John Wiley & Sons, LtdThe baseline incidence of grade 3‐4 diarrhoea treated with CDK4/6 inhibitors alone was reported as < 5% of patients in a systematic review including 2007 patients.
23
Therefore, the few reported instances of accelerated GI toxicity from pelvic RT‐palbociclib are likely a combined effect of the two anticancer treatments. Interestingly, a preclinical study had shown a protective effect of CDK4/6 inhibitors when delivered before a single fraction (SF) of RT, whereas fractionated RT led to an exacerbation of GI toxicity.
24
A higher proportion of surviving crypts in the small intestine was associated with SF‐RT improving the integrity of the GI mucosal barrier, which was lost with multiple treatments likely resulting from impaired regeneration.
The use of palliative RT to the pelvis can lead to the development of acute colitis, although grade 3 toxicities are rarely encountered with the commonly used palliative dose fractionations. The concurrent use of palbociclib in our case should raise a strong index of suspicion for synergistic toxicity. Kawamoto et al. had witnessed GI toxicity with the use of conformal RT technique.
13
It is not possible to conclude if conformal techniques would have had a clinical impact on reducing the likelihood of such toxicities. However, it will be reasonable to employ such techniques to reduce doses to bowel anticipating a dose‐dependent effect until stronger evidence is available. Similarly, there are no guidelines yet to suggest withholding the CDK4/6 inhibitors during RT can reduce toxicities. From the few instances of reported GI toxicity and with the introduction of more potent CDK4/6 inhibitors like abemaciclib (with higher events of GI toxicity), we empirically recommend the drugs should be avoided with RT.
Given the paucity of data and heterogeneity of treatments from the available literature, larger, possibly multi‐institutional studies are required to guide appropriate clinical practice. Here we postulate some strategies which can be adopted when pelvic RT is to be given to a patient taking a CDK4/6 inhibitor.
Consideration of stopping the CDK4/6 inhibitors 1 week before, during RT, and for 1 week minimally following the last day RT is delivered. Patients can continue endocrine therapy without interruption.
To plan for 5 fractions of RT (20 Gy/5 fractions) to minimise the treatment gap as opposed to relatively longer courses like 30 Gy/10 fractions.
Consideration of SBRT in appropriate patients (delivered in 5 or fewer fractions).
In patients with previous GI or haematological toxicities and GI comorbidities, careful monitoring of symptoms during RT and the following week. Consideration of extending the treatment break till all symptoms resolve (including minor effects).
Conformal techniques (intensity‐modulated radiotherapy/ volumetric‐modulated arc therapy) should be considered if that leads to a reduction of the bowel dose.
Funding
No funding was involved with the current manuscript.
Conflict of Interest
Archya Dasgupta: None; Arjun Sahgal: Advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board), Board Member: International Stereotactic Radiosurgery Society (ISRS). Past educational seminars with Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon. Research grant with Elekta AB. Travel accommodations/expenses by Elekta, Varian, BrainLAB. Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia; Ellen Warner: None; Gregory Czarnota: None.
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What was the outcome of reaction 'Colitis'?
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Safety of palbociclib concurrent with palliative pelvic radiotherapy: discussion of a case of increased toxicity and brief review of literature.
Several cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are indicated in the treatment of metastatic hormone receptor-positive (HR)/ human epidermal growth factor receptor 2 (HER2) negative breast cancer which includes palbociclib, ribociclib and abemaciclib. Pelvic radiation therapy (RT) is often indicated for symptomatic or progressive bone metastasis. There are limited data on concurrent use of CDK4/6 inhibitors with pelvic RT with few retrospective studies in the literature involving a small number of patients. The major side effects of these agents include haematological toxicities, while non-haematological toxicities are less severe. There are concerns for an increased possibility of synergistic toxicity with concurrent use of CDK4/6 inhibitors with pelvic RT. Here we describe an instance of acute grade 3 gastrointestinal toxicity and discuss the relevant literature. A 77-year-old lady treated with palliative conventional RT 30 Gy/ 10 fractions concurrently with palbociclib to left hemipelvis and proximal femur, developed severe pancolitis starting 5 days from last RT. She needed inpatient care for 3 weeks and recovered with mesalamine and supportive care. We also postulate a few strategies that can be adopted in patients receiving palliative RT in such a scenario. The agents should be stopped 1 week before, during and for a time (1 week minimally) after RT. A shorter course of 5 fractions (and ablative RT as indicated) can be considered to minimise treatment gaps. Highly conformal techniques (intensity-modulated radiotherapy/ volumetric-modulated arc therapy) can significantly reduce bowel dose and should be considered in patients with pre-existing GI comorbidities or prior GI toxicity with these agents.
Introduction
Palbociclib, taken in conjunction with an antiestrogen agent, is indicated for the treatment of hormone receptor‐positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2–) metastatic breast cancer and was approved by the Food and Drug Administration (FDA) on an accelerated basis in 2015.
1
,
2
,
3
Palbociclib is a selective inhibitor of cyclin‐dependent kinases 4/6 (CDK4/6) controlling the G1/S checkpoint of the cell cycle. In patients with HR + breast cancer, oestrogen signalling works coupled with cyclin D‐CDK4/6‐INK4‐Rb pathways.
4
Thus the use of CDK4/6 inhibitors along with endocrinal therapy, can lead to more efficient blockade of cell division and overcome resistance to hormonal therapy alone. The standard regimen is oral administration once daily for 3 weeks, followed by 1 week off, in a 28‐day cycle. The most common grade 3 or 4 adverse event when used along with letrozole
2
or fulvestrant
1
is neutropenia (50% to 65%), although febrile neutropenia is rare. Minor toxicities include fatigue, nausea, arthralgias and anaemia. Although median progression‐free survival (PFS) in the 1st line setting is approximately 24 months, almost double the PFS with hormonal therapy alone, drug resistance and progressive disease eventually occur.
2
,
5
Radiation therapy (RT) plays an integral role in the palliation of metastatic breast cancer, and there is emerging evidence of a positive impact of ablative RT on survival for patients with oligometastatic disease.
6
,
7
Bones, particularly the spine and pelvis, are the most frequent site of metastatic disease in HR + HER2‐ breast cancer. Patients with newly diagnosed metastatic disease are frequently started on systemic therapy with palbociclib plus either an aromatase inhibitor or fulvestrant, and concurrently referred for palliative RT to symptomatic sites of disease. It is also not uncommon for patients who have had a fairly long duration of disease response or stability from endocrine therapy plus palbociclib, but develop progressive disease at one or two bone sites, to be referred for palliative RT to that site while the systemic therapy is left unchanged with the goal of delaying the switch to chemotherapy. With pelvic bones and sacrum accounting for approximately 35% active bone marrow in adults
8
and the radiation field to these areas including a significant amount of bowel,
9
,
10
,
11
there may be concerns of synergistic haematological as well gastrointestinal (GI) toxicity when RT is delivered concurrently with palbociclib. Being a relatively newer drug introduced in clinical practice within the last 5 years, we have limited data regarding the safety of combining RT with palbociclib.
12
,
13
,
14
,
15
,
16
,
17
We present an instance of accelerated GI toxicity in a patient receiving palliative RT to pelvis concurrently with palbociclib and letrozole and subsequently discuss the related literature. Consent for the use of de‐identified patient information was obtained as per institutional policy (Sunnybrook Health Sciences Centre).
Case Discussion
A 77‐year‐old lady was diagnosed initially with left‐sided HR+/HER2‐ breast cancer, for which she had undergone mastectomy and axillary lymph node dissection revealing a 3.5 cm invasive ductal carcinoma, grade 2, with six lymph nodes involved with macrometastasis out of 10 dissected. She was treated with adjuvant chemotherapy (5‐fluorouracil, epirubicin, cyclophosphamide and docetaxel). She received adjuvant radiotherapy to the left chest wall and ipsilateral regional nodal volumes (axilla, supraclavicular fossa, internal mammary chain) 50 Gy in 25 fractions according to standard institutional practice. She continued endocrine therapy with exemestane for 6 years until she had a recurrence involving the subcutaneous left chest wall and multiple bones (spine, pelvis) associated with mild intermittent pain. She was switched to tamoxifen, which resulted in good pain relief and disease control. After 3 years, she developed clinically asymptomatic progression of disease in her bones and chest wall. She was started on palbociclib (100 mg orally, 3 weeks on, 1 week off) and letrozole (2.5 mg daily). She tolerated the regimen well without major toxicities (mild arthralgia during the initial few months) and did not require any dose modification. After 30 months, she complained of increasing left hip pain. The bone scan was unchanged from previous imaging, but computed tomography (CT) of chest, abdomen, pelvis demonstrated oligoprogression with an increase in size of a prior metastasis in the left ilium, and a new area involving the left femoral head (Fig. 1). There was no evidence of visceral metastases. She was referred to the radiation oncology clinic. She described mechanical pain of moderate‐intensity related to the iliac metastasis that was not relieved by regular use of analgesics. She denied any limitation in her activities of daily living. Her comorbidities included hypertension, hyperlipidaemia and type 2 diabetes mellitus (well controlled on oral medications).
Figure 1 Bone scintigraphy (A) and computed tomography coronal view (B) showing the site of metastatic disease in bone involving left ilium and left femur (represented with arrows).
She was presented with the options of either stereotactic body radiotherapy (SBRT) or conventionally fractionated radiotherapy (CRT), and the pros and cons of both techniques were discussed with her. She preferred CRT and received 30 Gy in 10 fractions over 2 weeks using parallel opposed portals to the left hemipelvis and proximal femur. The maximum dose delivered to bowel bag and rectum was 30.98 Gy and 32.18 Gy, respectively (RT isodose and dose volume histogram shown in Fig. 2). It was decided to include intervening areas of disease involving the left pelvis along with the target areas of progressive disease. She continued her palbociclib‐letrozole during RT, as she had tolerated it very well previously. Five days following completion of RT, she presented to the emergency with acute onset bloody diarrhoea and severe abdominal cramping without any fever. She was managed in the inpatient setting, and investigations turned out negative for any infective aetiology. CT abdomen showed generalised thickening of the colon predominantly affecting the rectum, sigmoid and descending colon suggestive of pancolitis (Fig. 3). Colonoscopy demonstrated fragile mucosa extending 20 cm from the anal verge, and biopsy showed inflammatory changes. The patient was treated with mesalamine in tapering dose (10 mg daily for 1 week, 2.5 mg daily 1 week) and supportive care. Her symptoms had sufficiently improved 3 weeks after admission to enable discharge and she reported significant improvement of her left hip pain. Palbociclib was held during the entire course of inpatient care and for the subsequent 3 weeks. Letrozole was switched to exemestane. Last follow‐up (4 months post‐RT), she remained free of gastrointestinal symptoms but complained of recurrence of pain in her left hip. Exemestane will be discontinued and replaced with fulvestrant.
Figure 2 The isodose curves for the radiation plan on the planning computed tomography axial view (A). The dose volume histograms for bowel bag, rectum and urinary bladder are shown in Figure B.
Figure 3 Figure A is the computed tomography axial view done at 5 days after completion of radiation (during admission) showing colitis represented as thickening of mucosa most apparent in the descending colon and rectosigmoid junction (arrows). Figure B shows the repeat computed tomography at 3 weeks from radiation completion with a resolution of the mucosal thickening.
Discussion
We have recently witnessed a paradigm shift in the systemic therapy of cancer with the introduction of newer targeted agents, immunotherapies, cell cycle inhibitors and antiangiogenic therapies. The biological behaviour and clinical consequences of these agents, when used along with RT, need to be better understood, as there are concerns of possible increased toxicity from interactions.
18
,
19
The CDK4/6 inhibitors currently approved for use in HR + HER2‐ metastatic breast cancer include palbociclib, ribociclib and abemaciclib, and their clinical indications are likely to expand in the coming years.
20
Patients with HR + metastatic breast cancer usually have protracted survival, particularly when the disease is confined to bone only, in which case the median survival can extend to five years or longer.
21
,
22
Therefore, a significant proportion of patients may require RT to the bony pelvis while they are on treatment with CDK4/6 inhibitors. It is crucial to establish safe and effective protocols for combining RT with new targeted drugs, to avoid escalating toxicities and minimise interruption of systemic therapy.
There are few reports available related to the use of CDK4/6 inhibitors concurrent with palliative RT, and those reports involve a limited number of patients. Chowdhury et al. described 16 patients receiving RT to various metastatic sites within 2 weeks of use of palbociclib.
15
The most common indication was bone metastases in 11 patients (including 4 pelvic RT), brain metastasis in 4 patients and mediastinal RT in 1 patient. The authors reported excellent tolerance with only grade 2 haematological toxicities in 2 patients, all other toxicities (cutaneous, neurologic and GI) were grade 1 only. Another series by Ippolito et al. reported the use of palbociclib and ribociclib concurrently with RT in 13 and 3 patients (total 24 courses of treatment), respectively, including RT to the pelvis in 6.
16
Grade 3 or higher toxicity was haematological (neutropenia) in 5 patients (sites treated‐humerus, lumbar spine, chest wall, femur neck, scapula), with 60% of them experiencing neutropenia during the previous cycles of palbociclib/ ribociclib. No GI toxicity was observed in any patients from 6 courses of treatment to pelvis and 4 to the abdomen (spine). In a recent series by Beddok et al., palbociclib was used in 30 patients, and the most common toxicities reported were radiation dermatitis and neutropenia.
17
Nine patients received palbociclib concurrently with loco‐regional RT and palbociclib was discontinued in two patients due to toxicity (grade 3 dermatitis and febrile neutropenia in 1 patient, grade 2 dysphagia in 1 patient).
In contrast, like the patient described in our report, Kawamoto et al. observed severe acute enterocolitis in a patient treated with palliative RT (30 Gy/10 fractions for iliac and sacral metastases) concurrently with palbociclib‐fulvestrant.
13
However, unlike the present case, the patient had previously experienced grade 1 diarrhoea on palbociclib. The patient recovered from the acute RT toxicity in 3 weeks with supportive care. We have briefly summarised the different studies describing the association of use of RT with CDK4/6 inhibitors in Table 1.
Table 1 Studies reporting use of CDK4/6 inhibitors along with radiotherapy in breast cancer.
Study Patients CDK4/6 inhibitors used Radiation sites Radiation dose Radiation techniques Toxicity profile
Hans et al.
12
5 Palbociclib
Vertebra (2)
Sacroiliac (1)
Scapula‐humerus (1)
Liver (1)
Bone metastasis (20 Gy/5 fractions)
Liver‐60 Gy/10
Liver‐radiosurgery
Grade 3 neutropenia (2)
Grade 3 anaemia (1)
Grade 3 thrombocytopenia (2)
Grade 2 mucositis (1)
Grade 1 mucositis (1)
Kawamoto et al.
13
1 Palbociclib Pelvis 30 Gy/10 Conformal
Grade 1 diarrhoea (during RT)
Grade 3 colitis (resolved with supportive care)
Meattini et al.
14
5 Ribociclib
Femur (2)
Hip (1)
Lumbar vertebra (1)
Cervical‐thoracic vertebra (1)
20 Gy/5 (4)
30 Gy/5 (1, femur neck)
3DCRT (4)
VMAT (1)
Grade 3‐4 neutropenia (1)
Grade 3‐4 diarrhoea/ vomiting (1, RT to hip)
Chowdhary et al.
15
16 Palbociclib
Vertebra (9)
Pelvic bone (2)
Hip (2)
Shoulder (1)
Femur/ Knee (2)
Ribs (1)
Calvarium (1)
Brain (4)
Mediastinum (1)
Bone SBRT: 18 Gy/1; 30 Gy/3
Bone 3DCRT:30 Gy/10; 35 Gy/14; 37.5 Gy/15
Brain WBRT: 30 Gy/10: 35 Gy/14
Mediastinum: 36 Gy/18
Bones: 3DCRT‐15, SBRT‐2, IMRT‐1)
Brain: WBRT‐3, Cavity SRS‐1
Mediastinum: IMRT
Grade 2 haematological toxicity (2)
No grade 3‐4 haematological toxicity
No grade 2‐4 cutaneous, neurological, gastrointestinal toxicity
Ippolito et al.
16
16
Palbociclib (13)
Ribociclib (3)
Thorax non‐spine (8)
Pelvis non‐spine (6)
Thoracic vertebra (4)
Abdominal vertebra (4)
Skin (1)
IMN (1)
Median dose for palliative RT 30 Gy, range 8‐36 Gy)
5 patients with oligometastasis/ recurrence (sternum, spine, humerus, skin, IMN): median dose 50 Gy (range, 39.6‐60 Gy)
3DCRT (19)
VMAT (3)
IMRT (2)
Grade 3‐4 neutropenia (5)
No grade 2‐4 anaemia, thrombocytopenia
Grade 2 dermatitis (1, RT for skin)
No other grade 2‐4 non‐haematological toxicity
Beddok et al.
17
30 Palbociclib
LR (9)
Bone (24)
Brain (2)
LRRT‐50 Gy/25 (7)
50.4 Gy with SIB of 64.4 Gy in 28 (2)
Metastatic sites
20 Gy/5 (13)
30 Gy/10 (10)
8 Gy/1 (3)
SRS‐18 Gy/1 (1)
LRRT‐IMRT
3DCRT‐majority of RT to metastatic sites
SRS for brain
Grade 2 or higher toxicities were seen in 13 patients (neutropenia in 9, dermatitis in 2, dysphagia in 1, pain in 1)
Palbociclib was discontinued in 2 patients receiving LRRT
Current study 1 Palbociclib Pelvis 30 Gy/10 2‐field opposing portals Grade 3 colitis (resolved with supportive care)
CDK4/6 inhibitor: cyclin‐dependent kinase 4/6 inhibitor; RT: radiation; 3DCRT: 3‐dimensional conformal radiotherapy; VMAT: volumetric‐modulated arc therapy; SBRT: stereotactic body radiotherapy; WBRT: whole brain radiotherapy; SRS‐stereotactic radiosurgery; IMRT: intensity‐modulated radiation therapy; IMN: internal mammary node. LR: loco‐regional.
John Wiley & Sons, LtdThe baseline incidence of grade 3‐4 diarrhoea treated with CDK4/6 inhibitors alone was reported as < 5% of patients in a systematic review including 2007 patients.
23
Therefore, the few reported instances of accelerated GI toxicity from pelvic RT‐palbociclib are likely a combined effect of the two anticancer treatments. Interestingly, a preclinical study had shown a protective effect of CDK4/6 inhibitors when delivered before a single fraction (SF) of RT, whereas fractionated RT led to an exacerbation of GI toxicity.
24
A higher proportion of surviving crypts in the small intestine was associated with SF‐RT improving the integrity of the GI mucosal barrier, which was lost with multiple treatments likely resulting from impaired regeneration.
The use of palliative RT to the pelvis can lead to the development of acute colitis, although grade 3 toxicities are rarely encountered with the commonly used palliative dose fractionations. The concurrent use of palbociclib in our case should raise a strong index of suspicion for synergistic toxicity. Kawamoto et al. had witnessed GI toxicity with the use of conformal RT technique.
13
It is not possible to conclude if conformal techniques would have had a clinical impact on reducing the likelihood of such toxicities. However, it will be reasonable to employ such techniques to reduce doses to bowel anticipating a dose‐dependent effect until stronger evidence is available. Similarly, there are no guidelines yet to suggest withholding the CDK4/6 inhibitors during RT can reduce toxicities. From the few instances of reported GI toxicity and with the introduction of more potent CDK4/6 inhibitors like abemaciclib (with higher events of GI toxicity), we empirically recommend the drugs should be avoided with RT.
Given the paucity of data and heterogeneity of treatments from the available literature, larger, possibly multi‐institutional studies are required to guide appropriate clinical practice. Here we postulate some strategies which can be adopted when pelvic RT is to be given to a patient taking a CDK4/6 inhibitor.
Consideration of stopping the CDK4/6 inhibitors 1 week before, during RT, and for 1 week minimally following the last day RT is delivered. Patients can continue endocrine therapy without interruption.
To plan for 5 fractions of RT (20 Gy/5 fractions) to minimise the treatment gap as opposed to relatively longer courses like 30 Gy/10 fractions.
Consideration of SBRT in appropriate patients (delivered in 5 or fewer fractions).
In patients with previous GI or haematological toxicities and GI comorbidities, careful monitoring of symptoms during RT and the following week. Consideration of extending the treatment break till all symptoms resolve (including minor effects).
Conformal techniques (intensity‐modulated radiotherapy/ volumetric‐modulated arc therapy) should be considered if that leads to a reduction of the bowel dose.
Funding
No funding was involved with the current manuscript.
Conflict of Interest
Archya Dasgupta: None; Arjun Sahgal: Advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board), Board Member: International Stereotactic Radiosurgery Society (ISRS). Past educational seminars with Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon. Research grant with Elekta AB. Travel accommodations/expenses by Elekta, Varian, BrainLAB. Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia; Ellen Warner: None; Gregory Czarnota: None.
|
Recovered
|
ReactionOutcome
|
CC BY
|
32985794
| 19,170,004
|
2021-03
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'.
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
BETAMETHASONE, ECULIZUMAB, FERROUS FUMARATE, FOLIC ACID, MECLIZINE\PYRIDOXINE, MESALAMINE, METOCLOPRAMIDE, NADROPARIN, NIFEDIPINE, POLYETHYLENE GLYCOLS
|
DrugsGivenReaction
|
CC BY-NC
|
32986871
| 19,592,741
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypoglycaemia'.
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
BETAMETHASONE, ECULIZUMAB, FERROUS FUMARATE, FOLIC ACID, MECLIZINE\PYRIDOXINE, MESALAMINE, METOCLOPRAMIDE, NADROPARIN, NIFEDIPINE, POLYETHYLENE GLYCOLS
|
DrugsGivenReaction
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Premature delivery'.
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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BETAMETHASONE, ECULIZUMAB, FERROUS FUMARATE, FOLIC ACID, MECLIZINE\PYRIDOXINE, MESALAMINE, METOCLOPRAMIDE, NADROPARIN, NIFEDIPINE, POLYETHYLENE GLYCOLS
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DrugsGivenReaction
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CC BY-NC
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32986871
| 19,592,741
|
2021-04
|
What was the administration route of drug 'BETAMETHASONE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Transplacental
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DrugAdministrationRoute
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CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'ECULIZUMAB'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'FERROUS FUMARATE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'FOLIC ACID'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'MECLIZINE HYDROCHLORIDE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the administration route of drug 'MECLIZINE\PYRIDOXINE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'MESALAMINE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'METOCLOPRAMIDE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'NADROPARIN'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'NIFEDIPINE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the administration route of drug 'POLYETHYLENE GLYCOLS'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
Transplacental
|
DrugAdministrationRoute
|
CC BY-NC
|
32986871
| 19,592,738
|
2021-04
|
What was the dosage of drug 'BETAMETHASONE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'FERROUS FUMARATE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'FOLIC ACID'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'MECLIZINE HYDROCHLORIDE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'MESALAMINE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'METOCLOPRAMIDE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'NADROPARIN'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
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2021-04
|
What was the dosage of drug 'NIFEDIPINE'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the dosage of drug 'POLYETHYLENE GLYCOLS'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
|
MATERNAL DOSE: UNK
|
DrugDosageText
|
CC BY-NC
|
32986871
| 18,480,112
|
2021-04
|
What was the outcome of reaction 'Hypoglycaemia neonatal'?
|
Placental disposition of eculizumab, C5 and C5-eculizumab in two pregnancies of a woman with paroxysmal nocturnal haemoglobinuria.
Eculizumab is known to cross the placenta to a limited degree, but recently therapeutic drug levels in cord blood were found in a single case. We report maternal, cord and placental levels of unbound eculizumab, C5 and C5-eculizumab in two pregnancies of a paroxysmal nocturnal haemoglobinuria patient who received 900 mg eculizumab every 2 weeks. In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL, while C5-eculizumab levels were 22 and 26 μg/mL, suggesting that a considerable fraction of C5 was blocked in the newborn. Concentrations in each placenta of unbound eculizumab were 41 ± 3 and 45 ± 4 μg/g tissue, of C5-eculizumab 19 ± 2 and 32 ± 3 μg/g, and of C5 20 ± 3 and 30 ± 2 μg/g (mean ± SD, in three tissue samples per placenta). Placental levels of unbound eculizumab were higher than those of C5-eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta.
What is already known about this subject
Eculizumab crosses the placental barrier to a limited degree and in most cases cord blood levels of eculizumab are low. Recently, a case has been described in which therapeutic eculizumab levels were found in cord blood, indicating more extensive placental transfer. 1
What this study adds
In this case study, two pregnancies are described in which placental disposition of eculizumab has been investigated. Concentrations of unbound eculizumab, C5 and C5‐eculizumab were quantified in cord and maternal blood, as well as in placental tissue.
1 INTRODUCTION
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare condition affecting women of reproductive age. Pregnancy is known to serve as a disease trigger and increases the risk for thrombosis and haemorrhage in these women. The management of PNH during pregnancy has become feasible with the introduction of eculizumab, a humanized IgG2/IgG4 anti‐complement C5 antibody. Eculizumab treatment has reduced the typically high mortality rates associated with PNH during pregnancy, and has greatly improved foetal and maternal pregnancy outcomes. 2 Given the fact that eculizumab is also administered during pregnancy in women with atypical haemolytic uremic syndrome (aHUS) 3 and its potential as a therapeutic option in preeclampsia treatment, 4 , 5 it has become increasingly relevant to report on its use during pregnancy. Eculizumab was reported to cross the placenta to a limited degree. Cord blood concentrations of eculizumab varying from undetectable up to 20% of the maternal levels have been reported in several studies. 1 , 6 To date, only one case has been described with eculizumab concentrations of 69 μg/mL in cord blood in which complement activation in the newborn was fully blocked. 1 Although eculizumab levels in maternal and cord blood have been analysed previously, studies on the passage of the drug through the placenta have not yet been performed. Therefore, here we aimed to more extensively characterize placental disposition as compared to previous studies. Given the varying concentrations of eculizumab that have been reported in cord blood so far, investigating the fate of eculizumab within placental tissue will contribute to a better understanding of the mechanism of its placental transfer. Additionally, quantifying both eculizumab unbound and bound to C5 better reflects actual exposure to the drug. In the current study, we report maternal, cord and placental concentrations of unbound eculizumab, C5 and C5‐eculizumab complexes in two pregnancies of a PNH patient who received 900 mg of eculizumab every 2 weeks throughout both pregnancies.
2 METHODS
2.1 Case presentation
We report two successive pregnancies of a PNH patient. Written informed consent was obtained at routine prenatal care visits at 30 weeks of pregnancy. The study was approved by the Regional Committee on Research involving Human Subjects (file no. 2016‐2744). The patient received 900 mg of eculizumab every 2 weeks throughout both pregnancies and the last eculizumab administration was 4 days before both deliveries. The first neonate was born after a spontaneous vaginal delivery at 36+6 weeks, was healthy despite transient hypoglycaemia and had a weight at the 50th percentile. The second neonate was also born after a vaginal delivery at 38+0 weeks, was healthy and had a weight at the 5‐10th percentile. Both neonates did not show signs of infection. In addition to eculizumab, the patient used the following medication for prolonged periods of time during the first pregnancy: nadroparine, meclozine/pyridoxine, metoclopramide, ferro fumarate, macrogol, folic acid, mesalazine, betametasone and nifedipine. During the second pregnancy mesalazine, bisacodyl, magnesium sulphate, nadroparine, meclozine/pyridoxine, metoclopramide, amoxicilline, beclometasone, nifidepine, progesterone, folic acid and paracetamol were used. We are not aware of any literature that demonstrate an effect of comedication on the disposition of eculizumab, C5 or eculizumab‐C5 complex.
2.2 Blood and placenta sample collection and preparation
The whole placenta and maternal and cord blood samples were stored at 4 °C directly after delivery. Serum was stored at −80 °C until analysis. Within 24 hours, 1 cm3 sized samples of villous tissue were excised at random areas midway between the umbilical cord and distal edge of the placenta. The samples were snap frozen and stored at −80 °C.
Twenty percent (weight/volume) tissue homogenates, based on tissue wet weight, were prepared in Radioimmunoprecipitation assay (RIPA) buffer containing 5mM Tris‐HCl buffer pH 7.4, 150mM NaCl, 1% Triton‐X100, 0.5% sodium deoxycholate and one Roche complete proteinase inhibitor tablet per 10 mL of buffer (Roche, Penzberg, Germany). Homogenates were prepared on ice with a T10 basic Ultra‐Turrax disperser (IKA, Staufen, Germany). Thereafter the samples were mixed and kept on ice for 1 hour, followed by mixing and centrifugation for 5 minutes at 5000 g. The supernatant was stored at −80 °C until analysis.
2.3 Quantification of unbound eculizumab, C5 and C5‐eculizumab complexes
Concentrations were measured with an in‐house ELISA according to previously described methods for eculizumab, 7 C5 8 and C5‐eculizumab complexes. 9 Standard curves for eculizumab measurements were prepared by dilution of eculizumab (Alexion Pharmaceuticals, Cheshire, CT, USA) (0.1‐38 ng/mL) in phosphate‐buffered saline (PBS) with 1% bovine serum albumin (BSA) and for C5 measurements by diluting purified C5 (3.9‐150 ng/mL) (Calbiochem, San Diego, CA, USA) in PBS with 0.05% Tween (PBST), supplemented with 0.2% BSA. The standard curve of C5‐eculizumab complexes (1‐192 ng/mL) was prepared by adding eculizumab to a normal serum pool from 20 healthy blood donors, supplemented with 20 mM ethylenediaminetetraacetic acid (EDTA) and further dilution in PBST‐EDTA. The intra‐ and interassay variabilities were 2.9% and 5.2%, 7% and 14%, 8.5% and 17.8% for eculizumab, C5 and C5‐eculizumab complexes, respectively. The ELISAs were applied to measure concentrations in cord blood (serum), maternal blood (serum) and placental tissue homogenates (20% placental tissue in RIPA buffer). Three homogenate samples per placenta were analysed. For each serum and tissue homogenate sample, two technical replicates were used.
3 RESULTS
Table 1 represents the concentrations of unbound eculizumab, C5 and bound eculizumab to C5 (C5‐eculizumab) in maternal blood, cord blood and placental tissue from both pregnancies. Unbound eculizumab and C5‐eculizumab complexes were detected in maternal blood and cord blood, suggestive of placental transfer. Maternal serum concentrations of unbound eculizumab and C5‐eculizumab complexes were far above 100 μg/mL, which is the concentration necessary to fully block complement activity. 7 In both pregnancies, cord blood concentrations of unbound eculizumab were below 4 μg/mL while for C5‐eculizumab concentrations of 22 and 26 μg/mL were found. In placental tissue, unbound eculizumab concentrations were substantially higher than those of C5‐eculizumab complexes. Placental levels of C5 in exposed tissue did not differ from those in the placental tissue of healthy controls.
TABLE 1 Eculizumab, C5 and C5‐eculizumab concentrations in serum and placental tissue
[Eculizumab] [C5] a [C5‐Eculizumab]
μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue μg/mL serum or μg/g tissue
Pregnancy 1 Maternal 259 118 234
Cord 3.5 73 26
Placenta (mean ± SD) b 41 ± 3 20 ± 3 19 ± 3
Pregnancy 2 Maternal 232 152 252
Cord 2.7 78 22
Placenta (mean ± SD) b 45 ± 4 30 ± 2 32 ± 2
a The concentration C5 in cord blood relative to maternal blood was in agreement with a previously reported range of 54‐61%. 16 Reference values of C5 in adults are 42‐93 μg/mL. 8
b Placental concentrations represent the mean ± SD of three samples per placenta, excised at random areas midway between the cord and distal edge of the placenta.
4 DISCUSSION
The low levels of unbound eculizumab in cord blood that we report here indicate that most of the available eculizumab was bound to C5. This is supported by the presence of high concentrations of C5‐eculizumab complexes (22 and 26 μg/mL) in cord blood. In the light of free C5 concentrations of 73 and 78 μg/mL, this suggests blockade of a considerable fraction of C5 in the newborns. Previously, Hallstensen et al reported C5‐eculizumab concentrations of approximately 8 μg/mL in term neonatal blood corresponding to 6‐7% of maternal levels. 9 While we found higher values, C5‐eculizumab concentrations relative to maternal levels were similar in our study. To date, only one case report has been described with therapeutic eculizumab blood levels in a newborn and complete complement blockade, but unfortunately C5‐eculizumab concentrations were not quantified in that study. 1 In cases with (partial) complement blockade by eculizumab, innate immunity in the newborn may be severely compromised and prophylactic treatment with antibiotics may be recommended. Also, during pregnancy, treatment with eculizumab may affect foetal outcomes. In a case series of 75 pregnancies, a high rate (29%) of premature births was observed. 2 However, as prematurity has been prominent in PNH pregnancies before the availability of eculizumab, it remains difficult to assess to what extent this is related to eculizumab treatment.
With respect to placental eculizumab levels, we observed higher placental concentrations of unbound eculizumab than of C5‐eculizumab complexes, while maternal concentrations were approximately equal, suggesting selective transport of unbound eculizumab across the placenta. This indicates that either unbound eculizumab is taken up better into the placenta or the C5‐eculizumab complex is more extensively degraded in lysosomes. Furthermore, partial dissociation of C5‐eculizumab in endosomes may also contribute to higher placental eculizumab levels. Once taken up in the endosomes, transplacental transfer of IgGs occurs via binding to the neonatal Fc‐receptor (FcRn). 10 The C5‐eculizumab complex does not efficiently dissociate and may bind to the FcRn similarly as free eculizumab. 11 Therefore, it remains possible that placental transfer of C5‐eculizumab complex is also driven by binding to FcRn, although to a smaller extent. Detectable levels of C5‐eculizumab complexes coinciding with low levels of unbound eculizumab in cord blood may be explained by complete scavenging of eculizumab by C5 at low drug concentrations. At higher eculizumab concentrations, the proportion of measured unbound drug increases. It should therefore be noted that quantifying unbound eculizumab only, will underestimate the actual exposure in cord blood. More clinical data is needed to investigate the factors that influence the placental disposition of eculizumab and its binding to C5 in the placenta and foetal blood. For future cases it is recommended to report on C5‐eculizumab levels in maternal blood, cord blood and placental tissue to study the relationship between treatment regimens, gestational age and eculizumab distribution across the placenta. It would also be important to perform histopathological studies of the placenta, as an affected syncytiotrophoblast layer can presumably lead to enhanced foetal eculizumab levels.
Placental passage of eculizumab is limited, particularly in comparison to transfer of full IgG1 therapeutics, such as infliximab, for which cord blood concentrations may even exceed maternal concentrations in the third trimester. 12 Eculizumab is an IgG2/4 hybrid with a similar serum half‐life and binding affinity to the FcRn as full IgG1 therapeutics. 9 FcRn prolongs the half‐life of IgG1, IgG2 and IgG4 equally in endothelial cells, although placental transfer of IgG2 is significantly less efficient compared to that of IgG1 and IgG4. 13 , 14 Still, IgG2 transfer is more extensive than eculizumab transfer as cord‐to‐maternal ratios of endogenous IgG2 are on average 1, 15 which is not the case for eculizumab transfer ratios. Intracellular trafficking of eculizumab in the syncytiotrophoblast is therefore different from endogenous IgGs and requires further investigation.
Although challenging for this type of biological molecules, conducting ex vivo placental perfusions could be an approach to chart differences in placental handling between unbound eculizumab and C5‐eculizumab complexes. This type of study would also allow the investigation of placental handling of these molecules separate from clearance processes taking place elsewhere in the foetus. To better understand the disposition and effects of eculizumab and C5‐eculizumab complexes in the unborn child, future studies are needed on the mechanisms of placental uptake, trafficking and release.
ACKNOWLEDGEMENTS
G.E. was supported by a personal grant from the Radboud University Medical Center.
COMPETING INTERESTS
All authors declare that they have no competing interests.
CONTRIBUTORS
G.E., P.vdB. and A.S. acquired and analysed the data. O.vdH. and S.L. had direct clinical responsibility for the patient described. G.E., J.vD., R.G., E.V. and F.R. contributed to the study idea, design and drafted the manuscript. All authors were involved in revising the manuscript and approved the final version.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Recovered
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ReactionOutcome
|
CC BY-NC
|
32986871
| 19,541,122
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.
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The efficacy of the submucosal injection of lidocaine during endoscopic submucosal dissection for colorectal neoplasms: a multicenter randomized controlled study.
Endoscopic submucosal dissection (ESD) is currently a common procedure although it requires a long procedural time. We conducted a prospective study to determine the efficacy and safety of lidocaine injection for shortening the procedural time and relieving bowel peristalsis during ESD.
A multicenter randomized controlled study was conducted in three hospitals. Ninety-one patients who underwent colorectal ESD were enrolled. Patients were randomly divided into two groups using the envelope method: the lidocaine group and saline group. The primary endpoint was the procedural time, and the secondary endpoints were the procedural time in each part of the colon and the grade of bowel peristalsis and the incidence and amounts of antispasmodic drugs use and adverse events.
The patients' demographics were not markedly different between the two groups. The mean procedural time in the lidocaine group was not markedly different from that in the saline group. In contrast, at the proximal site, the procedural time in the lidocaine group (57 min) was significantly shorter in the saline group (80 min). The grade of bowel peristalsis in the lidocaine group (0.67) was significantly lower than in the saline group (1.17). Antispasmodic drug use was significantly rarer in the lidocaine group than in the saline group. The incidence of adverse events was not markedly different between the two groups.
Local lidocaine injection is a feasible option for preventing bowel peristalsis, particularly in the proximal colon, leading to a reduced procedural time for ESD and decreased antispasmodic drug use. University Hospital Medical Information Network Center (UMIN number: 000022843).
Endoscopic submucosal dissection (ESD) is a common procedure for the treatment of colorectal T1 cancer, particularly large lesions. However, ESD carries a high risk of perforation and requires a longer procedural time than other endoscopic procedures, including polypectomy and endoscopic mucosal resection [1]. Submucosal fibrosis, difficulties maintaining scope positioning, and bowel peristalsis are thought to underlie the long procedural time [2–4].
Several new cutting devices have been developed to easily cut through submucosal fibrosis [5, 6], and pocket-creation methods [7] have been used to maintain a good endoscopic view. However, few procedures for controlling bowel peristalsis have been developed. Anticholinergic drugs, such as butylscopolamine, are frequently used to relieve bowel peristalsis, although these drugs have some adverse effects, including tachycardia, an increased intraocular pressure, and dipsesis. Glucagon is used as a substitute of butylscopolamine in patients with cardiac diseases or glaucoma, although that drug carries risks of inducing hyperglycemia and late-onset hypoglycemia [8]. For these reasons, the administrable amounts of these drugs are limited, particularly in elderly patients or patients with such comorbidities.
Lidocaine is a local analgesic that has long been in use, and its safety in appropriate amounts has been established. The safety of local lidocaine injection during ESD in patients with gastric cancer has recently been proposed [9], and the efficacy of lidocaine spraying during colonoscopy has also been reported [10]. However, the efficacy and safety of lidocaine injection during ESD in patients with colorectal cancer has not yet been explored.
We conducted a multicenter randomized control study to determine the efficacy and safety of lidocaine injection during ESD for the treatment of colorectal T1 cancer.
Methods
Study design and ethical considerations
This is a multicenter randomized non-blinded control study that was approved by the Ethics Committees of Asahikawa Medical University (15089-3) and other participating institutes and registered with the University Hospital Medical Information Network Center (UMIN number: 000022843). Written informed consent was obtained from all patients enrolled.
Participants
From November 2015 to March 2019, 91 patients diagnosed with colorectal adenomas, T1 cancers, or neuroendocrine tumors that were indicated for ESD were enrolled in this study. The exclusion criteria were as follows: patients with severe cardiac disease, severe renal disease, severe cardiac infectious disease, severe diabetes, severe dehydration or malnutrition, and hemorrhagic diathesis as well as those in whom participation was deemed difficult by physician and those < 16 years old.
Randomization
The envelope method was used for randomization. Before ESD, patients were divided into two groups at a 1:1 ratio: the lidocaine group and the saline (placebo) group.
Procedures
Colonoscopy was started with sedation of 5–10 mg midazolam with no scopolamine butylbromide and/or glucagon. During the insertion of the colonoscope, 20 mg scopolamine butylbromide and/or 1 mg glucagon were injected only when the endoscopist called for an injection. Glucagon was used for patients with heart disease, prostate hypertrophy, and glaucoma as well as those ≥ 75 years old, and scopolamine butylbromide was used for all other patients.
On reaching the lesion, 1% lidocaine or saline was injected at both the oral and anal sides of the lesion before starting ESD. After starting ESD, 1% lidocaine or saline was injected every 15 min. A maximum of 20 ml of 1% lidocaine or saline was injected. If ESD could not be successfully completed after injecting ≥ 20 ml of 1% lidocaine or saline, then the procedure was performed without the injection of 1% lidocaine or saline. Scopolamine butylbromide and/or glucagon were injected when the endoscopist considered antispasmodic drugs necessary.
The grade of bowel peristalsis was classified as follows: score 0, no peristalsis; score 1, less peristalsis with no influence for ESD; score 2, mild peristalsis with influence for ESD; score 3, severe peristalsis in which ESD was able to be continued with some treatment.
Endpoints
The primary endpoint was the procedural time of ESD. The secondary endpoints were the bowel peristalsis score, amounts of antispasmodic drugs used, safety of lidocaine injection, and procedural time in each location. A subgroup analysis was performed to analyze the differences according to the location (proximal colon which included the cecum and ascending colon or distal colon).
Statistical analyses
The IBM SPSS statistics software program, version 25, was used for the statistical analysis. A t-test or Mann–Whitney U-test was used for the analysis of continuous variables. The Chi-square test or Fisher’s exact test was for nominal variables. P values of less than 0.05 were judged to indicate significance.
Results
Demographics of enrolled patients
Ninety-one patients were enrolled in this prospective study. These patients were randomly divided into the lidocaine group (n = 54) and saline group (n = 37) using the envelop method. One patient in whom sedation did not work and 2 in whom ESD was not completed due to severe fibrosis were excluded from this study, leaving 51 patients in the lidocaine group and 37 in the saline group for the analysis (Fig. 1). The age, gender, comorbidities, lesion location, histological type, invasion depth, tumor size, and grade of histological fibrosis were not markedly different between the lidocaine and saline groups (Table 1).Fig. 1 Flowchart of the patients enrolled in this study
Table 1 Patients’ demographics
Lidocaine group (n = 51) Saline group (n = 37) P value
Sex (male: female) 30:21:00 19:18 P = 0.32
Age (mean ± SD) 69.2 ± 11.9 70.8 ± 8.2 P = 0.60
Comorbidities 20 (39%) 14 (38%) P = 0.54
Location
Proximal colon:distal colon 19:32 17:20 P = 0.27
Histological type
Adenoma:carcinoma:NET 30:19:02 22:14:01 P = 0.95
Invasion depth
M:SM 15:06 9:05 P = 0.47
Tumor size(mm) 20 (20, 30) 25 (20, 40) P = 0.39
Proximal colon 25 (20, 30) 30 (20, 42.5) P = 0.10
Distal colon 22.5 (13.75, 30) 20 (20, 30) P = 0.62
Median(Q1, Q3)
Fibrosis 9 (18%) 5 (14%) P = 0.41
Primary endpoints
The median procedural time in the lidocaine group (62 min) was similar to that in the saline group (69 min). No significant difference in the procedural time was observed between the groups (Fig. 2).Fig. 2 Procedural times in the lidocaine and saline groups in the whole colon. The procedural time in the lidocaine group (62 min) was not significantly different from that in the saline group (69 min) (p = 0.49)
Secondary endpoints
The median procedural time in the lidocaine group for removing tumors in the proximal colon (57 min), which included the cecum and ascending colon, was significantly shorter than that in the saline group (p = 0.05), while no marked differences in the procedural time were observed between the groups in the distal colon, which included the transverse colon, descending colon, sigmoid colon, and rectum (Fig. 3). The bowel peristalsis score of the lidocaine group (0.67) was significantly lower than that of the saline group (p < 0.05) (Fig. 4). The median bowel peristalsis score of the lidocaine group in the proximal colon was significantly lower than that in the saline group (p < 0.01), and the median bowel peristalsis score in the distal colon of the lidocaine group was significantly lower than that in the distal colon of the saline group (p = 0.01) (Fig. 5). The rate of using additional antispasmodic drugs in the lidocaine group (6%) was significantly lower than that in the saline group (35%) (p < 0.05) (Table 2). The incidence of adverse events, including perforation, penetration, bleeding, hypotension, bradycardia, tachycardia, and hypoxemia, was similar between the groups (Table 3).Fig. 3 Procedural times at the proximal and distal sites of the colon. In the proximal colon, the mean procedural times in the lidocaine and saline groups were 57 and 80 min, respectively. The time in the lidocaine group was significantly shorter than in the saline group (p < 0.05). In the distal colon, there was no marked difference between the groups
Fig. 4 Bowel peristalsis scores in the lidocaine and saline groups. The mean bowel peristalsis scores in the lidocaine and saline groups were 0.67 and 1.17, respectively. The score was significantly higher in the lidocaine group than in the saline group (p < 0.05)
Fig. 5 Bowel peristalsis scores at the proximal and distal sites of the colon. In the proximal colon, the mean bowel peristalsis scores in the lidocaine and saline groups were 0.67 and 1.25, respectively. The bowel peristalsis scores in the lidocaine group were significantly lower than in the saline group (p < 0.01). In the distal colon, the mean bowel peristalsis scores in the lidocaine and saline groups were 0.61 and 1.00, respectively. The bowel peristalsis scores in the lidocaine group were significantly lower than in the saline group (p = 0.01)
Table 2 Amount and incidence of antispasmodic drug use
Lidocaine group (n = 51) Saline group (n = 37) P value
Total volume (ml) 8 (6, 12) 10 (6, 15) P = 0.17
Cases using additional antispasmodic agents n = 3 (6%) n = 13 (35%) P = 0.001
Butyl scopolamine bromide n = 1 n = 4
Glucagon n = 2 n = 9
Table 3 Adverse events
Lidocaine group (n = 51) Saline group (n = 37) P value
Minor perforation* 4 (8%) 1 (3%) P = 0.30
Perforation** 0 (0%) 2 (5%) P = 0.17
Bleeding 2 (4%) 2 (5%) P = 0.56
Hypotension 1 (2%) 1 (3%) P = 0.67
Tachycardia 1 (2%) 0 (0%) P = 0.58
Bradycardia 0 (0%) 2 (5%) P = 0.17
Decrease of SpO2 1 (2%) 0 (0%) P = 0.58
*Cases with suspected perforation during ESD without any symptoms associated with the perforation
**Cases with perforation with obvious clinical symptom associated with the perforation
Discussion
While the safety of local lidocaine injection in gastric ESD has been proposed [5], the present prospective study investigated the efficacy and safety of local lidocaine injection in colorectal tumors for the first time, illustrating that local lidocaine injection prevented bowel peristalsis during ESD and shortened the procedural time in the proximal colon. The study also showed the high safety of local lidocaine injection, suggesting the usefulness of local lidocaine injection for efficient and safe ESD.
Submucosal fibrosis, difficulties maintaining the scope position, and bowel peristalsis are known to underlie the long procedural time of ESD [2–4]. A number of new cutting devices have been developed for easily cutting submucosal fibrosis. In addition, traction devices, such as the S–O clip [5], as well as the balloon overtube-guided technique [6] and pocket-creation methods [7] have been used to maintain a good endoscopic view. However, few procedures for controlling bowel peristalsis have been developed. While spraying lidocaine has been proposed as a potential procedure for controlling bowel peristalsis, there is no established procedure that can be applied for the minutes-long slowing of peristalsis. The present study proposed for the first time the feasibility of a local lidocaine injection when applied for minutes-long slowing of peristalsis. The combination of new cutting devices, traction devices, and local lidocaine injection may be suitable when performing ESD in difficult cases with large-sized colorectal tumors, submucosal fibrosis, and/or a poor endoscopic view.
ESD at the hepatic and splenic flexures has been considered difficult [11, 12]. Operating an endoscope at the proximal colon has been recognized as more difficult in comparison to the distal colon due to the presence of numerous high semilunar folds and the long scope insertion. In the present study, the procedural time in the proximal colon in the lidocaine group was significantly shorter than that in the saline group, while the procedural time in the distal colon was not markedly different between the two groups, suggesting that relief of the bowel peristalsis might contribute to the shortening of the procedural time in the proximal colon. Based on the results, local lidocaine injection is thought to be recommended for removing colorectal tumors, particularly those in the proximal colon. Antispasmodic drug use was significantly rarer in the lidocaine group than in the saline group, although the procedural time was not markedly different between the two groups. When avoiding antispasmodic drug use during ESD in high-risk cases, such as older patients and/or those with severe comorbidities, local lidocaine injection is recommended even in the distal colon.
Lidocaine blocks the sodium channel and decreases the entry of sodium into neuron cells, thereby inhibiting the activities of both sensory and motor nerves [13]. While it is not clear why lidocaine inhibited bowel peristalsis, we assumed that lidocaine decreased the sensitivity of the mucosal surface, leading to the stimulation of bowel peristalsis by factors in the intestinal lumen. Another possibility was that the submucosal injection of lidocaine directly suppressed the nerve plexus.
Two limitations associated with this study warrant mention. First, this study was blinded for patients but not for endoscopists, which might have influenced the results, including the procedural time and amount of antispasmodic drugs used. Second, the study did not optimize the amount or interval of lidocaine injection. Further double-blinded studies are therefore needed in order to clarify the appropriate amount and interval of lidocaine injection for preventing bowel peristalsis during colorectal ESD.
In conclusion, local lidocaine injection is a feasible option for preventing bowel peristalsis, particularly in the proximal colon, thereby reducing the ESD procedural time and antispasmodic drug use.
Author contributions
MI and TS and MF provided major input into the conceptual development of the studies, wrote the manuscript and supervised all of the investigations. TI, AS, TD, YM, TK, KT, KA, NU, SK, and MT managed and treated the enrolled patients and collected and analyzed the data. KT, KM, HT, YS and TO helped design the studies, interpret the data, and prepare/review the manuscript. All of the authors read and approved the final manuscript.
Compliance with ethical standards
Disclosure statement
Dr. Fujiya reports grants and personal fees from EA Pharma Co., Ltd., personal fees from Sanofi K.K., personal fees from OLYNPUS Co., Ltd., during the conduct of the study; grants from Kamui Pharma. Inc., grants from Fuji Chemical Industries Co., Ltd., grants and personal fees from AYUMI Pharmaceutical Corporation, grants from JIMRO Co., Ltd., grants from Nobelpharma Co., Ltd., grants and personal fees from Takeda Pharmaceutical Company Limited, grants and personal fees from Nippon Kayaku Co., Ltd., grants and personal fees from AbbVie Inc, grants and personal fees from EA Pharma Co., Ltd., grants and personal fees from Mitsubishi Tanabe Pharma Corporation, grants and personal fees from Janssen Pharmaceutical K.K., grants and personal fees from Pfizer Inc, grants and personal fees from Bristol-Myers Company, grants and personal fees from KYORIN Pharmaceutical Co., Ltd., grants and personal fees from Daiichi Sankyo Company, Limited, grants from Yakult Honsha Co., Ltd., grants and personal fees from MOCHIDA PHARMACEUTICAL Co., Ltd., grants and personal fees from ZERIA Pharmaceutical Co., Ltd., personal fees from Horii Pharmaceutical Ind., Ltd., personal fees from Sanofi K.K., personal fees from OLYNPUS Co., Ltd., personal fees from Celltrionhealthcare Japan. Co., Ltd., personal fees from Medical Tribune. Inc., personal fees from Astrazeneca.co.jp, personal fees from Nobelpharma Co., Ltd., personal fees from TAIHO Pharmaceutical Co., Ltd., personal fees from Technical Information Institute Co., Ltd., personal fees from Boehringer lngelheim GmbH, personal fees from SHIONOGl & Co., Ltd., personal fees from Chugai Pharmaceutical Co., Ltd., personal fees from TEIJIN PHARMA LIMITED., personal fees from Aspen Japan K.K., personal fees from Kissei Pharmaceutical Co., Ltd., outside the submitted work. Dr. Okumura reports grants from JA Hokkaido Kousei Agricultural Cooperative Association during the conduct of the study.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Masami Ijiri, Takahiro Sasaki, and Mikihiro Fujiya contributed equally to this study.
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LIDOCAINE
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DrugsGivenReaction
|
CC BY
|
32989543
| 20,768,331
|
2021-09
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19'.
|
Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection.
Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.
The current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.
The liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.
On the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.
Summary
Liver injury from COVID-19 infection is increasingly being identified, with a dearth of corresponding liver biopsy data to date. The unique liver histology of 2 patients who both recovered with severe COVID-19 hepatitis is presented. Liver involvement may be the only manifestation of COVID-19 infection.
Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2), is a global pandemic of unprecedented proportions.1 During the months of March and April 2020, New York City became the epicenter of the COVID-19 pandemic, and Mount Sinai Hospital was one of the major hospitals in the region that took care of several thousand COVID-19 patients. In the midst of the pandemic, ongoing liver transplantation (LT) and referrals of patients with severe liver disease continued unabated.2
Initial reports focused on COVID-19 as mainly involving the lungs and being the main cause of morbidity and mortality.3 However, neurologic, cardiac, renal, hepatobiliary, and gastrointestinal tract involvements are increasingly being recognized.3 The reported incidence of liver injury in patients with COVID-19 ranges from 14% to 53%.4, 5, 6 Those studies are mainly based on abnormal liver enzyme elevations in the absence of tissue examination. In one study, a significant number of cases were noted to have elevation of liver enzymes occurring at approximately the tenth day of hospitalization and associated with lopinavir/ritonavir treatment.7 The authors also found that prolonged hospital stays were associated with abnormal liver enzymes noted at the time of initial admission.7 Risk factors included underlying chronic liver disease such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD).4 In a study involving 252 COVID-19 patients, the investigators found that patients having NAFLD had a significantly higher risk of disease progression, a higher likelihood of developing abnormal liver tests during hospitalization, and longer viral shedding times as compared with patients without NAFLD.6
In a previous study of postmortem examinations, liver histology showed lobular lymphocytic inflammation and centrilobular sinusoidal dilatation, with only a few cases showing parenchymal necrosis.8 Furthermore, in another autopsy study of a 51-year-old man, microvesicular steatosis and mild lobular and portal inflammation were noted.9 At the present time, no detailed histologic, immunohistochemical, and ultrastructural findings have been reported in the literature regarding infection of the liver by COVID-19. Herein we report 2 patients who presented with high aminotransferases and underwent liver biopsy that showed acute hepatitis. A detailed histologic analysis along with in situ hybridization and electron microscopy (EM) were performed on liver tissue to suggest direct hepatic involvement by the novel coronavirus SARS-CoV-2.
Clinical Histories
Case 1
The patient is a 63-year-old man who underwent LT in 2017 for hepatitis C (HCV) and alcohol-related liver disease. He received a genotype 1b HCV (+) donor with a pre-perfusion liver biopsy showing no underlying fibrosis and mild portal inflammation. He underwent antiviral therapy with sofosbuvir/ledipasvir starting 3 months after LT and achieved a sustained virologic response. He had developed dialysis-dependent chronic renal failure related to calcineurin inhibitor nephrotoxicity, hypertension, and insulin-dependent diabetes mellitus but always had normal liver chemistry tests and never previously had an episode of acute cellular rejection (ACR). The patient was stable for 2 years after LT until he suffered a stroke in January 2020. Laboratory tests on discharge from the transplant center after his stroke were normal with aspartate aminotransferase 12 U/L, alanine aminotransferase 14 U/L, alkaline phosphatase 68 U/L, and normal serum bilirubin. The tacrolimus dose was stable with a level of 4–6 ng/mL. He was discharged to a rehabilitation facility on regular doses of his medications, which included aminosalicylic acid 81 mg, atorvastatin, calcium acetate, dorzolamide drops, famotidine, insulin, labetalol, nifedipine, ropinirole, sodium bicarbonate, tacrolimus 2 mg twice a day, and tamsulosin. While residing at the rehabilitation facility, the patient developed constitutional symptoms and was found to be COVID-19 (+) via nasopharyngeal swab testing and referred to a local hospital where the liver enzymes were noted to be abnormal (Table 1). The patient was started on N-acetyl cysteine and acyclovir empirically; however, follow-up laboratory tests showed rising liver enzymes.Table 1 Liver Enzyme Values of Case 1 and Case 2
AST, U/L (1–35) ALT, U/L (1–45) Alk Phos, U/L (38–126) T bili, mg/dL (0.1–1.2) D-dimer, μg/mL (0–0.5) Ferritin, ng/mL (30–400) Procalcitonin, ng/mL (<0.49) CRP, mg/L (0–5)
Case 1
HD 1 1083 1035 824 1.1
HD 2 2074 1761 907 3.1
HD 3 1691 1578 915 3.9 1.84 4677 5.24 24.5
HD 6 769 994 1363 7.1 1.38 2863 3.57 11.3
HD 9 541 776 1568 9.3 0.77 2520 1.16 7.0
Case 2
HD 1 2786 2909 210 13.8 827 0.35 8.4
HD 8 1700 1856 132 20.6 1290 1558 0.26 0.7
HD 15 591 650 184 31.5 172 0.9
HD 18 506 616 241 33.5 0.27 224 0.28 0.7
HD 24 200 221 166 10.7
Alk Phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HD, hospital day; T bili, total bilirubin.
He was transferred to Mount Sinai Hospital for further management. Reverse transcription polymerase chain reaction (PCR) on a repeat nasopharyngeal swab specimen confirmed SARS-CoV-2 infection, and the tacrolimus dose was increased to 3 mg twice a day in the setting of a trough level of 3.0 ng/mL. On presentation, the aminotransferases and alkaline phosphatase levels were elevated, as was the total serum bilirubin. Doppler ultrasonography showed no vascular or biliary abnormalities. The following additional lab results were obtained: undetectable PCR for herpes simplex 1 and 2, HCV, hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, undetectable antibody to hepatitis E, and undetectable immunoglobulin M for hepatitis A virus. The triglyceride level was 483 mg/dL (0–150). Inflammatory markers were significantly elevated (Table 1) including lactate dehydrogenase of 702 U/L (reference range, 100–220). The platelet count was 132 × 103, and the white blood cell count was 3.9 × 103. The patient’s clinical and serologic features supported the diagnosis of COVID-19 infection.
A liver biopsy was performed 9 days after the initial presentation and on hospital day 6. The histologic changes are highlighted in Figure 1. The majority of the portal tracts uniformly showed a mixed inflammatory infiltrate with a few eosinophils, prominent bile duct damage, and endotheliitis (Figure 1a). The lobule showed disarray with many apoptotic bodies, foci of necrosis, and abundant mitotic figures (Figure 1b). Focal central venulitis was noted. C4d immunostain was positive in a few endothelial cells lining the portal and central venules. CD61 immunostain to determine the presence of fibrin thrombi was negative. In rare portal tracts, severe bile duct damage with cholangiocytes undergoing apoptosis was seen (Figure 1c). A diagnosis of ACR and concomitant severe acute hepatitis was rendered.Figure 1 Liver biopsy findings of case 1. (a) Portal tract showing mixed inflammatory infiltrate consisting of lymphocytes, blast-like cells, and eosinophils, along with mild endotheliitis and severe bile duct damage. Bile duct is barely unrecognizable, and in its place are apoptotic cholangiocytes (arrowheads). Open arrowhead indicates accompanying hepatic arteriole. H&E, original magnification ×40. Black stars indicate a damaged bile duct. (b) Lobule shows disarray with many hepatocytes undergoing apoptosis in various stages (black arrowheads), while there is also concomitant increased mitotic activity (white arrows). H&E, original magnification ×40. (c) A few portal tracts are devoid of inflammation. Because of paucity of inflammation in this particular portal tract, one can visualize the cholangiocytes undergoing apoptosis (arrow). H&E, original magnification ×40. (d) RNA localization of COV-S protein using RNAScope showing dot-like particles (black arrow) in cytoplasm of an infected endothelial cell.
Slides for RNAScope for SARS-CoV-2 spike protein showed positive staining in rare cells and were seen as cytoplasmic dotted signals. In the absence of double immunostaining, the type of cells with positive staining could not be identified with certainty (Figure 1d). Throughout the entire 3.2-cm length of the liver biopsy, only 8 such cells were found to be positive. No cells were positive for the SARS-CoV-2 spike protein anti-sense strand probe, indicating that no active replication could be detected.
EM revealed the presence of viral-like particles displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average, consistent with members of the Coronaviridae family10, 11, 12 (Figure 2a). The virions were mostly located within intracytoplasmic vesicles in close proximity to the endoplasmic reticulum. After the biopsy, the tacrolimus level was optimized to achieve a trough level of approximately 10. Infectious diseases department was consulted and recommended that the patient did not warrant medical treatment for COVID-19 infection because he was oxygenating normally and had a normal chest x-ray. Under observation, the patient’s liver chemistry tests slowly down trended, as did all of the inflammatory markers (Table 1) until discharge.Figure 2 Electron microscopy photos of case 1 and case 2. (a) EM showing presence of viral-like particles (encircled) displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average. (b) Viral-like particles (encircled) measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections appearing to be within sinusoidal endothelial cells.
Case 2
The patient is a 36-year-old previously healthy woman who presented to a local hospital with 6 days of progressive nausea, vomiting, and scleral icterus. She also had anorexia, myalgias, and fevers 1 week before her presentation, taking approximately 1.5 g acetaminophen and no other prescription or over-the-counter medications. Initial laboratory tests at presentation on April 6, 2020 showed markedly elevated aminotransferases, total serum bilirubin, and a mildly elevated alkaline phosphatase (Table 1). The international normalized ratio was 1.3. Additional serologic markers included antinuclear antibodies + 1:160, liver-kidney microsomal antibody negative, anti-smooth muscle antibody negative, cytomegalovirus immunoglobulin M negative, Epstein-Barr virus PCR negative, herpes simplex virus (–), human immunodeficiency virus (–), and negative acute serologies for hepatitis A virus, hepatitis B virus, and HCV. Serologic tests are outlined in Table 1. She had normal magnetic resonance imaging of the liver; a nasopharyngeal swab was (+) for COVID-19. The patient was started on an infusion of N-acetyl cysteine, and a liver biopsy was performed on hospital day 7. She was thereafter transferred to Mount Sinai Hospital.
Review of the liver biopsy (Figure 3) showed severe acute hepatitis with marked lobular disarray characterized by inflammatory infiltrates, many acidophilic bodies, ballooned hepatocytes, scattered ceroid-laden macrophages, Kupffer cell hyperplasia, and activated sinusoidal lining cells. Portal areas showed mild to moderate mixed inflammation composed of lymphocytes, few plasma cells, scattered eosinophils and neutrophils, accompanied by mild interface hepatitis and mild ductular reaction (Figure 3a and b). Centrilobular hepatocyte necrosis with dropout and focal confluent necrosis were seen. Mild endotheliitis was noted, and most of the interlobular bile ducts were severely damaged. The severe damage was characterized by cholangiocytes having eosinophilic cytoplasm and densely pyknotic nuclei indicative of apoptosis (Figure 3c). CD61 immunostaining showed granular positive staining along the sinusoidal endothelial lining and in some of the terminal hepatic venules, indicative of the presence of non-occlusive fibrin thrombi (Figure 3d).Figure 3 Liver biopsy findings of case 2. (a) Portal tract with mixed inflammation, including eosinophils, activated lymphocytes, and rare plasma cells. Bile ducts are severely damaged (arrowheads), with some cholangiocytes undergoing acidophilic change and apoptosis. Detached necrotic cholangiocytes are seen in the lumen (bottom right). H&E, original magnification ×40. (b) High power view of lobule showing scattered hepatocytes undergoing apoptosis (arrowheads), with rest of the lobule showing ballooning degeneration of hepatocytes and foci of necroinflammation. H&E, original magnification ×40. (c) Portal tract containing dense mixed inflammatory infiltrate with bile duct showing cholangiocytes undergoing acidophilic change (arrowheads). H&E, original magnification ×40. (d) Immunostain for CD61 shows granular lace-like pattern of staining decorating the endothelial lining of the sinusoids as well as terminal hepatic venule (arrowhead). Original magnification ×40. (e) In situ hybridization showing hepatocyte with intracytoplasmic granular staining for COV-Spike protein (arrow). Original magnification ×40.
Similar to what was seen in case 1, RNAScope for SARS-CoV-2 spike protein was positive in rare cells (Figure 3e). A total of 6 positive cells throughout the biopsy length of 3.8 cm were identified; no cells were positive for viral replication by spike protein anti-sense strand probe. Transmission electron microscopy showed viral-like particles measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections. Ultrastructurally, these virions appeared to be within sinusoidal endothelial cells10, 11, 12 (Figure 2b).
The patient was deemed not to require treatment for COVID-19 because she was oxygenating well and had no radiographic evidence of pneumonia. She was also found to have thyroid-stimulating hormone of .008 and was diagnosed with thyroiditis, which has recently been reported in COVID-19 infection,13 and she was started on cholestyramine and ursodiol. She had repeat negative PCR testing for SARS CoV-2 on hospital days 15, 18, and 24 at Mount Sinai. Because she was feeling much better she was discharged, with lactate dehydrogenase of 209 and D-dimer <0.27. Laboratory testing 1 week later showed an ongoing decrease in her liver enzymes, although the bilirubin was still elevated to 10.7 mg/dL with an indirect fraction of 7.8 mg/dL.
Discussion
The cases presented in the current report had markedly elevated liver enzymes at presentation, with both fitting the clinical course timeline as well as the histologic features of severe COVID-19 hepatitis. RNA localization of SARS-CoV-2 S protein using in situ hybridization and EM findings suggest that SARS-CoV-2 may have played a major role in the liver damage incurred by these 2 patients. Despite the initial presentation of severe liver damage, both patients recovered from COVID-19 hepatitis.
Currently, it is known that the development of abnormal liver chemistry tests and various forms of liver injury may result from COVID-19,14 with the majority of cases having mildly elevated liver enzymes.4 In a series of 99 COVID-19 patients, only 1 case presented with severe liver injury with markedly elevated liver enzymes, whereas 43 of 99 showed mild alanine aminotransferase and aspartate aminotransferase elevations (in 28% and 35%, respectively).15 In patients with significantly increased liver enzymes, there were longer hospital stays, and most patients were taking medications such as lopinavir/ritonavir, with the latter raising the possibility of drug-induced liver injury (DILI).7 A recent review concluded that significantly elevated aminotransferases are only found in severe cases of COVID-19.16 However, to date there are only case reports or small case series detailing the liver histologic findings found in patients with COVID-19 infection.4 Microvesicular steatosis and the presence of mild lymphocytic inflammation in the lobules and rarely in portal tracts are the main findings reported.4 Furthermore, there is a dearth of reported liver biopsies in COVID-19 infection of solid organ recipients.17 Aside from one post-LT pediatric case wherein a liver biopsy was performed several days after LT, no other cases have been reported.18
Liver biopsies from both patients in this study showed prominent mitoses of hepatocytes along with acidophilic bodies, ballooning degeneration, and mild inflammation. Histology also showed mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. Although these features are seen in acute T-cell–mediated rejection, which might conceivably explain the portal tract findings in patient 1, patient 2 did not have LT and yet showed a similar histology. Lagana et al18 reported the presence of increased mitotic activity and the presence of numerous apoptotic bodies in their post-LT case. A case series from the SARS epidemic in 2003 described the histology of 3 patients. These patients all had elevated liver enzymes in the 300–400 range, and liver histology showed prominent mitoses.19 The authors surmised that the prominent mitoses were likely due to a hyperproliferative state and cell cycle arrest. They further described ballooning degeneration and mild to moderate lobular inflammation. The authors ascribed these findings to what was previously reported in avian coronavirus and transmissible gastroenteritis coronavirus infections in which the coronavirus had exerted extensive cytopathic effect through the induction of apoptosis of host cells by activation of caspase.19, 20, 21 The 2 cases presented here appear to have similar cytopathic effect from SARS-CoV-2 due to the increased number of apoptotic bodies noted on both liver biopsies.
The proposed mechanism of liver injury from SARS-CoV-2 includes severe inflammatory responses and direct cytotoxicity due to active viral replication with angiotensin-converting enzyme receptors (ACE2) being abundant in the liver, particularly in cholangiocytes and endothelial cells.22 It has been shown that SARS-CoV-2 interacts with host receptors in liver cells. Gene expression of ACE2 transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) has been shown. All 3 receptors are abundant in cholangiocytes and hepatocytes as well as in endothelial cells. Because these 3 receptors are present in various liver cells, SARS-CoV-2 may cause direct injury via a cytopathic effect, either by lysis and/or by inducing necrosis and apoptosis.22, 23, 24 Therefore, the ballooning degeneration and apoptosis as well as the striking bile duct damage may possibly be due to direct viral injury, with in situ hybridization and EM demonstrating viral particles within the liver. Previous case reports have failed to demonstrate the detection of intrahepatic viral particles. SARS-CoV-2 can also infect the gastrointestinal tract because of the abundant ACE2 receptors present.24,25 Therefore, the possibility that SARS-CoV-2 may enter the liver via the portal vein (portal venous viremia) can also be entertained.23 Varga et al26 have shown SARS-CoV-2 can directly infect endothelial cells across vascular beds of different organs, although not specifically in the liver. Widespread endothelial cell dysfunction in heart, kidney, lung, and small intestine resulted in apoptosis and prominent endotheliitis of submucosal vessels.26 Another mechanism believed to be the underlying cause of liver injury is ischemic changes in those with severe COVID-19 and DILI.4,27,28 In addition to the direct damage, translocation, and DILI, immune-mediated liver injury is another mechanism to consider. This is especially important in light of the increased inflammatory markers noted on serologic testing.16 Although SARS-CoV-2 virus is a new virus and our understanding of its tissue and cellular localization and replication is very limited, the sparse distribution of the virus as seen in the liver in the 2 current cases is not surprising because of the comparable sporadic and occasional cellular distribution described with the first SARS-CoV coronavirus in the early and mid-2000s.29,30 Despite the fact that we could not prove that the virus is replicating within the liver tissue because we did not see positive signals for the anti-sense strand of the S gene of the virus, we could not rule out such a possibility because the viral particles are sparsely distributed, and there is a limited amount of liver tissue in these core needle biopsies.
The clinical picture of the 2 patients is that of a spontaneously resolving COVID-19 infection with the markedly elevated liver tests and inflammatory markers decreasing concurrently. Although the patients did not have severe pulmonary, cardiac, or neurologic manifestations of COVID-19 infection that warranted treatment, significant liver chemistry abnormalities developed that correlated with the histologic liver damage noted. Neither patient had known underlying intrinsic liver disease, but if they did in light of the severe histologic liver damage noted, it is possible that they might have developed acute-on-chronic liver failure due to COVID-19.14,31
Some of the histologic findings seen in Case 1 are also typically seen in ACR, such as mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. In addition, there was histologic evidence of acute hepatitis, likely because of COVID-19, ie, COVID-19 hepatitis. Lagana et al18 showed similar findings in their case that occurred 7 days after transplantation. Although it is possible that this patient had both mild ACR and concurrent COVID-19 hepatitis, it is more likely that the histologic features are due to COVID-19 because the magnitude of the aminotransferase elevation is not typical of mild ACR, and the substantive decline in liver tests with only a minimal increase in tacrolimus dose is not typical of ACR.
Although both of the reported post-LT cases may be episodes of ACR that were triggered by COVID-19, as can occur with other viral infections,32 it is more likely that these histologic features are all related to COVID-19 infection because case 2 in the current report had very similar features. The endotheliitis demonstrated in these 2 patients appears similar to that reported in other organs.26,33 The histology thus suggests both a direct viral cytopathic effect and an immunologic liver injury involving cholangiocytes, hepatocytes, and liver sinusoidal endothelial cells. The significant bile duct damage and apoptosis of cholangiocytes are very prominent in these cases. In the absence of intrinsic liver disease, resolution of the direct cytopathologic injury may occur with clearance of SARS-CoV-2, yet it will remain to be seen whether the immunologic component of the liver injury will as well. Thus, close follow-up of such patients is warranted.
In conclusion, the current report details the liver histologic findings of acute COVID-19 infection in 2 patients, which are supported by the use of in situ hybridization and EM studies. Apoptosis, especially of cholangiocytes, abundant mitoses, mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage are typical. This histology suggests a direct cytopathic viral injury most notably in sinusoidal endothelial cells and other liver cells, with concurrent immunologic features. Such histologic changes can resemble ACR, so LT physicians must consider this possibility in post-LT patients with COVID-19 infection. These cases also demonstrate that patients can have severe liver injury in the absence of significant involvement of other organs by COVID-19.
Materials and Methods
Histopathology
Transjugular needle liver biopsy was performed for patient 1, and a percutaneous liver biopsy was performed for patient 2. Core biopsy specimens were immediately placed in formalin and fixed for a minimum of 3 hours. Routine tissue processing through graded alcohols was performed. Thereafter, the liver biopsy tissues were embedded in paraffin (FFPE). Three 4-μm-thick sections were cut for H&E stain to assess different levels and one 4-μm section for Masson trichrome stain. H&E and trichrome-stained slides were analyzed by routine light microscopy. Adequacy of the specimen was determined including the linear length of tissue and the number of complete portal tracts. Morphologic evaluation was performed under light microscopy. Histopathologic features analyzed included degree of portal and lobular inflammation, parenchymal damage including apoptosis, presence of fibrosis, bile duct injury, and endothelial damage.
In Situ Hybridization
Sections at 3 μm in thickness were taken from FFPE for RNA in situ hybridization using the RNAscope HPV kit (Advanced Cell Diagnostics, Inc, Hayward, CA) according to the manufacturer’s instructions on a Leica Bond III automated stainer (Leica Biosystems, Buffalo Grove, IL). Tissue sections were hybridized separately with a target probe to the SARS-CoV-2 S gene encoding the spike protein (catalogue #848561) to detect viral proteins within the cells to indicate infected cells and SARS-CoV-2 antisense strand of the S gene (catalogue #845701) to detect active viral replication within the cells. Positive controls for the SARS-CoV-2 S and antisense strand of the genes were prepared in-house from SARS-CoV-2-infected Vero cell lines (cell lines gift from Dr Florian Krammer, Icahn School of Medicine at Mount Sinai, New York, NY). To assess for the RNA integrity, probes for the endogenous housekeeping gene UBC (catalogue #RS7760) were used. The preamplifier, amplifier, and horseradish peroxidase–labeled probes were then hybridized sequentially, followed by color development with DAB. Specific staining signals were identified as brown, punctate dots present in the cytoplasm and/or nucleus.
Transmission Electron Microscopy
The tissue processed for EM was received in paraffin blocks. Designated portions of the specimen were dissected out with a single edge razor blade and placed into xylene overnight to dissolve the paraffin. The tissue was then brought to water through decreasing concentrations of ethanol and then fixed with 3% glutaraldehyde in a 0.2 sodium cacodylate buffer at pH 7.4.The specimen was then post-fixed with 1% osmium tetroxide tissues and embedded in Epon 812. One micrometer plastic sections were cut and stained with methyl blue and azure II for light microscopic orientation and to select smaller representative areas. Ultrathin 60-nm sections were collected into 200 mesh copper grids and stained with lanthanum and lead citrate. Sections were examined in a Hitachi 7650 (Tokyo, Japan) transmission electron microscope at 80 kV.
All authors had access to the study data and reviewed and approved the final manuscript.
CRediT Authorship Contributions
Maria Isabel Fiel, MD (Conceptualization: Lead; Data curation: Lead; Methodology: Equal; Writing – original draft: Lead)
Siraj M. El Jamal, MD (Methodology: Supporting; Writing – original draft: Supporting)
Alberto Paniz-Mondolfi, MD (Methodology: Supporting; Writing – original draft: Supporting)
Ronald E. Gordon, PhD (Methodology: Supporting; Writing – original draft: Supporting)
Jason Reidy, PhD (Methodology: Supporting)
Jela Bandovic, MD (Methodology: Supporting; Visualization: Supporting)
Rashmi Advani, MD (Data curation: Supporting)
Saikiran Kilaru, MD (Data curation: Supporting)
Kamron Pourmand, MD (Data curation: Supporting)
Stephen Ward, MD, PhD (Formal analysis: Supporting)
Swan N. Thung, MD (Formal analysis: Supporting)
Thomas D. Schiano, MD (Conceptualization: Equal; Formal analysis: Equal; Writing – original draft: Equal)
Conflicts of interest The authors disclose no conflicts.
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TACROLIMUS
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DrugsGivenReaction
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CC BY-NC-ND
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32992052
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2021
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic kidney disease'.
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Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection.
Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.
The current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.
The liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.
On the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.
Summary
Liver injury from COVID-19 infection is increasingly being identified, with a dearth of corresponding liver biopsy data to date. The unique liver histology of 2 patients who both recovered with severe COVID-19 hepatitis is presented. Liver involvement may be the only manifestation of COVID-19 infection.
Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2), is a global pandemic of unprecedented proportions.1 During the months of March and April 2020, New York City became the epicenter of the COVID-19 pandemic, and Mount Sinai Hospital was one of the major hospitals in the region that took care of several thousand COVID-19 patients. In the midst of the pandemic, ongoing liver transplantation (LT) and referrals of patients with severe liver disease continued unabated.2
Initial reports focused on COVID-19 as mainly involving the lungs and being the main cause of morbidity and mortality.3 However, neurologic, cardiac, renal, hepatobiliary, and gastrointestinal tract involvements are increasingly being recognized.3 The reported incidence of liver injury in patients with COVID-19 ranges from 14% to 53%.4, 5, 6 Those studies are mainly based on abnormal liver enzyme elevations in the absence of tissue examination. In one study, a significant number of cases were noted to have elevation of liver enzymes occurring at approximately the tenth day of hospitalization and associated with lopinavir/ritonavir treatment.7 The authors also found that prolonged hospital stays were associated with abnormal liver enzymes noted at the time of initial admission.7 Risk factors included underlying chronic liver disease such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD).4 In a study involving 252 COVID-19 patients, the investigators found that patients having NAFLD had a significantly higher risk of disease progression, a higher likelihood of developing abnormal liver tests during hospitalization, and longer viral shedding times as compared with patients without NAFLD.6
In a previous study of postmortem examinations, liver histology showed lobular lymphocytic inflammation and centrilobular sinusoidal dilatation, with only a few cases showing parenchymal necrosis.8 Furthermore, in another autopsy study of a 51-year-old man, microvesicular steatosis and mild lobular and portal inflammation were noted.9 At the present time, no detailed histologic, immunohistochemical, and ultrastructural findings have been reported in the literature regarding infection of the liver by COVID-19. Herein we report 2 patients who presented with high aminotransferases and underwent liver biopsy that showed acute hepatitis. A detailed histologic analysis along with in situ hybridization and electron microscopy (EM) were performed on liver tissue to suggest direct hepatic involvement by the novel coronavirus SARS-CoV-2.
Clinical Histories
Case 1
The patient is a 63-year-old man who underwent LT in 2017 for hepatitis C (HCV) and alcohol-related liver disease. He received a genotype 1b HCV (+) donor with a pre-perfusion liver biopsy showing no underlying fibrosis and mild portal inflammation. He underwent antiviral therapy with sofosbuvir/ledipasvir starting 3 months after LT and achieved a sustained virologic response. He had developed dialysis-dependent chronic renal failure related to calcineurin inhibitor nephrotoxicity, hypertension, and insulin-dependent diabetes mellitus but always had normal liver chemistry tests and never previously had an episode of acute cellular rejection (ACR). The patient was stable for 2 years after LT until he suffered a stroke in January 2020. Laboratory tests on discharge from the transplant center after his stroke were normal with aspartate aminotransferase 12 U/L, alanine aminotransferase 14 U/L, alkaline phosphatase 68 U/L, and normal serum bilirubin. The tacrolimus dose was stable with a level of 4–6 ng/mL. He was discharged to a rehabilitation facility on regular doses of his medications, which included aminosalicylic acid 81 mg, atorvastatin, calcium acetate, dorzolamide drops, famotidine, insulin, labetalol, nifedipine, ropinirole, sodium bicarbonate, tacrolimus 2 mg twice a day, and tamsulosin. While residing at the rehabilitation facility, the patient developed constitutional symptoms and was found to be COVID-19 (+) via nasopharyngeal swab testing and referred to a local hospital where the liver enzymes were noted to be abnormal (Table 1). The patient was started on N-acetyl cysteine and acyclovir empirically; however, follow-up laboratory tests showed rising liver enzymes.Table 1 Liver Enzyme Values of Case 1 and Case 2
AST, U/L (1–35) ALT, U/L (1–45) Alk Phos, U/L (38–126) T bili, mg/dL (0.1–1.2) D-dimer, μg/mL (0–0.5) Ferritin, ng/mL (30–400) Procalcitonin, ng/mL (<0.49) CRP, mg/L (0–5)
Case 1
HD 1 1083 1035 824 1.1
HD 2 2074 1761 907 3.1
HD 3 1691 1578 915 3.9 1.84 4677 5.24 24.5
HD 6 769 994 1363 7.1 1.38 2863 3.57 11.3
HD 9 541 776 1568 9.3 0.77 2520 1.16 7.0
Case 2
HD 1 2786 2909 210 13.8 827 0.35 8.4
HD 8 1700 1856 132 20.6 1290 1558 0.26 0.7
HD 15 591 650 184 31.5 172 0.9
HD 18 506 616 241 33.5 0.27 224 0.28 0.7
HD 24 200 221 166 10.7
Alk Phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HD, hospital day; T bili, total bilirubin.
He was transferred to Mount Sinai Hospital for further management. Reverse transcription polymerase chain reaction (PCR) on a repeat nasopharyngeal swab specimen confirmed SARS-CoV-2 infection, and the tacrolimus dose was increased to 3 mg twice a day in the setting of a trough level of 3.0 ng/mL. On presentation, the aminotransferases and alkaline phosphatase levels were elevated, as was the total serum bilirubin. Doppler ultrasonography showed no vascular or biliary abnormalities. The following additional lab results were obtained: undetectable PCR for herpes simplex 1 and 2, HCV, hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, undetectable antibody to hepatitis E, and undetectable immunoglobulin M for hepatitis A virus. The triglyceride level was 483 mg/dL (0–150). Inflammatory markers were significantly elevated (Table 1) including lactate dehydrogenase of 702 U/L (reference range, 100–220). The platelet count was 132 × 103, and the white blood cell count was 3.9 × 103. The patient’s clinical and serologic features supported the diagnosis of COVID-19 infection.
A liver biopsy was performed 9 days after the initial presentation and on hospital day 6. The histologic changes are highlighted in Figure 1. The majority of the portal tracts uniformly showed a mixed inflammatory infiltrate with a few eosinophils, prominent bile duct damage, and endotheliitis (Figure 1a). The lobule showed disarray with many apoptotic bodies, foci of necrosis, and abundant mitotic figures (Figure 1b). Focal central venulitis was noted. C4d immunostain was positive in a few endothelial cells lining the portal and central venules. CD61 immunostain to determine the presence of fibrin thrombi was negative. In rare portal tracts, severe bile duct damage with cholangiocytes undergoing apoptosis was seen (Figure 1c). A diagnosis of ACR and concomitant severe acute hepatitis was rendered.Figure 1 Liver biopsy findings of case 1. (a) Portal tract showing mixed inflammatory infiltrate consisting of lymphocytes, blast-like cells, and eosinophils, along with mild endotheliitis and severe bile duct damage. Bile duct is barely unrecognizable, and in its place are apoptotic cholangiocytes (arrowheads). Open arrowhead indicates accompanying hepatic arteriole. H&E, original magnification ×40. Black stars indicate a damaged bile duct. (b) Lobule shows disarray with many hepatocytes undergoing apoptosis in various stages (black arrowheads), while there is also concomitant increased mitotic activity (white arrows). H&E, original magnification ×40. (c) A few portal tracts are devoid of inflammation. Because of paucity of inflammation in this particular portal tract, one can visualize the cholangiocytes undergoing apoptosis (arrow). H&E, original magnification ×40. (d) RNA localization of COV-S protein using RNAScope showing dot-like particles (black arrow) in cytoplasm of an infected endothelial cell.
Slides for RNAScope for SARS-CoV-2 spike protein showed positive staining in rare cells and were seen as cytoplasmic dotted signals. In the absence of double immunostaining, the type of cells with positive staining could not be identified with certainty (Figure 1d). Throughout the entire 3.2-cm length of the liver biopsy, only 8 such cells were found to be positive. No cells were positive for the SARS-CoV-2 spike protein anti-sense strand probe, indicating that no active replication could be detected.
EM revealed the presence of viral-like particles displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average, consistent with members of the Coronaviridae family10, 11, 12 (Figure 2a). The virions were mostly located within intracytoplasmic vesicles in close proximity to the endoplasmic reticulum. After the biopsy, the tacrolimus level was optimized to achieve a trough level of approximately 10. Infectious diseases department was consulted and recommended that the patient did not warrant medical treatment for COVID-19 infection because he was oxygenating normally and had a normal chest x-ray. Under observation, the patient’s liver chemistry tests slowly down trended, as did all of the inflammatory markers (Table 1) until discharge.Figure 2 Electron microscopy photos of case 1 and case 2. (a) EM showing presence of viral-like particles (encircled) displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average. (b) Viral-like particles (encircled) measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections appearing to be within sinusoidal endothelial cells.
Case 2
The patient is a 36-year-old previously healthy woman who presented to a local hospital with 6 days of progressive nausea, vomiting, and scleral icterus. She also had anorexia, myalgias, and fevers 1 week before her presentation, taking approximately 1.5 g acetaminophen and no other prescription or over-the-counter medications. Initial laboratory tests at presentation on April 6, 2020 showed markedly elevated aminotransferases, total serum bilirubin, and a mildly elevated alkaline phosphatase (Table 1). The international normalized ratio was 1.3. Additional serologic markers included antinuclear antibodies + 1:160, liver-kidney microsomal antibody negative, anti-smooth muscle antibody negative, cytomegalovirus immunoglobulin M negative, Epstein-Barr virus PCR negative, herpes simplex virus (–), human immunodeficiency virus (–), and negative acute serologies for hepatitis A virus, hepatitis B virus, and HCV. Serologic tests are outlined in Table 1. She had normal magnetic resonance imaging of the liver; a nasopharyngeal swab was (+) for COVID-19. The patient was started on an infusion of N-acetyl cysteine, and a liver biopsy was performed on hospital day 7. She was thereafter transferred to Mount Sinai Hospital.
Review of the liver biopsy (Figure 3) showed severe acute hepatitis with marked lobular disarray characterized by inflammatory infiltrates, many acidophilic bodies, ballooned hepatocytes, scattered ceroid-laden macrophages, Kupffer cell hyperplasia, and activated sinusoidal lining cells. Portal areas showed mild to moderate mixed inflammation composed of lymphocytes, few plasma cells, scattered eosinophils and neutrophils, accompanied by mild interface hepatitis and mild ductular reaction (Figure 3a and b). Centrilobular hepatocyte necrosis with dropout and focal confluent necrosis were seen. Mild endotheliitis was noted, and most of the interlobular bile ducts were severely damaged. The severe damage was characterized by cholangiocytes having eosinophilic cytoplasm and densely pyknotic nuclei indicative of apoptosis (Figure 3c). CD61 immunostaining showed granular positive staining along the sinusoidal endothelial lining and in some of the terminal hepatic venules, indicative of the presence of non-occlusive fibrin thrombi (Figure 3d).Figure 3 Liver biopsy findings of case 2. (a) Portal tract with mixed inflammation, including eosinophils, activated lymphocytes, and rare plasma cells. Bile ducts are severely damaged (arrowheads), with some cholangiocytes undergoing acidophilic change and apoptosis. Detached necrotic cholangiocytes are seen in the lumen (bottom right). H&E, original magnification ×40. (b) High power view of lobule showing scattered hepatocytes undergoing apoptosis (arrowheads), with rest of the lobule showing ballooning degeneration of hepatocytes and foci of necroinflammation. H&E, original magnification ×40. (c) Portal tract containing dense mixed inflammatory infiltrate with bile duct showing cholangiocytes undergoing acidophilic change (arrowheads). H&E, original magnification ×40. (d) Immunostain for CD61 shows granular lace-like pattern of staining decorating the endothelial lining of the sinusoids as well as terminal hepatic venule (arrowhead). Original magnification ×40. (e) In situ hybridization showing hepatocyte with intracytoplasmic granular staining for COV-Spike protein (arrow). Original magnification ×40.
Similar to what was seen in case 1, RNAScope for SARS-CoV-2 spike protein was positive in rare cells (Figure 3e). A total of 6 positive cells throughout the biopsy length of 3.8 cm were identified; no cells were positive for viral replication by spike protein anti-sense strand probe. Transmission electron microscopy showed viral-like particles measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections. Ultrastructurally, these virions appeared to be within sinusoidal endothelial cells10, 11, 12 (Figure 2b).
The patient was deemed not to require treatment for COVID-19 because she was oxygenating well and had no radiographic evidence of pneumonia. She was also found to have thyroid-stimulating hormone of .008 and was diagnosed with thyroiditis, which has recently been reported in COVID-19 infection,13 and she was started on cholestyramine and ursodiol. She had repeat negative PCR testing for SARS CoV-2 on hospital days 15, 18, and 24 at Mount Sinai. Because she was feeling much better she was discharged, with lactate dehydrogenase of 209 and D-dimer <0.27. Laboratory testing 1 week later showed an ongoing decrease in her liver enzymes, although the bilirubin was still elevated to 10.7 mg/dL with an indirect fraction of 7.8 mg/dL.
Discussion
The cases presented in the current report had markedly elevated liver enzymes at presentation, with both fitting the clinical course timeline as well as the histologic features of severe COVID-19 hepatitis. RNA localization of SARS-CoV-2 S protein using in situ hybridization and EM findings suggest that SARS-CoV-2 may have played a major role in the liver damage incurred by these 2 patients. Despite the initial presentation of severe liver damage, both patients recovered from COVID-19 hepatitis.
Currently, it is known that the development of abnormal liver chemistry tests and various forms of liver injury may result from COVID-19,14 with the majority of cases having mildly elevated liver enzymes.4 In a series of 99 COVID-19 patients, only 1 case presented with severe liver injury with markedly elevated liver enzymes, whereas 43 of 99 showed mild alanine aminotransferase and aspartate aminotransferase elevations (in 28% and 35%, respectively).15 In patients with significantly increased liver enzymes, there were longer hospital stays, and most patients were taking medications such as lopinavir/ritonavir, with the latter raising the possibility of drug-induced liver injury (DILI).7 A recent review concluded that significantly elevated aminotransferases are only found in severe cases of COVID-19.16 However, to date there are only case reports or small case series detailing the liver histologic findings found in patients with COVID-19 infection.4 Microvesicular steatosis and the presence of mild lymphocytic inflammation in the lobules and rarely in portal tracts are the main findings reported.4 Furthermore, there is a dearth of reported liver biopsies in COVID-19 infection of solid organ recipients.17 Aside from one post-LT pediatric case wherein a liver biopsy was performed several days after LT, no other cases have been reported.18
Liver biopsies from both patients in this study showed prominent mitoses of hepatocytes along with acidophilic bodies, ballooning degeneration, and mild inflammation. Histology also showed mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. Although these features are seen in acute T-cell–mediated rejection, which might conceivably explain the portal tract findings in patient 1, patient 2 did not have LT and yet showed a similar histology. Lagana et al18 reported the presence of increased mitotic activity and the presence of numerous apoptotic bodies in their post-LT case. A case series from the SARS epidemic in 2003 described the histology of 3 patients. These patients all had elevated liver enzymes in the 300–400 range, and liver histology showed prominent mitoses.19 The authors surmised that the prominent mitoses were likely due to a hyperproliferative state and cell cycle arrest. They further described ballooning degeneration and mild to moderate lobular inflammation. The authors ascribed these findings to what was previously reported in avian coronavirus and transmissible gastroenteritis coronavirus infections in which the coronavirus had exerted extensive cytopathic effect through the induction of apoptosis of host cells by activation of caspase.19, 20, 21 The 2 cases presented here appear to have similar cytopathic effect from SARS-CoV-2 due to the increased number of apoptotic bodies noted on both liver biopsies.
The proposed mechanism of liver injury from SARS-CoV-2 includes severe inflammatory responses and direct cytotoxicity due to active viral replication with angiotensin-converting enzyme receptors (ACE2) being abundant in the liver, particularly in cholangiocytes and endothelial cells.22 It has been shown that SARS-CoV-2 interacts with host receptors in liver cells. Gene expression of ACE2 transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) has been shown. All 3 receptors are abundant in cholangiocytes and hepatocytes as well as in endothelial cells. Because these 3 receptors are present in various liver cells, SARS-CoV-2 may cause direct injury via a cytopathic effect, either by lysis and/or by inducing necrosis and apoptosis.22, 23, 24 Therefore, the ballooning degeneration and apoptosis as well as the striking bile duct damage may possibly be due to direct viral injury, with in situ hybridization and EM demonstrating viral particles within the liver. Previous case reports have failed to demonstrate the detection of intrahepatic viral particles. SARS-CoV-2 can also infect the gastrointestinal tract because of the abundant ACE2 receptors present.24,25 Therefore, the possibility that SARS-CoV-2 may enter the liver via the portal vein (portal venous viremia) can also be entertained.23 Varga et al26 have shown SARS-CoV-2 can directly infect endothelial cells across vascular beds of different organs, although not specifically in the liver. Widespread endothelial cell dysfunction in heart, kidney, lung, and small intestine resulted in apoptosis and prominent endotheliitis of submucosal vessels.26 Another mechanism believed to be the underlying cause of liver injury is ischemic changes in those with severe COVID-19 and DILI.4,27,28 In addition to the direct damage, translocation, and DILI, immune-mediated liver injury is another mechanism to consider. This is especially important in light of the increased inflammatory markers noted on serologic testing.16 Although SARS-CoV-2 virus is a new virus and our understanding of its tissue and cellular localization and replication is very limited, the sparse distribution of the virus as seen in the liver in the 2 current cases is not surprising because of the comparable sporadic and occasional cellular distribution described with the first SARS-CoV coronavirus in the early and mid-2000s.29,30 Despite the fact that we could not prove that the virus is replicating within the liver tissue because we did not see positive signals for the anti-sense strand of the S gene of the virus, we could not rule out such a possibility because the viral particles are sparsely distributed, and there is a limited amount of liver tissue in these core needle biopsies.
The clinical picture of the 2 patients is that of a spontaneously resolving COVID-19 infection with the markedly elevated liver tests and inflammatory markers decreasing concurrently. Although the patients did not have severe pulmonary, cardiac, or neurologic manifestations of COVID-19 infection that warranted treatment, significant liver chemistry abnormalities developed that correlated with the histologic liver damage noted. Neither patient had known underlying intrinsic liver disease, but if they did in light of the severe histologic liver damage noted, it is possible that they might have developed acute-on-chronic liver failure due to COVID-19.14,31
Some of the histologic findings seen in Case 1 are also typically seen in ACR, such as mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. In addition, there was histologic evidence of acute hepatitis, likely because of COVID-19, ie, COVID-19 hepatitis. Lagana et al18 showed similar findings in their case that occurred 7 days after transplantation. Although it is possible that this patient had both mild ACR and concurrent COVID-19 hepatitis, it is more likely that the histologic features are due to COVID-19 because the magnitude of the aminotransferase elevation is not typical of mild ACR, and the substantive decline in liver tests with only a minimal increase in tacrolimus dose is not typical of ACR.
Although both of the reported post-LT cases may be episodes of ACR that were triggered by COVID-19, as can occur with other viral infections,32 it is more likely that these histologic features are all related to COVID-19 infection because case 2 in the current report had very similar features. The endotheliitis demonstrated in these 2 patients appears similar to that reported in other organs.26,33 The histology thus suggests both a direct viral cytopathic effect and an immunologic liver injury involving cholangiocytes, hepatocytes, and liver sinusoidal endothelial cells. The significant bile duct damage and apoptosis of cholangiocytes are very prominent in these cases. In the absence of intrinsic liver disease, resolution of the direct cytopathologic injury may occur with clearance of SARS-CoV-2, yet it will remain to be seen whether the immunologic component of the liver injury will as well. Thus, close follow-up of such patients is warranted.
In conclusion, the current report details the liver histologic findings of acute COVID-19 infection in 2 patients, which are supported by the use of in situ hybridization and EM studies. Apoptosis, especially of cholangiocytes, abundant mitoses, mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage are typical. This histology suggests a direct cytopathic viral injury most notably in sinusoidal endothelial cells and other liver cells, with concurrent immunologic features. Such histologic changes can resemble ACR, so LT physicians must consider this possibility in post-LT patients with COVID-19 infection. These cases also demonstrate that patients can have severe liver injury in the absence of significant involvement of other organs by COVID-19.
Materials and Methods
Histopathology
Transjugular needle liver biopsy was performed for patient 1, and a percutaneous liver biopsy was performed for patient 2. Core biopsy specimens were immediately placed in formalin and fixed for a minimum of 3 hours. Routine tissue processing through graded alcohols was performed. Thereafter, the liver biopsy tissues were embedded in paraffin (FFPE). Three 4-μm-thick sections were cut for H&E stain to assess different levels and one 4-μm section for Masson trichrome stain. H&E and trichrome-stained slides were analyzed by routine light microscopy. Adequacy of the specimen was determined including the linear length of tissue and the number of complete portal tracts. Morphologic evaluation was performed under light microscopy. Histopathologic features analyzed included degree of portal and lobular inflammation, parenchymal damage including apoptosis, presence of fibrosis, bile duct injury, and endothelial damage.
In Situ Hybridization
Sections at 3 μm in thickness were taken from FFPE for RNA in situ hybridization using the RNAscope HPV kit (Advanced Cell Diagnostics, Inc, Hayward, CA) according to the manufacturer’s instructions on a Leica Bond III automated stainer (Leica Biosystems, Buffalo Grove, IL). Tissue sections were hybridized separately with a target probe to the SARS-CoV-2 S gene encoding the spike protein (catalogue #848561) to detect viral proteins within the cells to indicate infected cells and SARS-CoV-2 antisense strand of the S gene (catalogue #845701) to detect active viral replication within the cells. Positive controls for the SARS-CoV-2 S and antisense strand of the genes were prepared in-house from SARS-CoV-2-infected Vero cell lines (cell lines gift from Dr Florian Krammer, Icahn School of Medicine at Mount Sinai, New York, NY). To assess for the RNA integrity, probes for the endogenous housekeeping gene UBC (catalogue #RS7760) were used. The preamplifier, amplifier, and horseradish peroxidase–labeled probes were then hybridized sequentially, followed by color development with DAB. Specific staining signals were identified as brown, punctate dots present in the cytoplasm and/or nucleus.
Transmission Electron Microscopy
The tissue processed for EM was received in paraffin blocks. Designated portions of the specimen were dissected out with a single edge razor blade and placed into xylene overnight to dissolve the paraffin. The tissue was then brought to water through decreasing concentrations of ethanol and then fixed with 3% glutaraldehyde in a 0.2 sodium cacodylate buffer at pH 7.4.The specimen was then post-fixed with 1% osmium tetroxide tissues and embedded in Epon 812. One micrometer plastic sections were cut and stained with methyl blue and azure II for light microscopic orientation and to select smaller representative areas. Ultrathin 60-nm sections were collected into 200 mesh copper grids and stained with lanthanum and lead citrate. Sections were examined in a Hitachi 7650 (Tokyo, Japan) transmission electron microscope at 80 kV.
All authors had access to the study data and reviewed and approved the final manuscript.
CRediT Authorship Contributions
Maria Isabel Fiel, MD (Conceptualization: Lead; Data curation: Lead; Methodology: Equal; Writing – original draft: Lead)
Siraj M. El Jamal, MD (Methodology: Supporting; Writing – original draft: Supporting)
Alberto Paniz-Mondolfi, MD (Methodology: Supporting; Writing – original draft: Supporting)
Ronald E. Gordon, PhD (Methodology: Supporting; Writing – original draft: Supporting)
Jason Reidy, PhD (Methodology: Supporting)
Jela Bandovic, MD (Methodology: Supporting; Visualization: Supporting)
Rashmi Advani, MD (Data curation: Supporting)
Saikiran Kilaru, MD (Data curation: Supporting)
Kamron Pourmand, MD (Data curation: Supporting)
Stephen Ward, MD, PhD (Formal analysis: Supporting)
Swan N. Thung, MD (Formal analysis: Supporting)
Thomas D. Schiano, MD (Conceptualization: Equal; Formal analysis: Equal; Writing – original draft: Equal)
Conflicts of interest The authors disclose no conflicts.
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TACROLIMUS
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DrugsGivenReaction
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CC BY-NC-ND
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32992052
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2021
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy toxic'.
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Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection.
Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.
The current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.
The liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.
On the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.
Summary
Liver injury from COVID-19 infection is increasingly being identified, with a dearth of corresponding liver biopsy data to date. The unique liver histology of 2 patients who both recovered with severe COVID-19 hepatitis is presented. Liver involvement may be the only manifestation of COVID-19 infection.
Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2), is a global pandemic of unprecedented proportions.1 During the months of March and April 2020, New York City became the epicenter of the COVID-19 pandemic, and Mount Sinai Hospital was one of the major hospitals in the region that took care of several thousand COVID-19 patients. In the midst of the pandemic, ongoing liver transplantation (LT) and referrals of patients with severe liver disease continued unabated.2
Initial reports focused on COVID-19 as mainly involving the lungs and being the main cause of morbidity and mortality.3 However, neurologic, cardiac, renal, hepatobiliary, and gastrointestinal tract involvements are increasingly being recognized.3 The reported incidence of liver injury in patients with COVID-19 ranges from 14% to 53%.4, 5, 6 Those studies are mainly based on abnormal liver enzyme elevations in the absence of tissue examination. In one study, a significant number of cases were noted to have elevation of liver enzymes occurring at approximately the tenth day of hospitalization and associated with lopinavir/ritonavir treatment.7 The authors also found that prolonged hospital stays were associated with abnormal liver enzymes noted at the time of initial admission.7 Risk factors included underlying chronic liver disease such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD).4 In a study involving 252 COVID-19 patients, the investigators found that patients having NAFLD had a significantly higher risk of disease progression, a higher likelihood of developing abnormal liver tests during hospitalization, and longer viral shedding times as compared with patients without NAFLD.6
In a previous study of postmortem examinations, liver histology showed lobular lymphocytic inflammation and centrilobular sinusoidal dilatation, with only a few cases showing parenchymal necrosis.8 Furthermore, in another autopsy study of a 51-year-old man, microvesicular steatosis and mild lobular and portal inflammation were noted.9 At the present time, no detailed histologic, immunohistochemical, and ultrastructural findings have been reported in the literature regarding infection of the liver by COVID-19. Herein we report 2 patients who presented with high aminotransferases and underwent liver biopsy that showed acute hepatitis. A detailed histologic analysis along with in situ hybridization and electron microscopy (EM) were performed on liver tissue to suggest direct hepatic involvement by the novel coronavirus SARS-CoV-2.
Clinical Histories
Case 1
The patient is a 63-year-old man who underwent LT in 2017 for hepatitis C (HCV) and alcohol-related liver disease. He received a genotype 1b HCV (+) donor with a pre-perfusion liver biopsy showing no underlying fibrosis and mild portal inflammation. He underwent antiviral therapy with sofosbuvir/ledipasvir starting 3 months after LT and achieved a sustained virologic response. He had developed dialysis-dependent chronic renal failure related to calcineurin inhibitor nephrotoxicity, hypertension, and insulin-dependent diabetes mellitus but always had normal liver chemistry tests and never previously had an episode of acute cellular rejection (ACR). The patient was stable for 2 years after LT until he suffered a stroke in January 2020. Laboratory tests on discharge from the transplant center after his stroke were normal with aspartate aminotransferase 12 U/L, alanine aminotransferase 14 U/L, alkaline phosphatase 68 U/L, and normal serum bilirubin. The tacrolimus dose was stable with a level of 4–6 ng/mL. He was discharged to a rehabilitation facility on regular doses of his medications, which included aminosalicylic acid 81 mg, atorvastatin, calcium acetate, dorzolamide drops, famotidine, insulin, labetalol, nifedipine, ropinirole, sodium bicarbonate, tacrolimus 2 mg twice a day, and tamsulosin. While residing at the rehabilitation facility, the patient developed constitutional symptoms and was found to be COVID-19 (+) via nasopharyngeal swab testing and referred to a local hospital where the liver enzymes were noted to be abnormal (Table 1). The patient was started on N-acetyl cysteine and acyclovir empirically; however, follow-up laboratory tests showed rising liver enzymes.Table 1 Liver Enzyme Values of Case 1 and Case 2
AST, U/L (1–35) ALT, U/L (1–45) Alk Phos, U/L (38–126) T bili, mg/dL (0.1–1.2) D-dimer, μg/mL (0–0.5) Ferritin, ng/mL (30–400) Procalcitonin, ng/mL (<0.49) CRP, mg/L (0–5)
Case 1
HD 1 1083 1035 824 1.1
HD 2 2074 1761 907 3.1
HD 3 1691 1578 915 3.9 1.84 4677 5.24 24.5
HD 6 769 994 1363 7.1 1.38 2863 3.57 11.3
HD 9 541 776 1568 9.3 0.77 2520 1.16 7.0
Case 2
HD 1 2786 2909 210 13.8 827 0.35 8.4
HD 8 1700 1856 132 20.6 1290 1558 0.26 0.7
HD 15 591 650 184 31.5 172 0.9
HD 18 506 616 241 33.5 0.27 224 0.28 0.7
HD 24 200 221 166 10.7
Alk Phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HD, hospital day; T bili, total bilirubin.
He was transferred to Mount Sinai Hospital for further management. Reverse transcription polymerase chain reaction (PCR) on a repeat nasopharyngeal swab specimen confirmed SARS-CoV-2 infection, and the tacrolimus dose was increased to 3 mg twice a day in the setting of a trough level of 3.0 ng/mL. On presentation, the aminotransferases and alkaline phosphatase levels were elevated, as was the total serum bilirubin. Doppler ultrasonography showed no vascular or biliary abnormalities. The following additional lab results were obtained: undetectable PCR for herpes simplex 1 and 2, HCV, hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, undetectable antibody to hepatitis E, and undetectable immunoglobulin M for hepatitis A virus. The triglyceride level was 483 mg/dL (0–150). Inflammatory markers were significantly elevated (Table 1) including lactate dehydrogenase of 702 U/L (reference range, 100–220). The platelet count was 132 × 103, and the white blood cell count was 3.9 × 103. The patient’s clinical and serologic features supported the diagnosis of COVID-19 infection.
A liver biopsy was performed 9 days after the initial presentation and on hospital day 6. The histologic changes are highlighted in Figure 1. The majority of the portal tracts uniformly showed a mixed inflammatory infiltrate with a few eosinophils, prominent bile duct damage, and endotheliitis (Figure 1a). The lobule showed disarray with many apoptotic bodies, foci of necrosis, and abundant mitotic figures (Figure 1b). Focal central venulitis was noted. C4d immunostain was positive in a few endothelial cells lining the portal and central venules. CD61 immunostain to determine the presence of fibrin thrombi was negative. In rare portal tracts, severe bile duct damage with cholangiocytes undergoing apoptosis was seen (Figure 1c). A diagnosis of ACR and concomitant severe acute hepatitis was rendered.Figure 1 Liver biopsy findings of case 1. (a) Portal tract showing mixed inflammatory infiltrate consisting of lymphocytes, blast-like cells, and eosinophils, along with mild endotheliitis and severe bile duct damage. Bile duct is barely unrecognizable, and in its place are apoptotic cholangiocytes (arrowheads). Open arrowhead indicates accompanying hepatic arteriole. H&E, original magnification ×40. Black stars indicate a damaged bile duct. (b) Lobule shows disarray with many hepatocytes undergoing apoptosis in various stages (black arrowheads), while there is also concomitant increased mitotic activity (white arrows). H&E, original magnification ×40. (c) A few portal tracts are devoid of inflammation. Because of paucity of inflammation in this particular portal tract, one can visualize the cholangiocytes undergoing apoptosis (arrow). H&E, original magnification ×40. (d) RNA localization of COV-S protein using RNAScope showing dot-like particles (black arrow) in cytoplasm of an infected endothelial cell.
Slides for RNAScope for SARS-CoV-2 spike protein showed positive staining in rare cells and were seen as cytoplasmic dotted signals. In the absence of double immunostaining, the type of cells with positive staining could not be identified with certainty (Figure 1d). Throughout the entire 3.2-cm length of the liver biopsy, only 8 such cells were found to be positive. No cells were positive for the SARS-CoV-2 spike protein anti-sense strand probe, indicating that no active replication could be detected.
EM revealed the presence of viral-like particles displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average, consistent with members of the Coronaviridae family10, 11, 12 (Figure 2a). The virions were mostly located within intracytoplasmic vesicles in close proximity to the endoplasmic reticulum. After the biopsy, the tacrolimus level was optimized to achieve a trough level of approximately 10. Infectious diseases department was consulted and recommended that the patient did not warrant medical treatment for COVID-19 infection because he was oxygenating normally and had a normal chest x-ray. Under observation, the patient’s liver chemistry tests slowly down trended, as did all of the inflammatory markers (Table 1) until discharge.Figure 2 Electron microscopy photos of case 1 and case 2. (a) EM showing presence of viral-like particles (encircled) displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average. (b) Viral-like particles (encircled) measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections appearing to be within sinusoidal endothelial cells.
Case 2
The patient is a 36-year-old previously healthy woman who presented to a local hospital with 6 days of progressive nausea, vomiting, and scleral icterus. She also had anorexia, myalgias, and fevers 1 week before her presentation, taking approximately 1.5 g acetaminophen and no other prescription or over-the-counter medications. Initial laboratory tests at presentation on April 6, 2020 showed markedly elevated aminotransferases, total serum bilirubin, and a mildly elevated alkaline phosphatase (Table 1). The international normalized ratio was 1.3. Additional serologic markers included antinuclear antibodies + 1:160, liver-kidney microsomal antibody negative, anti-smooth muscle antibody negative, cytomegalovirus immunoglobulin M negative, Epstein-Barr virus PCR negative, herpes simplex virus (–), human immunodeficiency virus (–), and negative acute serologies for hepatitis A virus, hepatitis B virus, and HCV. Serologic tests are outlined in Table 1. She had normal magnetic resonance imaging of the liver; a nasopharyngeal swab was (+) for COVID-19. The patient was started on an infusion of N-acetyl cysteine, and a liver biopsy was performed on hospital day 7. She was thereafter transferred to Mount Sinai Hospital.
Review of the liver biopsy (Figure 3) showed severe acute hepatitis with marked lobular disarray characterized by inflammatory infiltrates, many acidophilic bodies, ballooned hepatocytes, scattered ceroid-laden macrophages, Kupffer cell hyperplasia, and activated sinusoidal lining cells. Portal areas showed mild to moderate mixed inflammation composed of lymphocytes, few plasma cells, scattered eosinophils and neutrophils, accompanied by mild interface hepatitis and mild ductular reaction (Figure 3a and b). Centrilobular hepatocyte necrosis with dropout and focal confluent necrosis were seen. Mild endotheliitis was noted, and most of the interlobular bile ducts were severely damaged. The severe damage was characterized by cholangiocytes having eosinophilic cytoplasm and densely pyknotic nuclei indicative of apoptosis (Figure 3c). CD61 immunostaining showed granular positive staining along the sinusoidal endothelial lining and in some of the terminal hepatic venules, indicative of the presence of non-occlusive fibrin thrombi (Figure 3d).Figure 3 Liver biopsy findings of case 2. (a) Portal tract with mixed inflammation, including eosinophils, activated lymphocytes, and rare plasma cells. Bile ducts are severely damaged (arrowheads), with some cholangiocytes undergoing acidophilic change and apoptosis. Detached necrotic cholangiocytes are seen in the lumen (bottom right). H&E, original magnification ×40. (b) High power view of lobule showing scattered hepatocytes undergoing apoptosis (arrowheads), with rest of the lobule showing ballooning degeneration of hepatocytes and foci of necroinflammation. H&E, original magnification ×40. (c) Portal tract containing dense mixed inflammatory infiltrate with bile duct showing cholangiocytes undergoing acidophilic change (arrowheads). H&E, original magnification ×40. (d) Immunostain for CD61 shows granular lace-like pattern of staining decorating the endothelial lining of the sinusoids as well as terminal hepatic venule (arrowhead). Original magnification ×40. (e) In situ hybridization showing hepatocyte with intracytoplasmic granular staining for COV-Spike protein (arrow). Original magnification ×40.
Similar to what was seen in case 1, RNAScope for SARS-CoV-2 spike protein was positive in rare cells (Figure 3e). A total of 6 positive cells throughout the biopsy length of 3.8 cm were identified; no cells were positive for viral replication by spike protein anti-sense strand probe. Transmission electron microscopy showed viral-like particles measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections. Ultrastructurally, these virions appeared to be within sinusoidal endothelial cells10, 11, 12 (Figure 2b).
The patient was deemed not to require treatment for COVID-19 because she was oxygenating well and had no radiographic evidence of pneumonia. She was also found to have thyroid-stimulating hormone of .008 and was diagnosed with thyroiditis, which has recently been reported in COVID-19 infection,13 and she was started on cholestyramine and ursodiol. She had repeat negative PCR testing for SARS CoV-2 on hospital days 15, 18, and 24 at Mount Sinai. Because she was feeling much better she was discharged, with lactate dehydrogenase of 209 and D-dimer <0.27. Laboratory testing 1 week later showed an ongoing decrease in her liver enzymes, although the bilirubin was still elevated to 10.7 mg/dL with an indirect fraction of 7.8 mg/dL.
Discussion
The cases presented in the current report had markedly elevated liver enzymes at presentation, with both fitting the clinical course timeline as well as the histologic features of severe COVID-19 hepatitis. RNA localization of SARS-CoV-2 S protein using in situ hybridization and EM findings suggest that SARS-CoV-2 may have played a major role in the liver damage incurred by these 2 patients. Despite the initial presentation of severe liver damage, both patients recovered from COVID-19 hepatitis.
Currently, it is known that the development of abnormal liver chemistry tests and various forms of liver injury may result from COVID-19,14 with the majority of cases having mildly elevated liver enzymes.4 In a series of 99 COVID-19 patients, only 1 case presented with severe liver injury with markedly elevated liver enzymes, whereas 43 of 99 showed mild alanine aminotransferase and aspartate aminotransferase elevations (in 28% and 35%, respectively).15 In patients with significantly increased liver enzymes, there were longer hospital stays, and most patients were taking medications such as lopinavir/ritonavir, with the latter raising the possibility of drug-induced liver injury (DILI).7 A recent review concluded that significantly elevated aminotransferases are only found in severe cases of COVID-19.16 However, to date there are only case reports or small case series detailing the liver histologic findings found in patients with COVID-19 infection.4 Microvesicular steatosis and the presence of mild lymphocytic inflammation in the lobules and rarely in portal tracts are the main findings reported.4 Furthermore, there is a dearth of reported liver biopsies in COVID-19 infection of solid organ recipients.17 Aside from one post-LT pediatric case wherein a liver biopsy was performed several days after LT, no other cases have been reported.18
Liver biopsies from both patients in this study showed prominent mitoses of hepatocytes along with acidophilic bodies, ballooning degeneration, and mild inflammation. Histology also showed mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. Although these features are seen in acute T-cell–mediated rejection, which might conceivably explain the portal tract findings in patient 1, patient 2 did not have LT and yet showed a similar histology. Lagana et al18 reported the presence of increased mitotic activity and the presence of numerous apoptotic bodies in their post-LT case. A case series from the SARS epidemic in 2003 described the histology of 3 patients. These patients all had elevated liver enzymes in the 300–400 range, and liver histology showed prominent mitoses.19 The authors surmised that the prominent mitoses were likely due to a hyperproliferative state and cell cycle arrest. They further described ballooning degeneration and mild to moderate lobular inflammation. The authors ascribed these findings to what was previously reported in avian coronavirus and transmissible gastroenteritis coronavirus infections in which the coronavirus had exerted extensive cytopathic effect through the induction of apoptosis of host cells by activation of caspase.19, 20, 21 The 2 cases presented here appear to have similar cytopathic effect from SARS-CoV-2 due to the increased number of apoptotic bodies noted on both liver biopsies.
The proposed mechanism of liver injury from SARS-CoV-2 includes severe inflammatory responses and direct cytotoxicity due to active viral replication with angiotensin-converting enzyme receptors (ACE2) being abundant in the liver, particularly in cholangiocytes and endothelial cells.22 It has been shown that SARS-CoV-2 interacts with host receptors in liver cells. Gene expression of ACE2 transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) has been shown. All 3 receptors are abundant in cholangiocytes and hepatocytes as well as in endothelial cells. Because these 3 receptors are present in various liver cells, SARS-CoV-2 may cause direct injury via a cytopathic effect, either by lysis and/or by inducing necrosis and apoptosis.22, 23, 24 Therefore, the ballooning degeneration and apoptosis as well as the striking bile duct damage may possibly be due to direct viral injury, with in situ hybridization and EM demonstrating viral particles within the liver. Previous case reports have failed to demonstrate the detection of intrahepatic viral particles. SARS-CoV-2 can also infect the gastrointestinal tract because of the abundant ACE2 receptors present.24,25 Therefore, the possibility that SARS-CoV-2 may enter the liver via the portal vein (portal venous viremia) can also be entertained.23 Varga et al26 have shown SARS-CoV-2 can directly infect endothelial cells across vascular beds of different organs, although not specifically in the liver. Widespread endothelial cell dysfunction in heart, kidney, lung, and small intestine resulted in apoptosis and prominent endotheliitis of submucosal vessels.26 Another mechanism believed to be the underlying cause of liver injury is ischemic changes in those with severe COVID-19 and DILI.4,27,28 In addition to the direct damage, translocation, and DILI, immune-mediated liver injury is another mechanism to consider. This is especially important in light of the increased inflammatory markers noted on serologic testing.16 Although SARS-CoV-2 virus is a new virus and our understanding of its tissue and cellular localization and replication is very limited, the sparse distribution of the virus as seen in the liver in the 2 current cases is not surprising because of the comparable sporadic and occasional cellular distribution described with the first SARS-CoV coronavirus in the early and mid-2000s.29,30 Despite the fact that we could not prove that the virus is replicating within the liver tissue because we did not see positive signals for the anti-sense strand of the S gene of the virus, we could not rule out such a possibility because the viral particles are sparsely distributed, and there is a limited amount of liver tissue in these core needle biopsies.
The clinical picture of the 2 patients is that of a spontaneously resolving COVID-19 infection with the markedly elevated liver tests and inflammatory markers decreasing concurrently. Although the patients did not have severe pulmonary, cardiac, or neurologic manifestations of COVID-19 infection that warranted treatment, significant liver chemistry abnormalities developed that correlated with the histologic liver damage noted. Neither patient had known underlying intrinsic liver disease, but if they did in light of the severe histologic liver damage noted, it is possible that they might have developed acute-on-chronic liver failure due to COVID-19.14,31
Some of the histologic findings seen in Case 1 are also typically seen in ACR, such as mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. In addition, there was histologic evidence of acute hepatitis, likely because of COVID-19, ie, COVID-19 hepatitis. Lagana et al18 showed similar findings in their case that occurred 7 days after transplantation. Although it is possible that this patient had both mild ACR and concurrent COVID-19 hepatitis, it is more likely that the histologic features are due to COVID-19 because the magnitude of the aminotransferase elevation is not typical of mild ACR, and the substantive decline in liver tests with only a minimal increase in tacrolimus dose is not typical of ACR.
Although both of the reported post-LT cases may be episodes of ACR that were triggered by COVID-19, as can occur with other viral infections,32 it is more likely that these histologic features are all related to COVID-19 infection because case 2 in the current report had very similar features. The endotheliitis demonstrated in these 2 patients appears similar to that reported in other organs.26,33 The histology thus suggests both a direct viral cytopathic effect and an immunologic liver injury involving cholangiocytes, hepatocytes, and liver sinusoidal endothelial cells. The significant bile duct damage and apoptosis of cholangiocytes are very prominent in these cases. In the absence of intrinsic liver disease, resolution of the direct cytopathologic injury may occur with clearance of SARS-CoV-2, yet it will remain to be seen whether the immunologic component of the liver injury will as well. Thus, close follow-up of such patients is warranted.
In conclusion, the current report details the liver histologic findings of acute COVID-19 infection in 2 patients, which are supported by the use of in situ hybridization and EM studies. Apoptosis, especially of cholangiocytes, abundant mitoses, mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage are typical. This histology suggests a direct cytopathic viral injury most notably in sinusoidal endothelial cells and other liver cells, with concurrent immunologic features. Such histologic changes can resemble ACR, so LT physicians must consider this possibility in post-LT patients with COVID-19 infection. These cases also demonstrate that patients can have severe liver injury in the absence of significant involvement of other organs by COVID-19.
Materials and Methods
Histopathology
Transjugular needle liver biopsy was performed for patient 1, and a percutaneous liver biopsy was performed for patient 2. Core biopsy specimens were immediately placed in formalin and fixed for a minimum of 3 hours. Routine tissue processing through graded alcohols was performed. Thereafter, the liver biopsy tissues were embedded in paraffin (FFPE). Three 4-μm-thick sections were cut for H&E stain to assess different levels and one 4-μm section for Masson trichrome stain. H&E and trichrome-stained slides were analyzed by routine light microscopy. Adequacy of the specimen was determined including the linear length of tissue and the number of complete portal tracts. Morphologic evaluation was performed under light microscopy. Histopathologic features analyzed included degree of portal and lobular inflammation, parenchymal damage including apoptosis, presence of fibrosis, bile duct injury, and endothelial damage.
In Situ Hybridization
Sections at 3 μm in thickness were taken from FFPE for RNA in situ hybridization using the RNAscope HPV kit (Advanced Cell Diagnostics, Inc, Hayward, CA) according to the manufacturer’s instructions on a Leica Bond III automated stainer (Leica Biosystems, Buffalo Grove, IL). Tissue sections were hybridized separately with a target probe to the SARS-CoV-2 S gene encoding the spike protein (catalogue #848561) to detect viral proteins within the cells to indicate infected cells and SARS-CoV-2 antisense strand of the S gene (catalogue #845701) to detect active viral replication within the cells. Positive controls for the SARS-CoV-2 S and antisense strand of the genes were prepared in-house from SARS-CoV-2-infected Vero cell lines (cell lines gift from Dr Florian Krammer, Icahn School of Medicine at Mount Sinai, New York, NY). To assess for the RNA integrity, probes for the endogenous housekeeping gene UBC (catalogue #RS7760) were used. The preamplifier, amplifier, and horseradish peroxidase–labeled probes were then hybridized sequentially, followed by color development with DAB. Specific staining signals were identified as brown, punctate dots present in the cytoplasm and/or nucleus.
Transmission Electron Microscopy
The tissue processed for EM was received in paraffin blocks. Designated portions of the specimen were dissected out with a single edge razor blade and placed into xylene overnight to dissolve the paraffin. The tissue was then brought to water through decreasing concentrations of ethanol and then fixed with 3% glutaraldehyde in a 0.2 sodium cacodylate buffer at pH 7.4.The specimen was then post-fixed with 1% osmium tetroxide tissues and embedded in Epon 812. One micrometer plastic sections were cut and stained with methyl blue and azure II for light microscopic orientation and to select smaller representative areas. Ultrathin 60-nm sections were collected into 200 mesh copper grids and stained with lanthanum and lead citrate. Sections were examined in a Hitachi 7650 (Tokyo, Japan) transmission electron microscope at 80 kV.
All authors had access to the study data and reviewed and approved the final manuscript.
CRediT Authorship Contributions
Maria Isabel Fiel, MD (Conceptualization: Lead; Data curation: Lead; Methodology: Equal; Writing – original draft: Lead)
Siraj M. El Jamal, MD (Methodology: Supporting; Writing – original draft: Supporting)
Alberto Paniz-Mondolfi, MD (Methodology: Supporting; Writing – original draft: Supporting)
Ronald E. Gordon, PhD (Methodology: Supporting; Writing – original draft: Supporting)
Jason Reidy, PhD (Methodology: Supporting)
Jela Bandovic, MD (Methodology: Supporting; Visualization: Supporting)
Rashmi Advani, MD (Data curation: Supporting)
Saikiran Kilaru, MD (Data curation: Supporting)
Kamron Pourmand, MD (Data curation: Supporting)
Stephen Ward, MD, PhD (Formal analysis: Supporting)
Swan N. Thung, MD (Formal analysis: Supporting)
Thomas D. Schiano, MD (Conceptualization: Equal; Formal analysis: Equal; Writing – original draft: Equal)
Conflicts of interest The authors disclose no conflicts.
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TACROLIMUS
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DrugsGivenReaction
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CC BY-NC-ND
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32992052
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2021
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Severe acute respiratory syndrome'.
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Findings of Hepatic Severe Acute Respiratory Syndrome Coronavirus-2 Infection.
Liver injury due to coronavirus disease 2019 (COVID-19) is being increasingly recognized. Abnormal liver chemistry tests of varying severities occur in a majority of patients. However, there is a dearth of accompanying liver histologic studies in these patients.
The current report details the clinical courses of 2 patients having severe COVID-19 hepatitis. Liver biopsies were analyzed under light microscopy, portions of liver tissue were hybridized with a target probe to the severe acute respiratory syndrome coronavirus-2 S gene, and small sections from formalin-fixed paraffin-embedded liver tissue were processed for electron microscopy.
The liver histology of both cases showed a mixed inflammatory infiltrate with prominent bile duct damage, endotheliitis, and many apoptotic bodies. In situ hybridization and electron microscopy suggest the intrahepatic presence of severe acute respiratory syndrome coronavirus-2, the findings of which may indicate the possibility of direct cell injury.
On the basis of the abundant apoptosis and severe cholangiocyte injury, these histopathologic changes suggest a direct cytopathic injury. Furthermore, some of the histopathologic changes may resemble acute cellular rejection occurring after liver transplantation. These 2 cases demonstrate that severe COVID-19 hepatitis can occur even in the absence of significant involvement of other organs.
Summary
Liver injury from COVID-19 infection is increasingly being identified, with a dearth of corresponding liver biopsy data to date. The unique liver histology of 2 patients who both recovered with severe COVID-19 hepatitis is presented. Liver involvement may be the only manifestation of COVID-19 infection.
Coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2), is a global pandemic of unprecedented proportions.1 During the months of March and April 2020, New York City became the epicenter of the COVID-19 pandemic, and Mount Sinai Hospital was one of the major hospitals in the region that took care of several thousand COVID-19 patients. In the midst of the pandemic, ongoing liver transplantation (LT) and referrals of patients with severe liver disease continued unabated.2
Initial reports focused on COVID-19 as mainly involving the lungs and being the main cause of morbidity and mortality.3 However, neurologic, cardiac, renal, hepatobiliary, and gastrointestinal tract involvements are increasingly being recognized.3 The reported incidence of liver injury in patients with COVID-19 ranges from 14% to 53%.4, 5, 6 Those studies are mainly based on abnormal liver enzyme elevations in the absence of tissue examination. In one study, a significant number of cases were noted to have elevation of liver enzymes occurring at approximately the tenth day of hospitalization and associated with lopinavir/ritonavir treatment.7 The authors also found that prolonged hospital stays were associated with abnormal liver enzymes noted at the time of initial admission.7 Risk factors included underlying chronic liver disease such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD).4 In a study involving 252 COVID-19 patients, the investigators found that patients having NAFLD had a significantly higher risk of disease progression, a higher likelihood of developing abnormal liver tests during hospitalization, and longer viral shedding times as compared with patients without NAFLD.6
In a previous study of postmortem examinations, liver histology showed lobular lymphocytic inflammation and centrilobular sinusoidal dilatation, with only a few cases showing parenchymal necrosis.8 Furthermore, in another autopsy study of a 51-year-old man, microvesicular steatosis and mild lobular and portal inflammation were noted.9 At the present time, no detailed histologic, immunohistochemical, and ultrastructural findings have been reported in the literature regarding infection of the liver by COVID-19. Herein we report 2 patients who presented with high aminotransferases and underwent liver biopsy that showed acute hepatitis. A detailed histologic analysis along with in situ hybridization and electron microscopy (EM) were performed on liver tissue to suggest direct hepatic involvement by the novel coronavirus SARS-CoV-2.
Clinical Histories
Case 1
The patient is a 63-year-old man who underwent LT in 2017 for hepatitis C (HCV) and alcohol-related liver disease. He received a genotype 1b HCV (+) donor with a pre-perfusion liver biopsy showing no underlying fibrosis and mild portal inflammation. He underwent antiviral therapy with sofosbuvir/ledipasvir starting 3 months after LT and achieved a sustained virologic response. He had developed dialysis-dependent chronic renal failure related to calcineurin inhibitor nephrotoxicity, hypertension, and insulin-dependent diabetes mellitus but always had normal liver chemistry tests and never previously had an episode of acute cellular rejection (ACR). The patient was stable for 2 years after LT until he suffered a stroke in January 2020. Laboratory tests on discharge from the transplant center after his stroke were normal with aspartate aminotransferase 12 U/L, alanine aminotransferase 14 U/L, alkaline phosphatase 68 U/L, and normal serum bilirubin. The tacrolimus dose was stable with a level of 4–6 ng/mL. He was discharged to a rehabilitation facility on regular doses of his medications, which included aminosalicylic acid 81 mg, atorvastatin, calcium acetate, dorzolamide drops, famotidine, insulin, labetalol, nifedipine, ropinirole, sodium bicarbonate, tacrolimus 2 mg twice a day, and tamsulosin. While residing at the rehabilitation facility, the patient developed constitutional symptoms and was found to be COVID-19 (+) via nasopharyngeal swab testing and referred to a local hospital where the liver enzymes were noted to be abnormal (Table 1). The patient was started on N-acetyl cysteine and acyclovir empirically; however, follow-up laboratory tests showed rising liver enzymes.Table 1 Liver Enzyme Values of Case 1 and Case 2
AST, U/L (1–35) ALT, U/L (1–45) Alk Phos, U/L (38–126) T bili, mg/dL (0.1–1.2) D-dimer, μg/mL (0–0.5) Ferritin, ng/mL (30–400) Procalcitonin, ng/mL (<0.49) CRP, mg/L (0–5)
Case 1
HD 1 1083 1035 824 1.1
HD 2 2074 1761 907 3.1
HD 3 1691 1578 915 3.9 1.84 4677 5.24 24.5
HD 6 769 994 1363 7.1 1.38 2863 3.57 11.3
HD 9 541 776 1568 9.3 0.77 2520 1.16 7.0
Case 2
HD 1 2786 2909 210 13.8 827 0.35 8.4
HD 8 1700 1856 132 20.6 1290 1558 0.26 0.7
HD 15 591 650 184 31.5 172 0.9
HD 18 506 616 241 33.5 0.27 224 0.28 0.7
HD 24 200 221 166 10.7
Alk Phos, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HD, hospital day; T bili, total bilirubin.
He was transferred to Mount Sinai Hospital for further management. Reverse transcription polymerase chain reaction (PCR) on a repeat nasopharyngeal swab specimen confirmed SARS-CoV-2 infection, and the tacrolimus dose was increased to 3 mg twice a day in the setting of a trough level of 3.0 ng/mL. On presentation, the aminotransferases and alkaline phosphatase levels were elevated, as was the total serum bilirubin. Doppler ultrasonography showed no vascular or biliary abnormalities. The following additional lab results were obtained: undetectable PCR for herpes simplex 1 and 2, HCV, hepatitis B virus, Epstein-Barr virus, and cytomegalovirus, undetectable antibody to hepatitis E, and undetectable immunoglobulin M for hepatitis A virus. The triglyceride level was 483 mg/dL (0–150). Inflammatory markers were significantly elevated (Table 1) including lactate dehydrogenase of 702 U/L (reference range, 100–220). The platelet count was 132 × 103, and the white blood cell count was 3.9 × 103. The patient’s clinical and serologic features supported the diagnosis of COVID-19 infection.
A liver biopsy was performed 9 days after the initial presentation and on hospital day 6. The histologic changes are highlighted in Figure 1. The majority of the portal tracts uniformly showed a mixed inflammatory infiltrate with a few eosinophils, prominent bile duct damage, and endotheliitis (Figure 1a). The lobule showed disarray with many apoptotic bodies, foci of necrosis, and abundant mitotic figures (Figure 1b). Focal central venulitis was noted. C4d immunostain was positive in a few endothelial cells lining the portal and central venules. CD61 immunostain to determine the presence of fibrin thrombi was negative. In rare portal tracts, severe bile duct damage with cholangiocytes undergoing apoptosis was seen (Figure 1c). A diagnosis of ACR and concomitant severe acute hepatitis was rendered.Figure 1 Liver biopsy findings of case 1. (a) Portal tract showing mixed inflammatory infiltrate consisting of lymphocytes, blast-like cells, and eosinophils, along with mild endotheliitis and severe bile duct damage. Bile duct is barely unrecognizable, and in its place are apoptotic cholangiocytes (arrowheads). Open arrowhead indicates accompanying hepatic arteriole. H&E, original magnification ×40. Black stars indicate a damaged bile duct. (b) Lobule shows disarray with many hepatocytes undergoing apoptosis in various stages (black arrowheads), while there is also concomitant increased mitotic activity (white arrows). H&E, original magnification ×40. (c) A few portal tracts are devoid of inflammation. Because of paucity of inflammation in this particular portal tract, one can visualize the cholangiocytes undergoing apoptosis (arrow). H&E, original magnification ×40. (d) RNA localization of COV-S protein using RNAScope showing dot-like particles (black arrow) in cytoplasm of an infected endothelial cell.
Slides for RNAScope for SARS-CoV-2 spike protein showed positive staining in rare cells and were seen as cytoplasmic dotted signals. In the absence of double immunostaining, the type of cells with positive staining could not be identified with certainty (Figure 1d). Throughout the entire 3.2-cm length of the liver biopsy, only 8 such cells were found to be positive. No cells were positive for the SARS-CoV-2 spike protein anti-sense strand probe, indicating that no active replication could be detected.
EM revealed the presence of viral-like particles displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average, consistent with members of the Coronaviridae family10, 11, 12 (Figure 2a). The virions were mostly located within intracytoplasmic vesicles in close proximity to the endoplasmic reticulum. After the biopsy, the tacrolimus level was optimized to achieve a trough level of approximately 10. Infectious diseases department was consulted and recommended that the patient did not warrant medical treatment for COVID-19 infection because he was oxygenating normally and had a normal chest x-ray. Under observation, the patient’s liver chemistry tests slowly down trended, as did all of the inflammatory markers (Table 1) until discharge.Figure 2 Electron microscopy photos of case 1 and case 2. (a) EM showing presence of viral-like particles (encircled) displaying a double membrane electron-dense periphery with characteristic outward projecting processes consistent with a peplomer-like arrangement and measuring 100 nm on average. (b) Viral-like particles (encircled) measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections appearing to be within sinusoidal endothelial cells.
Case 2
The patient is a 36-year-old previously healthy woman who presented to a local hospital with 6 days of progressive nausea, vomiting, and scleral icterus. She also had anorexia, myalgias, and fevers 1 week before her presentation, taking approximately 1.5 g acetaminophen and no other prescription or over-the-counter medications. Initial laboratory tests at presentation on April 6, 2020 showed markedly elevated aminotransferases, total serum bilirubin, and a mildly elevated alkaline phosphatase (Table 1). The international normalized ratio was 1.3. Additional serologic markers included antinuclear antibodies + 1:160, liver-kidney microsomal antibody negative, anti-smooth muscle antibody negative, cytomegalovirus immunoglobulin M negative, Epstein-Barr virus PCR negative, herpes simplex virus (–), human immunodeficiency virus (–), and negative acute serologies for hepatitis A virus, hepatitis B virus, and HCV. Serologic tests are outlined in Table 1. She had normal magnetic resonance imaging of the liver; a nasopharyngeal swab was (+) for COVID-19. The patient was started on an infusion of N-acetyl cysteine, and a liver biopsy was performed on hospital day 7. She was thereafter transferred to Mount Sinai Hospital.
Review of the liver biopsy (Figure 3) showed severe acute hepatitis with marked lobular disarray characterized by inflammatory infiltrates, many acidophilic bodies, ballooned hepatocytes, scattered ceroid-laden macrophages, Kupffer cell hyperplasia, and activated sinusoidal lining cells. Portal areas showed mild to moderate mixed inflammation composed of lymphocytes, few plasma cells, scattered eosinophils and neutrophils, accompanied by mild interface hepatitis and mild ductular reaction (Figure 3a and b). Centrilobular hepatocyte necrosis with dropout and focal confluent necrosis were seen. Mild endotheliitis was noted, and most of the interlobular bile ducts were severely damaged. The severe damage was characterized by cholangiocytes having eosinophilic cytoplasm and densely pyknotic nuclei indicative of apoptosis (Figure 3c). CD61 immunostaining showed granular positive staining along the sinusoidal endothelial lining and in some of the terminal hepatic venules, indicative of the presence of non-occlusive fibrin thrombi (Figure 3d).Figure 3 Liver biopsy findings of case 2. (a) Portal tract with mixed inflammation, including eosinophils, activated lymphocytes, and rare plasma cells. Bile ducts are severely damaged (arrowheads), with some cholangiocytes undergoing acidophilic change and apoptosis. Detached necrotic cholangiocytes are seen in the lumen (bottom right). H&E, original magnification ×40. (b) High power view of lobule showing scattered hepatocytes undergoing apoptosis (arrowheads), with rest of the lobule showing ballooning degeneration of hepatocytes and foci of necroinflammation. H&E, original magnification ×40. (c) Portal tract containing dense mixed inflammatory infiltrate with bile duct showing cholangiocytes undergoing acidophilic change (arrowheads). H&E, original magnification ×40. (d) Immunostain for CD61 shows granular lace-like pattern of staining decorating the endothelial lining of the sinusoids as well as terminal hepatic venule (arrowhead). Original magnification ×40. (e) In situ hybridization showing hepatocyte with intracytoplasmic granular staining for COV-Spike protein (arrow). Original magnification ×40.
Similar to what was seen in case 1, RNAScope for SARS-CoV-2 spike protein was positive in rare cells (Figure 3e). A total of 6 positive cells throughout the biopsy length of 3.8 cm were identified; no cells were positive for viral replication by spike protein anti-sense strand probe. Transmission electron microscopy showed viral-like particles measuring approximately 100 nm on average, with noticeable surface (peplomeric) projections. Ultrastructurally, these virions appeared to be within sinusoidal endothelial cells10, 11, 12 (Figure 2b).
The patient was deemed not to require treatment for COVID-19 because she was oxygenating well and had no radiographic evidence of pneumonia. She was also found to have thyroid-stimulating hormone of .008 and was diagnosed with thyroiditis, which has recently been reported in COVID-19 infection,13 and she was started on cholestyramine and ursodiol. She had repeat negative PCR testing for SARS CoV-2 on hospital days 15, 18, and 24 at Mount Sinai. Because she was feeling much better she was discharged, with lactate dehydrogenase of 209 and D-dimer <0.27. Laboratory testing 1 week later showed an ongoing decrease in her liver enzymes, although the bilirubin was still elevated to 10.7 mg/dL with an indirect fraction of 7.8 mg/dL.
Discussion
The cases presented in the current report had markedly elevated liver enzymes at presentation, with both fitting the clinical course timeline as well as the histologic features of severe COVID-19 hepatitis. RNA localization of SARS-CoV-2 S protein using in situ hybridization and EM findings suggest that SARS-CoV-2 may have played a major role in the liver damage incurred by these 2 patients. Despite the initial presentation of severe liver damage, both patients recovered from COVID-19 hepatitis.
Currently, it is known that the development of abnormal liver chemistry tests and various forms of liver injury may result from COVID-19,14 with the majority of cases having mildly elevated liver enzymes.4 In a series of 99 COVID-19 patients, only 1 case presented with severe liver injury with markedly elevated liver enzymes, whereas 43 of 99 showed mild alanine aminotransferase and aspartate aminotransferase elevations (in 28% and 35%, respectively).15 In patients with significantly increased liver enzymes, there were longer hospital stays, and most patients were taking medications such as lopinavir/ritonavir, with the latter raising the possibility of drug-induced liver injury (DILI).7 A recent review concluded that significantly elevated aminotransferases are only found in severe cases of COVID-19.16 However, to date there are only case reports or small case series detailing the liver histologic findings found in patients with COVID-19 infection.4 Microvesicular steatosis and the presence of mild lymphocytic inflammation in the lobules and rarely in portal tracts are the main findings reported.4 Furthermore, there is a dearth of reported liver biopsies in COVID-19 infection of solid organ recipients.17 Aside from one post-LT pediatric case wherein a liver biopsy was performed several days after LT, no other cases have been reported.18
Liver biopsies from both patients in this study showed prominent mitoses of hepatocytes along with acidophilic bodies, ballooning degeneration, and mild inflammation. Histology also showed mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. Although these features are seen in acute T-cell–mediated rejection, which might conceivably explain the portal tract findings in patient 1, patient 2 did not have LT and yet showed a similar histology. Lagana et al18 reported the presence of increased mitotic activity and the presence of numerous apoptotic bodies in their post-LT case. A case series from the SARS epidemic in 2003 described the histology of 3 patients. These patients all had elevated liver enzymes in the 300–400 range, and liver histology showed prominent mitoses.19 The authors surmised that the prominent mitoses were likely due to a hyperproliferative state and cell cycle arrest. They further described ballooning degeneration and mild to moderate lobular inflammation. The authors ascribed these findings to what was previously reported in avian coronavirus and transmissible gastroenteritis coronavirus infections in which the coronavirus had exerted extensive cytopathic effect through the induction of apoptosis of host cells by activation of caspase.19, 20, 21 The 2 cases presented here appear to have similar cytopathic effect from SARS-CoV-2 due to the increased number of apoptotic bodies noted on both liver biopsies.
The proposed mechanism of liver injury from SARS-CoV-2 includes severe inflammatory responses and direct cytotoxicity due to active viral replication with angiotensin-converting enzyme receptors (ACE2) being abundant in the liver, particularly in cholangiocytes and endothelial cells.22 It has been shown that SARS-CoV-2 interacts with host receptors in liver cells. Gene expression of ACE2 transmembrane serine protease 2 (TMPRSS2) and paired basic amino acid cleaving enzyme (FURIN) has been shown. All 3 receptors are abundant in cholangiocytes and hepatocytes as well as in endothelial cells. Because these 3 receptors are present in various liver cells, SARS-CoV-2 may cause direct injury via a cytopathic effect, either by lysis and/or by inducing necrosis and apoptosis.22, 23, 24 Therefore, the ballooning degeneration and apoptosis as well as the striking bile duct damage may possibly be due to direct viral injury, with in situ hybridization and EM demonstrating viral particles within the liver. Previous case reports have failed to demonstrate the detection of intrahepatic viral particles. SARS-CoV-2 can also infect the gastrointestinal tract because of the abundant ACE2 receptors present.24,25 Therefore, the possibility that SARS-CoV-2 may enter the liver via the portal vein (portal venous viremia) can also be entertained.23 Varga et al26 have shown SARS-CoV-2 can directly infect endothelial cells across vascular beds of different organs, although not specifically in the liver. Widespread endothelial cell dysfunction in heart, kidney, lung, and small intestine resulted in apoptosis and prominent endotheliitis of submucosal vessels.26 Another mechanism believed to be the underlying cause of liver injury is ischemic changes in those with severe COVID-19 and DILI.4,27,28 In addition to the direct damage, translocation, and DILI, immune-mediated liver injury is another mechanism to consider. This is especially important in light of the increased inflammatory markers noted on serologic testing.16 Although SARS-CoV-2 virus is a new virus and our understanding of its tissue and cellular localization and replication is very limited, the sparse distribution of the virus as seen in the liver in the 2 current cases is not surprising because of the comparable sporadic and occasional cellular distribution described with the first SARS-CoV coronavirus in the early and mid-2000s.29,30 Despite the fact that we could not prove that the virus is replicating within the liver tissue because we did not see positive signals for the anti-sense strand of the S gene of the virus, we could not rule out such a possibility because the viral particles are sparsely distributed, and there is a limited amount of liver tissue in these core needle biopsies.
The clinical picture of the 2 patients is that of a spontaneously resolving COVID-19 infection with the markedly elevated liver tests and inflammatory markers decreasing concurrently. Although the patients did not have severe pulmonary, cardiac, or neurologic manifestations of COVID-19 infection that warranted treatment, significant liver chemistry abnormalities developed that correlated with the histologic liver damage noted. Neither patient had known underlying intrinsic liver disease, but if they did in light of the severe histologic liver damage noted, it is possible that they might have developed acute-on-chronic liver failure due to COVID-19.14,31
Some of the histologic findings seen in Case 1 are also typically seen in ACR, such as mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage. In addition, there was histologic evidence of acute hepatitis, likely because of COVID-19, ie, COVID-19 hepatitis. Lagana et al18 showed similar findings in their case that occurred 7 days after transplantation. Although it is possible that this patient had both mild ACR and concurrent COVID-19 hepatitis, it is more likely that the histologic features are due to COVID-19 because the magnitude of the aminotransferase elevation is not typical of mild ACR, and the substantive decline in liver tests with only a minimal increase in tacrolimus dose is not typical of ACR.
Although both of the reported post-LT cases may be episodes of ACR that were triggered by COVID-19, as can occur with other viral infections,32 it is more likely that these histologic features are all related to COVID-19 infection because case 2 in the current report had very similar features. The endotheliitis demonstrated in these 2 patients appears similar to that reported in other organs.26,33 The histology thus suggests both a direct viral cytopathic effect and an immunologic liver injury involving cholangiocytes, hepatocytes, and liver sinusoidal endothelial cells. The significant bile duct damage and apoptosis of cholangiocytes are very prominent in these cases. In the absence of intrinsic liver disease, resolution of the direct cytopathologic injury may occur with clearance of SARS-CoV-2, yet it will remain to be seen whether the immunologic component of the liver injury will as well. Thus, close follow-up of such patients is warranted.
In conclusion, the current report details the liver histologic findings of acute COVID-19 infection in 2 patients, which are supported by the use of in situ hybridization and EM studies. Apoptosis, especially of cholangiocytes, abundant mitoses, mixed inflammatory infiltrate in portal tracts, endotheliitis, and severe bile duct damage are typical. This histology suggests a direct cytopathic viral injury most notably in sinusoidal endothelial cells and other liver cells, with concurrent immunologic features. Such histologic changes can resemble ACR, so LT physicians must consider this possibility in post-LT patients with COVID-19 infection. These cases also demonstrate that patients can have severe liver injury in the absence of significant involvement of other organs by COVID-19.
Materials and Methods
Histopathology
Transjugular needle liver biopsy was performed for patient 1, and a percutaneous liver biopsy was performed for patient 2. Core biopsy specimens were immediately placed in formalin and fixed for a minimum of 3 hours. Routine tissue processing through graded alcohols was performed. Thereafter, the liver biopsy tissues were embedded in paraffin (FFPE). Three 4-μm-thick sections were cut for H&E stain to assess different levels and one 4-μm section for Masson trichrome stain. H&E and trichrome-stained slides were analyzed by routine light microscopy. Adequacy of the specimen was determined including the linear length of tissue and the number of complete portal tracts. Morphologic evaluation was performed under light microscopy. Histopathologic features analyzed included degree of portal and lobular inflammation, parenchymal damage including apoptosis, presence of fibrosis, bile duct injury, and endothelial damage.
In Situ Hybridization
Sections at 3 μm in thickness were taken from FFPE for RNA in situ hybridization using the RNAscope HPV kit (Advanced Cell Diagnostics, Inc, Hayward, CA) according to the manufacturer’s instructions on a Leica Bond III automated stainer (Leica Biosystems, Buffalo Grove, IL). Tissue sections were hybridized separately with a target probe to the SARS-CoV-2 S gene encoding the spike protein (catalogue #848561) to detect viral proteins within the cells to indicate infected cells and SARS-CoV-2 antisense strand of the S gene (catalogue #845701) to detect active viral replication within the cells. Positive controls for the SARS-CoV-2 S and antisense strand of the genes were prepared in-house from SARS-CoV-2-infected Vero cell lines (cell lines gift from Dr Florian Krammer, Icahn School of Medicine at Mount Sinai, New York, NY). To assess for the RNA integrity, probes for the endogenous housekeeping gene UBC (catalogue #RS7760) were used. The preamplifier, amplifier, and horseradish peroxidase–labeled probes were then hybridized sequentially, followed by color development with DAB. Specific staining signals were identified as brown, punctate dots present in the cytoplasm and/or nucleus.
Transmission Electron Microscopy
The tissue processed for EM was received in paraffin blocks. Designated portions of the specimen were dissected out with a single edge razor blade and placed into xylene overnight to dissolve the paraffin. The tissue was then brought to water through decreasing concentrations of ethanol and then fixed with 3% glutaraldehyde in a 0.2 sodium cacodylate buffer at pH 7.4.The specimen was then post-fixed with 1% osmium tetroxide tissues and embedded in Epon 812. One micrometer plastic sections were cut and stained with methyl blue and azure II for light microscopic orientation and to select smaller representative areas. Ultrathin 60-nm sections were collected into 200 mesh copper grids and stained with lanthanum and lead citrate. Sections were examined in a Hitachi 7650 (Tokyo, Japan) transmission electron microscope at 80 kV.
All authors had access to the study data and reviewed and approved the final manuscript.
CRediT Authorship Contributions
Maria Isabel Fiel, MD (Conceptualization: Lead; Data curation: Lead; Methodology: Equal; Writing – original draft: Lead)
Siraj M. El Jamal, MD (Methodology: Supporting; Writing – original draft: Supporting)
Alberto Paniz-Mondolfi, MD (Methodology: Supporting; Writing – original draft: Supporting)
Ronald E. Gordon, PhD (Methodology: Supporting; Writing – original draft: Supporting)
Jason Reidy, PhD (Methodology: Supporting)
Jela Bandovic, MD (Methodology: Supporting; Visualization: Supporting)
Rashmi Advani, MD (Data curation: Supporting)
Saikiran Kilaru, MD (Data curation: Supporting)
Kamron Pourmand, MD (Data curation: Supporting)
Stephen Ward, MD, PhD (Formal analysis: Supporting)
Swan N. Thung, MD (Formal analysis: Supporting)
Thomas D. Schiano, MD (Conceptualization: Equal; Formal analysis: Equal; Writing – original draft: Equal)
Conflicts of interest The authors disclose no conflicts.
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TACROLIMUS
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DrugsGivenReaction
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CC BY-NC-ND
|
32992052
| 19,840,647
|
2021
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Contrast encephalopathy'.
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Low-dose Contrast-induced Encephalopathy During Diagnostic Cerebral Angiography.
Contrast-induced encephalopathy (CIE) is a rare complication of contrast agent use. We herein report a case of acute lacunar infarction in a 70-year-old woman. During diagnostic cerebral angiography for asymptomatic common carotid stenosis, she experienced transient drowsiness. After angiography, generalized tonic-clonic seizures occurred in her left arm and leg, with eye deviation to the left. The patient was diagnosed with CIE due to the acute onset of symptoms during angiography and characteristic computed tomography findings of high-density signaling in the cortex. Our findings suggest that it is important to pay close attention to acute neurological symptoms during and immediately after examinations, even with small amounts of contrast agents.
Introduction
Contrast-induced encephalopathy (CIE) is a rare complication of angiography. The first cases of CIE were reported in 1961, and transient blindness was observed after the use of ionic contrast agents (1). In recent years, although nonionic contrast agents have been used, some cases of CIE resulting from coronary angiography or cerebral endovascular therapy have been reported (2). In addition, CIE can also occur with examinations using low-dose contrast agents; thus, caution should be exercised.
We herein report a case of CIE during cerebral diagnostic angiography with small amounts of contrast agents.
Case Report
A 70-year-old woman with no relevant medical history, such as hypertension, renal dysfunction, or allergic disorders, presented with sudden-onset dysarthria, right facial palsy, and monoparesis of the right arm. Diffusion-weighted imaging (DWI) revealed a high intensity in the left corona radiata. Fluid-attenuated inversion-recovery (FLAIR) imaging showed periventricular and white matter lesions. Magnetic resonance (MR) angiography indicated mild stenosis in the right common carotid bifurcation (Fig. 1). The patient was diagnosed with acute lacunar infarction and asymptomatic right carotid artery stenosis. She received antithrombotic and edaravone treatment.
Figure 1. Magnetic resonance imaging on admission. Diffusion-weighted and fluid-attenuated inversion-recovery (FLAIR) imaging revealed a high-intensity lesion in the left corona radiata (A, B). FLAIR imaging also showed periventricular hyperintensity and a subcortical white matter lesion. Magnetic resonance angiography indicated left vertebral artery occlusion (C) and mild stenosis in <50% of the right carotid bifurcation, suggesting a small ulcer (D, arrow).
A close examination showed a high brachial-ankle pulse wave velocity (baPWV; R, 3,297 cm/s; L, 2,778 cm/s) and microalbuminuria level (51.8 mg/gCr). The mini-mental state examination score was 24/30. We performed diagnostic cerebral angiography to examine the carotid artery stenosis at 10 days post-onset. After the innominate artery and right common carotid artery (CCA) were imaged with iopamidol (iodine concentration, 300 mg/mL; osmotic pressure, 620 mOsm/kg H2O), which is a nonionic water-soluble iodine contrast agent (Fig. 2A, B), she became drowsy, and her blood pressure increased to 201/101 mmHg. She presented with mild unconsciousness with Glasgow Coma Scale (E4 V4 M5) scores of 13, and she had no headache nausea or anisocoria. Dysarthria was detected, but symptoms such as visual field defect, diplopia, new paralysis, involuntary movement, or sensory disturbances were not found. The total contrast agent volume at that time was 43 mL. Re-angiography of the right CCA indicated no occlusion of the right internal carotid artery (ICA), middle cerebral artery, or cerebral venous sinus. Cone-beam computed tomography (CT) revealed no hemorrhaging in the whole brain but showed high-density signaling in the cortex in the right ICA territory (Fig. 2C, D). She recovered after about six minutes, and her blood pressure returned to normal immediately.
Figure 2. Cerebral angiography at 10 days after onset. Common carotid artery (CCA) angiography revealed mild stenosis at the bifurcation of the right carotid artery (A, arrow). The posterior cerebral artery is depicted via the posterior communicating artery, and the A1 segment of the right anterior cerebral artery is absent (B). After angiography of the right CCA, she exhibited transient consciousness disturbance. Immediate right CCA angiography revealed no occlusion (C). Cone-beam computed tomography indicated no intracranial hemorrhaging. Retrospectively, the cerebral cortex in the right internal carotid artery exhibited a high signal density (D, arrowheads).
Three hours after angiography, she became drowsy again, and generalized tonic-clonic seizures occurred in her left arm and leg, with eye deviation to the left. Head CT revealed swelling of the right cerebral cortex (Fig. 3A). DWI, the apparent diffusion coefficient map, and FLAIR imaging depicted a high signal intensity in her temporal lobe (Fig. 3C-E). Electroencephalography indicated no epileptic discharges. The patient was diagnosed with CIE based on the acute onset of symptoms during cerebral angiography and distinctive CT findings (swelling and high-density signaling) in the cortex (2). We initiated methylprednisolone pulse therapy for CIE and levetiracetam treatment for symptomatic epilepsy caused by CIE. Her symptoms disappeared, and the right cerebral swelling on head CT improved on the following day (Fig. 3B). The high signal intensity in the right temporal lobe on the FLAIR imaging gradually disappeared over a period of 2 weeks after cerebral angiography (Fig. 3F).
Figure 3. Imaging after cerebral angiography. Head computed tomography (CT) indicated swelling of the cerebral cortex in the right internal carotid artery (A, arrowheads). Diffusion-weighted imaging (C), apparent diffusion coefficient map (D), and FLAIR imaging (E) revealed a slightly high intensity in the right temporal lobe (arrowhead). The known ischemic area in the left corona radiata was not enlarged. Head CT on the following day revealed no swelling in the right cerebral cortex (B). The high intensity in the right temporal lobe on FLAIR imaging improved gradually until 14 days after angiography (F).
To determine the effects of low-dose contrast agents on encephalopathy, we performed an electronic search in PubMed for all relevant English-language articles on CIE associated with ≤50 mL of nonionic contrast agent use between 1990 to 2020, as well as cases in literature reviews reported during the same period. The results are summarized in Table.
Table. Contrast-induced Encephalopathy That Developed with ≤50mL of Contrast Agents.
Reference Age (years) Sex Arteriography Indication for study Possible risk factors Previous angiography Contrast agents Amount of contrast agents (mL) Neurological presentation CT brain region involved Clinical resolution CT brain resolution
8 71 M Bilateral carotid artery, vertebral artery Carotid artery stenosis Not reported No Iohexol 46 Cortical blindness, confusion, and ophthalomoplegia Bilateral occipital 10 day N/A
8 68 F Carotid artery, Vertebral artery Pcom aneurysm Not reported No Iohexol 24 Cortical blindness, confusion, and amnesia Bilateral occipital 6 day N/A
9 71 F Right common carotid artery Carotid artery stenting Hypertension, after transient ischemic attack No Iopromide 370 25 Confusion, disorientation, and hemiparesis The territory of the right internal carotid artery 1 day 1 day
Our case 70 F Innominate artery, right common carotid artery Carotid artery stenosis After cerebral infarction No Iopamidol 300 43 Confusion and generalized tonic-clonic seizures The territory of the right internal carotid artery 1 day 1 day
CT: computed tomography, M: male, F: female, Pcom: posterior communicating artery, N/A: not applicable
Discussion
CIE is a rare complication of contrast agent use and manifests as various neurological disorders, such as impaired consciousness, convulsions, cortical blindness, and transient amnesia (2). It has been suggested that the hyperosmotic contrast agent breaks the blood-brain barrier and leaks into the cortex and subarachnoid space, thereby causing acute encephalopathy due to toxicity of the contrast agent (3,4). One report described complications of cerebral angiography, including puncture site hematoma (0.5-4.2%), pseudoaneurysm of arteriovenous fistula (0.04-0.1%), vessel occlusion (0.14-0.76%), puncture site infection (0-1.0%), transient neurological symptoms due to embolism (1.2-2.5%), ischemic stroke (0.1-1.0%), severe allergic reaction to contrast agent (0.05-0.1%), and contrast agent-related nephropathy (0-3.13%) (5). A previous review from 1981 to 2012 showed that CIE occurs in 0.06% of cases after coronary angiography, 0.3-1.0% of cases after vertebral arteriography, and 2.9% of cases after endovascular coil treatment of posterior circulation aneurysms (2); notably, the CIE incidence seems to be lower in recent years than in the past due to the increased use of nonionic contrast agents. CIE associated with cerebral endovascular therapy often occurs in the territory of blood vessels where the contrast agent has been repeatedly injected. However, CIE associated with coronary angiography often affects the vertebral basilar artery region (2).
Previous reports have indicated that hypertension, renal disorder, and the low temperature of contrast agents might be risk factors for CIE (2,3,6). Acute cerebral infarction is also reported to be a risk factor for CIE (7). In addition, several reports have described CIE associated with endovascular surgery, which might require a higher dose of contrast agents. However, there are some cases of CIE occurring during diagnostic angiography, which does not require a high dose of contrast agents (2). In the present case, it is unlikely that the right cerebral cortex was vulnerable to ischemia tolerance because the right carotid bifurcation stenosis was not severe. Furthermore, the total amount of contrast agents used in this case was lower than that in previous reports (2). Table shows CIE cases with contrast agent use of ≤50 mL (8,9). Our case was characterized by the absence of known risk factors in addition to the acute phase of cerebral infarction. This case presented with lacunar infarction, periventricular and white matter lesion, a high level of baPWV, and mild cognitive impairment, which might be the underlying pathogenesis of cerebral small vessel disease with a certain degree of vascular endothelial damage. We hypothesized that the repeated injection of contrast agents into the right cerebral cortex with vascular endothelial damage as small vessel disease disrupted the blood-brain barrier, thereby leading to localized vasogenic edema and leakage of the contrast agent, which resulted in confusion and a temporarily elevated blood pressure due to localized encephalopathy, followed by generalized tonic-clonic seizures.
We diagnosed CIE based on the acute onset of symptoms during cerebral angiography, typical CT findings, and rapid improvement in clinical and imaging findings (2). Posterior reversible encephalopathy syndrome (PRES) and hypertensive encephalopathy are also known to cause disorientation and brain imaging changes associated with angiography. In the present case, unconsciousness and elevated blood pressure improved immediately after six minutes. Therefore, the transient elevated blood pressure might have been due to the localized encephalopathy because of contrast agent toxicity. Furthermore, PRES or hypertensive encephalopathy generally results in bilateral lesions; however, the lesion in this case was related to the site of contrast injection, providing a further basis for diagnosing this patient with CIE. A few cases have been diagnosed with CIE by measuring the concentration of iodine in the cerebrospinal fluid (4), but we did not examine the cerebrospinal fluid because due to concerns of brain hernia.
The efficacy of corticosteroid therapy for CIE is controversial because most cases of CIE improve smoothly without any immunotherapy (2). However, the use of corticosteroids in severe cases to induce anti-inflammatory effects has been reported (2,8,10). The present case was also a severe case of CIE with generalized seizure, and treatment with corticosteroids resulted in improved symptoms by the next day. Further investigations will be necessary to develop evidence-based treatment for CIE.
In conclusion, we encountered a case of CIE with acute neurological symptoms during and immediately after diagnostic cerebral angiography with small amounts of contrast agents. The findings suggest that CIE should be considered in the differential diagnosis if any acute neurological symptoms are noted during and immediately after examinations with even small amounts of contrast agents.
The authors state that they have no Conflict of Interest (COI).
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IOPAMIDOL
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DrugsGivenReaction
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CC BY-NC-ND
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32999223
| 19,725,577
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2021-02-15
|
What was the dosage of drug 'IOPAMIDOL'?
|
Low-dose Contrast-induced Encephalopathy During Diagnostic Cerebral Angiography.
Contrast-induced encephalopathy (CIE) is a rare complication of contrast agent use. We herein report a case of acute lacunar infarction in a 70-year-old woman. During diagnostic cerebral angiography for asymptomatic common carotid stenosis, she experienced transient drowsiness. After angiography, generalized tonic-clonic seizures occurred in her left arm and leg, with eye deviation to the left. The patient was diagnosed with CIE due to the acute onset of symptoms during angiography and characteristic computed tomography findings of high-density signaling in the cortex. Our findings suggest that it is important to pay close attention to acute neurological symptoms during and immediately after examinations, even with small amounts of contrast agents.
Introduction
Contrast-induced encephalopathy (CIE) is a rare complication of angiography. The first cases of CIE were reported in 1961, and transient blindness was observed after the use of ionic contrast agents (1). In recent years, although nonionic contrast agents have been used, some cases of CIE resulting from coronary angiography or cerebral endovascular therapy have been reported (2). In addition, CIE can also occur with examinations using low-dose contrast agents; thus, caution should be exercised.
We herein report a case of CIE during cerebral diagnostic angiography with small amounts of contrast agents.
Case Report
A 70-year-old woman with no relevant medical history, such as hypertension, renal dysfunction, or allergic disorders, presented with sudden-onset dysarthria, right facial palsy, and monoparesis of the right arm. Diffusion-weighted imaging (DWI) revealed a high intensity in the left corona radiata. Fluid-attenuated inversion-recovery (FLAIR) imaging showed periventricular and white matter lesions. Magnetic resonance (MR) angiography indicated mild stenosis in the right common carotid bifurcation (Fig. 1). The patient was diagnosed with acute lacunar infarction and asymptomatic right carotid artery stenosis. She received antithrombotic and edaravone treatment.
Figure 1. Magnetic resonance imaging on admission. Diffusion-weighted and fluid-attenuated inversion-recovery (FLAIR) imaging revealed a high-intensity lesion in the left corona radiata (A, B). FLAIR imaging also showed periventricular hyperintensity and a subcortical white matter lesion. Magnetic resonance angiography indicated left vertebral artery occlusion (C) and mild stenosis in <50% of the right carotid bifurcation, suggesting a small ulcer (D, arrow).
A close examination showed a high brachial-ankle pulse wave velocity (baPWV; R, 3,297 cm/s; L, 2,778 cm/s) and microalbuminuria level (51.8 mg/gCr). The mini-mental state examination score was 24/30. We performed diagnostic cerebral angiography to examine the carotid artery stenosis at 10 days post-onset. After the innominate artery and right common carotid artery (CCA) were imaged with iopamidol (iodine concentration, 300 mg/mL; osmotic pressure, 620 mOsm/kg H2O), which is a nonionic water-soluble iodine contrast agent (Fig. 2A, B), she became drowsy, and her blood pressure increased to 201/101 mmHg. She presented with mild unconsciousness with Glasgow Coma Scale (E4 V4 M5) scores of 13, and she had no headache nausea or anisocoria. Dysarthria was detected, but symptoms such as visual field defect, diplopia, new paralysis, involuntary movement, or sensory disturbances were not found. The total contrast agent volume at that time was 43 mL. Re-angiography of the right CCA indicated no occlusion of the right internal carotid artery (ICA), middle cerebral artery, or cerebral venous sinus. Cone-beam computed tomography (CT) revealed no hemorrhaging in the whole brain but showed high-density signaling in the cortex in the right ICA territory (Fig. 2C, D). She recovered after about six minutes, and her blood pressure returned to normal immediately.
Figure 2. Cerebral angiography at 10 days after onset. Common carotid artery (CCA) angiography revealed mild stenosis at the bifurcation of the right carotid artery (A, arrow). The posterior cerebral artery is depicted via the posterior communicating artery, and the A1 segment of the right anterior cerebral artery is absent (B). After angiography of the right CCA, she exhibited transient consciousness disturbance. Immediate right CCA angiography revealed no occlusion (C). Cone-beam computed tomography indicated no intracranial hemorrhaging. Retrospectively, the cerebral cortex in the right internal carotid artery exhibited a high signal density (D, arrowheads).
Three hours after angiography, she became drowsy again, and generalized tonic-clonic seizures occurred in her left arm and leg, with eye deviation to the left. Head CT revealed swelling of the right cerebral cortex (Fig. 3A). DWI, the apparent diffusion coefficient map, and FLAIR imaging depicted a high signal intensity in her temporal lobe (Fig. 3C-E). Electroencephalography indicated no epileptic discharges. The patient was diagnosed with CIE based on the acute onset of symptoms during cerebral angiography and distinctive CT findings (swelling and high-density signaling) in the cortex (2). We initiated methylprednisolone pulse therapy for CIE and levetiracetam treatment for symptomatic epilepsy caused by CIE. Her symptoms disappeared, and the right cerebral swelling on head CT improved on the following day (Fig. 3B). The high signal intensity in the right temporal lobe on the FLAIR imaging gradually disappeared over a period of 2 weeks after cerebral angiography (Fig. 3F).
Figure 3. Imaging after cerebral angiography. Head computed tomography (CT) indicated swelling of the cerebral cortex in the right internal carotid artery (A, arrowheads). Diffusion-weighted imaging (C), apparent diffusion coefficient map (D), and FLAIR imaging (E) revealed a slightly high intensity in the right temporal lobe (arrowhead). The known ischemic area in the left corona radiata was not enlarged. Head CT on the following day revealed no swelling in the right cerebral cortex (B). The high intensity in the right temporal lobe on FLAIR imaging improved gradually until 14 days after angiography (F).
To determine the effects of low-dose contrast agents on encephalopathy, we performed an electronic search in PubMed for all relevant English-language articles on CIE associated with ≤50 mL of nonionic contrast agent use between 1990 to 2020, as well as cases in literature reviews reported during the same period. The results are summarized in Table.
Table. Contrast-induced Encephalopathy That Developed with ≤50mL of Contrast Agents.
Reference Age (years) Sex Arteriography Indication for study Possible risk factors Previous angiography Contrast agents Amount of contrast agents (mL) Neurological presentation CT brain region involved Clinical resolution CT brain resolution
8 71 M Bilateral carotid artery, vertebral artery Carotid artery stenosis Not reported No Iohexol 46 Cortical blindness, confusion, and ophthalomoplegia Bilateral occipital 10 day N/A
8 68 F Carotid artery, Vertebral artery Pcom aneurysm Not reported No Iohexol 24 Cortical blindness, confusion, and amnesia Bilateral occipital 6 day N/A
9 71 F Right common carotid artery Carotid artery stenting Hypertension, after transient ischemic attack No Iopromide 370 25 Confusion, disorientation, and hemiparesis The territory of the right internal carotid artery 1 day 1 day
Our case 70 F Innominate artery, right common carotid artery Carotid artery stenosis After cerebral infarction No Iopamidol 300 43 Confusion and generalized tonic-clonic seizures The territory of the right internal carotid artery 1 day 1 day
CT: computed tomography, M: male, F: female, Pcom: posterior communicating artery, N/A: not applicable
Discussion
CIE is a rare complication of contrast agent use and manifests as various neurological disorders, such as impaired consciousness, convulsions, cortical blindness, and transient amnesia (2). It has been suggested that the hyperosmotic contrast agent breaks the blood-brain barrier and leaks into the cortex and subarachnoid space, thereby causing acute encephalopathy due to toxicity of the contrast agent (3,4). One report described complications of cerebral angiography, including puncture site hematoma (0.5-4.2%), pseudoaneurysm of arteriovenous fistula (0.04-0.1%), vessel occlusion (0.14-0.76%), puncture site infection (0-1.0%), transient neurological symptoms due to embolism (1.2-2.5%), ischemic stroke (0.1-1.0%), severe allergic reaction to contrast agent (0.05-0.1%), and contrast agent-related nephropathy (0-3.13%) (5). A previous review from 1981 to 2012 showed that CIE occurs in 0.06% of cases after coronary angiography, 0.3-1.0% of cases after vertebral arteriography, and 2.9% of cases after endovascular coil treatment of posterior circulation aneurysms (2); notably, the CIE incidence seems to be lower in recent years than in the past due to the increased use of nonionic contrast agents. CIE associated with cerebral endovascular therapy often occurs in the territory of blood vessels where the contrast agent has been repeatedly injected. However, CIE associated with coronary angiography often affects the vertebral basilar artery region (2).
Previous reports have indicated that hypertension, renal disorder, and the low temperature of contrast agents might be risk factors for CIE (2,3,6). Acute cerebral infarction is also reported to be a risk factor for CIE (7). In addition, several reports have described CIE associated with endovascular surgery, which might require a higher dose of contrast agents. However, there are some cases of CIE occurring during diagnostic angiography, which does not require a high dose of contrast agents (2). In the present case, it is unlikely that the right cerebral cortex was vulnerable to ischemia tolerance because the right carotid bifurcation stenosis was not severe. Furthermore, the total amount of contrast agents used in this case was lower than that in previous reports (2). Table shows CIE cases with contrast agent use of ≤50 mL (8,9). Our case was characterized by the absence of known risk factors in addition to the acute phase of cerebral infarction. This case presented with lacunar infarction, periventricular and white matter lesion, a high level of baPWV, and mild cognitive impairment, which might be the underlying pathogenesis of cerebral small vessel disease with a certain degree of vascular endothelial damage. We hypothesized that the repeated injection of contrast agents into the right cerebral cortex with vascular endothelial damage as small vessel disease disrupted the blood-brain barrier, thereby leading to localized vasogenic edema and leakage of the contrast agent, which resulted in confusion and a temporarily elevated blood pressure due to localized encephalopathy, followed by generalized tonic-clonic seizures.
We diagnosed CIE based on the acute onset of symptoms during cerebral angiography, typical CT findings, and rapid improvement in clinical and imaging findings (2). Posterior reversible encephalopathy syndrome (PRES) and hypertensive encephalopathy are also known to cause disorientation and brain imaging changes associated with angiography. In the present case, unconsciousness and elevated blood pressure improved immediately after six minutes. Therefore, the transient elevated blood pressure might have been due to the localized encephalopathy because of contrast agent toxicity. Furthermore, PRES or hypertensive encephalopathy generally results in bilateral lesions; however, the lesion in this case was related to the site of contrast injection, providing a further basis for diagnosing this patient with CIE. A few cases have been diagnosed with CIE by measuring the concentration of iodine in the cerebrospinal fluid (4), but we did not examine the cerebrospinal fluid because due to concerns of brain hernia.
The efficacy of corticosteroid therapy for CIE is controversial because most cases of CIE improve smoothly without any immunotherapy (2). However, the use of corticosteroids in severe cases to induce anti-inflammatory effects has been reported (2,8,10). The present case was also a severe case of CIE with generalized seizure, and treatment with corticosteroids resulted in improved symptoms by the next day. Further investigations will be necessary to develop evidence-based treatment for CIE.
In conclusion, we encountered a case of CIE with acute neurological symptoms during and immediately after diagnostic cerebral angiography with small amounts of contrast agents. The findings suggest that CIE should be considered in the differential diagnosis if any acute neurological symptoms are noted during and immediately after examinations with even small amounts of contrast agents.
The authors state that they have no Conflict of Interest (COI).
|
43 ML, SINGLE
|
DrugDosageText
|
CC BY-NC-ND
|
32999223
| 19,725,577
|
2021-02-15
|
What was the outcome of reaction 'Contrast encephalopathy'?
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Low-dose Contrast-induced Encephalopathy During Diagnostic Cerebral Angiography.
Contrast-induced encephalopathy (CIE) is a rare complication of contrast agent use. We herein report a case of acute lacunar infarction in a 70-year-old woman. During diagnostic cerebral angiography for asymptomatic common carotid stenosis, she experienced transient drowsiness. After angiography, generalized tonic-clonic seizures occurred in her left arm and leg, with eye deviation to the left. The patient was diagnosed with CIE due to the acute onset of symptoms during angiography and characteristic computed tomography findings of high-density signaling in the cortex. Our findings suggest that it is important to pay close attention to acute neurological symptoms during and immediately after examinations, even with small amounts of contrast agents.
Introduction
Contrast-induced encephalopathy (CIE) is a rare complication of angiography. The first cases of CIE were reported in 1961, and transient blindness was observed after the use of ionic contrast agents (1). In recent years, although nonionic contrast agents have been used, some cases of CIE resulting from coronary angiography or cerebral endovascular therapy have been reported (2). In addition, CIE can also occur with examinations using low-dose contrast agents; thus, caution should be exercised.
We herein report a case of CIE during cerebral diagnostic angiography with small amounts of contrast agents.
Case Report
A 70-year-old woman with no relevant medical history, such as hypertension, renal dysfunction, or allergic disorders, presented with sudden-onset dysarthria, right facial palsy, and monoparesis of the right arm. Diffusion-weighted imaging (DWI) revealed a high intensity in the left corona radiata. Fluid-attenuated inversion-recovery (FLAIR) imaging showed periventricular and white matter lesions. Magnetic resonance (MR) angiography indicated mild stenosis in the right common carotid bifurcation (Fig. 1). The patient was diagnosed with acute lacunar infarction and asymptomatic right carotid artery stenosis. She received antithrombotic and edaravone treatment.
Figure 1. Magnetic resonance imaging on admission. Diffusion-weighted and fluid-attenuated inversion-recovery (FLAIR) imaging revealed a high-intensity lesion in the left corona radiata (A, B). FLAIR imaging also showed periventricular hyperintensity and a subcortical white matter lesion. Magnetic resonance angiography indicated left vertebral artery occlusion (C) and mild stenosis in <50% of the right carotid bifurcation, suggesting a small ulcer (D, arrow).
A close examination showed a high brachial-ankle pulse wave velocity (baPWV; R, 3,297 cm/s; L, 2,778 cm/s) and microalbuminuria level (51.8 mg/gCr). The mini-mental state examination score was 24/30. We performed diagnostic cerebral angiography to examine the carotid artery stenosis at 10 days post-onset. After the innominate artery and right common carotid artery (CCA) were imaged with iopamidol (iodine concentration, 300 mg/mL; osmotic pressure, 620 mOsm/kg H2O), which is a nonionic water-soluble iodine contrast agent (Fig. 2A, B), she became drowsy, and her blood pressure increased to 201/101 mmHg. She presented with mild unconsciousness with Glasgow Coma Scale (E4 V4 M5) scores of 13, and she had no headache nausea or anisocoria. Dysarthria was detected, but symptoms such as visual field defect, diplopia, new paralysis, involuntary movement, or sensory disturbances were not found. The total contrast agent volume at that time was 43 mL. Re-angiography of the right CCA indicated no occlusion of the right internal carotid artery (ICA), middle cerebral artery, or cerebral venous sinus. Cone-beam computed tomography (CT) revealed no hemorrhaging in the whole brain but showed high-density signaling in the cortex in the right ICA territory (Fig. 2C, D). She recovered after about six minutes, and her blood pressure returned to normal immediately.
Figure 2. Cerebral angiography at 10 days after onset. Common carotid artery (CCA) angiography revealed mild stenosis at the bifurcation of the right carotid artery (A, arrow). The posterior cerebral artery is depicted via the posterior communicating artery, and the A1 segment of the right anterior cerebral artery is absent (B). After angiography of the right CCA, she exhibited transient consciousness disturbance. Immediate right CCA angiography revealed no occlusion (C). Cone-beam computed tomography indicated no intracranial hemorrhaging. Retrospectively, the cerebral cortex in the right internal carotid artery exhibited a high signal density (D, arrowheads).
Three hours after angiography, she became drowsy again, and generalized tonic-clonic seizures occurred in her left arm and leg, with eye deviation to the left. Head CT revealed swelling of the right cerebral cortex (Fig. 3A). DWI, the apparent diffusion coefficient map, and FLAIR imaging depicted a high signal intensity in her temporal lobe (Fig. 3C-E). Electroencephalography indicated no epileptic discharges. The patient was diagnosed with CIE based on the acute onset of symptoms during cerebral angiography and distinctive CT findings (swelling and high-density signaling) in the cortex (2). We initiated methylprednisolone pulse therapy for CIE and levetiracetam treatment for symptomatic epilepsy caused by CIE. Her symptoms disappeared, and the right cerebral swelling on head CT improved on the following day (Fig. 3B). The high signal intensity in the right temporal lobe on the FLAIR imaging gradually disappeared over a period of 2 weeks after cerebral angiography (Fig. 3F).
Figure 3. Imaging after cerebral angiography. Head computed tomography (CT) indicated swelling of the cerebral cortex in the right internal carotid artery (A, arrowheads). Diffusion-weighted imaging (C), apparent diffusion coefficient map (D), and FLAIR imaging (E) revealed a slightly high intensity in the right temporal lobe (arrowhead). The known ischemic area in the left corona radiata was not enlarged. Head CT on the following day revealed no swelling in the right cerebral cortex (B). The high intensity in the right temporal lobe on FLAIR imaging improved gradually until 14 days after angiography (F).
To determine the effects of low-dose contrast agents on encephalopathy, we performed an electronic search in PubMed for all relevant English-language articles on CIE associated with ≤50 mL of nonionic contrast agent use between 1990 to 2020, as well as cases in literature reviews reported during the same period. The results are summarized in Table.
Table. Contrast-induced Encephalopathy That Developed with ≤50mL of Contrast Agents.
Reference Age (years) Sex Arteriography Indication for study Possible risk factors Previous angiography Contrast agents Amount of contrast agents (mL) Neurological presentation CT brain region involved Clinical resolution CT brain resolution
8 71 M Bilateral carotid artery, vertebral artery Carotid artery stenosis Not reported No Iohexol 46 Cortical blindness, confusion, and ophthalomoplegia Bilateral occipital 10 day N/A
8 68 F Carotid artery, Vertebral artery Pcom aneurysm Not reported No Iohexol 24 Cortical blindness, confusion, and amnesia Bilateral occipital 6 day N/A
9 71 F Right common carotid artery Carotid artery stenting Hypertension, after transient ischemic attack No Iopromide 370 25 Confusion, disorientation, and hemiparesis The territory of the right internal carotid artery 1 day 1 day
Our case 70 F Innominate artery, right common carotid artery Carotid artery stenosis After cerebral infarction No Iopamidol 300 43 Confusion and generalized tonic-clonic seizures The territory of the right internal carotid artery 1 day 1 day
CT: computed tomography, M: male, F: female, Pcom: posterior communicating artery, N/A: not applicable
Discussion
CIE is a rare complication of contrast agent use and manifests as various neurological disorders, such as impaired consciousness, convulsions, cortical blindness, and transient amnesia (2). It has been suggested that the hyperosmotic contrast agent breaks the blood-brain barrier and leaks into the cortex and subarachnoid space, thereby causing acute encephalopathy due to toxicity of the contrast agent (3,4). One report described complications of cerebral angiography, including puncture site hematoma (0.5-4.2%), pseudoaneurysm of arteriovenous fistula (0.04-0.1%), vessel occlusion (0.14-0.76%), puncture site infection (0-1.0%), transient neurological symptoms due to embolism (1.2-2.5%), ischemic stroke (0.1-1.0%), severe allergic reaction to contrast agent (0.05-0.1%), and contrast agent-related nephropathy (0-3.13%) (5). A previous review from 1981 to 2012 showed that CIE occurs in 0.06% of cases after coronary angiography, 0.3-1.0% of cases after vertebral arteriography, and 2.9% of cases after endovascular coil treatment of posterior circulation aneurysms (2); notably, the CIE incidence seems to be lower in recent years than in the past due to the increased use of nonionic contrast agents. CIE associated with cerebral endovascular therapy often occurs in the territory of blood vessels where the contrast agent has been repeatedly injected. However, CIE associated with coronary angiography often affects the vertebral basilar artery region (2).
Previous reports have indicated that hypertension, renal disorder, and the low temperature of contrast agents might be risk factors for CIE (2,3,6). Acute cerebral infarction is also reported to be a risk factor for CIE (7). In addition, several reports have described CIE associated with endovascular surgery, which might require a higher dose of contrast agents. However, there are some cases of CIE occurring during diagnostic angiography, which does not require a high dose of contrast agents (2). In the present case, it is unlikely that the right cerebral cortex was vulnerable to ischemia tolerance because the right carotid bifurcation stenosis was not severe. Furthermore, the total amount of contrast agents used in this case was lower than that in previous reports (2). Table shows CIE cases with contrast agent use of ≤50 mL (8,9). Our case was characterized by the absence of known risk factors in addition to the acute phase of cerebral infarction. This case presented with lacunar infarction, periventricular and white matter lesion, a high level of baPWV, and mild cognitive impairment, which might be the underlying pathogenesis of cerebral small vessel disease with a certain degree of vascular endothelial damage. We hypothesized that the repeated injection of contrast agents into the right cerebral cortex with vascular endothelial damage as small vessel disease disrupted the blood-brain barrier, thereby leading to localized vasogenic edema and leakage of the contrast agent, which resulted in confusion and a temporarily elevated blood pressure due to localized encephalopathy, followed by generalized tonic-clonic seizures.
We diagnosed CIE based on the acute onset of symptoms during cerebral angiography, typical CT findings, and rapid improvement in clinical and imaging findings (2). Posterior reversible encephalopathy syndrome (PRES) and hypertensive encephalopathy are also known to cause disorientation and brain imaging changes associated with angiography. In the present case, unconsciousness and elevated blood pressure improved immediately after six minutes. Therefore, the transient elevated blood pressure might have been due to the localized encephalopathy because of contrast agent toxicity. Furthermore, PRES or hypertensive encephalopathy generally results in bilateral lesions; however, the lesion in this case was related to the site of contrast injection, providing a further basis for diagnosing this patient with CIE. A few cases have been diagnosed with CIE by measuring the concentration of iodine in the cerebrospinal fluid (4), but we did not examine the cerebrospinal fluid because due to concerns of brain hernia.
The efficacy of corticosteroid therapy for CIE is controversial because most cases of CIE improve smoothly without any immunotherapy (2). However, the use of corticosteroids in severe cases to induce anti-inflammatory effects has been reported (2,8,10). The present case was also a severe case of CIE with generalized seizure, and treatment with corticosteroids resulted in improved symptoms by the next day. Further investigations will be necessary to develop evidence-based treatment for CIE.
In conclusion, we encountered a case of CIE with acute neurological symptoms during and immediately after diagnostic cerebral angiography with small amounts of contrast agents. The findings suggest that CIE should be considered in the differential diagnosis if any acute neurological symptoms are noted during and immediately after examinations with even small amounts of contrast agents.
The authors state that they have no Conflict of Interest (COI).
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
32999223
| 19,725,577
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Left ventricular dysfunction'.
|
An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.
A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.
Introduction
Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).
We experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.
Case Report
A 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.
An echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.
Coronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.
Two and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).
Three years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).
Figure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).
Figure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.
Although medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).
The patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.
Figure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance
Discussion
We demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.
The administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.
Replacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.
Conclusion
We herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.
The authors state that they have no Conflict of Interest (COI).
|
CARVEDILOL, PERINDOPRIL, SPIRONOLACTONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
32999224
| 19,844,191
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocardial fibrosis'.
|
An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.
A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.
Introduction
Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).
We experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.
Case Report
A 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.
An echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.
Coronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.
Two and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).
Three years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).
Figure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).
Figure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.
Although medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).
The patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.
Figure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance
Discussion
We demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.
The administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.
Replacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.
Conclusion
We herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.
The authors state that they have no Conflict of Interest (COI).
|
CARVEDILOL, PERINDOPRIL, SPIRONOLACTONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
32999224
| 19,844,191
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Withdrawal syndrome'.
|
An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.
A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.
Introduction
Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).
We experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.
Case Report
A 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.
An echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.
Coronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.
Two and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).
Three years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).
Figure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).
Figure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.
Although medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).
The patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.
Figure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance
Discussion
We demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.
The administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.
Replacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.
Conclusion
We herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.
The authors state that they have no Conflict of Interest (COI).
|
CARVEDILOL, PERINDOPRIL, SPIRONOLACTONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
32999224
| 19,844,191
|
2021-02-15
|
What was the outcome of reaction 'Left ventricular dysfunction'?
|
An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.
A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.
Introduction
Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).
We experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.
Case Report
A 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.
An echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.
Coronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.
Two and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).
Three years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).
Figure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).
Figure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.
Although medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).
The patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.
Figure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance
Discussion
We demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.
The administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.
Replacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.
Conclusion
We herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.
The authors state that they have no Conflict of Interest (COI).
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
32999224
| 19,844,191
|
2021-02-15
|
What was the outcome of reaction 'Myocardial fibrosis'?
|
An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.
A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.
Introduction
Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).
We experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.
Case Report
A 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.
An echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.
Coronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.
Two and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).
Three years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).
Figure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).
Figure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.
Although medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).
The patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.
Figure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance
Discussion
We demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.
The administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.
Replacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.
Conclusion
We herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.
The authors state that they have no Conflict of Interest (COI).
|
Fatal
|
ReactionOutcome
|
CC BY-NC-ND
|
32999224
| 19,844,191
|
2021-02-15
|
What was the outcome of reaction 'Withdrawal syndrome'?
|
An Irreversible Worsening Cardiac Function after Withdrawing Medical Treatments in a Patient with Dilated Cardiomyopathy: A Pathological Analysis.
A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.
Introduction
Dilated cardiomyopathy (DCM) is characterized by left ventricular (LV) dilatation and impaired LV contractility. Some patients with DCM demonstrate LV reverse remodeling after the introduction of medication, including beta-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors. LV reverse remodeling is characterized by a reduction in LV volume and an improvement in LV contractility (1). In addition, it has been also shown that the withdrawal of medical treatments is associated with re-worsening of LV contractility (2,3).
We experienced a patient with DCM in whom the once-recovered cardiac function did not improve again after the withdrawal of medical treatment. We herein report the clinical course by cardiac magnetic resonance (CMR) imaging and an endomyocardial biopsy.
Case Report
A 44-year-old man was admitted to our hospital with acute decompensated heart failure (HF). Seven years before the patient's admission, he had first been admitted for the treatment of acute decompensated HF. The patient had a history of hypertension. His blood pressure was 140/80 mmHg when he was not taking any medication.
An echocardiogram showed LV systolic dysfunction and dilatation with no significant valvular disease. The degree of mitral regurgitation at the diagnosis was mild. The LV wall thickness was 8.0 mm. Blood urine examinations did not reveal secondary or infiltrative cardiomyopathy, with the following measurements: white blood cell count, 9,900/μL; C-reactive protein, 0.28 mg/dL; thyroid-stimulating hormone, 0.57 μIU/mL; free thyroxine, 1.71 ng/dL; anti-nuclear antibody negative; immunoglobulin G, 1,363 mg/dL; angiotensin-converting enzyme, 6.8 IU/L; and urinary Bence-Jones protein negative. The patient had no history of drug or alcohol consumption that could have caused LV dysfunction.
Coronary angiography demonstrated no significant coronary disease. 18F-fluorodeoxyglucose positron emission tomography and 67Ga-scintigraphy showed no abnormal uptake in the LV. CMR showed no high-intensity regions on T2-weighted imaging or late gadolinium enhancement (LGE). An endomyocardial biopsy showed myocardial degeneration and mild interstitial fibrosis, but secondary cardiomyopathy was not observed. Therefore, the patient was diagnosed with idiopathic DCM.
Two and a half years after the first admission, the LV diastolic diameter decreased from 60 to 51 mm, and the LV ejection fraction (LVEF) increased from 10% to 67% after the administration of medication, including beta-blockers (carvedilol, 10 mg/day) and RAAS inhibitors (perindopril, 8 mg/day; spironolactone, 25 mg/day).
Three years after the first admission, the patient stopped taking medication of his own volition against medical advice. His LVEF decreased from 67% to 25%, and the LV diastolic diameter increased from 51 to 72 mm. After the patient discontinued medical treatment, his systolic blood pressure increased from 131 to 162 mmHg. A 12-lead electrocardiogram showed sinus rhythm with a ventricular rate of 99 bpm, which was not significantly different from the value before the discontinuation of therapy (97 bpm). We performed coronary angiography; however, no coronary stenosis was observed. In addition, secondary cardiomyopathy was investigated again by blood and urine examinations, but no significant observations were made. We also performed CMR imaging and an endomyocardial biopsy again. CMR at follow-up demonstrated an appearance of linear LGE in the ventricular septum, which was not observed at the baseline (Fig. 1). An endomyocardial biopsy also demonstrated a significant increase in interstitial fibrosis and the development of replacement fibrosis compared with the baseline evaluation (Fig. 2).
Figure 1. (A) At the time of the diagnosis, cardiac magnetic resonance (CMR) imaging showed no delayed enhancement. (B) At re-admission, CMR imaging showed delayed linear enhancement of the ventricular septum (arrowheads).
Figure 2. (A, B) Moderate myocardial hypertrophy and cellular degeneration were observed. No inflammatory cell infiltration was observed [Hematoxylin and Eosin (H&E) staining, magnification: ×40, ×200]. (C, D) Only mild interstitial fibrosis was observed in the left ventricular myocardium at the diagnosis (Masson’s trichrome staining, magnification: ×40, ×200). (E, F) A high degree of myocardial hypertrophy and cellular degeneration were observed (H&E staining, magnification: ×40, ×200). (G, H) Increased interstitial fibrosis and replacement fibrosis were observed in the right ventricular myocardium at re-admission (Masson’s trichrome staining, magnification: ×40, ×200). The collagenous volume fraction increased from 10% to 20%.
Although medications were re-introduced and the patient's compliance was good, the LV performance gradually worsened, and the B-type natriuretic peptide concentration increased over several years. Because of first-degree atrioventricular block and temporal complete atrioventricular block, beta-blockers could not be up-titrated to the target dose (final dose of carvedilol: 10 mg/day).
The patient was repeatedly admitted to the hospital because of HF (Fig. 3). Although adaptive servo-ventilation was introduced, the effect was poor. At this time point, the patient was considered to be indicated for cardiac resynchronization therapy (CRT) for the further up-titration of beta-blockers. However, a CRT device was not implanted since it was difficult to anticipate whether or not the patient might achieve reverse remodeling with the further up-titration of beta-blockers, causing biventricular pacing to potentially negatively affect his cardiac performance. A ventricular assist device and heart transplantation were repeatedly considered; however, the patient did not want to undergo therapy. The patient ultimately died four years later due to worsening HF.
Figure 3. At the time of the diagnosis, LVEF was 10%, and the LV diastolic dimension was 60 mm. The LVEF recovered after administration of medication, including carvedilol and perindopril. After withdrawal of medication, the LV performance worsened. Despite the re-introduction of medication, the LV performance did not improve. The patient was repeatedly hospitalized due to worsening heart failure (arrows). LVEF: left ventricular ejection fraction, LVDd: left ventricular diastolic dimension, BNP: B-type natriuretic peptide, CMR: cardiac magnetic resonance
Discussion
We demonstrated the significant development of cardiac fibrosis and a worsening LV systolic function after the withdrawal of medical treatment in a patient with DCM. The present case indicates the possible pathophysiological mechanism underlying the re-worsening of LV performance after the withdrawal of medical treatments in cases of HF with a reduced LVEF.
The administration of anti-neurohumoral agents, such as beta-blockers and RAAS inhibitors, has a strong impact on improving the prognosis in patients with HF and reduced LVEF by inhibiting LV remodeling (4,5). Withdrawal of these medications is associated with increased mortality and admission for worsening HF (2,3). Similar results were observed in a recent prospective randomized trial. It is important to note that improvements in the cardiac function following treatment reflect not a full and sustained recovery but rather remission (6). A previous case report showed increased sensitivity to the chronotropic effects of beta-agonists after the withdrawal of propranolol (7). Beta-blockers are reported to decrease myocardial oxygen consumption and improve the efficiency of myocardial metabolisms (8). Therefore, mid-term withdrawal of beta-blockers might be related to irreversible changes in myocardial metabolism. Withdrawal of RAAS inhibitors is also reported to cause LV remodeling, increased blood pressure, and endothelial dysfunction. Increments in neurohumoral activation, including plasma catecholamine concentrations and RAAS activity, play a key role in worsening of the LV performance in patients who have withdrawn from medical treatment (9). In contrast, there have been no reports demonstrating the irreversibility of cardiac performance after the re-introduction of anti-neurohumoral agents. The present case showed no improvement in the LV systolic function despite the re-introduction of medication. The dose of carvedilol could not be increased above 10 mg/day due to the patient's atrioventricular block. Because carvedilol produced dose-related improvements in the LVEF (10), it is recommended to reach the target dose. Not only withdrawing medical treatments but also underdosing of beta-blockers might have been related to the lack of improvement in the LV function in this patient.
Replacement or scarring fibrosis corresponds to the replacement of myocytes by plexiform fibrosis after cell damage or necrosis. Replacement fibrosis is observed as advanced myocardial damage in the later stages of cardiomyopathies. LGE by CMR, which has been reported as representative of replacement fibrosis, is associated with an increased mortality rate and lack of LV recovery after treatment in patients with DCM (11,12). In the present case, CMR imaging showed a new LGE lesion after withdrawal of medical treatment, which indicated the progression of myocardial damage. Thus, the myocardial damage was considered to have been an inhibiting factor of LV reverse remodeling. As a pathophysiological mechanism, high plasma catecholamine concentrations have been reported to induce myocardial necrosis, leading to progressive myocardial degeneration (4). Withdrawal of medical treatment may have induced advanced myocardial damage through persistently high neurohumoral activation in this patient.
Conclusion
We herein report a case of DCM with irreversible LV dysfunction and the development of cardiac fibrosis after withdrawing medical treatment. The present findings suggest that the response to treatment differs with the progression of myocardial damage, even in the same patient. We emphasize the importance of continued anti-neurohumoral therapy, even after LV reverse remodeling, to prevent progression of myocardial damage.
The authors state that they have no Conflict of Interest (COI).
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Fatal
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ReactionOutcome
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CC BY-NC-ND
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32999224
| 19,844,191
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2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperglycaemia'.
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The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia.
Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.
Introduction
Cryoglobulins are immunoglobulins that aggregate at low temperatures both in vitro and in vivo. In the human body, temperatures below normal body temperature cause them to accumulate in various organs (1); this is a disease state known as cryoglobulinemia. The clinical manifestations of cryoglobulinemia are hyperviscosity syndrome and systemic vasculitis. Renal involvement is common and manifests as rapidly progressive glomerulonephritis with membranous proliferative glomerulonephritis as the characteristic histological finding (1). Decades ago, treatments for cryoglobulinemia were similar to those for other forms of systemic vasculitis; in 1991, however, it was shown that about 90% of cases of mixed cryoglobulinemia are associated with hepatitis C virus (HCV) infection (2) and that chronic HCV infection triggers B-cell expansion, which results in the production of cryoglobulins (3).
Rituximab was reported as an efficacious treatment in 2003 (4,5) and became the recommended immunosuppressive treatment for patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2018 (6). In addition, direct-acting antiviral agents (DAAs) have been used for the last decade to improve the clearance of HCV (7). Although these treatments are expected to improve the clinical outcomes of cryoglobulinemia, several cases of treatment failure or relapse after rituximab and DAAs have recently been reported (8,9).
We herein report a case of serologically persistent cryoglobulinemia in which glomerulonephritis was successfully treated with rituximab, DAAs, occasional plasmapheresis and long-term steroid.
Case Report
A 68-year-old man was referred to our nephrology department because of progressive renal insufficiency and proteinuria. He had been diagnosed with chronic hepatitis C in his teens but had not been treated for it. He had been diagnosed with diabetes mellitus at 55 years old. He had a history of myocardial infarction at 59 and 63 years old. In addition, one year previously, he had been hospitalized due to worsening depression. One month before the present admission, his serum creatinine level had increased from 1.61 to 2.11 mg/dL. At that time, he had noted bilateral leg edema. He was admitted to our hospital to investigate the cause of his worsening renal function and edema.
On admission, his height and weight were 160.7 cm and 61.7 kg, respectively. He did not notice any weight gain because he did not weigh himself regularly. His vital signs were as follows: blood pressure 153/89 mmHg, pulse 63 beats/min and temperature 36.3°C. A physical examination revealed bilateral leg pitting edema, no purpura, no cutaneous ulcer and no paresthesia, with otherwise normal findings. A complete blood count revealed a hemoglobin concentration of 8.8 g/dL. A laboratory examination showed aspartate aminotransferase of 44 U/L, alanine transaminase of 46 U/L, lactate dehydrogenase of 268 U/L, total protein of 5.0 g/dL, albumin of 2.3 g/dL, creatinine of 2.45 mg/dL and total cholesterol of 213 mg/dL (Table). Occult blood and proteinuria were positive on a urinalysis, and the 24-hour urinary protein excretion was 7.4 g/day. Hemoglobin A1c was 5.9%. Immunological tests revealed negative results for anti-nuclear antibody, anti-DNA antibody, proteinase-3 antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase ANCA and anti-glomerular basement membrane antibody. Cryoglobulins were detected through a qualitative analysis, and cryocrit was 5%. Immunoglobulin M (IgM) was elevated to 692 mg/dL (reference range: 27-205 mg/dL). Rheumatoid factor (RF) was also elevated to 2018 IU/mL (reference range: 0-15.0 IU/mL). Complements were suppressed, as follows: complement C3 at 56.3 mg/dL (reference range: 70.5-125.6 mg/dL) and complement C4 at 2.6 mg/dL (reference range: 10.6-33.0 mg/dL). A virologic test showed serotype 1 HCV RNA of 7.0 LogIU/mL.
Table. Laboratory Data on Admission, at Discharge and 27 Months after Discharge.
Laboratory test At diagnosis At discharge 27 months after discharge
Complete Blood Count
WBC (/µL) 6,990 6,010 11,970
RBC (/µL) 294 330 441
Hb (g/dL) 8.8 9.7 13.6
PLT (×104/µL) 20.5 28.4 32.1
Blood Chemistry
AST (U/L) 44 15 23
ALT (U/L) 46 11 23
LDH (U/L) 268 235 163
TP (g/dL) 5 5.2 6.7
Alb (g/dL) 2.3 3 4.1
CK (U/L) 102 28 53
BUN (mg/dL) 35 27 25
Cr (mg/dL) 2.45 2.34 1.66
eGFR (mL/min/1.73 m2) 21.7 22.8 32.9
T-CHO (mg/dL) 213 199 120
Na (mEq/L) 140 141 132
K (mEq/L) 3.8 5.2 4.1
Cl (mEq/L) 110 110 94
Ca (mg/dL) 7.7 8.4 9.5
P (mg/dL) 3.9 3.4 2.5
Mg (mg/dL) 2 2.7 2.2
Immunological Examination
CRP (mg/dL) 0.1 0.1> 0.1>
IgG (mg/dL) 600 449 792
IgA (mg/dL) 138 155 146
IgM (mg/dL) 692 445 479
C3 (mg/dL) 56.3 69.5 67.1
C4 (mg/dL) 2.6 2.7 2.8
CH50 (mg/dL) 10> 10> 16
RF (IU/mL) 2,018 1,727 1,832
HbA1c (%) 5.9 6.3
PR3-ANCA negative
MPO-ANCA negative
anti-nuclear antibody negative
anti-DNA antibody negative
anti-GBM antibody negative
Serum immunoelectrophoresis IgM-κ IgM-κ
Cryoglobulin positive positive positive
Cryocrit (%) 5 4 4
HCV RNA (LogIU/mL) 7 1.2> undetectable
Urinalysis
RBC (/HPF) 30-49 100< 5-9
proteinuria (g/gCr) 9.4 3 0.35
24-hour urinary protein excretion (g/day) 7.4
NAG (U/L) 54 9.9 13.4
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, TP: total protein, Alb: albumin, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, T-CHO: total cholesterol, Na: sodium, K: potasium, Cl: chlorine, Ca: calcium, P: phosphorus, Mg: magnesium, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM, immunoglobulin M, C3: complement component 3, C4: complement component 4, RF: rheumatoid factor, HbA1c: hemoglobin A1c, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-DNA antibody: anti-deoxyribonucleic acid antibody, anti-GBM antibody: anti-glomerular basement membrane antibody, HCV RNA: hepatitis C virus ribonucleic acid, NAG: N-acetyl-β-D-glucosaminidase
Based on these findings, the patient was diagnosed with rapidly progressive glomerulonephritis accompanied by nephrotic syndrome.
Renal biopsy findings
A renal biopsy performed on day 6 revealed mesangial expansion, double contour of the glomerular basement membrane in most of the glomeruli and global sclerosis in 30% of the glomeruli (Fig. 1A). Tufts were segmentally ballooned and filled with eosinophilic materials, which were immunohistochemically positive for IgM and thought to be hyaline thrombi (Fig. 1B, C). Immunofluorescent staining was strongly positive for IgG, IgM, and C3 in the glomerular capillary loops. Kappa and lambda light chains were equally positive in the glomerular capillary loops. Electron microscopy revealed abundant electron-dense deposits in the subendothelial areas, with cylinder-like structures visible at high magnification (Fig. 1D, E). Based on these findings, we made a diagnosis of HCV-associated cryoglobulinemic glomerulonephritis.
Figure 1. Renal pathological findings. Double contour of glomerular basement membrane (arrow), mesangial interposition and endocapillary hypercellularity (arrowhead) were globally observed (periodic acid-methenamine-silver; PAM stain, original magnification ×200) (A). Hyaline thrombi (*) were also detected as immunohistochemically positive for IgM (B, C). Electron microscopy showed abundant electron-dense deposits in subendothelial areas (D) (scale bar 10 μm). High magnification of the area shown in the box revealed cylinder-like structures (E) (scale bar 1.0 μm).
Clinical course
The clinical course during the patient's hospitalization is shown in Fig. 2. On day 9, he became oliguric, and his serum creatinine level increased to 3.08 mg/dL. Simultaneous hemodialysis and cryofiltration were performed on days 9 and 10. Subsequently, cryofiltration was performed weekly. On day 16, based on the diagnosis of cryoglobulinemic glomerulonephritis, 30 mg of prednisolone was initiated. Subsequently, proteinuria decreased significantly, but marked hyperglycemia appeared, and the patient was started on insulin before every meal. On day 21, glecaprevir-pibrentasvir was started for HCV infection. Because massive proteinuria (around 4 g/gCr) and microscopic hematuria persisted, 500 mg of methylprednisolone (mPSL) was administered for 3 consecutive days starting on day 27, and 375 mg/m2 of weekly rituximab for 4 weeks was started after that. During the four weeks of rituximab administration, the dose of the oral steroid was tapered week by week. After oral mPSL was decreased to 8 mg, his proteinuria improved to 3.0 g/gCr, and his edema disappeared. HCV-RNA decreased to less than 1.2 LogIU/mL on day 49. He was discharged from our hospital on day 53.
Figure 2. The patient’s clinical course during hospitalization. Before the diagnosis with cryoglobulinemic glomerulonephritis, the patient needed hemodialysis twice. Cryofiltration was also performed. After the diagnosis, prednisolone, glecaprevir-pibrentasvir and rituximab were started on a weekly basis. Prednisolone was tapered early because of worsening hyperglycemia. On the 53rd day of hospitalization, he was discharged, although proteinuria persisted at around 3 g/gCr. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, GLE: glecaprevir, PIB: pibrentasvir
Shortly after discharge (Fig. 3), the patient's proteinuria increased to ＞8 g/gCr. A test for HCV-RNA reported undetectable levels, and glecaprevir-pibrentasvir was withdrawn after the eight-week treatment. We suspected that cryoglobulin had persisted in his body and was worsening his glomerulonephritis based on his persistent high levels of RF. To treat this, we performed plasma exchange (PE). Although PE removed more than 60% of his cryoglobulins, his RF level increased after PE, and complement C3 continued to be consumed. When mPSL was tapered to 6 mg at 2 months after discharge, proteinuria increased, and PE was performed again. Subsequently he was maintained on 8 mg of mPSL and his proteinuria gradually declined. Six months after discharge, a final session of PE was performed because of the increasing proteinuria and decreasing complement C3.
Figure 3. Long-term follow-up showing cryoglobulinemic hallmarks. Soon after discharge, proteinuria was exacerbated, but one session of plasma exchange relieved this symptom. Later, proteinuria had ameliorated, but the RF level had rebounded, and complement C3 was still being consumed. After the steroid dosage was decreased, proteinuria increased again. Accordingly, plasma exchange was performed again, and his mPSL dosage was increased, leading to decreased proteinuria. Although the patient's RF level remained high throughout the clinical course, the consumption of C3 was diminished, and proteinuria eventually fell to around 0.3 g/gCr. For details concerning the patient's clinical course during hospitalization, please see Figure 2 above. RF: rheumatoid factor, DAAs: direct-acting antiviral agents, PE: plasma exchange
Over the long-term, HCV-RNA remained undetectable throughout follow-up, and the CD20+ B-cell count was as low as 0.4% at 22 months after discharge, yet cryoglobulin remained at detectable levels, and the cryocrit remained at 4% at 25 months after discharge. Finally, 27 months after discharge, the patient remained on 6 mg of mPSL, and his RF levels were still ＞1,800 IU/mL, but his proteinuria had decreased to around 0.3 g/gCr, and he had never exhibited any symptoms of cryoglobulinemic vasculitis. His serum creatinine level at this time was stable around 1.6 mg/dL, as it was before the illness (Table).
Discussion
In the present case, cryoglobulinemia persisted, and glomerulonephritis appeared imminent despite treatment with rituximab, DAAs, a high-dose steroid and plasmapheresis. As the patient's proteinuria began to worsen, we continued low-dose steroid treatment and performed PE occasionally. Over the long term, his proteinuria gradually improved. Finally, the patient achieved remission for glomerulonephritis, although his cryoglobulinemia persisted.
Notably, this is a rare case of persistent cryoglobulinemia after B-cell depletion had been achieved and the virologic response had been maintained with rituximab and DAAs. There have been several previous reports of persistent cryoglobulinemia after HCV eradication by DAAs (10-13). These can be explained by the presence of persistent B-cell clones producing cryoglobulins after HCV eradication (10). Therefore, B-cell depletion therapy is needed to treat these cases of cryoglobulinemia. Rituximab is a B-cell-depleting monoclonal antibody targeting CD20 that is widely expressed among B-cell-lineage cells, except for plasmablasts and plasma cells. Thus, plasmablasts and plasma cells can still produce cryoglobulins after rituximab treatment until they are eradicated by other means. Indeed, in previous studies of HCV-associated cryoglobulinemic glomerulonephritis treated with rituximab, it took a few months for the RF and IgM levels to decrease after rituximab treatment (4,14). In the present case, however, the RF and IgM levels remained high, almost as high as they had been at the diagnosis, even 27 months after treatment. This persistent elevation of cryoglobulinemic hallmarks can be explained by the presence of long-lived plasma cells (LLPCs), which are observed in the bone marrow or spleens of patients with immune thrombocytopenia for up to six months following the start of rituximab treatment (15,16). LLPCs have special gene profiles that are programmed for long life and are characterized by CD19- CD38hi CD138+ cells by flow cytometry (17). We did not confirm the presence of LLPCs in our patient, but we speculate that LLPCs might have continued to produce the cryoglobulins that persisted in our patient.
Importantly, we should emphasize that this patient's cryoglobulinemic glomerulonephritis was successfully treated despite the persistence of cryoglobulinemia. We believe that occasional plasmapheresis after rituximab treatment, administered in response to worsening proteinuria or decreasing C3, was an effective means of controlling his glomerulonephritis. Plasmapheresis is generally effective in urgent, life-threatening cryoglobulinemia cases in advance of the initiation of fundamental treatment (1). However, we also consider it a reasonable means of removing cryoglobulins that may still be produced by LLPCs even after rituximab therapy. Indeed, there is one reported case in which long-term plasmapheresis after rituximab improved cutaneous lesions of cryoglobulinemia (18). Our case indicates that plasmapheresis after rituximab is also effective for cryoglobulinemic glomerulonephritis. We selected PE as the modality for plasmapheresis after rituximab in order to supply immunoglobulin at the same time. A variety of plasmapheresis protocols have been reported, and further studies will be needed in order to identify more effective protocols for conducting plasmapheresis in combination with rituximab.
In addition, continuous low-dose steroid administration after rituximab was effective for our patient. In previous reports, steroids were withdrawn early or avoided in rituximab protocols for cryoglobulinemia (4,14). In our case, however, when mPSL was tapered to 6 mg, glomerulonephritis deteriorated, so we continued 8 mg of mPSL for long-term maintenance. This may be due to the difference in the baseline activities of cryoglobulinemic glomerulonephritis between the previous report and our present case (proteinuria: previous report 2.3±2.1 g/day vs. our case 7.4 g/day; C3, previous report 125.7±60.8 mg/dL vs. our case 56.3 mg/dL) (14). As steroid is a conventional immunosuppressive agent, its effectiveness in treating cryoglobulinemia has long been recognized, and various mechanisms have been proposed. In the present case, we suspect a putative mechanism associated with complement C5 activation, which is reported to play a prominent role in the pathogenesis of cryoglobulinemic glomerulonephritis (19). Low-dose steroid can prevent complement C5 activation caused by cryoglobulins, which might have improved the cryoglobulinemic glomerulonephritis, although cryoglobulinemia was persistent. In addition, another putative mechanism of steroid is related to LLPCs, a special population of plasma cells which is mentioned above. LLPCs are reportedly surrounded by CD4+ T-cells, which are assumed to produce survival signals for LLPCs (20). Low-dose steroid can suppress CD4+ T-cell activities and LLPC proliferation, which might enhance the efficacy of rituximab. In this way, a low-dose steroid may be effective in combination with rituximab for suppressing C5 activation and LLPC proliferation, especially in patients with persistent cryoglobulinemia.
In conclusion, we described a case of the successful treatment of HCV-associated cryoglobulinemia with serologically persistent cryoglobulinemia using rituximab, DAAs, occasional plasmapheresis and a long-term steroid. When patients show persistent cryoglobulinemia after rituximab treatment, the presence of LLPCs should be considered. Occasional plasmapheresis is a reasonable treatment even after rituximab for such patients. Low-dose steroid administration can also suppress glomerulonephritis and improve the efficacy of rituximab, especially in patients with persistent cryoglobulinemia. Our ability to treat HCV-associated cryoglobulinemia is continuously improving through the emergence of new protocols for rituximab and DAA administration. Thus far, however, little evidence has been established for new treatments. Further investigations will be needed to establish an optimal regimen.
Author's disclosure of potential Conflicts of Interest (COI).
Motoko Yanagita: Honoraria, Kyowa Kirin and Chugai Pharmaceutical; Research funding, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim and Kyowa Kirin.
Acknowledgement
We thank Dr. Shinji Sumiyoshi (Department of Diagnostic Pathology, Kyoto University Hospital) for making the histological diagnosis and Dr. Nozomi Kubo and Dr. Shunsuke Takayanagi (Medical Intern, Kyoto University Hospital) for the immensely helpful clinical discussion.
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METHYLPREDNISOLONE, PREDNISOLONE
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DrugsGivenReaction
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CC BY-NC-ND
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32999232
| 19,870,219
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2021-02-15
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What is the weight of the patient?
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The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia.
Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.
Introduction
Cryoglobulins are immunoglobulins that aggregate at low temperatures both in vitro and in vivo. In the human body, temperatures below normal body temperature cause them to accumulate in various organs (1); this is a disease state known as cryoglobulinemia. The clinical manifestations of cryoglobulinemia are hyperviscosity syndrome and systemic vasculitis. Renal involvement is common and manifests as rapidly progressive glomerulonephritis with membranous proliferative glomerulonephritis as the characteristic histological finding (1). Decades ago, treatments for cryoglobulinemia were similar to those for other forms of systemic vasculitis; in 1991, however, it was shown that about 90% of cases of mixed cryoglobulinemia are associated with hepatitis C virus (HCV) infection (2) and that chronic HCV infection triggers B-cell expansion, which results in the production of cryoglobulins (3).
Rituximab was reported as an efficacious treatment in 2003 (4,5) and became the recommended immunosuppressive treatment for patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2018 (6). In addition, direct-acting antiviral agents (DAAs) have been used for the last decade to improve the clearance of HCV (7). Although these treatments are expected to improve the clinical outcomes of cryoglobulinemia, several cases of treatment failure or relapse after rituximab and DAAs have recently been reported (8,9).
We herein report a case of serologically persistent cryoglobulinemia in which glomerulonephritis was successfully treated with rituximab, DAAs, occasional plasmapheresis and long-term steroid.
Case Report
A 68-year-old man was referred to our nephrology department because of progressive renal insufficiency and proteinuria. He had been diagnosed with chronic hepatitis C in his teens but had not been treated for it. He had been diagnosed with diabetes mellitus at 55 years old. He had a history of myocardial infarction at 59 and 63 years old. In addition, one year previously, he had been hospitalized due to worsening depression. One month before the present admission, his serum creatinine level had increased from 1.61 to 2.11 mg/dL. At that time, he had noted bilateral leg edema. He was admitted to our hospital to investigate the cause of his worsening renal function and edema.
On admission, his height and weight were 160.7 cm and 61.7 kg, respectively. He did not notice any weight gain because he did not weigh himself regularly. His vital signs were as follows: blood pressure 153/89 mmHg, pulse 63 beats/min and temperature 36.3°C. A physical examination revealed bilateral leg pitting edema, no purpura, no cutaneous ulcer and no paresthesia, with otherwise normal findings. A complete blood count revealed a hemoglobin concentration of 8.8 g/dL. A laboratory examination showed aspartate aminotransferase of 44 U/L, alanine transaminase of 46 U/L, lactate dehydrogenase of 268 U/L, total protein of 5.0 g/dL, albumin of 2.3 g/dL, creatinine of 2.45 mg/dL and total cholesterol of 213 mg/dL (Table). Occult blood and proteinuria were positive on a urinalysis, and the 24-hour urinary protein excretion was 7.4 g/day. Hemoglobin A1c was 5.9%. Immunological tests revealed negative results for anti-nuclear antibody, anti-DNA antibody, proteinase-3 antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase ANCA and anti-glomerular basement membrane antibody. Cryoglobulins were detected through a qualitative analysis, and cryocrit was 5%. Immunoglobulin M (IgM) was elevated to 692 mg/dL (reference range: 27-205 mg/dL). Rheumatoid factor (RF) was also elevated to 2018 IU/mL (reference range: 0-15.0 IU/mL). Complements were suppressed, as follows: complement C3 at 56.3 mg/dL (reference range: 70.5-125.6 mg/dL) and complement C4 at 2.6 mg/dL (reference range: 10.6-33.0 mg/dL). A virologic test showed serotype 1 HCV RNA of 7.0 LogIU/mL.
Table. Laboratory Data on Admission, at Discharge and 27 Months after Discharge.
Laboratory test At diagnosis At discharge 27 months after discharge
Complete Blood Count
WBC (/µL) 6,990 6,010 11,970
RBC (/µL) 294 330 441
Hb (g/dL) 8.8 9.7 13.6
PLT (×104/µL) 20.5 28.4 32.1
Blood Chemistry
AST (U/L) 44 15 23
ALT (U/L) 46 11 23
LDH (U/L) 268 235 163
TP (g/dL) 5 5.2 6.7
Alb (g/dL) 2.3 3 4.1
CK (U/L) 102 28 53
BUN (mg/dL) 35 27 25
Cr (mg/dL) 2.45 2.34 1.66
eGFR (mL/min/1.73 m2) 21.7 22.8 32.9
T-CHO (mg/dL) 213 199 120
Na (mEq/L) 140 141 132
K (mEq/L) 3.8 5.2 4.1
Cl (mEq/L) 110 110 94
Ca (mg/dL) 7.7 8.4 9.5
P (mg/dL) 3.9 3.4 2.5
Mg (mg/dL) 2 2.7 2.2
Immunological Examination
CRP (mg/dL) 0.1 0.1> 0.1>
IgG (mg/dL) 600 449 792
IgA (mg/dL) 138 155 146
IgM (mg/dL) 692 445 479
C3 (mg/dL) 56.3 69.5 67.1
C4 (mg/dL) 2.6 2.7 2.8
CH50 (mg/dL) 10> 10> 16
RF (IU/mL) 2,018 1,727 1,832
HbA1c (%) 5.9 6.3
PR3-ANCA negative
MPO-ANCA negative
anti-nuclear antibody negative
anti-DNA antibody negative
anti-GBM antibody negative
Serum immunoelectrophoresis IgM-κ IgM-κ
Cryoglobulin positive positive positive
Cryocrit (%) 5 4 4
HCV RNA (LogIU/mL) 7 1.2> undetectable
Urinalysis
RBC (/HPF) 30-49 100< 5-9
proteinuria (g/gCr) 9.4 3 0.35
24-hour urinary protein excretion (g/day) 7.4
NAG (U/L) 54 9.9 13.4
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, TP: total protein, Alb: albumin, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, T-CHO: total cholesterol, Na: sodium, K: potasium, Cl: chlorine, Ca: calcium, P: phosphorus, Mg: magnesium, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM, immunoglobulin M, C3: complement component 3, C4: complement component 4, RF: rheumatoid factor, HbA1c: hemoglobin A1c, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-DNA antibody: anti-deoxyribonucleic acid antibody, anti-GBM antibody: anti-glomerular basement membrane antibody, HCV RNA: hepatitis C virus ribonucleic acid, NAG: N-acetyl-β-D-glucosaminidase
Based on these findings, the patient was diagnosed with rapidly progressive glomerulonephritis accompanied by nephrotic syndrome.
Renal biopsy findings
A renal biopsy performed on day 6 revealed mesangial expansion, double contour of the glomerular basement membrane in most of the glomeruli and global sclerosis in 30% of the glomeruli (Fig. 1A). Tufts were segmentally ballooned and filled with eosinophilic materials, which were immunohistochemically positive for IgM and thought to be hyaline thrombi (Fig. 1B, C). Immunofluorescent staining was strongly positive for IgG, IgM, and C3 in the glomerular capillary loops. Kappa and lambda light chains were equally positive in the glomerular capillary loops. Electron microscopy revealed abundant electron-dense deposits in the subendothelial areas, with cylinder-like structures visible at high magnification (Fig. 1D, E). Based on these findings, we made a diagnosis of HCV-associated cryoglobulinemic glomerulonephritis.
Figure 1. Renal pathological findings. Double contour of glomerular basement membrane (arrow), mesangial interposition and endocapillary hypercellularity (arrowhead) were globally observed (periodic acid-methenamine-silver; PAM stain, original magnification ×200) (A). Hyaline thrombi (*) were also detected as immunohistochemically positive for IgM (B, C). Electron microscopy showed abundant electron-dense deposits in subendothelial areas (D) (scale bar 10 μm). High magnification of the area shown in the box revealed cylinder-like structures (E) (scale bar 1.0 μm).
Clinical course
The clinical course during the patient's hospitalization is shown in Fig. 2. On day 9, he became oliguric, and his serum creatinine level increased to 3.08 mg/dL. Simultaneous hemodialysis and cryofiltration were performed on days 9 and 10. Subsequently, cryofiltration was performed weekly. On day 16, based on the diagnosis of cryoglobulinemic glomerulonephritis, 30 mg of prednisolone was initiated. Subsequently, proteinuria decreased significantly, but marked hyperglycemia appeared, and the patient was started on insulin before every meal. On day 21, glecaprevir-pibrentasvir was started for HCV infection. Because massive proteinuria (around 4 g/gCr) and microscopic hematuria persisted, 500 mg of methylprednisolone (mPSL) was administered for 3 consecutive days starting on day 27, and 375 mg/m2 of weekly rituximab for 4 weeks was started after that. During the four weeks of rituximab administration, the dose of the oral steroid was tapered week by week. After oral mPSL was decreased to 8 mg, his proteinuria improved to 3.0 g/gCr, and his edema disappeared. HCV-RNA decreased to less than 1.2 LogIU/mL on day 49. He was discharged from our hospital on day 53.
Figure 2. The patient’s clinical course during hospitalization. Before the diagnosis with cryoglobulinemic glomerulonephritis, the patient needed hemodialysis twice. Cryofiltration was also performed. After the diagnosis, prednisolone, glecaprevir-pibrentasvir and rituximab were started on a weekly basis. Prednisolone was tapered early because of worsening hyperglycemia. On the 53rd day of hospitalization, he was discharged, although proteinuria persisted at around 3 g/gCr. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, GLE: glecaprevir, PIB: pibrentasvir
Shortly after discharge (Fig. 3), the patient's proteinuria increased to ＞8 g/gCr. A test for HCV-RNA reported undetectable levels, and glecaprevir-pibrentasvir was withdrawn after the eight-week treatment. We suspected that cryoglobulin had persisted in his body and was worsening his glomerulonephritis based on his persistent high levels of RF. To treat this, we performed plasma exchange (PE). Although PE removed more than 60% of his cryoglobulins, his RF level increased after PE, and complement C3 continued to be consumed. When mPSL was tapered to 6 mg at 2 months after discharge, proteinuria increased, and PE was performed again. Subsequently he was maintained on 8 mg of mPSL and his proteinuria gradually declined. Six months after discharge, a final session of PE was performed because of the increasing proteinuria and decreasing complement C3.
Figure 3. Long-term follow-up showing cryoglobulinemic hallmarks. Soon after discharge, proteinuria was exacerbated, but one session of plasma exchange relieved this symptom. Later, proteinuria had ameliorated, but the RF level had rebounded, and complement C3 was still being consumed. After the steroid dosage was decreased, proteinuria increased again. Accordingly, plasma exchange was performed again, and his mPSL dosage was increased, leading to decreased proteinuria. Although the patient's RF level remained high throughout the clinical course, the consumption of C3 was diminished, and proteinuria eventually fell to around 0.3 g/gCr. For details concerning the patient's clinical course during hospitalization, please see Figure 2 above. RF: rheumatoid factor, DAAs: direct-acting antiviral agents, PE: plasma exchange
Over the long-term, HCV-RNA remained undetectable throughout follow-up, and the CD20+ B-cell count was as low as 0.4% at 22 months after discharge, yet cryoglobulin remained at detectable levels, and the cryocrit remained at 4% at 25 months after discharge. Finally, 27 months after discharge, the patient remained on 6 mg of mPSL, and his RF levels were still ＞1,800 IU/mL, but his proteinuria had decreased to around 0.3 g/gCr, and he had never exhibited any symptoms of cryoglobulinemic vasculitis. His serum creatinine level at this time was stable around 1.6 mg/dL, as it was before the illness (Table).
Discussion
In the present case, cryoglobulinemia persisted, and glomerulonephritis appeared imminent despite treatment with rituximab, DAAs, a high-dose steroid and plasmapheresis. As the patient's proteinuria began to worsen, we continued low-dose steroid treatment and performed PE occasionally. Over the long term, his proteinuria gradually improved. Finally, the patient achieved remission for glomerulonephritis, although his cryoglobulinemia persisted.
Notably, this is a rare case of persistent cryoglobulinemia after B-cell depletion had been achieved and the virologic response had been maintained with rituximab and DAAs. There have been several previous reports of persistent cryoglobulinemia after HCV eradication by DAAs (10-13). These can be explained by the presence of persistent B-cell clones producing cryoglobulins after HCV eradication (10). Therefore, B-cell depletion therapy is needed to treat these cases of cryoglobulinemia. Rituximab is a B-cell-depleting monoclonal antibody targeting CD20 that is widely expressed among B-cell-lineage cells, except for plasmablasts and plasma cells. Thus, plasmablasts and plasma cells can still produce cryoglobulins after rituximab treatment until they are eradicated by other means. Indeed, in previous studies of HCV-associated cryoglobulinemic glomerulonephritis treated with rituximab, it took a few months for the RF and IgM levels to decrease after rituximab treatment (4,14). In the present case, however, the RF and IgM levels remained high, almost as high as they had been at the diagnosis, even 27 months after treatment. This persistent elevation of cryoglobulinemic hallmarks can be explained by the presence of long-lived plasma cells (LLPCs), which are observed in the bone marrow or spleens of patients with immune thrombocytopenia for up to six months following the start of rituximab treatment (15,16). LLPCs have special gene profiles that are programmed for long life and are characterized by CD19- CD38hi CD138+ cells by flow cytometry (17). We did not confirm the presence of LLPCs in our patient, but we speculate that LLPCs might have continued to produce the cryoglobulins that persisted in our patient.
Importantly, we should emphasize that this patient's cryoglobulinemic glomerulonephritis was successfully treated despite the persistence of cryoglobulinemia. We believe that occasional plasmapheresis after rituximab treatment, administered in response to worsening proteinuria or decreasing C3, was an effective means of controlling his glomerulonephritis. Plasmapheresis is generally effective in urgent, life-threatening cryoglobulinemia cases in advance of the initiation of fundamental treatment (1). However, we also consider it a reasonable means of removing cryoglobulins that may still be produced by LLPCs even after rituximab therapy. Indeed, there is one reported case in which long-term plasmapheresis after rituximab improved cutaneous lesions of cryoglobulinemia (18). Our case indicates that plasmapheresis after rituximab is also effective for cryoglobulinemic glomerulonephritis. We selected PE as the modality for plasmapheresis after rituximab in order to supply immunoglobulin at the same time. A variety of plasmapheresis protocols have been reported, and further studies will be needed in order to identify more effective protocols for conducting plasmapheresis in combination with rituximab.
In addition, continuous low-dose steroid administration after rituximab was effective for our patient. In previous reports, steroids were withdrawn early or avoided in rituximab protocols for cryoglobulinemia (4,14). In our case, however, when mPSL was tapered to 6 mg, glomerulonephritis deteriorated, so we continued 8 mg of mPSL for long-term maintenance. This may be due to the difference in the baseline activities of cryoglobulinemic glomerulonephritis between the previous report and our present case (proteinuria: previous report 2.3±2.1 g/day vs. our case 7.4 g/day; C3, previous report 125.7±60.8 mg/dL vs. our case 56.3 mg/dL) (14). As steroid is a conventional immunosuppressive agent, its effectiveness in treating cryoglobulinemia has long been recognized, and various mechanisms have been proposed. In the present case, we suspect a putative mechanism associated with complement C5 activation, which is reported to play a prominent role in the pathogenesis of cryoglobulinemic glomerulonephritis (19). Low-dose steroid can prevent complement C5 activation caused by cryoglobulins, which might have improved the cryoglobulinemic glomerulonephritis, although cryoglobulinemia was persistent. In addition, another putative mechanism of steroid is related to LLPCs, a special population of plasma cells which is mentioned above. LLPCs are reportedly surrounded by CD4+ T-cells, which are assumed to produce survival signals for LLPCs (20). Low-dose steroid can suppress CD4+ T-cell activities and LLPC proliferation, which might enhance the efficacy of rituximab. In this way, a low-dose steroid may be effective in combination with rituximab for suppressing C5 activation and LLPC proliferation, especially in patients with persistent cryoglobulinemia.
In conclusion, we described a case of the successful treatment of HCV-associated cryoglobulinemia with serologically persistent cryoglobulinemia using rituximab, DAAs, occasional plasmapheresis and a long-term steroid. When patients show persistent cryoglobulinemia after rituximab treatment, the presence of LLPCs should be considered. Occasional plasmapheresis is a reasonable treatment even after rituximab for such patients. Low-dose steroid administration can also suppress glomerulonephritis and improve the efficacy of rituximab, especially in patients with persistent cryoglobulinemia. Our ability to treat HCV-associated cryoglobulinemia is continuously improving through the emergence of new protocols for rituximab and DAA administration. Thus far, however, little evidence has been established for new treatments. Further investigations will be needed to establish an optimal regimen.
Author's disclosure of potential Conflicts of Interest (COI).
Motoko Yanagita: Honoraria, Kyowa Kirin and Chugai Pharmaceutical; Research funding, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim and Kyowa Kirin.
Acknowledgement
We thank Dr. Shinji Sumiyoshi (Department of Diagnostic Pathology, Kyoto University Hospital) for making the histological diagnosis and Dr. Nozomi Kubo and Dr. Shunsuke Takayanagi (Medical Intern, Kyoto University Hospital) for the immensely helpful clinical discussion.
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61.7 kg.
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Weight
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CC BY-NC-ND
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32999232
| 19,870,219
|
2021-02-15
|
What was the administration route of drug 'METHYLPREDNISOLONE'?
|
The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia.
Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.
Introduction
Cryoglobulins are immunoglobulins that aggregate at low temperatures both in vitro and in vivo. In the human body, temperatures below normal body temperature cause them to accumulate in various organs (1); this is a disease state known as cryoglobulinemia. The clinical manifestations of cryoglobulinemia are hyperviscosity syndrome and systemic vasculitis. Renal involvement is common and manifests as rapidly progressive glomerulonephritis with membranous proliferative glomerulonephritis as the characteristic histological finding (1). Decades ago, treatments for cryoglobulinemia were similar to those for other forms of systemic vasculitis; in 1991, however, it was shown that about 90% of cases of mixed cryoglobulinemia are associated with hepatitis C virus (HCV) infection (2) and that chronic HCV infection triggers B-cell expansion, which results in the production of cryoglobulins (3).
Rituximab was reported as an efficacious treatment in 2003 (4,5) and became the recommended immunosuppressive treatment for patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2018 (6). In addition, direct-acting antiviral agents (DAAs) have been used for the last decade to improve the clearance of HCV (7). Although these treatments are expected to improve the clinical outcomes of cryoglobulinemia, several cases of treatment failure or relapse after rituximab and DAAs have recently been reported (8,9).
We herein report a case of serologically persistent cryoglobulinemia in which glomerulonephritis was successfully treated with rituximab, DAAs, occasional plasmapheresis and long-term steroid.
Case Report
A 68-year-old man was referred to our nephrology department because of progressive renal insufficiency and proteinuria. He had been diagnosed with chronic hepatitis C in his teens but had not been treated for it. He had been diagnosed with diabetes mellitus at 55 years old. He had a history of myocardial infarction at 59 and 63 years old. In addition, one year previously, he had been hospitalized due to worsening depression. One month before the present admission, his serum creatinine level had increased from 1.61 to 2.11 mg/dL. At that time, he had noted bilateral leg edema. He was admitted to our hospital to investigate the cause of his worsening renal function and edema.
On admission, his height and weight were 160.7 cm and 61.7 kg, respectively. He did not notice any weight gain because he did not weigh himself regularly. His vital signs were as follows: blood pressure 153/89 mmHg, pulse 63 beats/min and temperature 36.3°C. A physical examination revealed bilateral leg pitting edema, no purpura, no cutaneous ulcer and no paresthesia, with otherwise normal findings. A complete blood count revealed a hemoglobin concentration of 8.8 g/dL. A laboratory examination showed aspartate aminotransferase of 44 U/L, alanine transaminase of 46 U/L, lactate dehydrogenase of 268 U/L, total protein of 5.0 g/dL, albumin of 2.3 g/dL, creatinine of 2.45 mg/dL and total cholesterol of 213 mg/dL (Table). Occult blood and proteinuria were positive on a urinalysis, and the 24-hour urinary protein excretion was 7.4 g/day. Hemoglobin A1c was 5.9%. Immunological tests revealed negative results for anti-nuclear antibody, anti-DNA antibody, proteinase-3 antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase ANCA and anti-glomerular basement membrane antibody. Cryoglobulins were detected through a qualitative analysis, and cryocrit was 5%. Immunoglobulin M (IgM) was elevated to 692 mg/dL (reference range: 27-205 mg/dL). Rheumatoid factor (RF) was also elevated to 2018 IU/mL (reference range: 0-15.0 IU/mL). Complements were suppressed, as follows: complement C3 at 56.3 mg/dL (reference range: 70.5-125.6 mg/dL) and complement C4 at 2.6 mg/dL (reference range: 10.6-33.0 mg/dL). A virologic test showed serotype 1 HCV RNA of 7.0 LogIU/mL.
Table. Laboratory Data on Admission, at Discharge and 27 Months after Discharge.
Laboratory test At diagnosis At discharge 27 months after discharge
Complete Blood Count
WBC (/µL) 6,990 6,010 11,970
RBC (/µL) 294 330 441
Hb (g/dL) 8.8 9.7 13.6
PLT (×104/µL) 20.5 28.4 32.1
Blood Chemistry
AST (U/L) 44 15 23
ALT (U/L) 46 11 23
LDH (U/L) 268 235 163
TP (g/dL) 5 5.2 6.7
Alb (g/dL) 2.3 3 4.1
CK (U/L) 102 28 53
BUN (mg/dL) 35 27 25
Cr (mg/dL) 2.45 2.34 1.66
eGFR (mL/min/1.73 m2) 21.7 22.8 32.9
T-CHO (mg/dL) 213 199 120
Na (mEq/L) 140 141 132
K (mEq/L) 3.8 5.2 4.1
Cl (mEq/L) 110 110 94
Ca (mg/dL) 7.7 8.4 9.5
P (mg/dL) 3.9 3.4 2.5
Mg (mg/dL) 2 2.7 2.2
Immunological Examination
CRP (mg/dL) 0.1 0.1> 0.1>
IgG (mg/dL) 600 449 792
IgA (mg/dL) 138 155 146
IgM (mg/dL) 692 445 479
C3 (mg/dL) 56.3 69.5 67.1
C4 (mg/dL) 2.6 2.7 2.8
CH50 (mg/dL) 10> 10> 16
RF (IU/mL) 2,018 1,727 1,832
HbA1c (%) 5.9 6.3
PR3-ANCA negative
MPO-ANCA negative
anti-nuclear antibody negative
anti-DNA antibody negative
anti-GBM antibody negative
Serum immunoelectrophoresis IgM-κ IgM-κ
Cryoglobulin positive positive positive
Cryocrit (%) 5 4 4
HCV RNA (LogIU/mL) 7 1.2> undetectable
Urinalysis
RBC (/HPF) 30-49 100< 5-9
proteinuria (g/gCr) 9.4 3 0.35
24-hour urinary protein excretion (g/day) 7.4
NAG (U/L) 54 9.9 13.4
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, TP: total protein, Alb: albumin, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, T-CHO: total cholesterol, Na: sodium, K: potasium, Cl: chlorine, Ca: calcium, P: phosphorus, Mg: magnesium, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM, immunoglobulin M, C3: complement component 3, C4: complement component 4, RF: rheumatoid factor, HbA1c: hemoglobin A1c, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-DNA antibody: anti-deoxyribonucleic acid antibody, anti-GBM antibody: anti-glomerular basement membrane antibody, HCV RNA: hepatitis C virus ribonucleic acid, NAG: N-acetyl-β-D-glucosaminidase
Based on these findings, the patient was diagnosed with rapidly progressive glomerulonephritis accompanied by nephrotic syndrome.
Renal biopsy findings
A renal biopsy performed on day 6 revealed mesangial expansion, double contour of the glomerular basement membrane in most of the glomeruli and global sclerosis in 30% of the glomeruli (Fig. 1A). Tufts were segmentally ballooned and filled with eosinophilic materials, which were immunohistochemically positive for IgM and thought to be hyaline thrombi (Fig. 1B, C). Immunofluorescent staining was strongly positive for IgG, IgM, and C3 in the glomerular capillary loops. Kappa and lambda light chains were equally positive in the glomerular capillary loops. Electron microscopy revealed abundant electron-dense deposits in the subendothelial areas, with cylinder-like structures visible at high magnification (Fig. 1D, E). Based on these findings, we made a diagnosis of HCV-associated cryoglobulinemic glomerulonephritis.
Figure 1. Renal pathological findings. Double contour of glomerular basement membrane (arrow), mesangial interposition and endocapillary hypercellularity (arrowhead) were globally observed (periodic acid-methenamine-silver; PAM stain, original magnification ×200) (A). Hyaline thrombi (*) were also detected as immunohistochemically positive for IgM (B, C). Electron microscopy showed abundant electron-dense deposits in subendothelial areas (D) (scale bar 10 μm). High magnification of the area shown in the box revealed cylinder-like structures (E) (scale bar 1.0 μm).
Clinical course
The clinical course during the patient's hospitalization is shown in Fig. 2. On day 9, he became oliguric, and his serum creatinine level increased to 3.08 mg/dL. Simultaneous hemodialysis and cryofiltration were performed on days 9 and 10. Subsequently, cryofiltration was performed weekly. On day 16, based on the diagnosis of cryoglobulinemic glomerulonephritis, 30 mg of prednisolone was initiated. Subsequently, proteinuria decreased significantly, but marked hyperglycemia appeared, and the patient was started on insulin before every meal. On day 21, glecaprevir-pibrentasvir was started for HCV infection. Because massive proteinuria (around 4 g/gCr) and microscopic hematuria persisted, 500 mg of methylprednisolone (mPSL) was administered for 3 consecutive days starting on day 27, and 375 mg/m2 of weekly rituximab for 4 weeks was started after that. During the four weeks of rituximab administration, the dose of the oral steroid was tapered week by week. After oral mPSL was decreased to 8 mg, his proteinuria improved to 3.0 g/gCr, and his edema disappeared. HCV-RNA decreased to less than 1.2 LogIU/mL on day 49. He was discharged from our hospital on day 53.
Figure 2. The patient’s clinical course during hospitalization. Before the diagnosis with cryoglobulinemic glomerulonephritis, the patient needed hemodialysis twice. Cryofiltration was also performed. After the diagnosis, prednisolone, glecaprevir-pibrentasvir and rituximab were started on a weekly basis. Prednisolone was tapered early because of worsening hyperglycemia. On the 53rd day of hospitalization, he was discharged, although proteinuria persisted at around 3 g/gCr. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, GLE: glecaprevir, PIB: pibrentasvir
Shortly after discharge (Fig. 3), the patient's proteinuria increased to ＞8 g/gCr. A test for HCV-RNA reported undetectable levels, and glecaprevir-pibrentasvir was withdrawn after the eight-week treatment. We suspected that cryoglobulin had persisted in his body and was worsening his glomerulonephritis based on his persistent high levels of RF. To treat this, we performed plasma exchange (PE). Although PE removed more than 60% of his cryoglobulins, his RF level increased after PE, and complement C3 continued to be consumed. When mPSL was tapered to 6 mg at 2 months after discharge, proteinuria increased, and PE was performed again. Subsequently he was maintained on 8 mg of mPSL and his proteinuria gradually declined. Six months after discharge, a final session of PE was performed because of the increasing proteinuria and decreasing complement C3.
Figure 3. Long-term follow-up showing cryoglobulinemic hallmarks. Soon after discharge, proteinuria was exacerbated, but one session of plasma exchange relieved this symptom. Later, proteinuria had ameliorated, but the RF level had rebounded, and complement C3 was still being consumed. After the steroid dosage was decreased, proteinuria increased again. Accordingly, plasma exchange was performed again, and his mPSL dosage was increased, leading to decreased proteinuria. Although the patient's RF level remained high throughout the clinical course, the consumption of C3 was diminished, and proteinuria eventually fell to around 0.3 g/gCr. For details concerning the patient's clinical course during hospitalization, please see Figure 2 above. RF: rheumatoid factor, DAAs: direct-acting antiviral agents, PE: plasma exchange
Over the long-term, HCV-RNA remained undetectable throughout follow-up, and the CD20+ B-cell count was as low as 0.4% at 22 months after discharge, yet cryoglobulin remained at detectable levels, and the cryocrit remained at 4% at 25 months after discharge. Finally, 27 months after discharge, the patient remained on 6 mg of mPSL, and his RF levels were still ＞1,800 IU/mL, but his proteinuria had decreased to around 0.3 g/gCr, and he had never exhibited any symptoms of cryoglobulinemic vasculitis. His serum creatinine level at this time was stable around 1.6 mg/dL, as it was before the illness (Table).
Discussion
In the present case, cryoglobulinemia persisted, and glomerulonephritis appeared imminent despite treatment with rituximab, DAAs, a high-dose steroid and plasmapheresis. As the patient's proteinuria began to worsen, we continued low-dose steroid treatment and performed PE occasionally. Over the long term, his proteinuria gradually improved. Finally, the patient achieved remission for glomerulonephritis, although his cryoglobulinemia persisted.
Notably, this is a rare case of persistent cryoglobulinemia after B-cell depletion had been achieved and the virologic response had been maintained with rituximab and DAAs. There have been several previous reports of persistent cryoglobulinemia after HCV eradication by DAAs (10-13). These can be explained by the presence of persistent B-cell clones producing cryoglobulins after HCV eradication (10). Therefore, B-cell depletion therapy is needed to treat these cases of cryoglobulinemia. Rituximab is a B-cell-depleting monoclonal antibody targeting CD20 that is widely expressed among B-cell-lineage cells, except for plasmablasts and plasma cells. Thus, plasmablasts and plasma cells can still produce cryoglobulins after rituximab treatment until they are eradicated by other means. Indeed, in previous studies of HCV-associated cryoglobulinemic glomerulonephritis treated with rituximab, it took a few months for the RF and IgM levels to decrease after rituximab treatment (4,14). In the present case, however, the RF and IgM levels remained high, almost as high as they had been at the diagnosis, even 27 months after treatment. This persistent elevation of cryoglobulinemic hallmarks can be explained by the presence of long-lived plasma cells (LLPCs), which are observed in the bone marrow or spleens of patients with immune thrombocytopenia for up to six months following the start of rituximab treatment (15,16). LLPCs have special gene profiles that are programmed for long life and are characterized by CD19- CD38hi CD138+ cells by flow cytometry (17). We did not confirm the presence of LLPCs in our patient, but we speculate that LLPCs might have continued to produce the cryoglobulins that persisted in our patient.
Importantly, we should emphasize that this patient's cryoglobulinemic glomerulonephritis was successfully treated despite the persistence of cryoglobulinemia. We believe that occasional plasmapheresis after rituximab treatment, administered in response to worsening proteinuria or decreasing C3, was an effective means of controlling his glomerulonephritis. Plasmapheresis is generally effective in urgent, life-threatening cryoglobulinemia cases in advance of the initiation of fundamental treatment (1). However, we also consider it a reasonable means of removing cryoglobulins that may still be produced by LLPCs even after rituximab therapy. Indeed, there is one reported case in which long-term plasmapheresis after rituximab improved cutaneous lesions of cryoglobulinemia (18). Our case indicates that plasmapheresis after rituximab is also effective for cryoglobulinemic glomerulonephritis. We selected PE as the modality for plasmapheresis after rituximab in order to supply immunoglobulin at the same time. A variety of plasmapheresis protocols have been reported, and further studies will be needed in order to identify more effective protocols for conducting plasmapheresis in combination with rituximab.
In addition, continuous low-dose steroid administration after rituximab was effective for our patient. In previous reports, steroids were withdrawn early or avoided in rituximab protocols for cryoglobulinemia (4,14). In our case, however, when mPSL was tapered to 6 mg, glomerulonephritis deteriorated, so we continued 8 mg of mPSL for long-term maintenance. This may be due to the difference in the baseline activities of cryoglobulinemic glomerulonephritis between the previous report and our present case (proteinuria: previous report 2.3±2.1 g/day vs. our case 7.4 g/day; C3, previous report 125.7±60.8 mg/dL vs. our case 56.3 mg/dL) (14). As steroid is a conventional immunosuppressive agent, its effectiveness in treating cryoglobulinemia has long been recognized, and various mechanisms have been proposed. In the present case, we suspect a putative mechanism associated with complement C5 activation, which is reported to play a prominent role in the pathogenesis of cryoglobulinemic glomerulonephritis (19). Low-dose steroid can prevent complement C5 activation caused by cryoglobulins, which might have improved the cryoglobulinemic glomerulonephritis, although cryoglobulinemia was persistent. In addition, another putative mechanism of steroid is related to LLPCs, a special population of plasma cells which is mentioned above. LLPCs are reportedly surrounded by CD4+ T-cells, which are assumed to produce survival signals for LLPCs (20). Low-dose steroid can suppress CD4+ T-cell activities and LLPC proliferation, which might enhance the efficacy of rituximab. In this way, a low-dose steroid may be effective in combination with rituximab for suppressing C5 activation and LLPC proliferation, especially in patients with persistent cryoglobulinemia.
In conclusion, we described a case of the successful treatment of HCV-associated cryoglobulinemia with serologically persistent cryoglobulinemia using rituximab, DAAs, occasional plasmapheresis and a long-term steroid. When patients show persistent cryoglobulinemia after rituximab treatment, the presence of LLPCs should be considered. Occasional plasmapheresis is a reasonable treatment even after rituximab for such patients. Low-dose steroid administration can also suppress glomerulonephritis and improve the efficacy of rituximab, especially in patients with persistent cryoglobulinemia. Our ability to treat HCV-associated cryoglobulinemia is continuously improving through the emergence of new protocols for rituximab and DAA administration. Thus far, however, little evidence has been established for new treatments. Further investigations will be needed to establish an optimal regimen.
Author's disclosure of potential Conflicts of Interest (COI).
Motoko Yanagita: Honoraria, Kyowa Kirin and Chugai Pharmaceutical; Research funding, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim and Kyowa Kirin.
Acknowledgement
We thank Dr. Shinji Sumiyoshi (Department of Diagnostic Pathology, Kyoto University Hospital) for making the histological diagnosis and Dr. Nozomi Kubo and Dr. Shunsuke Takayanagi (Medical Intern, Kyoto University Hospital) for the immensely helpful clinical discussion.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
32999232
| 19,870,219
|
2021-02-15
|
What was the administration route of drug 'PREDNISOLONE'?
|
The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia.
Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.
Introduction
Cryoglobulins are immunoglobulins that aggregate at low temperatures both in vitro and in vivo. In the human body, temperatures below normal body temperature cause them to accumulate in various organs (1); this is a disease state known as cryoglobulinemia. The clinical manifestations of cryoglobulinemia are hyperviscosity syndrome and systemic vasculitis. Renal involvement is common and manifests as rapidly progressive glomerulonephritis with membranous proliferative glomerulonephritis as the characteristic histological finding (1). Decades ago, treatments for cryoglobulinemia were similar to those for other forms of systemic vasculitis; in 1991, however, it was shown that about 90% of cases of mixed cryoglobulinemia are associated with hepatitis C virus (HCV) infection (2) and that chronic HCV infection triggers B-cell expansion, which results in the production of cryoglobulins (3).
Rituximab was reported as an efficacious treatment in 2003 (4,5) and became the recommended immunosuppressive treatment for patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2018 (6). In addition, direct-acting antiviral agents (DAAs) have been used for the last decade to improve the clearance of HCV (7). Although these treatments are expected to improve the clinical outcomes of cryoglobulinemia, several cases of treatment failure or relapse after rituximab and DAAs have recently been reported (8,9).
We herein report a case of serologically persistent cryoglobulinemia in which glomerulonephritis was successfully treated with rituximab, DAAs, occasional plasmapheresis and long-term steroid.
Case Report
A 68-year-old man was referred to our nephrology department because of progressive renal insufficiency and proteinuria. He had been diagnosed with chronic hepatitis C in his teens but had not been treated for it. He had been diagnosed with diabetes mellitus at 55 years old. He had a history of myocardial infarction at 59 and 63 years old. In addition, one year previously, he had been hospitalized due to worsening depression. One month before the present admission, his serum creatinine level had increased from 1.61 to 2.11 mg/dL. At that time, he had noted bilateral leg edema. He was admitted to our hospital to investigate the cause of his worsening renal function and edema.
On admission, his height and weight were 160.7 cm and 61.7 kg, respectively. He did not notice any weight gain because he did not weigh himself regularly. His vital signs were as follows: blood pressure 153/89 mmHg, pulse 63 beats/min and temperature 36.3°C. A physical examination revealed bilateral leg pitting edema, no purpura, no cutaneous ulcer and no paresthesia, with otherwise normal findings. A complete blood count revealed a hemoglobin concentration of 8.8 g/dL. A laboratory examination showed aspartate aminotransferase of 44 U/L, alanine transaminase of 46 U/L, lactate dehydrogenase of 268 U/L, total protein of 5.0 g/dL, albumin of 2.3 g/dL, creatinine of 2.45 mg/dL and total cholesterol of 213 mg/dL (Table). Occult blood and proteinuria were positive on a urinalysis, and the 24-hour urinary protein excretion was 7.4 g/day. Hemoglobin A1c was 5.9%. Immunological tests revealed negative results for anti-nuclear antibody, anti-DNA antibody, proteinase-3 antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase ANCA and anti-glomerular basement membrane antibody. Cryoglobulins were detected through a qualitative analysis, and cryocrit was 5%. Immunoglobulin M (IgM) was elevated to 692 mg/dL (reference range: 27-205 mg/dL). Rheumatoid factor (RF) was also elevated to 2018 IU/mL (reference range: 0-15.0 IU/mL). Complements were suppressed, as follows: complement C3 at 56.3 mg/dL (reference range: 70.5-125.6 mg/dL) and complement C4 at 2.6 mg/dL (reference range: 10.6-33.0 mg/dL). A virologic test showed serotype 1 HCV RNA of 7.0 LogIU/mL.
Table. Laboratory Data on Admission, at Discharge and 27 Months after Discharge.
Laboratory test At diagnosis At discharge 27 months after discharge
Complete Blood Count
WBC (/µL) 6,990 6,010 11,970
RBC (/µL) 294 330 441
Hb (g/dL) 8.8 9.7 13.6
PLT (×104/µL) 20.5 28.4 32.1
Blood Chemistry
AST (U/L) 44 15 23
ALT (U/L) 46 11 23
LDH (U/L) 268 235 163
TP (g/dL) 5 5.2 6.7
Alb (g/dL) 2.3 3 4.1
CK (U/L) 102 28 53
BUN (mg/dL) 35 27 25
Cr (mg/dL) 2.45 2.34 1.66
eGFR (mL/min/1.73 m2) 21.7 22.8 32.9
T-CHO (mg/dL) 213 199 120
Na (mEq/L) 140 141 132
K (mEq/L) 3.8 5.2 4.1
Cl (mEq/L) 110 110 94
Ca (mg/dL) 7.7 8.4 9.5
P (mg/dL) 3.9 3.4 2.5
Mg (mg/dL) 2 2.7 2.2
Immunological Examination
CRP (mg/dL) 0.1 0.1> 0.1>
IgG (mg/dL) 600 449 792
IgA (mg/dL) 138 155 146
IgM (mg/dL) 692 445 479
C3 (mg/dL) 56.3 69.5 67.1
C4 (mg/dL) 2.6 2.7 2.8
CH50 (mg/dL) 10> 10> 16
RF (IU/mL) 2,018 1,727 1,832
HbA1c (%) 5.9 6.3
PR3-ANCA negative
MPO-ANCA negative
anti-nuclear antibody negative
anti-DNA antibody negative
anti-GBM antibody negative
Serum immunoelectrophoresis IgM-κ IgM-κ
Cryoglobulin positive positive positive
Cryocrit (%) 5 4 4
HCV RNA (LogIU/mL) 7 1.2> undetectable
Urinalysis
RBC (/HPF) 30-49 100< 5-9
proteinuria (g/gCr) 9.4 3 0.35
24-hour urinary protein excretion (g/day) 7.4
NAG (U/L) 54 9.9 13.4
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, TP: total protein, Alb: albumin, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, T-CHO: total cholesterol, Na: sodium, K: potasium, Cl: chlorine, Ca: calcium, P: phosphorus, Mg: magnesium, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM, immunoglobulin M, C3: complement component 3, C4: complement component 4, RF: rheumatoid factor, HbA1c: hemoglobin A1c, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-DNA antibody: anti-deoxyribonucleic acid antibody, anti-GBM antibody: anti-glomerular basement membrane antibody, HCV RNA: hepatitis C virus ribonucleic acid, NAG: N-acetyl-β-D-glucosaminidase
Based on these findings, the patient was diagnosed with rapidly progressive glomerulonephritis accompanied by nephrotic syndrome.
Renal biopsy findings
A renal biopsy performed on day 6 revealed mesangial expansion, double contour of the glomerular basement membrane in most of the glomeruli and global sclerosis in 30% of the glomeruli (Fig. 1A). Tufts were segmentally ballooned and filled with eosinophilic materials, which were immunohistochemically positive for IgM and thought to be hyaline thrombi (Fig. 1B, C). Immunofluorescent staining was strongly positive for IgG, IgM, and C3 in the glomerular capillary loops. Kappa and lambda light chains were equally positive in the glomerular capillary loops. Electron microscopy revealed abundant electron-dense deposits in the subendothelial areas, with cylinder-like structures visible at high magnification (Fig. 1D, E). Based on these findings, we made a diagnosis of HCV-associated cryoglobulinemic glomerulonephritis.
Figure 1. Renal pathological findings. Double contour of glomerular basement membrane (arrow), mesangial interposition and endocapillary hypercellularity (arrowhead) were globally observed (periodic acid-methenamine-silver; PAM stain, original magnification ×200) (A). Hyaline thrombi (*) were also detected as immunohistochemically positive for IgM (B, C). Electron microscopy showed abundant electron-dense deposits in subendothelial areas (D) (scale bar 10 μm). High magnification of the area shown in the box revealed cylinder-like structures (E) (scale bar 1.0 μm).
Clinical course
The clinical course during the patient's hospitalization is shown in Fig. 2. On day 9, he became oliguric, and his serum creatinine level increased to 3.08 mg/dL. Simultaneous hemodialysis and cryofiltration were performed on days 9 and 10. Subsequently, cryofiltration was performed weekly. On day 16, based on the diagnosis of cryoglobulinemic glomerulonephritis, 30 mg of prednisolone was initiated. Subsequently, proteinuria decreased significantly, but marked hyperglycemia appeared, and the patient was started on insulin before every meal. On day 21, glecaprevir-pibrentasvir was started for HCV infection. Because massive proteinuria (around 4 g/gCr) and microscopic hematuria persisted, 500 mg of methylprednisolone (mPSL) was administered for 3 consecutive days starting on day 27, and 375 mg/m2 of weekly rituximab for 4 weeks was started after that. During the four weeks of rituximab administration, the dose of the oral steroid was tapered week by week. After oral mPSL was decreased to 8 mg, his proteinuria improved to 3.0 g/gCr, and his edema disappeared. HCV-RNA decreased to less than 1.2 LogIU/mL on day 49. He was discharged from our hospital on day 53.
Figure 2. The patient’s clinical course during hospitalization. Before the diagnosis with cryoglobulinemic glomerulonephritis, the patient needed hemodialysis twice. Cryofiltration was also performed. After the diagnosis, prednisolone, glecaprevir-pibrentasvir and rituximab were started on a weekly basis. Prednisolone was tapered early because of worsening hyperglycemia. On the 53rd day of hospitalization, he was discharged, although proteinuria persisted at around 3 g/gCr. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, GLE: glecaprevir, PIB: pibrentasvir
Shortly after discharge (Fig. 3), the patient's proteinuria increased to ＞8 g/gCr. A test for HCV-RNA reported undetectable levels, and glecaprevir-pibrentasvir was withdrawn after the eight-week treatment. We suspected that cryoglobulin had persisted in his body and was worsening his glomerulonephritis based on his persistent high levels of RF. To treat this, we performed plasma exchange (PE). Although PE removed more than 60% of his cryoglobulins, his RF level increased after PE, and complement C3 continued to be consumed. When mPSL was tapered to 6 mg at 2 months after discharge, proteinuria increased, and PE was performed again. Subsequently he was maintained on 8 mg of mPSL and his proteinuria gradually declined. Six months after discharge, a final session of PE was performed because of the increasing proteinuria and decreasing complement C3.
Figure 3. Long-term follow-up showing cryoglobulinemic hallmarks. Soon after discharge, proteinuria was exacerbated, but one session of plasma exchange relieved this symptom. Later, proteinuria had ameliorated, but the RF level had rebounded, and complement C3 was still being consumed. After the steroid dosage was decreased, proteinuria increased again. Accordingly, plasma exchange was performed again, and his mPSL dosage was increased, leading to decreased proteinuria. Although the patient's RF level remained high throughout the clinical course, the consumption of C3 was diminished, and proteinuria eventually fell to around 0.3 g/gCr. For details concerning the patient's clinical course during hospitalization, please see Figure 2 above. RF: rheumatoid factor, DAAs: direct-acting antiviral agents, PE: plasma exchange
Over the long-term, HCV-RNA remained undetectable throughout follow-up, and the CD20+ B-cell count was as low as 0.4% at 22 months after discharge, yet cryoglobulin remained at detectable levels, and the cryocrit remained at 4% at 25 months after discharge. Finally, 27 months after discharge, the patient remained on 6 mg of mPSL, and his RF levels were still ＞1,800 IU/mL, but his proteinuria had decreased to around 0.3 g/gCr, and he had never exhibited any symptoms of cryoglobulinemic vasculitis. His serum creatinine level at this time was stable around 1.6 mg/dL, as it was before the illness (Table).
Discussion
In the present case, cryoglobulinemia persisted, and glomerulonephritis appeared imminent despite treatment with rituximab, DAAs, a high-dose steroid and plasmapheresis. As the patient's proteinuria began to worsen, we continued low-dose steroid treatment and performed PE occasionally. Over the long term, his proteinuria gradually improved. Finally, the patient achieved remission for glomerulonephritis, although his cryoglobulinemia persisted.
Notably, this is a rare case of persistent cryoglobulinemia after B-cell depletion had been achieved and the virologic response had been maintained with rituximab and DAAs. There have been several previous reports of persistent cryoglobulinemia after HCV eradication by DAAs (10-13). These can be explained by the presence of persistent B-cell clones producing cryoglobulins after HCV eradication (10). Therefore, B-cell depletion therapy is needed to treat these cases of cryoglobulinemia. Rituximab is a B-cell-depleting monoclonal antibody targeting CD20 that is widely expressed among B-cell-lineage cells, except for plasmablasts and plasma cells. Thus, plasmablasts and plasma cells can still produce cryoglobulins after rituximab treatment until they are eradicated by other means. Indeed, in previous studies of HCV-associated cryoglobulinemic glomerulonephritis treated with rituximab, it took a few months for the RF and IgM levels to decrease after rituximab treatment (4,14). In the present case, however, the RF and IgM levels remained high, almost as high as they had been at the diagnosis, even 27 months after treatment. This persistent elevation of cryoglobulinemic hallmarks can be explained by the presence of long-lived plasma cells (LLPCs), which are observed in the bone marrow or spleens of patients with immune thrombocytopenia for up to six months following the start of rituximab treatment (15,16). LLPCs have special gene profiles that are programmed for long life and are characterized by CD19- CD38hi CD138+ cells by flow cytometry (17). We did not confirm the presence of LLPCs in our patient, but we speculate that LLPCs might have continued to produce the cryoglobulins that persisted in our patient.
Importantly, we should emphasize that this patient's cryoglobulinemic glomerulonephritis was successfully treated despite the persistence of cryoglobulinemia. We believe that occasional plasmapheresis after rituximab treatment, administered in response to worsening proteinuria or decreasing C3, was an effective means of controlling his glomerulonephritis. Plasmapheresis is generally effective in urgent, life-threatening cryoglobulinemia cases in advance of the initiation of fundamental treatment (1). However, we also consider it a reasonable means of removing cryoglobulins that may still be produced by LLPCs even after rituximab therapy. Indeed, there is one reported case in which long-term plasmapheresis after rituximab improved cutaneous lesions of cryoglobulinemia (18). Our case indicates that plasmapheresis after rituximab is also effective for cryoglobulinemic glomerulonephritis. We selected PE as the modality for plasmapheresis after rituximab in order to supply immunoglobulin at the same time. A variety of plasmapheresis protocols have been reported, and further studies will be needed in order to identify more effective protocols for conducting plasmapheresis in combination with rituximab.
In addition, continuous low-dose steroid administration after rituximab was effective for our patient. In previous reports, steroids were withdrawn early or avoided in rituximab protocols for cryoglobulinemia (4,14). In our case, however, when mPSL was tapered to 6 mg, glomerulonephritis deteriorated, so we continued 8 mg of mPSL for long-term maintenance. This may be due to the difference in the baseline activities of cryoglobulinemic glomerulonephritis between the previous report and our present case (proteinuria: previous report 2.3±2.1 g/day vs. our case 7.4 g/day; C3, previous report 125.7±60.8 mg/dL vs. our case 56.3 mg/dL) (14). As steroid is a conventional immunosuppressive agent, its effectiveness in treating cryoglobulinemia has long been recognized, and various mechanisms have been proposed. In the present case, we suspect a putative mechanism associated with complement C5 activation, which is reported to play a prominent role in the pathogenesis of cryoglobulinemic glomerulonephritis (19). Low-dose steroid can prevent complement C5 activation caused by cryoglobulins, which might have improved the cryoglobulinemic glomerulonephritis, although cryoglobulinemia was persistent. In addition, another putative mechanism of steroid is related to LLPCs, a special population of plasma cells which is mentioned above. LLPCs are reportedly surrounded by CD4+ T-cells, which are assumed to produce survival signals for LLPCs (20). Low-dose steroid can suppress CD4+ T-cell activities and LLPC proliferation, which might enhance the efficacy of rituximab. In this way, a low-dose steroid may be effective in combination with rituximab for suppressing C5 activation and LLPC proliferation, especially in patients with persistent cryoglobulinemia.
In conclusion, we described a case of the successful treatment of HCV-associated cryoglobulinemia with serologically persistent cryoglobulinemia using rituximab, DAAs, occasional plasmapheresis and a long-term steroid. When patients show persistent cryoglobulinemia after rituximab treatment, the presence of LLPCs should be considered. Occasional plasmapheresis is a reasonable treatment even after rituximab for such patients. Low-dose steroid administration can also suppress glomerulonephritis and improve the efficacy of rituximab, especially in patients with persistent cryoglobulinemia. Our ability to treat HCV-associated cryoglobulinemia is continuously improving through the emergence of new protocols for rituximab and DAA administration. Thus far, however, little evidence has been established for new treatments. Further investigations will be needed to establish an optimal regimen.
Author's disclosure of potential Conflicts of Interest (COI).
Motoko Yanagita: Honoraria, Kyowa Kirin and Chugai Pharmaceutical; Research funding, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim and Kyowa Kirin.
Acknowledgement
We thank Dr. Shinji Sumiyoshi (Department of Diagnostic Pathology, Kyoto University Hospital) for making the histological diagnosis and Dr. Nozomi Kubo and Dr. Shunsuke Takayanagi (Medical Intern, Kyoto University Hospital) for the immensely helpful clinical discussion.
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What was the outcome of reaction 'Hyperglycaemia'?
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The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia.
Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.
Introduction
Cryoglobulins are immunoglobulins that aggregate at low temperatures both in vitro and in vivo. In the human body, temperatures below normal body temperature cause them to accumulate in various organs (1); this is a disease state known as cryoglobulinemia. The clinical manifestations of cryoglobulinemia are hyperviscosity syndrome and systemic vasculitis. Renal involvement is common and manifests as rapidly progressive glomerulonephritis with membranous proliferative glomerulonephritis as the characteristic histological finding (1). Decades ago, treatments for cryoglobulinemia were similar to those for other forms of systemic vasculitis; in 1991, however, it was shown that about 90% of cases of mixed cryoglobulinemia are associated with hepatitis C virus (HCV) infection (2) and that chronic HCV infection triggers B-cell expansion, which results in the production of cryoglobulins (3).
Rituximab was reported as an efficacious treatment in 2003 (4,5) and became the recommended immunosuppressive treatment for patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in 2018 (6). In addition, direct-acting antiviral agents (DAAs) have been used for the last decade to improve the clearance of HCV (7). Although these treatments are expected to improve the clinical outcomes of cryoglobulinemia, several cases of treatment failure or relapse after rituximab and DAAs have recently been reported (8,9).
We herein report a case of serologically persistent cryoglobulinemia in which glomerulonephritis was successfully treated with rituximab, DAAs, occasional plasmapheresis and long-term steroid.
Case Report
A 68-year-old man was referred to our nephrology department because of progressive renal insufficiency and proteinuria. He had been diagnosed with chronic hepatitis C in his teens but had not been treated for it. He had been diagnosed with diabetes mellitus at 55 years old. He had a history of myocardial infarction at 59 and 63 years old. In addition, one year previously, he had been hospitalized due to worsening depression. One month before the present admission, his serum creatinine level had increased from 1.61 to 2.11 mg/dL. At that time, he had noted bilateral leg edema. He was admitted to our hospital to investigate the cause of his worsening renal function and edema.
On admission, his height and weight were 160.7 cm and 61.7 kg, respectively. He did not notice any weight gain because he did not weigh himself regularly. His vital signs were as follows: blood pressure 153/89 mmHg, pulse 63 beats/min and temperature 36.3°C. A physical examination revealed bilateral leg pitting edema, no purpura, no cutaneous ulcer and no paresthesia, with otherwise normal findings. A complete blood count revealed a hemoglobin concentration of 8.8 g/dL. A laboratory examination showed aspartate aminotransferase of 44 U/L, alanine transaminase of 46 U/L, lactate dehydrogenase of 268 U/L, total protein of 5.0 g/dL, albumin of 2.3 g/dL, creatinine of 2.45 mg/dL and total cholesterol of 213 mg/dL (Table). Occult blood and proteinuria were positive on a urinalysis, and the 24-hour urinary protein excretion was 7.4 g/day. Hemoglobin A1c was 5.9%. Immunological tests revealed negative results for anti-nuclear antibody, anti-DNA antibody, proteinase-3 antineutrophil cytoplasmic antibody (ANCA), myeloperoxidase ANCA and anti-glomerular basement membrane antibody. Cryoglobulins were detected through a qualitative analysis, and cryocrit was 5%. Immunoglobulin M (IgM) was elevated to 692 mg/dL (reference range: 27-205 mg/dL). Rheumatoid factor (RF) was also elevated to 2018 IU/mL (reference range: 0-15.0 IU/mL). Complements were suppressed, as follows: complement C3 at 56.3 mg/dL (reference range: 70.5-125.6 mg/dL) and complement C4 at 2.6 mg/dL (reference range: 10.6-33.0 mg/dL). A virologic test showed serotype 1 HCV RNA of 7.0 LogIU/mL.
Table. Laboratory Data on Admission, at Discharge and 27 Months after Discharge.
Laboratory test At diagnosis At discharge 27 months after discharge
Complete Blood Count
WBC (/µL) 6,990 6,010 11,970
RBC (/µL) 294 330 441
Hb (g/dL) 8.8 9.7 13.6
PLT (×104/µL) 20.5 28.4 32.1
Blood Chemistry
AST (U/L) 44 15 23
ALT (U/L) 46 11 23
LDH (U/L) 268 235 163
TP (g/dL) 5 5.2 6.7
Alb (g/dL) 2.3 3 4.1
CK (U/L) 102 28 53
BUN (mg/dL) 35 27 25
Cr (mg/dL) 2.45 2.34 1.66
eGFR (mL/min/1.73 m2) 21.7 22.8 32.9
T-CHO (mg/dL) 213 199 120
Na (mEq/L) 140 141 132
K (mEq/L) 3.8 5.2 4.1
Cl (mEq/L) 110 110 94
Ca (mg/dL) 7.7 8.4 9.5
P (mg/dL) 3.9 3.4 2.5
Mg (mg/dL) 2 2.7 2.2
Immunological Examination
CRP (mg/dL) 0.1 0.1> 0.1>
IgG (mg/dL) 600 449 792
IgA (mg/dL) 138 155 146
IgM (mg/dL) 692 445 479
C3 (mg/dL) 56.3 69.5 67.1
C4 (mg/dL) 2.6 2.7 2.8
CH50 (mg/dL) 10> 10> 16
RF (IU/mL) 2,018 1,727 1,832
HbA1c (%) 5.9 6.3
PR3-ANCA negative
MPO-ANCA negative
anti-nuclear antibody negative
anti-DNA antibody negative
anti-GBM antibody negative
Serum immunoelectrophoresis IgM-κ IgM-κ
Cryoglobulin positive positive positive
Cryocrit (%) 5 4 4
HCV RNA (LogIU/mL) 7 1.2> undetectable
Urinalysis
RBC (/HPF) 30-49 100< 5-9
proteinuria (g/gCr) 9.4 3 0.35
24-hour urinary protein excretion (g/day) 7.4
NAG (U/L) 54 9.9 13.4
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, PLT: platelet, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, TP: total protein, Alb: albumin, CK: creatine kinase, BUN: blood urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration rate, T-CHO: total cholesterol, Na: sodium, K: potasium, Cl: chlorine, Ca: calcium, P: phosphorus, Mg: magnesium, CRP: C-reactive protein, IgG: immunoglobulin G, IgA: immunoglobulin A, IgM, immunoglobulin M, C3: complement component 3, C4: complement component 4, RF: rheumatoid factor, HbA1c: hemoglobin A1c, PR3-ANCA: proteinase 3-anti-neutrophil cytoplasmic antibody, MPO-ANCA: myeloperoxidase-anti-neutrophil cytoplasmic antibody, anti-DNA antibody: anti-deoxyribonucleic acid antibody, anti-GBM antibody: anti-glomerular basement membrane antibody, HCV RNA: hepatitis C virus ribonucleic acid, NAG: N-acetyl-β-D-glucosaminidase
Based on these findings, the patient was diagnosed with rapidly progressive glomerulonephritis accompanied by nephrotic syndrome.
Renal biopsy findings
A renal biopsy performed on day 6 revealed mesangial expansion, double contour of the glomerular basement membrane in most of the glomeruli and global sclerosis in 30% of the glomeruli (Fig. 1A). Tufts were segmentally ballooned and filled with eosinophilic materials, which were immunohistochemically positive for IgM and thought to be hyaline thrombi (Fig. 1B, C). Immunofluorescent staining was strongly positive for IgG, IgM, and C3 in the glomerular capillary loops. Kappa and lambda light chains were equally positive in the glomerular capillary loops. Electron microscopy revealed abundant electron-dense deposits in the subendothelial areas, with cylinder-like structures visible at high magnification (Fig. 1D, E). Based on these findings, we made a diagnosis of HCV-associated cryoglobulinemic glomerulonephritis.
Figure 1. Renal pathological findings. Double contour of glomerular basement membrane (arrow), mesangial interposition and endocapillary hypercellularity (arrowhead) were globally observed (periodic acid-methenamine-silver; PAM stain, original magnification ×200) (A). Hyaline thrombi (*) were also detected as immunohistochemically positive for IgM (B, C). Electron microscopy showed abundant electron-dense deposits in subendothelial areas (D) (scale bar 10 μm). High magnification of the area shown in the box revealed cylinder-like structures (E) (scale bar 1.0 μm).
Clinical course
The clinical course during the patient's hospitalization is shown in Fig. 2. On day 9, he became oliguric, and his serum creatinine level increased to 3.08 mg/dL. Simultaneous hemodialysis and cryofiltration were performed on days 9 and 10. Subsequently, cryofiltration was performed weekly. On day 16, based on the diagnosis of cryoglobulinemic glomerulonephritis, 30 mg of prednisolone was initiated. Subsequently, proteinuria decreased significantly, but marked hyperglycemia appeared, and the patient was started on insulin before every meal. On day 21, glecaprevir-pibrentasvir was started for HCV infection. Because massive proteinuria (around 4 g/gCr) and microscopic hematuria persisted, 500 mg of methylprednisolone (mPSL) was administered for 3 consecutive days starting on day 27, and 375 mg/m2 of weekly rituximab for 4 weeks was started after that. During the four weeks of rituximab administration, the dose of the oral steroid was tapered week by week. After oral mPSL was decreased to 8 mg, his proteinuria improved to 3.0 g/gCr, and his edema disappeared. HCV-RNA decreased to less than 1.2 LogIU/mL on day 49. He was discharged from our hospital on day 53.
Figure 2. The patient’s clinical course during hospitalization. Before the diagnosis with cryoglobulinemic glomerulonephritis, the patient needed hemodialysis twice. Cryofiltration was also performed. After the diagnosis, prednisolone, glecaprevir-pibrentasvir and rituximab were started on a weekly basis. Prednisolone was tapered early because of worsening hyperglycemia. On the 53rd day of hospitalization, he was discharged, although proteinuria persisted at around 3 g/gCr. PSL: prednisolone, mPSL: methylprednisolone, RTX: rituximab, GLE: glecaprevir, PIB: pibrentasvir
Shortly after discharge (Fig. 3), the patient's proteinuria increased to ＞8 g/gCr. A test for HCV-RNA reported undetectable levels, and glecaprevir-pibrentasvir was withdrawn after the eight-week treatment. We suspected that cryoglobulin had persisted in his body and was worsening his glomerulonephritis based on his persistent high levels of RF. To treat this, we performed plasma exchange (PE). Although PE removed more than 60% of his cryoglobulins, his RF level increased after PE, and complement C3 continued to be consumed. When mPSL was tapered to 6 mg at 2 months after discharge, proteinuria increased, and PE was performed again. Subsequently he was maintained on 8 mg of mPSL and his proteinuria gradually declined. Six months after discharge, a final session of PE was performed because of the increasing proteinuria and decreasing complement C3.
Figure 3. Long-term follow-up showing cryoglobulinemic hallmarks. Soon after discharge, proteinuria was exacerbated, but one session of plasma exchange relieved this symptom. Later, proteinuria had ameliorated, but the RF level had rebounded, and complement C3 was still being consumed. After the steroid dosage was decreased, proteinuria increased again. Accordingly, plasma exchange was performed again, and his mPSL dosage was increased, leading to decreased proteinuria. Although the patient's RF level remained high throughout the clinical course, the consumption of C3 was diminished, and proteinuria eventually fell to around 0.3 g/gCr. For details concerning the patient's clinical course during hospitalization, please see Figure 2 above. RF: rheumatoid factor, DAAs: direct-acting antiviral agents, PE: plasma exchange
Over the long-term, HCV-RNA remained undetectable throughout follow-up, and the CD20+ B-cell count was as low as 0.4% at 22 months after discharge, yet cryoglobulin remained at detectable levels, and the cryocrit remained at 4% at 25 months after discharge. Finally, 27 months after discharge, the patient remained on 6 mg of mPSL, and his RF levels were still ＞1,800 IU/mL, but his proteinuria had decreased to around 0.3 g/gCr, and he had never exhibited any symptoms of cryoglobulinemic vasculitis. His serum creatinine level at this time was stable around 1.6 mg/dL, as it was before the illness (Table).
Discussion
In the present case, cryoglobulinemia persisted, and glomerulonephritis appeared imminent despite treatment with rituximab, DAAs, a high-dose steroid and plasmapheresis. As the patient's proteinuria began to worsen, we continued low-dose steroid treatment and performed PE occasionally. Over the long term, his proteinuria gradually improved. Finally, the patient achieved remission for glomerulonephritis, although his cryoglobulinemia persisted.
Notably, this is a rare case of persistent cryoglobulinemia after B-cell depletion had been achieved and the virologic response had been maintained with rituximab and DAAs. There have been several previous reports of persistent cryoglobulinemia after HCV eradication by DAAs (10-13). These can be explained by the presence of persistent B-cell clones producing cryoglobulins after HCV eradication (10). Therefore, B-cell depletion therapy is needed to treat these cases of cryoglobulinemia. Rituximab is a B-cell-depleting monoclonal antibody targeting CD20 that is widely expressed among B-cell-lineage cells, except for plasmablasts and plasma cells. Thus, plasmablasts and plasma cells can still produce cryoglobulins after rituximab treatment until they are eradicated by other means. Indeed, in previous studies of HCV-associated cryoglobulinemic glomerulonephritis treated with rituximab, it took a few months for the RF and IgM levels to decrease after rituximab treatment (4,14). In the present case, however, the RF and IgM levels remained high, almost as high as they had been at the diagnosis, even 27 months after treatment. This persistent elevation of cryoglobulinemic hallmarks can be explained by the presence of long-lived plasma cells (LLPCs), which are observed in the bone marrow or spleens of patients with immune thrombocytopenia for up to six months following the start of rituximab treatment (15,16). LLPCs have special gene profiles that are programmed for long life and are characterized by CD19- CD38hi CD138+ cells by flow cytometry (17). We did not confirm the presence of LLPCs in our patient, but we speculate that LLPCs might have continued to produce the cryoglobulins that persisted in our patient.
Importantly, we should emphasize that this patient's cryoglobulinemic glomerulonephritis was successfully treated despite the persistence of cryoglobulinemia. We believe that occasional plasmapheresis after rituximab treatment, administered in response to worsening proteinuria or decreasing C3, was an effective means of controlling his glomerulonephritis. Plasmapheresis is generally effective in urgent, life-threatening cryoglobulinemia cases in advance of the initiation of fundamental treatment (1). However, we also consider it a reasonable means of removing cryoglobulins that may still be produced by LLPCs even after rituximab therapy. Indeed, there is one reported case in which long-term plasmapheresis after rituximab improved cutaneous lesions of cryoglobulinemia (18). Our case indicates that plasmapheresis after rituximab is also effective for cryoglobulinemic glomerulonephritis. We selected PE as the modality for plasmapheresis after rituximab in order to supply immunoglobulin at the same time. A variety of plasmapheresis protocols have been reported, and further studies will be needed in order to identify more effective protocols for conducting plasmapheresis in combination with rituximab.
In addition, continuous low-dose steroid administration after rituximab was effective for our patient. In previous reports, steroids were withdrawn early or avoided in rituximab protocols for cryoglobulinemia (4,14). In our case, however, when mPSL was tapered to 6 mg, glomerulonephritis deteriorated, so we continued 8 mg of mPSL for long-term maintenance. This may be due to the difference in the baseline activities of cryoglobulinemic glomerulonephritis between the previous report and our present case (proteinuria: previous report 2.3±2.1 g/day vs. our case 7.4 g/day; C3, previous report 125.7±60.8 mg/dL vs. our case 56.3 mg/dL) (14). As steroid is a conventional immunosuppressive agent, its effectiveness in treating cryoglobulinemia has long been recognized, and various mechanisms have been proposed. In the present case, we suspect a putative mechanism associated with complement C5 activation, which is reported to play a prominent role in the pathogenesis of cryoglobulinemic glomerulonephritis (19). Low-dose steroid can prevent complement C5 activation caused by cryoglobulins, which might have improved the cryoglobulinemic glomerulonephritis, although cryoglobulinemia was persistent. In addition, another putative mechanism of steroid is related to LLPCs, a special population of plasma cells which is mentioned above. LLPCs are reportedly surrounded by CD4+ T-cells, which are assumed to produce survival signals for LLPCs (20). Low-dose steroid can suppress CD4+ T-cell activities and LLPC proliferation, which might enhance the efficacy of rituximab. In this way, a low-dose steroid may be effective in combination with rituximab for suppressing C5 activation and LLPC proliferation, especially in patients with persistent cryoglobulinemia.
In conclusion, we described a case of the successful treatment of HCV-associated cryoglobulinemia with serologically persistent cryoglobulinemia using rituximab, DAAs, occasional plasmapheresis and a long-term steroid. When patients show persistent cryoglobulinemia after rituximab treatment, the presence of LLPCs should be considered. Occasional plasmapheresis is a reasonable treatment even after rituximab for such patients. Low-dose steroid administration can also suppress glomerulonephritis and improve the efficacy of rituximab, especially in patients with persistent cryoglobulinemia. Our ability to treat HCV-associated cryoglobulinemia is continuously improving through the emergence of new protocols for rituximab and DAA administration. Thus far, however, little evidence has been established for new treatments. Further investigations will be needed to establish an optimal regimen.
Author's disclosure of potential Conflicts of Interest (COI).
Motoko Yanagita: Honoraria, Kyowa Kirin and Chugai Pharmaceutical; Research funding, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim and Kyowa Kirin.
Acknowledgement
We thank Dr. Shinji Sumiyoshi (Department of Diagnostic Pathology, Kyoto University Hospital) for making the histological diagnosis and Dr. Nozomi Kubo and Dr. Shunsuke Takayanagi (Medical Intern, Kyoto University Hospital) for the immensely helpful clinical discussion.
|
Recovered
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ReactionOutcome
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CC BY-NC-ND
|
32999232
| 19,870,219
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abortion spontaneous'.
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Anti-glomerular Basement Membrane Glomerulonephritis During the First Trimester of Pregnancy.
A 28-year-old woman was admitted during the eighth week of her pregnancy because her clinical course was consistent with rapid progressive glomerulonephritis (RPGN). Anti-glomerular basement membrane antibody (anti-GBM Ab) and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, and the anti-GBM Ab titer being extremely high. She was treated with hemodialysis, plasma exchange and prednisolone. She survived the illness; however, neither the fetus nor her kidney function could be rescued. She had human leukocyte antigen (HLA)-DRB1*1502:01, which differs from the DRB1*1501 associated with anti-GBM GN. When patients have particular symptoms, we should check the urine and serum creatinine to exclude RPGN, even in cases of pregnancy.
Introduction
Anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), also called Goodpasture's syndrome, is an autoimmune-mediated disorder, and patients with anti-GBM antibody disease develop rapidly progressive glomerulonephritis (RPGN), leading to severe kidney deterioration. Despite various aggressive treatments, the prognosis of anti-GBM GN is very poor, often leading to renal failure and/or death (1). Once anti-GBM GN patients begin dialysis, they usually remain dialysis-dependent (2). Anti-GBM GN is well known to occur in young and elderly patients (3) and is a rare cause of renal insufficiency in young patients, especially in association with pregnancy.
We herein report a case of anti-GBM GN disease requiring dialysis that presented in early pregnancy.
Case Report
A 28-year-old woman was introduced to our hospital because of generalized edema associated with a reduced urine output in the eighth week of pregnancy. She had no abnormality recorded in her previous medical examinations. This was her first pregnancy, and she had had no miscarriages. At a medical examination one year earlier, her serum creatinine level had been 0.64 mg/dL, and urine protein and urine occult blood were negative. There was no familial history of renal disease. She had had gross hematuria, a fever, nausea and diarrhea for about three weeks. She visited a local obstetrics clinic and was treated with amoxicillin for a suspected urinary tract infection. Treatment with antibiotics did not improve her symptoms, and she was referred urgently to our hospital because of severe kidney dysfunction.
On a clinical examination, she had bilateral pitting pedal edema, abdominal fullness, due to ascites fluid, and anemia. Her blood pressure was 134/81 mmHg, her pulse rate was 89/minute and her body temperature was 37.7℃. She had no hemosputum or hypoxemia, and the remainder of her systemic examination findings, including those for her chest, were within normal limits.
The laboratory findings on admission are shown in Table 1. She had severe renal dysfunction with urinary abnormality, severe inflammation, anemia, hypoproteinemia, hyperkalemia, hyperphosphatemia and hyperuricemia. Anti-GBM Ab and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, with the anti-GBM Ab titer (>680 U/mL) being extremely high, unlike the MPO-ANCA titer (16.1 U/mL). Both anti-nuclear Ab (ANA) and PR3-ANCA were negative. There was no reduction in the complement value and no monoclonal protein. Ultrasound imaging of the abdomen showed her right kidney to be 10.5 cm ×4.0 cm and left kidney to be 10.6 cm ×4.3 cm, with bilateral increased echogenicity. Chest X-ray showed no interstitial pneumonia or alveolar hemorrhaging, which are typically seen in Goodpasture's syndrome. The values of Krebs von den Lungen-6 (KL-6), Surfactant Protein A (SP-A) Surfactant Protein D (SP-D) were within normal limits.
Table 1. Laboratory Findings on Admission.
Peripheral blood tests Na 123 mEq/L KL-6 115 U/mL
WBC 13,000 /μL K 6.6 mEq/L SP-A 8.3 ng/mL
Neu 87.1 % Cl 88 mEq/L SP-D 17.2 ng/mL
Ly 5.2 % Ca 7.9 mg/dL
Mo 6.7 % IP 7.6 mg/dL Urinalysis
Eo 0.8 % CRP 15.5 mg/dL Protein 2+
RBC 339×104 /μL Blood sugar 99 mg/dL 0.17 g/day
Hb 9.4 g/dL HbAlc (NGSP) 5.4 % Occult blood 3+
Ht 27.5 % IgG 1,020 mg/dL Sugar sediment -
Platelet 53.7×104 /μL IgA 108 mg/dL RBC >100 HPF
Blood chemistry tests IgM 141 mg/dL WBC 0 HPF
TP 5.9 g/dL MPO-ANCA 16.1 U/mL hyaline cast 1-4 HPF
Alb 2.5 g/dL PR3-ANCA <1.0 U/mL granular cast 1-4 HPF
T-Bil 0.3 mg/dL Anti-GBM Ab >680 U/mL Urine chemistry
AST 16 U/L ANA <40 times NAG 15.3 U/L
ALT 15 U/L Anti-DNA Ab <2 times β2MG 57,815 ng/mL
LDH 179 U/L Anti-cardiolipin-beta2
glycoprotein 1 complex Ab negative
CPK 97 U/L
UA 8.2 mg/dL
BUN 62.5 mg/dL antiphospholipid Ab negative
Cr 12.52 mg/dL
Ab: antibody, Alb: albumin, ALT: alanine aminotransferase, ANA: antinuclear antibody, ANCA: antineutrophil cytoplasmic antibody, AST: aspartate aminotransferase, β2MG: beta-2 microglobulin, BUN: blood urea nitrogen, Ca: calcium, CPK: creatine phosphokinase, Cr: creatinine, CRP: C-reactive protein, DNA: deoxyribonucleic acid, Eo: eosinophils, Hb: hemoglobin, Ht: hematocrit, Ig: immunoglobulin, IP: Inorganic phosphorus, K: potassium, KL-6: Krebs von den Lungen-6, LDH: lactate dehydrogenase, Ly: lymphocytes, Mo: monocytes, MPO: myeloperoxidase, Na: sodium, NAG: N-acetyl-beta-D-glucosaminidase, Neu: neutrophils, NGSP: National Glycohemoglobin Standardization Program, PR3: proteinase3, RBC: red blood cells, SP-A: Surfactant Protein A, SP-D: Surfactant Protein D, T-Bil: total-bilirubin, TP: total protein, UA: uric acid, WBC: white blood cells
Her clinical course suggested RPGN with severe renal dysfunction due to anti-GBM GN. In an effort to rescue her fetus and her kidney function, she was treated with hemodialysis and plasma exchange (PE) and started on 30 mg/day of prednisolone. Her clinical course is shown in Fig. 1. On admission, obstetric ultrasound findings showed five weeks of gestation, which differed from the estimated 8 weeks of gestation from her last menstruation, and miscarriage was strongly suspected. After reconfirmation, a fetal heartbeat could not be detected, so dilatation and curettage were performed on the 15th day of admission. All of our efforts were then directed to saving her kidneys and life.
Figure 1. Clinical course of the patient.
She was examined by a renal biopsy on the 24th day of admission. The biopsy revealed 27 glomeruli, of which 1 had segmental necrosis with nuclear debris and hyaline thrombi within glomerular capillaries. There were fibrocellular crescents in 26 glomeruli. The underlying tufts did not show significant endocapillary proliferation. Lymphocyte infiltration around the tubulointerstitium was found near the glomerulus (Fig. 2A) and mainly formed fibrocellular crescents (Fig. 2B). Immunofluorescence staining revealed linear IgG (Fig. 2C) and C3 staining along glomerular capillary loops. IgA, IgM and C1q were negative, and fibrinogen was weakly positive. A diagnosis of crescentic glomerulonephritis was made, which was consistent with anti-GBM GN disease with diffuse global glomerulosclerosis. Based on the kidney biopsy result, we suspected a low probability of improving her renal function. Although plasma exchange was performed 14 times and immunosuppressive therapy continued, anuria persisted, and her kidney function did not improve; she could not discontinue hemodialysis despite a reduction in the anti-GBM Ab titer (42.3 U/mL) and C-reactive protein (CRP) on the 71st hospital day. On that day, her serum blood urea nitrogen (BUN) was 55.1 mg/dL and creatinine 11.6 mg/dL (Fig. 1). The high titer level of anti-GBM Ab persisted, and no improvement in the kidney function could be expected, but fortunately, there were no signs of respiratory symptoms or the development of lung lesions, which was important in deciding to withdraw treatment. Her life was saved; however, give the loss of her renal function, renal transplantation in the near future is desirable.
Figure 2. Histological findings in the kidney. (A) Fibrocellular crescents in the glomeruli and lymphocyte infiltration around the tubulointerstitium, near the glomerulus [Periodic Acid-Methenamine Silver (PAM) staining ×100]. (B) The fibrocellular crescents, indicated by an arrow [Periodic Acid Schiff (PAS) staining ×400]. (C) Immunofluorescence staining revealed linear staining along the glomerular capillary loops (IgG staining ×400).
Discussion
There are only a few case reports of anti-GBM GN disease during pregnancy in the literature, especially in the early phase of pregnancy (4). We summarized the reports of anti-GBM GN in pregnancy in Table 2 (5-13). There have been some reports of a severe renal outcome and prognosis in pregnancy (5-7,9). For example, Qin et al. reported both maternal and fetal death in a case of Goodpasture's syndrome during pregnancy (5).
Table 2. Maternal and Fetal Outocomes and Treatments in Anti-GBM GN in Pregnancy.
Maternal Fetal outcomes Treatments
Reference numbers Age Onset week of pregnancy, weeks Kidney outocomes Respiratory symptoms Livebirth Weeks gestation Small for gestational age PE Medicine
5 17 13 Maternal death Hemoptysis Maternal death (-) corticosteroid
6 21 12 HD, RTx Normal (+) 35 NR (+) corticosteroid, CY
7 19 19 HD, RTx Normal (-); SB 28 SB (+) corticosteroid, CY
8 23 13 Full recovery Dyspnea (-); TA 15 TA (+) corticosteroid, CY
9 30 28 HD Dyspnea (+) 34 (+) (+) corticosteroid
10 34 18 Partial recovery Hemoptysis (+) 27 (+) (+) corticosteroid, AZA
11 28 Prepregnancy Normal Hemoptysis, Dyspnea (+) 37 (-) (+) corticosteroid, CY
12 30 13 Normal Hemoptysis (+) 38 (+) (+) corticosteroid, CY, RT
13 17 6 Full recovery Normal (-); SA 8 SA (+) corticosteroid,CY
This case 28 8 HD Normal (-); SA 8 SA (+) corticosteroid
AZA: azathioprine, CY: cyclophosphamide, HD: hemodialysis, PE: plasma exchange, RT: rituximab, RTx: renal transplantation, SA: spontaneous abortion, SB: stillbirth, TA: therapeutic abortion, NR: not reported
However, there have been some reports in which the kidney function was rescued by aggressive treatment with corticosteroid, immunosuppressive agents and PE (8,10-13). Vasiliou et al. described a 34-year-old woman who presented with RPGN with anti-GBM GN at 18 weeks of pregnancy, and her baby was born alive after 27 weeks of gestation (10). She was treated with acute dialysis for renal failure and received intensive treatment with PE, corticosteroid and azathioprine, resulting in the partial recovery of her kidney function. A renal biopsy showed 80% crescentic GN with linear immune fluorescence. Yankowitz et al. reported the case of a 28-year-old woman with anti-GBM GN 3 months before pregnancy who was treated with intensive hemodialysis along with corticosteroid and delivered at 37 weeks of gestation (11). Anti-GBM Ab, which had been negative during pregnancy, was detected again after delivery. Sprenger-Mähr et al. described the case of a 30-year-old woman with anti-GBM GN and who was treated with PE, corticosteroid, cyclophosphamide and rituximab and delivered at 38 weeks of gestation (12). Although the differences between the reports with good and poor renal prognoses are unclear, it seems that anti-GBM GN requires aggressive treatment, even during pregnancy. In our case, the anti-GBM antibody titers were very high, even during pregnancy, and did not become negative after treatment. She also obtained a very poor renal recovery with immunosuppression, along with intensive plasma exchange and hemodialysis.
The outcomes of the infants of mothers with anti-GBM GN during pregnancy are generally poor, often resulting in stillbirth and both natural and artificial abortion (7,8,13). Nilssen et al. reported a 19-year-old woman who was treated with RPGN with anti-GBM GN in the second trimester of pregnancy and had a stillbirth at 28 weeks of gestation (7). Nair et al. described the case of a 23-year-old woman who presented with Goodpasture's syndrome during the 13th week of pregnancy (8). She was started on corticosteroid and cytotoxic agents, along with intensive PE and alternate day hemodialysis. Her pregnancy was terminated at 15 weeks. The patient improved dramatically with treatment, her renal function normalized, and her anti-GBM Ab became undetectable. However, some reports have described successful deliveries of live infants, despite poor kidney outcomes. Al-Harbi et al. reported a 30-year-old woman with acute kidney injury at 28 weeks of gestation who was treated with intensive hemodialysis along with corticosteroid (9). The patient did not recover bad kidney function and required regular maintenance hemodialysis, but she delivered at 34 weeks of gestation. In summary, pregnant women complicated with anti-GBM GN are unlikely but still able to deliver a newborn baby, although many such infants have low birth weights.
The titers of anti-GBM Ab decline in response to immunosuppression and plasma exchange. Plasma exchange is generally considered low risk in pregnancy (14). Anti-GBM Ab binds human placental antigens (15); however, the clinical outcome of this phenomenon is controversial (4). Deubner et al. discussed a protective aspect of the placental binding of anti-GBM antibodies, resulting in decreased transfer to the fetus and reduced maternal total anti-GBM Ab levels (6). However, anti-GBM Ab binding to the placenta might increase the risk of placental dysfunction if not treated aggressively. Anti-GBM Ab comprises IgG antibodies and is transported across the placenta via placental transporters. There is the possibility that the fetus may be exposed to maternal IgG antibodies, including anti-GBM antibodies. In the present patient, no placenta was observed in the uterine contents, and anti-IgG staining of the uterine contents was not apparent.
We investigated the human leukocyte antigen (HLA) genotypes through an external examination center (LSI Medience Corporation, Tokyo, Japan). HLA-DRB1*1501 is known to have a strong relationship with anti-GBM GN pathogenesis (16-18). HLA-DR15 confers a markedly increased disease risk; an autoreactive CD4+ T-cell self-epitope, derived from the α3 chain of type IV collagen, is expanded in patients with Goodpasture syndrome (19). The present patient had HLA-DRB1*1502:01, which was not consistent with the previous report. The only difference between DRB1*1501 and DRB1*1502 is the 86th amino acid in pocket 4; here, a valine residue in HLA-DRB1*1501 is substituted by a glycine residue in DRB1*1502 (17). However, the relationship between HLA-DRB1*1502:01 and the pathogenesis of the anti-GBM GN in this case was not clear.
We need to consider the relationship between pregnancy and renal failure. First, we discuss the relationship with hypertensive disorders of pregnancy (HDP) (20). Because this case had <20 weeks of gestation, it did not meet the definitions of pre-eclampsia, gestational hypertension or superimposed pre-eclampsia. In addition, the findings of a renal biopsy did not reveal endothelial injury, which is typical of HDP (21,22). While anti-GBM GN may have been exacerbated by pregnancy or developed during pregnancy, the anti-GBM Ab before pregnancy had not been measured, so we could not determine the pathogenesis of this disease.
Unfortunately, the patient's kidney function did not recover, and her fetus was stillborn. We consider it necessary to pay attention to the subjective symptoms of anti-GBM GN, which include a fever, macrohematuria, general fatigue and systemic edema, in the early stage of the disease. In particular, such a serious disease might exist in a pregnant woman who is diagnosed as a urinary tract infection. We should not ignore the possibility of RPGN and should check the urine and serum creatinine contents to avoid a misdiagnosis. We hope that this case report will improve awareness of a potential anti-GBM GN diagnosis and its appropriate treatment during pregnancy.
Informed consent was obtained from the patient described in this case report.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
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AMOXICILLIN, PREDNISOLONE
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DrugsGivenReaction
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CC BY-NC-ND
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32999239
| 19,271,789
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2021-03-01
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'.
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Anti-glomerular Basement Membrane Glomerulonephritis During the First Trimester of Pregnancy.
A 28-year-old woman was admitted during the eighth week of her pregnancy because her clinical course was consistent with rapid progressive glomerulonephritis (RPGN). Anti-glomerular basement membrane antibody (anti-GBM Ab) and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, and the anti-GBM Ab titer being extremely high. She was treated with hemodialysis, plasma exchange and prednisolone. She survived the illness; however, neither the fetus nor her kidney function could be rescued. She had human leukocyte antigen (HLA)-DRB1*1502:01, which differs from the DRB1*1501 associated with anti-GBM GN. When patients have particular symptoms, we should check the urine and serum creatinine to exclude RPGN, even in cases of pregnancy.
Introduction
Anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), also called Goodpasture's syndrome, is an autoimmune-mediated disorder, and patients with anti-GBM antibody disease develop rapidly progressive glomerulonephritis (RPGN), leading to severe kidney deterioration. Despite various aggressive treatments, the prognosis of anti-GBM GN is very poor, often leading to renal failure and/or death (1). Once anti-GBM GN patients begin dialysis, they usually remain dialysis-dependent (2). Anti-GBM GN is well known to occur in young and elderly patients (3) and is a rare cause of renal insufficiency in young patients, especially in association with pregnancy.
We herein report a case of anti-GBM GN disease requiring dialysis that presented in early pregnancy.
Case Report
A 28-year-old woman was introduced to our hospital because of generalized edema associated with a reduced urine output in the eighth week of pregnancy. She had no abnormality recorded in her previous medical examinations. This was her first pregnancy, and she had had no miscarriages. At a medical examination one year earlier, her serum creatinine level had been 0.64 mg/dL, and urine protein and urine occult blood were negative. There was no familial history of renal disease. She had had gross hematuria, a fever, nausea and diarrhea for about three weeks. She visited a local obstetrics clinic and was treated with amoxicillin for a suspected urinary tract infection. Treatment with antibiotics did not improve her symptoms, and she was referred urgently to our hospital because of severe kidney dysfunction.
On a clinical examination, she had bilateral pitting pedal edema, abdominal fullness, due to ascites fluid, and anemia. Her blood pressure was 134/81 mmHg, her pulse rate was 89/minute and her body temperature was 37.7℃. She had no hemosputum or hypoxemia, and the remainder of her systemic examination findings, including those for her chest, were within normal limits.
The laboratory findings on admission are shown in Table 1. She had severe renal dysfunction with urinary abnormality, severe inflammation, anemia, hypoproteinemia, hyperkalemia, hyperphosphatemia and hyperuricemia. Anti-GBM Ab and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) were positive, with the anti-GBM Ab titer (>680 U/mL) being extremely high, unlike the MPO-ANCA titer (16.1 U/mL). Both anti-nuclear Ab (ANA) and PR3-ANCA were negative. There was no reduction in the complement value and no monoclonal protein. Ultrasound imaging of the abdomen showed her right kidney to be 10.5 cm ×4.0 cm and left kidney to be 10.6 cm ×4.3 cm, with bilateral increased echogenicity. Chest X-ray showed no interstitial pneumonia or alveolar hemorrhaging, which are typically seen in Goodpasture's syndrome. The values of Krebs von den Lungen-6 (KL-6), Surfactant Protein A (SP-A) Surfactant Protein D (SP-D) were within normal limits.
Table 1. Laboratory Findings on Admission.
Peripheral blood tests Na 123 mEq/L KL-6 115 U/mL
WBC 13,000 /μL K 6.6 mEq/L SP-A 8.3 ng/mL
Neu 87.1 % Cl 88 mEq/L SP-D 17.2 ng/mL
Ly 5.2 % Ca 7.9 mg/dL
Mo 6.7 % IP 7.6 mg/dL Urinalysis
Eo 0.8 % CRP 15.5 mg/dL Protein 2+
RBC 339×104 /μL Blood sugar 99 mg/dL 0.17 g/day
Hb 9.4 g/dL HbAlc (NGSP) 5.4 % Occult blood 3+
Ht 27.5 % IgG 1,020 mg/dL Sugar sediment -
Platelet 53.7×104 /μL IgA 108 mg/dL RBC >100 HPF
Blood chemistry tests IgM 141 mg/dL WBC 0 HPF
TP 5.9 g/dL MPO-ANCA 16.1 U/mL hyaline cast 1-4 HPF
Alb 2.5 g/dL PR3-ANCA <1.0 U/mL granular cast 1-4 HPF
T-Bil 0.3 mg/dL Anti-GBM Ab >680 U/mL Urine chemistry
AST 16 U/L ANA <40 times NAG 15.3 U/L
ALT 15 U/L Anti-DNA Ab <2 times β2MG 57,815 ng/mL
LDH 179 U/L Anti-cardiolipin-beta2
glycoprotein 1 complex Ab negative
CPK 97 U/L
UA 8.2 mg/dL
BUN 62.5 mg/dL antiphospholipid Ab negative
Cr 12.52 mg/dL
Ab: antibody, Alb: albumin, ALT: alanine aminotransferase, ANA: antinuclear antibody, ANCA: antineutrophil cytoplasmic antibody, AST: aspartate aminotransferase, β2MG: beta-2 microglobulin, BUN: blood urea nitrogen, Ca: calcium, CPK: creatine phosphokinase, Cr: creatinine, CRP: C-reactive protein, DNA: deoxyribonucleic acid, Eo: eosinophils, Hb: hemoglobin, Ht: hematocrit, Ig: immunoglobulin, IP: Inorganic phosphorus, K: potassium, KL-6: Krebs von den Lungen-6, LDH: lactate dehydrogenase, Ly: lymphocytes, Mo: monocytes, MPO: myeloperoxidase, Na: sodium, NAG: N-acetyl-beta-D-glucosaminidase, Neu: neutrophils, NGSP: National Glycohemoglobin Standardization Program, PR3: proteinase3, RBC: red blood cells, SP-A: Surfactant Protein A, SP-D: Surfactant Protein D, T-Bil: total-bilirubin, TP: total protein, UA: uric acid, WBC: white blood cells
Her clinical course suggested RPGN with severe renal dysfunction due to anti-GBM GN. In an effort to rescue her fetus and her kidney function, she was treated with hemodialysis and plasma exchange (PE) and started on 30 mg/day of prednisolone. Her clinical course is shown in Fig. 1. On admission, obstetric ultrasound findings showed five weeks of gestation, which differed from the estimated 8 weeks of gestation from her last menstruation, and miscarriage was strongly suspected. After reconfirmation, a fetal heartbeat could not be detected, so dilatation and curettage were performed on the 15th day of admission. All of our efforts were then directed to saving her kidneys and life.
Figure 1. Clinical course of the patient.
She was examined by a renal biopsy on the 24th day of admission. The biopsy revealed 27 glomeruli, of which 1 had segmental necrosis with nuclear debris and hyaline thrombi within glomerular capillaries. There were fibrocellular crescents in 26 glomeruli. The underlying tufts did not show significant endocapillary proliferation. Lymphocyte infiltration around the tubulointerstitium was found near the glomerulus (Fig. 2A) and mainly formed fibrocellular crescents (Fig. 2B). Immunofluorescence staining revealed linear IgG (Fig. 2C) and C3 staining along glomerular capillary loops. IgA, IgM and C1q were negative, and fibrinogen was weakly positive. A diagnosis of crescentic glomerulonephritis was made, which was consistent with anti-GBM GN disease with diffuse global glomerulosclerosis. Based on the kidney biopsy result, we suspected a low probability of improving her renal function. Although plasma exchange was performed 14 times and immunosuppressive therapy continued, anuria persisted, and her kidney function did not improve; she could not discontinue hemodialysis despite a reduction in the anti-GBM Ab titer (42.3 U/mL) and C-reactive protein (CRP) on the 71st hospital day. On that day, her serum blood urea nitrogen (BUN) was 55.1 mg/dL and creatinine 11.6 mg/dL (Fig. 1). The high titer level of anti-GBM Ab persisted, and no improvement in the kidney function could be expected, but fortunately, there were no signs of respiratory symptoms or the development of lung lesions, which was important in deciding to withdraw treatment. Her life was saved; however, give the loss of her renal function, renal transplantation in the near future is desirable.
Figure 2. Histological findings in the kidney. (A) Fibrocellular crescents in the glomeruli and lymphocyte infiltration around the tubulointerstitium, near the glomerulus [Periodic Acid-Methenamine Silver (PAM) staining ×100]. (B) The fibrocellular crescents, indicated by an arrow [Periodic Acid Schiff (PAS) staining ×400]. (C) Immunofluorescence staining revealed linear staining along the glomerular capillary loops (IgG staining ×400).
Discussion
There are only a few case reports of anti-GBM GN disease during pregnancy in the literature, especially in the early phase of pregnancy (4). We summarized the reports of anti-GBM GN in pregnancy in Table 2 (5-13). There have been some reports of a severe renal outcome and prognosis in pregnancy (5-7,9). For example, Qin et al. reported both maternal and fetal death in a case of Goodpasture's syndrome during pregnancy (5).
Table 2. Maternal and Fetal Outocomes and Treatments in Anti-GBM GN in Pregnancy.
Maternal Fetal outcomes Treatments
Reference numbers Age Onset week of pregnancy, weeks Kidney outocomes Respiratory symptoms Livebirth Weeks gestation Small for gestational age PE Medicine
5 17 13 Maternal death Hemoptysis Maternal death (-) corticosteroid
6 21 12 HD, RTx Normal (+) 35 NR (+) corticosteroid, CY
7 19 19 HD, RTx Normal (-); SB 28 SB (+) corticosteroid, CY
8 23 13 Full recovery Dyspnea (-); TA 15 TA (+) corticosteroid, CY
9 30 28 HD Dyspnea (+) 34 (+) (+) corticosteroid
10 34 18 Partial recovery Hemoptysis (+) 27 (+) (+) corticosteroid, AZA
11 28 Prepregnancy Normal Hemoptysis, Dyspnea (+) 37 (-) (+) corticosteroid, CY
12 30 13 Normal Hemoptysis (+) 38 (+) (+) corticosteroid, CY, RT
13 17 6 Full recovery Normal (-); SA 8 SA (+) corticosteroid,CY
This case 28 8 HD Normal (-); SA 8 SA (+) corticosteroid
AZA: azathioprine, CY: cyclophosphamide, HD: hemodialysis, PE: plasma exchange, RT: rituximab, RTx: renal transplantation, SA: spontaneous abortion, SB: stillbirth, TA: therapeutic abortion, NR: not reported
However, there have been some reports in which the kidney function was rescued by aggressive treatment with corticosteroid, immunosuppressive agents and PE (8,10-13). Vasiliou et al. described a 34-year-old woman who presented with RPGN with anti-GBM GN at 18 weeks of pregnancy, and her baby was born alive after 27 weeks of gestation (10). She was treated with acute dialysis for renal failure and received intensive treatment with PE, corticosteroid and azathioprine, resulting in the partial recovery of her kidney function. A renal biopsy showed 80% crescentic GN with linear immune fluorescence. Yankowitz et al. reported the case of a 28-year-old woman with anti-GBM GN 3 months before pregnancy who was treated with intensive hemodialysis along with corticosteroid and delivered at 37 weeks of gestation (11). Anti-GBM Ab, which had been negative during pregnancy, was detected again after delivery. Sprenger-Mähr et al. described the case of a 30-year-old woman with anti-GBM GN and who was treated with PE, corticosteroid, cyclophosphamide and rituximab and delivered at 38 weeks of gestation (12). Although the differences between the reports with good and poor renal prognoses are unclear, it seems that anti-GBM GN requires aggressive treatment, even during pregnancy. In our case, the anti-GBM antibody titers were very high, even during pregnancy, and did not become negative after treatment. She also obtained a very poor renal recovery with immunosuppression, along with intensive plasma exchange and hemodialysis.
The outcomes of the infants of mothers with anti-GBM GN during pregnancy are generally poor, often resulting in stillbirth and both natural and artificial abortion (7,8,13). Nilssen et al. reported a 19-year-old woman who was treated with RPGN with anti-GBM GN in the second trimester of pregnancy and had a stillbirth at 28 weeks of gestation (7). Nair et al. described the case of a 23-year-old woman who presented with Goodpasture's syndrome during the 13th week of pregnancy (8). She was started on corticosteroid and cytotoxic agents, along with intensive PE and alternate day hemodialysis. Her pregnancy was terminated at 15 weeks. The patient improved dramatically with treatment, her renal function normalized, and her anti-GBM Ab became undetectable. However, some reports have described successful deliveries of live infants, despite poor kidney outcomes. Al-Harbi et al. reported a 30-year-old woman with acute kidney injury at 28 weeks of gestation who was treated with intensive hemodialysis along with corticosteroid (9). The patient did not recover bad kidney function and required regular maintenance hemodialysis, but she delivered at 34 weeks of gestation. In summary, pregnant women complicated with anti-GBM GN are unlikely but still able to deliver a newborn baby, although many such infants have low birth weights.
The titers of anti-GBM Ab decline in response to immunosuppression and plasma exchange. Plasma exchange is generally considered low risk in pregnancy (14). Anti-GBM Ab binds human placental antigens (15); however, the clinical outcome of this phenomenon is controversial (4). Deubner et al. discussed a protective aspect of the placental binding of anti-GBM antibodies, resulting in decreased transfer to the fetus and reduced maternal total anti-GBM Ab levels (6). However, anti-GBM Ab binding to the placenta might increase the risk of placental dysfunction if not treated aggressively. Anti-GBM Ab comprises IgG antibodies and is transported across the placenta via placental transporters. There is the possibility that the fetus may be exposed to maternal IgG antibodies, including anti-GBM antibodies. In the present patient, no placenta was observed in the uterine contents, and anti-IgG staining of the uterine contents was not apparent.
We investigated the human leukocyte antigen (HLA) genotypes through an external examination center (LSI Medience Corporation, Tokyo, Japan). HLA-DRB1*1501 is known to have a strong relationship with anti-GBM GN pathogenesis (16-18). HLA-DR15 confers a markedly increased disease risk; an autoreactive CD4+ T-cell self-epitope, derived from the α3 chain of type IV collagen, is expanded in patients with Goodpasture syndrome (19). The present patient had HLA-DRB1*1502:01, which was not consistent with the previous report. The only difference between DRB1*1501 and DRB1*1502 is the 86th amino acid in pocket 4; here, a valine residue in HLA-DRB1*1501 is substituted by a glycine residue in DRB1*1502 (17). However, the relationship between HLA-DRB1*1502:01 and the pathogenesis of the anti-GBM GN in this case was not clear.
We need to consider the relationship between pregnancy and renal failure. First, we discuss the relationship with hypertensive disorders of pregnancy (HDP) (20). Because this case had <20 weeks of gestation, it did not meet the definitions of pre-eclampsia, gestational hypertension or superimposed pre-eclampsia. In addition, the findings of a renal biopsy did not reveal endothelial injury, which is typical of HDP (21,22). While anti-GBM GN may have been exacerbated by pregnancy or developed during pregnancy, the anti-GBM Ab before pregnancy had not been measured, so we could not determine the pathogenesis of this disease.
Unfortunately, the patient's kidney function did not recover, and her fetus was stillborn. We consider it necessary to pay attention to the subjective symptoms of anti-GBM GN, which include a fever, macrohematuria, general fatigue and systemic edema, in the early stage of the disease. In particular, such a serious disease might exist in a pregnant woman who is diagnosed as a urinary tract infection. We should not ignore the possibility of RPGN and should check the urine and serum creatinine contents to avoid a misdiagnosis. We hope that this case report will improve awareness of a potential anti-GBM GN diagnosis and its appropriate treatment during pregnancy.
Informed consent was obtained from the patient described in this case report.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This study was supported in part by a Grant-in-Aid for Intractable Renal Diseases Research, Research on rare and intractable diseases, Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.
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AMOXICILLIN, PREDNISOLONE
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DrugsGivenReaction
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CC BY-NC-ND
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32999239
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2021-03-01
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'.
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Compromised barrier integrity of human feto-placental vessels from gestational diabetic pregnancies is related to downregulation of occludin expression.
Reduced occupancy of junctional occludin is a feature of human placental vessels in the diabetic milieu. However, the functional consequence of this and whether this loss is due to differential expression of occludin splice variants is not known. Our study aimed to investigate the effects of gestational diabetes mellitus (GDM), and its treatment, on endothelial junctional integrity, gene and protein expression of occludin splice variants, and potential regulation of expression by microRNAs (miRNAs).
Term placentas were obtained from normal pregnancies (n = 21), and pregnancies complicated by GDM where glucose levels were controlled by diet (n = 11) or metformin (n = 6). Gene and microRNA (miRNA) expression were determined by quantitative real-time PCR; protein expression by immunoblotting; endothelial junctional occupancy by fluorescence microscopy and systematic sampling; and paracellular leakage by perfusion of placental microvascular beds with 76 Mr dextran. Transfection studies of miRNAs that target OCLN were performed in HUVECs, and the trans-endothelial electrical resistance and tracer permeability of the HUVECs were measured.
All three predicted OCLN gene splice variants and two occludin protein isoforms were found in human placental samples. In placental samples from diet-controlled GDM (d-GDM) pregnancies we found a lower percentage of conduit vessels showing occludin immunoreactivity (12%, p < 0.01), decreased levels of the fully functional occludin isoform-A protein (29%), and differential gene expression of OCLN variant 2 (33% decrease), variant 3 (3.3-fold increase). These changes were not seen in samples from the group with metformin-controlled GDM. In d-GDM placentas, increased numbers of conduit microvessels demonstrated extravasation of 76 Mr dextran (2.0-fold). In d-GDM expression of one of the five potential miRNAs targeting OCLN, miR-181a-5p, expression was 2.1-fold that in normal pregnancies. Experimental overexpression of miR-181a-5p in HUVECs from normal pregnancies resulted in a highly significant downregulation of OCLN variant 1 (69%) and variant 2 (46%) gene expression, with decreased trans-endothelial resistance (78%) and increase in tracer permeability (1.3-fold).
Downregulation of expression of OCLN variant 2 and the fully functional occludin isoform-A protein are a feature of placentas in d-GDM pregnancies. These may be behind the loss of junctional occludin and the increased extravasation of exogenous dextran observed. miR-181a-5p was in part responsible for the downregulation of occludin in placentas from d-GDM pregnancies. Induced overexpression of miR-181a-5p compromised the integrity of the endothelial barrier. Our data suggest that, despite good glucose control, the adoption of lifestyle changes alone during a GDM pregnancy may not be enough to prevent an alteration in the expression of occludin and the subsequent functional consequences in placentas and impaired vascular barrier function in offspring. Graphical abstract.
Introduction
Gestational diabetes mellitus (GDM) is defined as a carbohydrate intolerance resulting in any degree of hyperglycaemia first recognised during the second or third trimester of pregnancy [1]. GDM increases the risk of several negative consequences for the mother and the infants, the most significant of which is a predisposition to develop metabolic syndrome and type 2 diabetes [2, 3]. Placental pathophysiology in GDM also includes increased insulin resistance, inflammation, increased glucose uptake, alterations of glucose transporters and endothelial dysfunction (including junctional integrity) [4, 5]. The latter may affect fetal programming of adult cardiovascular disease. Following the UK National Institute for Health and Care Excellence (NICE) guidelines, all women diagnosed with diabetes are advised to adjust their diet and adopt a physical exercise routine if they are planning a pregnancy or are pregnant [6]. Lifestyle changes are sufficient to control hyperglycaemia in 80–90% of women with GDM [7]. If a diet change is insufficient, metformin or insulin are used [6].
The placenta, a fetal end organ, forms a semi-permeable barrier between mother and fetus. It is composed of numerous chorionic villi containing fetal exchange capillaries, which pick up nutrients, and conduit microvessels, which transport solutes back to the fetus via the chorionic plate venous network and single umbilical vein [8]. The villous outer lining is a single multinucleated layer of syncytiotrophoblast, which is in direct contact with maternal blood. The haemodynamics here will influence solute uptake and oxygenation [8]. Hydrophilic solutes have to cross both the syncytiotrophoblast and the endothelium to reach the fetal blood [9]. The endothelial layer acts as a barrier in series by containing well-defined junctions (adherens and tight junctions). Disruption here leads to reduced junctional restrictiveness, altered cleft dimensions [10], increased solute transit time and paracellular vascular leaks [11, 12], all impacting on optimal nutrient delivery to the developing fetus and impaired placental barrier function. In the blood–brain barrier, tight junction disruption has been shown to lead to changes in the efflux/influx of hydrophilic solutes [13]. Disruption of junctions by histamine can increase arterial flow and permeability of venules in the mouse ear [14]. Similar mechanisms may be at play in the human placenta.
A perfusion study using freshly delivered term placenta from pregnancies complicated with type 1 diabetes reported an increase in vascular leakage in all vessels of the microvascular bed [15]. This was correlated with perturbations of junctional proteins, phosphorylation of VE-cadherin and increased vascular endothelial growth factor (VEGF) protein expression [15]. Likewise, placentas from pregnancies complicated by GDM have shown loss of junctional proteins [5, 16]. However, studies into the genetic or epigenetic regulation of these transmembrane junctional proteins were not performed.
Occludin is a tight junctional strand protein that interacts with scaffolding proteins in the zonula occludens to adjoin cell–cell overlap of paracellular clefts and maintain the integrity of tight junctions. Loss of occludin and disrupted tight junctions are a feature of diabetic retinopathy [17], and this feature has also been reported in placental vessels in pregnancies complicated with GDM [5]. Whether differential expression of splice variants of the gene encoding occludin (OCLN) is behind these changes requires investigation. The human OCLN gene includes nine exons (Fig. 1a) and alternative splicing produces different mRNAs [18]. The NCBI database reports three predicted splice variants (Fig. 1b): OCLN variant 1 (NM_002538.3), variant 2 (NM_001205254.1) and variant 3 (NM_001205255.1). Differences in exon conformation and promoter regions lead to the translation of two different protein isoforms (Fig. 1c): occludin isoform-A (NP_002529.1) and isoform-B (NP_001192184.1). OCLN variant 1 and variant 2 translate into occludin isoform-A (~60 kDa), a complete and functional protein that can localise to the membranes of tight junctions and participate in homophilic binding. OCLN variant 3 translates into a truncated cytoplasmic occludin, known as isoform-B (~30 kDa). The function of isoform-B has not been described; however, a study using Madin-Darby Canine Kidney (MDCK) cells expressing chimeric occludin determined that a variant that lacks extracellular loops but presents the COOH-terminal cytoplasmic domain results in intracellular vesicular accumulation of all the scaffold of tight junction proteins [19].Fig. 1 Schematic representation of human occludin mRNA and protein products. (a) Gene structure of human occludin includes nine exons. Alternative splicing generates three variants. Alternative transcriptional start sites (TSS1 and TSS2, black arrows) and translational start sites (ATG1 and ATG2, orange arrows) in exons 1, 2 and 4 are indicated. The stop codon within exon 9 is also indicated (TGA, red arrow). (b) Three mRNA variants are generated. ATG1 forms OCLN variants 1 and 2, each of these two variants has a different transcriptional start site. ATG2 generates OCLN variant 3. (c) OCLN variant 1 and 2 translate into occludin isoform-A; a fully functional, membrane protein. OCLN variant 3 translates into occludin isoform-B, a truncated, cytoplasmic protein
Occludin expression can be epigenetically regulated. For example, the microRNAs (miRNAs) miR-18a-5p [20, 21], miR-181a-5p [22], miR-21-3p [23], miR-122-5p [24, 25], and miR-340-5p (DIANA database; http://diana.imis.athena-innovation.gr/DianaTools/index.php) have been reported to be expressed in human placenta and to target OCLN expression in different tissues. The relationship between each miRNA, human placenta, OCLN expression and GDM has not previously been analysed.
The aim of this study was to determine the effects of GDM on the integrity of the feto-placental vessels and the expression of occludin. We hypothesised that the type of treatment used to control glucose levels in pregnancies complicated by GDM influences the level to which the placental vasculature is affected.
Methods
Study population
Pregnant women, with singleton pregnancies, were recruited at the Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, UK. This study had the approval of the East Midland Nottingham 2 – Health Research Authority (Ref: OG010101). It was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).
Term placentas (N = 38; >37 weeks’ gestation) from elective Caesarean sections (C-sections) were collected after informed consent. We chose to collect placentas only from C-sections in order to minimise the effects of post-parturition hypoxia and ischaemia and obtain placentas that had not received labour signals. For protein localisation, protein expression and gene expression analysis, placental samples were obtained from three groups: normal pregnancies (n = 9), pregnancies complicated with GDM treated by a change of diet (n = 7) (d-GDM) or by metformin (n = 6) (m-GDM) (Table 1). For tracer leakage analysis, term placentas were collected from normal pregnancies (n = 4) and d-GDM pregnancies (n = 4) (Table 2). Transfection studies, trans-endothelial resistance and permeability experiments were done with HUVECs isolated from normal pregnancies (n = 8).Table 1 Clinical characteristics of the study population that had samples used for gene and protein expression
Characteristic Normal
(n = 9) d-GDM
(n = 7) m-GDM
(n = 6) p value
Maternal age, years 34.67 (6.04) 30.57 (6.78) 31.83 (4.71) 0.390
Maternal BMI, kg/m2 25.71 (4.27) 29.20 (7.54) 32.38 (6.89) 0.145
Gestational age at delivery, weeks 38.69 (1.18) 39.17 (0.26) 39.40 (0.37) 0.236
HbA1c, mmol/mol – 37.44 (3.99) 36.60 (2.97) 0.848
HbA1c, % – 5.57 (0.36) 5.60 (0.34) 0.924
Placental weight, g 674.4 (108.9) 674.4 (119.4) 644.2 (98.4) 0.848
Baby weight, kg 3.49 (0.37) 3.54 (0.69) 3.62 (0.71) 0.924
Individual birthweight centile [sex] 47.15th [M]
76.31th [F]
62.16th [M]
95.67th [M]
93.48th [M]
88.55th [F]
29.82th [M]
46.28th [M]
98.96th [M]
93.51th [F]
54.28th [F]
30.92th [F]
28.40th [M]
99.96th [M]
66.66th [F]
67.69th [M]
80.82th [M]
91.68th [F]
99.94th [M]
43.02th [F]
15.77th [F]
71.76th [M]
0.857
Data are presented as mean (SD); p value calculated by one-way ANOVA
[F], neonatal sex female; [M], neonatal sex male
Table 2 Clinical characteristics of the study population that had samples used for the placental permeability assay
Characteristic Normal pregnancy
(n = 4) d-GDM
(n = 4) p value
Maternal age, years 30.75 (3.76) 32.00 (7.53) 0.777
Maternal BMI, kg/m2 27.00 (2.83) 29.15 (3.37) 0.366
Gestational age at delivery, weeks 38.25 (0.96) 37.50 (1.30) 0.387
HbA1c, mmol/mol 38.50 (3.51)
HbA1c, % 5.68 (0.32)
Placental weight, g 817.8 (125.1) 898.5 (199.7) 0.519
Baby weight, kg 4.04 (0.49) 4.15 (0.31) 0.706
Individual birthweight centile [sex] 94.47th [M]
99.87th [M]
99.73th [F]
84.03th [F]
99.96th [F]
99.10th [M]
99.93th [F]
93.48th [M]
0.407
Data are presented as mean (SD); p value calculated by one-way ANOVA
[F], neonatal sex female; [M], neonatal sex male
Women in all groups were of similar age, had no vascular complications, pre-eclampsia or hypertension, were non-smokers and were not taking any other medications.
Tissue preparation and sampling
Placentas and umbilical cords were taken immediately after delivery. Chorionic villous biopsies were taken from four quadrants, midway between the umbilical cord insertion and the placental rim. For immunostaining, fresh tissue was fixed in 1% (wt/vol.) paraformaldehyde (PFA), frozen in nitrogen-cooled isopentane and stored at −80°C. For protein extraction, tissue was snap-frozen and stored at −80°C. For RNA isolation, tissue was placed in RNAlater solution (Sigma-Aldrich, USA) and stored at −20°C. For tracer leakage analysis, placentas were immediately processed as described below.
Systematic random sampling of junctional occludin in vascular profiles
An indirect immunofluorescence method was used [26]. Briefly, frozen placental sections were permeabilised with acetone and 0.1% Triton X-100, blocked with 5% normal human serum, and incubated with primary antibodies for occludin (2.5 μg/ml; rabbit polyclonal; catalogue no. 71-1500, Thermo Fisher, USA) and the endothelial marker platelet endothelial cell adhesion molecule 1 (PECAM-1) (2.5 μg/ml; mouse monoclonal; catalogue no. BBA7, R&D Systems, UK). Sections were washed thoroughly and incubated with the appropriate secondary antibodies: FITC-conjugated anti-rabbit (10 μg/ml; catalogue no. F0382, Sigma-Aldrich) and tetramethylrhodamine isothiocyanate (TRITC)-conjugated anti-mouse (10 μg/ml; catalogue no. T5393, Sigma-Aldrich). All antibodies were diluted in 0.1% (wt/vol.) BSA in 0.1 mol/l PBS.
Immunoreactivity in the sections was visualised (blind) using a Nikon microscope (LaboPhot-2, Nikon Instruments, UK). A systematic random sampling of fields of view was adopted and micrographs acquired. The number of vascular profiles showing immunoreactivity to occludin and PECAM-1 was counted using the unbiased ‘forbidden line’ counting principle [27]. No more than 150 vascular profiles were counted for each placenta to maintain sampling efficiency.
Protein isolation and western blotting
Placental tissue was homogenised in protein lysis buffer (50 mmol/l Tris pH 8.0, 150 mmol/l NaCl, 0.5% deoxycholate, 1% Triton X-100, 0.1% [wt/vol.] sodium dodecyl sulphate [SDS]) plus 2 mmol/l phenylmethylsulfonyl fluoride (PMSF), a protease (Roche, Germany) and phosphatase inhibitors cocktails (Sigma-Aldrich). Protein concentration was measured using the DC Protein Assay (Bio-Rad, USA).
Total protein (40 μg) was separated on a 4–20% SDS-PAGE gel (Bio-Rad). Nitrocellulose membranes were incubated with primary antibodies: polyclonal rabbit anti-occludin (0.5 μg/ml; catalogue no. 71-1500, Thermo Fisher), and monoclonal mouse anti-β-actin (7 μg/ml; catalogue no. A531, Sigma-Aldrich). Secondary antibodies: goat anti-rabbit (catalogue no. 926-32211, LI-COR, Germany), and goat anti-mouse (catalogue no. 925-68070, LI-COR) diluted to 0.1 μg/ml. Membranes were scanned with an Odyssey Infrared Imaging System 3.0 (LI-COR). Quantification of bands was performed with ImageJ Software Version 2.0 [28]. Fluorescence intensity of occludin bands was normalised to their respective loading control. All antibodies were diluted in blocking buffer (5% [wt/vol.] milk (in 1× Tris-Buffered Saline, 0.1% Tween 20 detergent).
A similar protocol was used for VEGF-A with minor modifications: 20 mg of total protein and primary antibody polyclonal rabbit anti-VEGF-A (3.6 μg/ml; catalogue no. ab183100, Abcam).
RNA isolation and qPCR
Total RNA was extracted using TRI Reagent (Sigma-Aldrich) and a TissueLyser LT (Qiagen, Australia) homogeniser. RNA quantity and quality were assessed using the NanoDrop spectrophotometer ND-2000 (Thermo Fisher).
Five μg of total RNA were reverse transcribed using SuperScript III Reverse Transcriptase (Invitrogen, USA) and random primers (Promega, USA). Quantitative real-time PCR (qPCR) reactions were performed in triplicate with SYBR Green JumpStart Taq ReadyMix (Sigma-Aldrich), and detection was performed using the Rotor-Gene 6000 cycler (Corbett Research, Mortlake, NSW, Australia). The thermal profile included 95°C for 10 min, 40 cycles of 95°C for 15 s, annealing temperature (specific of each primer) for 30 s, and 72°C for 40 s (Table 3). Gene expression was normalised to a geometric average of three reference genes (YWHAZ, TBP, SDHA) [29]. The relative expression changes were determined using the relative quantification (2−∆∆Ct) method [30].Table 3 Primer sequences
Gene Sequence Primer concentration (nmol/l) cDNA dilution Annealing temperature (°C)
YWHAZ F: 5′-TGGCTCGAGAATACAGAGAGAA-3′
R: 5′-TGGGGATCAAGAACTTTTCCAA-3′
200 1:256 58
TBP F: 5′-CCTAAAGACCATTGCACTTCGT-3′
R: 5′-TTCGTGGCTCTCTTATCCTCAT-3′
400 1:64 62
SDHA F: 5′-GTGCCGTGGTGTCATCGC-3′
R: 5′-CTGGTGTGGGCAGACGTG-3′
300 1:256 60a
OCLN variant 1 F: 5′- TGAATTGGTCACCGAGGGAG-3′
R: 5′- TAAACCAATCTGCTGCGTCCTA-3′
600 1:8 60a
OCLN variant 2 F: 5′- GGCGAGCGGATTGGTTTAT-3′
R: 5′- AAGGAGGTGGACTTTCAAGAGG-3′
600 1:64 58a
OCLN variant 3 F: 5′-CCTTACAGGCCTGATGAATTGC-3′
R: 5′-TGTCCATCTTTCTTCGAGTTTTC-3′
F 300 / R 800 1:8 62a
VEGF-A F: 5′- ATCTTCAAGCCATCCTGTGTGC-3′
R: 5′- TATGTGCTGGCCTTGGTGAG-3′
700 1:8 60b
a1 mmol/l betaine was needed for the specificity of the qPCR reaction
F, forward; R, reverse
Placental perfusion
A well-established dual-perfusion procedure was employed [9, 11, 12, 27]. Briefly, immediately after delivery by C-section, the placenta was transferred to a 37°C chamber with the umbilical cord kept clamped to prevent loss of blood and collapse of feto-placental vessels. Within 20 min, a chorionic vein and an artery supplying a chosen cotyledon were cannulated to establish the fetal circulation. Fetal arterial inflow and venous outflow was measured to ensure they were the same. Once venous outflow showed clear blood-free perfusate (several minutes), the placenta was inverted and the cotyledon clamped in a Perspex chamber to isolate it from the rest of the placenta. The independent maternal circulation was simulated by inserting five nasogastric tubes (equally spaced, one per lobule) into the intervillous space through the basal plate of the cotyledon and drained through an exit tube in the chamber. Fetal and maternal circulations were connected to peristaltic pumps providing a constant flow of 20 ml/min to the maternal circulation and a 5 ml/min flow to the fetal circulation. Maternal and fetal perfusion pressures were monitored continually by placing pressure transducers just prior to arterial inflows of both circuits. A maternal blood pressure of 18–20 mmHg and a fetal blood pressure of 40–80 mmHg was accepted as normal. Increases above these ranges led to abandonment of the experiment (one in five failure rate). Flow rates and perfusion pressures were visualised continually with ML866/P PowerLab 4/30 recording unit and LabChart Pro software (ADInstruments, UK).
A 20 min open circuit equilibration period was performed to reverse any post-parturition hypoxic changes [9]. During this period, both circuits were irrigated with oxygenated Medium 199 (Sigma-Aldrich), with added sodium bicarbonate (2.2 g/l), albumin (5 g/l), high-molecular-weight dextran (2000 Mr; 8 g/l) and heparin (5000 IU/l) (final pH 7.2–7.4). After equilibration, fetal oxygenation was stopped, 76 Mr dextran conjugated with TRITC (1 mg/ml; Sigma-Aldrich) was added as a bolus into the closed fetal circulation for 10 min. The maternal circuit remained open, oxygenated and tracer free. Finally, 1% (wt/vol.) PFA was introduced into the fetal circuit, the clamped Perspex chamber was removed to prevent bulk flow and the cotyledon perfusion fixed for 30 min. The cotyledon was excised, weighed (~50 g) and vertical slices (basal plate to chorionic plate) from fixed, blanched lobules only were taken for a further immersion fixation (1 h). Biopsies (villous trees) were frozen in nitrogen-cooled isopentane and stored. Cryosections were obtained, PECAM-1 detected by immunocytochemistry, and micrographs acquired by systematic random sampling of fields of view.
Tracer leakage sampling
The vascular profiles displaying tracer leakage (hotspots) were counted (blinded) using unbiased ‘forbidden line’ counting principle [12, 15, 27]. To maintain efficiency, between 100 and 200 vessels were counted in each placenta from each group. The number of vessels with hotspots (in terminal, intermediate and stem villi) was subsequently expressed as a percentage of total vessels counted (all vessels in the field of view). The percentages of conduit vessels in stem and intermediate villi from normal and d-GDM groups were analysed for this study.
Quantification of microRNA expression
Total RNA (5 ng) was reverse transcribed using a miRCURY LNATM Universal RT microRNA PCR Kit (Exiqon, Denmark) per manufacturer’s instructions. miRNAs that target OCLN expression were selected based on literature and a bioinformatics search using three databases: miRBase (www.mirbase.org), miRTarBase (http://mirtarbase.mbc.nctu.edu.tw) and DIANA (http://diana.imis.athena-innovation.gr/DianaTools/index.php). Five miRNAs were selected: miR-18a-5p, miR-21-3p, miR-122-5p, miR181a-5p and miR-340-5p. Exiqon primers were used for amplification (catalogue nos YP00204207, YP00204302, YP00205664, YP00206081 and YP00206068, respectively). qPCRs were conducted in triplicate using ExiLENT SYBR Green master mix (Exiqon). Detection was performed using the Rotor-Gene 6000 cycler; 95°C for 10 min, followed by 40 cycles of 95°C for 10 s, and 60°C for 1 min. Samples were diluted 1:80 before qPCR and 4 μl of the diluted samples were used in 10 μl reactions. U6 spliceosomal RNA gene was used as an internal control (catalogue no. YP00203907).
Transfection of HUVECs with miRNA
HUVECs were isolated from normal pregnancies (n = 4) following a standardised protocol [31]. HUVECs were used for transfection of miR-181a-5p mimic between passages 2 or 3. Optimisation of transfection was done following manufacturer’s instructions (Dharmacon Research, USA). Briefly, HUVECs were seeded into 12 well plates at ~2.0 × 105 cells/well in transcription medium (TM20, which is antibiotic-free M199 [catalogue no. 12340030, Thermo Fisher] with 20% FCS) and cultured overnight at 37°C in a humidified incubator with 5% CO2 in air. Each sample was treated under four conditions (n = 3 per condition, per sample): untreated control (TM20); transfection control (TM20 + transfection reagent); negative control (TM20 + transfection reagent + negative control mimic); miR-181a-5p transfection (TM20 + transfection reagent + miR-181a-5p mimic). Each reaction needed 0.75% DharmaFECT-1 transfection reagent (T-2001-01, Dharmacon), 15 nmol/l miRIDIAN miR-181a-5p mimic (C-300552-05-0005, Dharmacon), or 15 nmol/l miRIDIAN mimic negative control (CN-001000-01-05, Dharmacon). Cells were cultured for 24 h and the transfection medium was replaced with fresh TM20 for a further 24 h incubation. Finally, cells were washed and TRI Reagent was used to isolate RNA.
HUVEC permeability assays
For assessment of trans-endothelial electrical resistance (TEER), HUVECs isolated from normal pregnancies (n = 4) were seeded in triplicate onto gelatine-coated 12 transwell inserts (catalogue no. CLS3493, Corning, USA). TEER was measured in triplicate before transfection and every 24 h for the next 3 days using an EVOM volt meter (World Precision Instruments, UK). TEER values were subtracted from blank TEER values (inserts without cells) and multiplied by the surface area of the transwell.
For tracer leakage, an aliquot of the same HUVECs used for TEER (n = 4) was seeded under similar conditions. After HUVECs were transfected (48 h), medium was replaced with phenol-free M199 (catalogue no. 11043023, Thermo Fisher), apical 0.5 ml, basal 1.5 ml, ensuring same level in inner and outer well. FITC-conjugated dextran (molecular weight 76,000; 1 mg/ml; Thermo Fisher) was added to the apical chamber. Fifty microlitres of medium from the basal chamber were collected every 30 min for 2 h; the volume taken was replaced to ensure hydrostatic pressure remained balanced after each sample collection. Tracer leakage was measured by a fluorescence microplate reader (Labtechnologies FLUOstar Galaxy Microplate Reader, UK) at an emission/excitation wavelength of 485/520 nm. The concentration of tracer in each sample was calculated via linear regression of a standard curve. Absolute permeability (cm/s) was calculated as the ratio of the tracer leakage to the concentration gradient as follows [32]: P=Ct–Ct0×VA×t×C0
Where C(t) and C(t0) are the tracer concentrations (μg/ml) at 120 min and 0 min, respectively, estimated by linear regression; V is the volume in the lower compartment (1.5 cm3); A is the surface area of the transwell membrane (1.1 cm2); t is the duration of the flux (7200 s); and C0 is the initial concentration of the tracer on the apical side (1000 μg/ml).
Statistical analysis
Data are expressed as mean ± SEM. Data were tested for normality of the distribution by the D’Agostino–Pearson test with a confidence interval of 95%. Study population, protein localisation, protein expression, placental perfusion, miRNA expression, TEER and HUVEC tracer leakage were normally distributed. Statistical comparisons between two groups were performed by independent samples t test, and among the three groups by one-way ANOVA. Results from gene expression were not normally distributed. Statistical comparison here were performed by Mann–Whitney U test and Kruskal–Wallis test. Pearson’s and Spearman’s rank correlation coefficients were used depending on the normality distribution of the data. All statistics were calculated and graphs plotted with GraphPad Prism 6.0 (GraphPad Software, USA); p < 0.05 was considered statistically significant.
Results
Comparison of maternal characteristics
Comparisons of clinical details between each group, samples used for gene and protein expression (Table 1) and for placental vascular permeability (Table 2), showed no significant difference in maternal age, BMI, gestational age at delivery, placental weight, or baby weight (p > 0.05). The HbA1c from all women with GDM showed that glucose levels were under control with both diet and metformin approaches (HbA1c <39.0 mmol/mol or <5.7%).
Birthweight centiles revealed that some babies were above the 95th centile, and therefore classified as large for gestational age (LGA) [33] in both the normal and GDM groups. However, no significant differences were found between groups. There were no correlations between birthweight centiles and occludin protein or gene expression (Pearson’s correlation coefficient p > 0.01). In the perfused placentas, no significant correlation was detected (Spearman’s rank correlation coefficient; p > 0.01) between vascular leakage and selected variables, which included maternal HbA1c, birthweight, birthweight centile and placental weight.
Lower percentage of junctional occludin-positive vessels in d-GDM
The percentage of PECAM-1-positive vascular profiles in stem and intermediate villi showing junctional localisation of occludin were significantly different among the groups (p = 0.015) (Fig. 2). In terms of the proportion of occludin-positive vessels, the percentage value was 12% lower in d-GDM samples than in normal samples (p = 0.005) and 10% lower in d-GDM samples than m-GDM samples (p = 0.049). There was no difference in the percentage of occludin-positive vessels between the normal and m-GDM samples. Figure 3 shows localisation of occludin and PECAM-1 in conduit vessels from normal and GDM placental samples.Fig. 2 Reduced percentage of occludin-positive vessels in d-GDM pregnancies. Placental samples were taken from normal pregnancies (n = 9), and pregnancies complicated with d-GDM (n = 7) or m-GDM (n = 6) and the endothelial marker PECAM-1 and occludin were immunolabelled prior to systematic counts. The graph shows the percentage of vessels with junctional occludin in the samples from the three groups. Data are presented as mean ± SEM; missing data correspond to outliers. One-way ANOVA between groups (F(2, 15) = 5.57, p = 0.015); *p < 0.05, **p < 0.01 by post hoc unpaired t test
Fig. 3 Representative micrographs showing occludin and PECAM-1 localisation in conduit vessels from normal and GDM placentas. Placental samples were taken from normal pregnancies (n = 9), and d-GDM pregnancies (n = 7) or m-GDM pregnancies (n = 6). (a, b) Full junctional occupancy of occludin (FITC) (a) and PECAM-1 (TRITC) (b) can be seen in all vascular profiles in intermediate villi (iv) from normal pregnancies. (c, d) Micrographs showing a similar full occupancy of occludin (c) and PECAM-1 (d) in intermediate villous vessels from the metformin-treated study group. Figure 3c was taken at a different camera setting (higher gain), to ensure vascular localisation could be seen. (e–h) Micrographs from diet-controlled GDM placentas showing loss of occludin staining (e) from numerous PECAM-1-positive vascular profiles in intermediate villus (f). (g, h) A stem villus (sv) showing occludin immunostaining with TRITC--conjugated anti-rabbit IgG (g) and anti-PECAM-1 immunoreactivity with FITC-conjugated anti-mouse IgG (h). The arrow points to a large vessel with a reduced number of paracellular clefts showing occludin. Note the presence of occludin in the trophoblast layer in all study groups. Scale bar, 50 μm
Occludin protein expression is affected in d-GDM
Two occludin protein isoforms were detected in human placental samples (Fig. 4a). Occludin isoform-A expression was 29% lower in placental samples from d-GDM pregnancies compared with samples from normal pregnancies (p = 0.040) (Fig. 4b). Occludin isoform-B expression was similar among the groups (p = 0.938) (Fig. 4c). In placental samples from the m-GDM pregnancies, protein expression of these occludin isoforms was similar to that in samples from normal pregnancies.Fig. 4 Reduced occludin isoform-A protein expression in human placental tissue from d-GDM pregnancies. Placental samples were taken from normal pregnancies (n = 9), and pregnancies complicated with GDM where glucose levels were managed with diet (n = 7) or metformin (n = 6). (a) Representative western blots of occludin isoform-A (~60 kDa) and isoform-B (~ 30 kDa) from placental samples from normal (N), d-GDM (D), and m-GDM (M) pregnancies. β-Actin (~40 kDa) was used as a loading control. (b, c) Graphs of relative expression of occludin isoform-A (b) and occludin isoform-B (c) in samples from the three groups. Data are presented as mean ± SEM; missing data correspond to outliers. *p < 0.05 by post hoc unpaired t test
OCLN gene expression is affected in d-GDM
All three predicted OCLN splice variants were found in placental samples; OCLN variant 2 represents 67% of total OCLN gene expression in placental samples from normal pregnancies (Fig. 5a). OCLN variant 2 expression was 33% lower in d-GDM samples than in normal placental samples (p = 0.016) (Fig. 5c). In the d-GDM samples, OCLN variant 3 gene expression was 3.3-fold that in normal placental samples (p = 0.020) (Fig. 5d). OCLN variant 1 expression was similar in placental samples among the groups (p = 0.194) (Fig. 5b). Gene expression of these OCLN splice variants in placental samples from the m-GDM pregnancies was similar to that in samples from normal pregnancies.Fig. 5 Differential gene expression of OCLN in human placental tissue from d-GDM pregnancies. Placental samples were taken from normal pregnancies (n = 9), and d-GDM (n = 7) or m-GDM (n = 6) pregnancies. (a) Total OCLN gene expression is produced by three OCLN splice variants (var) in human placenta from normal pregnancies. (b–d) Gene expression of OCLN variant 1 (b), OCLN variant 2 (c) and OCLN variant 3 (d) in the three groups. Data are presented as mean ± SEM. *p < 0.05 by Mann–Whitney U test
Placental vascular permeability is compromised in d-GDM
In placentas from d-GDM pregnancies the percentage of placental conduit vessels (residing in intermediate and stem villi) associated with tracer hotspots was 2.0-fold that in placentas from the normal pregnancy group (p = 0.009) (Fig. 6). In the latter, the number of vessels associated with leaks was sparse (Fig. 6a, b), corresponding to 10.18% of the total observed vessels (Fig. 6f). Moreover, the leaks (number of associated hotspots) were discreet. Placental vessels from d-GDM pregnancies showed numerous (>2) hotspots per vessel (Fig. 6c–e) and 19.92% of the total observed vessels showed hotspots (Fig. 6f).Fig. 6 Increased tracer leakage in conduit vessels in placentas from d-GDM pregnancies. (a–e) Representative micrographs showing PECAM-1 (FITC channel) and dextran tracer (TRITC channel) from perfused placentas from normal pregnancies (n = 4), and d-GDM pregnancies (n = 4). (a, b) Fetal vessels in stem villi (sv) and intermediate villi (iv) from normal pregnancies showing no or discreet (<2 hotspots) leakage of 75 Mr TRITC-dextran. (c–e) In placentas from the d-GDM group, hotspots of tracer (red) can be seen trapped in the interstitium adjacent to vascular profiles in intermediate and stem villi. (e) A composite of the micrographs in (c) and (d) highlighting hotspots. Scale bar, 50 μm. (f) Comparison of percentage of conduit vessels with peri-vascular hotspots between the two groups. Data are presented as mean ± SEM. **p < 0.01 by unpaired t test
Increased miR-181a-5p expression in d-GDM placental samples
From the five miRNAs screened, three were found in the human placenta: miR-18a-5p, miR-21-3p, and miR-181a-5p (Fig. 7). The expression of miR-18a-5p (p = 0.293) (Fig. 7a) and miR-21-3p (p = 0.780) (Fig. 7b) was not different among the groups. In placental samples from d-GDM pregnancies, miR-181a-5p expression was 2.0-fold that in placental samples from normal samples (p = 0.043) (Fig. 7c). In placental samples from m-GDM pregnancies, expression of these miRNAs was not significantly different from that in samples from normal pregnancies.Fig. 7 Higher miR-181a-5p expression in d-GDM placental samples. Placental samples were taken from normal pregnancies (n = 9), and pregnancies complicated with d-GDM (n = 7) or metformin (n = 6). The expression of miR-18a-5p (a), miR-21-3p (b) and miR-181a-5p (c) in the three groups. Data are presented as mean ± SEM. *p < 0.05 by post hoc unpaired t test
Overexpression of miR-181a-5p downregulates OCLN variant 1 and 2 expression in HUVECs
Overexpression of miR-181a-5p was confirmed by comparing its expression under control conditions with that in miR-181a-5p mimic transfection conditions (p = 0.007) (Fig. 8a). The expression of OCLN variant 1 was stable among the three control conditions (p > 0.05), and 69% lower in miR-181a-5p mimic transfection compared with untreated control (p = 0.010), transfection control (p = 0.004) and negative control (p < 0.001) (Fig. 8b). Likewise, OCLN variant 2 expression was stable among the three control conditions (p > 0.05), and 46% lower in miR-181a-5p mimic transfection compared with untreated (p = 0.009) and transfection control (p = 0.018) (Fig. 8c). OCLN variant 3 expression was stable between conditions (p = 0.509) (Fig. 8d).Fig. 8 Overexpression of miR-181a-5p downregulates OCLN expression. HUVECs isolated from normal pregnancies (n = 4) were subject to four transfection conditions for 48 h: untreated control (UC), transfection control (TC), negative control (NC), and miR-181a-5p transfection (miR). (a) miR-181a-5p expression in HUVECs transfected with the mimic. (b–d) Expression of OCLN variant 1 (b), OCLN variant 2 (c) and OCLN variant 3 (d). Data are presented as mean ± SEM of four independent experiments, each condition performed in triplicate. *p < 0.05, **p < 0.01, ***p < 0.001 post hoc unpaired t test
Overexpression of miR-181a-5p decreased endothelial barrier integrity and increased permeability in HUVECs
TEER was measured to evaluate whether the overexpression of miR-181a-5p would affect endothelial barrier integrity (Fig. 9a). During the different timepoints, resistance was stable among the controls (p > 0.05). A reduction of resistance was seen 48 h after transfection, HUVECs overexpressing miR-181a-5p showed 35% lower resistance than controls (p < 0.05). This reduction was increased 72 h after transfection, showing 78% lower resistance than controls (p < 0.001).Fig. 9 Overexpression of miR-181a-5p reduces endothelial barrier integrity and increases permeability. HUVECs isolated from normal pregnancies (n = 4) were subject to four transfection conditions: untreated control (UC), transfection control (TC), negative control (NC) and miR-181a-5p transfection (miR). (a) TEER was measured every 24 h after transfection (t0) for 72 h. (b) Tracer leakage was measured 48 h after transfection. Data are presented as mean ± SEM of four independent experiments, each condition performed in triplicate. *p < 0.05, ***p < 0.001 by post hoc unpaired t test
Tracer leakage was measured to evaluate permeability in HUVECs overexpressing miR-181a-5p. At the end of the 2 h experiments, permeability was stable among the controls (p > 0.05). In HUVECs overexpressing miR-181a-5p permeability was 1.3-fold that in the untreated control HUVECS (p = 0.02) (Fig. 9b).
VEGF-A protein expression is affected in d-GDM samples
VEGF-A protein expression was 26% lower in placental samples from d-GDM pregnancies than in placental samples from normal pregnancies (p = 0.044; Fig. 10a). Placental samples from the m-GDM pregnancies showed stable VEGF-A protein expression compared with samples from normal pregnancies. Total VEGF-A gene expression was similar between groups (p = 0.370) (Fig. 10b).Fig. 10 Reduced VEGF-A protein expression in human placental tissue from d-GDM pregnancies. Placental samples were taken from normal pregnancies (n = 9), and pregnancies complicated with d-GDM (n = 7) or m-GDM (n = 6). VEGF-A protein (a) and gene expression (b) were analysed between groups. (c) Representative western blot bands of VEGF-A (~45 kDa) from normal, diet-controlled and metformin-controlled placental samples. β-actin (~40 kDa) used as a loading control. Data are presented as mean ± SEM. *p < 0.05 by post hoc unpaired t test
Discussion
This study is the first to show the presence of the three predicted OCLN splice variants and their two protein isoforms in human placenta. Our data from the d-GDM group suggests that well-controlled glucose may not be enough to protect against alterations to the OCLN gene and occludin protein expression or junctional localisation. Furthermore, we demonstrate that conduit placental microvessels of placental samples from d-GDM pregnancies have a higher percentage of leaky vessels than those in placental samples from normal pregnancies. Interestingly, occludin expression and junctional localisation were similar between placental samples from m-GDM pregnancies and normal pregnancies, and so it is tempting to speculate that metformin may help prevent alterations in occludin expression. Expression of miR-181a-5p was found to be significantly higher in placentas from d-GDM pregnancies. Overexpression of miR-181a-5p in HUVECs from normal pregnancies led to a downregulation of OCLN gene expression and reduced endothelial barrier integrity. It is therefore possible that the downregulation of OCLN expression in placentas from d-GDM pregnancies may have been epigenetically controlled, in part, by miR-181a-5p expression.
Analyses of junctional localisation of occludin revealed a 12% decrease in occludin-positive vessels in the d-GDM samples. This is in agreement with findings from a previous study showing reduced junctional occludin in placental vasculature in insulin-controlled GDM pregnancies [5]. In the present study, no changes were found in placental samples from the m-GDM group. This marked difference between the two GDM groups reinforces our hypothesis that the type of treatment used to control glucose levels in pregnancies complicated with GDM is an important factor to consider when analysing data. The loss of occludin from tight junction domains may be a consequence of inflammation. Indeed, phosphorylation of junctional adhesion molecules by VEGF-A, resulting in loss of anchorage and internalisation, is a well-established acute response [12, 15, 17, 27]. In our study we did not see increased expression of VEGF-A protein, but, rather, a decrease in the d-GDM placentas. Whether this was due to a reduction in the expression of VEGF-A165a or the anti-permeability VEGF-A165b splice variant remains to be shown. We have previously shown that perfusion with VEGF-A165a results in increased albumin leakage from placental vessels, whilst VEGF-A165b reduces paracellular leakage [12]. The altered expression of occludin isoforms seen in placentas from the d-GDM study group suggests that there is an additional mechanism at play.
Our study reports the expression of two occludin protein isoforms (occludin isoform-A and occludin isoform-B) in human placental vessels. As stated above, occludin isoform-A is a fully functional protein that oversees the stability of the membrane [34]; a decrease of this may affect junctional integrity. This hypothesis was confirmed by the 29% decrease seen in d-GDM samples, decreased percentage of occludin-positive vessels and increased vascular leakage in conduit vessels. Protein expression of occludin isoform-A was not altered in the m-GDM group vs the normal group. Curiously, the protein expression of occludin isoform-B, a truncated protein implicated in preventing claudin-4 from attaching to the tight junctions and increasing paracellular permeability [19], was similar among the three groups. Whether this isoform can hamper the barrier integrity function of occludin isoform-A in the placenta requires investigation.
The presence of two occludin protein isoforms suggested that the OCLN gene is regulated by alternative splicing. Our previous study confirmed, for the first time, the expression of three OCLN splice variants (OCLN variant 1, variant 2 and variant 3) in human placental tissue [35]. OCLN variant 2 represents ~67% of total OCLN expression in placental samples from normal pregnancies. This variant and OCLN variant 1 are responsible for the translation of occludin isoform-A. We found that OCLN variant 2 expression was decreased by 33% in d-GDM samples. This indicates that the reduction in endothelial junctional occludin from d-GDM samples is not only due to lower protein expression but also the result of a downregulation of OCLN variant 2 expression. OCLN variant 3 represents ~18% of total OCLN expression in normal pregnancy samples, and is translated into occludin isoform-B. Contrary to our results for isoform-B protein expression, in placental samples from the d-GDM group OCLN variant 3 expression was 3.3-fold that in samples from normal pregnancies. Therefore, there is still the possibility that the translation of OCLN variant 3 may be compromised.
The significant differences in the expression of OCLN variant 2 and isoform-A in placentas from the d-GDM group correlate with functional consequences. Perfusion of placental microvascular beds in d-GDM revealed a 100% increase in vessels associated with leaks of a 76 Mr tracer (slightly larger than albumin) compared with the physiological basal level of leakage exhibited by the vessels in placental samples from the normal pregnancy group (Fig. 6). In the placenta, paracellular permeability to hydrophilic solutes can be induced by VEGF and histamine. We previously reported that perfusion with VEGF-A resulted in reversible TRITC-labelled 76 Mr dextran leaks and loss of junctional adhesion molecules throughout the placental vascular tree [12], while histamine significantly increased the separation between adjoining endothelial membrane leaflets at tight junction regions (4.1–6.1 nm) but not at adherens junctional zones, leading to increased transport of the smaller molecules cyanocobalamin and EDTA, but not albumin [10]. In the present study, the d-GDM perfused placental leakage pattern suggests the influence of inflammatory conditions and altered structural composition of tight junctions induced by the reduced expression of the transmembrane isoform of occludin. The perfused placentas from the d-GDM group showing altered vascular leaks have not been interrogated with anti-occludin antibodies. The assumption here was that they would have a loss of occludin similar to that observed in the immunofluorescence studies of vascular profiles of the d-GDM study group. Nevertheless, the suboptimal functioning of the d-GDM placental endothelial barrier, i.e. the increased number of conduit vessels showing perivascular tracer hotspots, albeit mild, may have a detrimental effect on total placental function and, concurrently, the developing fetus whose vasculature is in continuum with the placental vasculature. GDM occurs late in gestation, from second trimester onwards, but this shorter exposure to the diabetic milieu still resulted in increased vascular leakage and changes in occludin expression.
Birthweight centiles revealed that some babies were LGA in both the normal and GDM groups. However, no correlations were found between birthweight centiles and occludin protein, gene expression or vascular leakage. Complex interactions of fetal hyperinsulinaemia, hypoxia and overnutrition are involved in the development fetal macrosomia and assessment of measures of these factors was beyond the scope of this study.
Given that OCLN expression was affected in the d-GDM group, we explored epigenetic control. Screening for miRNAs that target OCLN, revealed that miR-18a-5p, miR-21-3p and miR-181a-5p are expressed in human placenta. The expression of miR-18a-5p and miR-21-3p was similar among groups. However, expression of miR-181a-5p was higher in placental samples from d-GDM pregnancies compared with those from normal pregnancies. Overexpression of miR-181a-5p in HUVECs resulted in an impaired endothelial barrier (78% reduction in resistance), increased 76 Mr dextran permeability (1.3-fold), as well as the decrease in gene expression of OCLN variants 1 and 2. TEER is considered a better in vitro marker of tight junctional integrity in endothelial monolayers with discontinuous ‘kissing’ tight junctions, whilst permeability and transit time of molecules slightly larger than albumin reflect changes in wide zone composition and frequency of tight junctional strand discontinuities along the paracellular cleft [11]. Studies with human glioma endothelial cells showed that overexpression of miR-181a-5p reduces endothelial resistance and the gene expression of tight junction molecules OCLN, ZO-1 and CLDN-5 [36]. Higher expression of miR-181a was found in non-pregnant individuals with type 1 and type 2 diabetes [37–39] and women affected by a GDM pregnancy tested after 3–11 years [40]. There is evidence that placental miRNAs can traffic to the maternal and fetal circulation [41, 42], thus the possibility remains that the higher expression of miR-181a-5p observed in the d-GDM group could affect maternal and fetal tight junctions. Increased presence of miR-181a-5p in the circulation could lead to downregulation of occludin in different organs and may be behind diabetic retinopathy or nephropathy. The miRNA miR-181a-5p could be one of the factors responsible for the downregulation of occludin in d-GDM placental samples.
Metformin can cross the placenta and has been found in the fetal circulation [43]. It is used for different clinical conditions and reduces insulin resistance. A study using metformin treatment for GDM showed that insulin resistance decreased in blood samples at term compared with baseline [44]. The use of metformin in women with polycystic ovary syndrome (PCO) before conception and during pregnancy reduced serum insulin, insulin resistance and insulin secretion [45]. Several studies have focused on the outcome of offspring from pregnancies treated with metformin. These found no apparent reason for concern on short-term [46–48], or long-term, effects of fetal exposure to metformin [49–51]. In our study, there were no differences in neonatal weight between normal and m-GDM pregnancies; however, the gestational age of the latter was >39 weeks. We did find that m-GDM placentas presented stable expression of occludin gene and protein levels. These results suggest a regulatory effect of metformin over occludin expression in GDM pregnancies but further investigation is required to determine the underlying mechanism.
In conclusion, feto-placental vessels from pregnancies complicated with d-GDM allow the extravasation of normally restricted macromolecules. Beyond phosphorylation of junctional molecules, loss of junctional occludin may be, in part, due to the downregulation of occludin expression and decreased localisation to tight junctions, altered splicing and elevated miR-181a-5p expression. These effects were only visible in the d-GDM group; treatment with metformin appeared to normalise the effects. Our study suggests that lifestyle changes (diet and exercise) in GDM may not be enough to prevent alterations in the expression of occludin and the endothelial barrier integrity. Moreover, these placental changes may be reflecting impaired vascular barrier function in the offspring and their increased vulnerability to inflammatory insults.
Abbreviations
C-sectionCaesarean section
d-GDMDiet-controlled gestational diabetes mellitus
GDMGestational diabetes mellitus
LGALarge for gestational age
m-GDMMetformin-controlled GDM
microRNAmiRNA
PECAM-1Platelet endothelial cell adhesion molecule 1
PFAParaformaldehyde
qPCRQuantitative real-time PCR
TEERTrans-endothelial electrical resistance
TRITCTetramethylrhodamine isothiocyanate
VEGFVascular endothelial growth factor
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Acknowledgements
We would like to thank the clinical staff and midwives at the Labour Ward, Queens Medical Centre, Nottingham University Hospital for the timely retrieval of the placenta. We would also like to thank the mothers who agreed to be part of the study and donated their placentas. We wish to thank K. Reeve, R. Newman and M. Garrioch, School of Life Sciences, University of Nottingham, for their assistance with the placental perfusion experiments during their Honours project semester in the Leach lab. Special thanks to R. S. Villota for his help with designing the graphical abstract.
Authors’ relationships and activities
The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
Contribution statement
LL and MTR were involved in the conception and design of this study. SDV performed the experiments, acquired the data and performed the statistical analyses. LL, assisted by K. Reeve, R. Newman and M. Garrioch, executed the tracer leakage perfusions and analyses. MTR designed and directed the gene expression and microRNA elements; LL designed and directed the physiological and immuno-imaging elements of the project. All authors were involved in the final analyses and interpretation of data, writing the manuscript, critical revision and have approved the final manuscript. LL is the guarantor of this work.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. SDV was funded by The Ecuadorian Government through the ‘Secretaría de Educación Superior, Ciencia, Tecnología e Innovación’ scholarship.
Data availability
The data are available from the corresponding author on request.
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Papilloedema'.
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Growth Hormone Treatment and Papilledema: A Prospective Pilot Study
To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.
Prospective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.
Two hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.
GH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.
What is already known on this topic?
Growth hormone (GH) replacement therapy is a risk factor for secondary pseudotumor cerebri. The incidence of this complication can vary depending on different GH indications.
What this study adds?
Children with intracranial hypertension could be asymptomatic, so the diagnosis should be based on fundus examination and not on patient’s symptoms. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. A previous history of pseudotumor cerebri should be investigated.
Introduction
Pseudotumor cerebri syndrome (PTCS) is a condition defined by elevated intracranial pressure (ICP) in the absence of clinical, laboratory or radiologic evidence of infection, vascular abnormality, intracranial space-occupying lesion or hydrocephalus (1,2). It can be primary, or secondary if there are any identifiable risk factors. Primary PTCS most commonly occurs in obese adult women of childbearing age (12-32/100,000). However, it is a rare condition in childhood (0.5-0.9/100,000) with an identifiable risk factor in 53-77% of paediatric cases (3,4,5). Papilledema is a hallmark in PTCS, which is not a benign disorder; there is a risk of severe and permanent visual loss. Even patients with mild visual loss experience reduction in quality of life (6).
Growth hormone (GH) replacement therapy was first associated with PTCS by The Food and Drug Administration in 1993 (7). Since then, multiple publications have described this association. Reeves and Doyle (8) found that the prevalence in the GH treated population was approximately 100 times greater than in the general paediatric population. This complication usually occurs in the first weeks after initiating treatment (approximately 2-12 weeks) and the papilledema (optic disc swelling from raised ICP) resolves on stopping treatment (8,9).
Pseudopapilledema is an elevated optic disc with obscured margins that may occur in hyperopic eyes and in the presence of buried optic disc drusen, rather than from raised ICP. Optic disc drusen are acellular deposits located within the optic disc. Sometimes it can be very difficult to differentiate between pseudopapilledema and papilledema, requiring the opinion of a suitably experienced ophthalmologist and complementary tests (10).
The aim of this study was to investigate the incidence of PTCS in children treated with GH in a paediatric hospital and to identify risk factors for this complication. A secondary aim was to identify which children really need fundus examination during GH treatment in order to detect this complication.
Methods
A prospective pilot study was conducted in paediatric patients who started GH treatment from February 2013 to September 2017. Inclusion criteria were patients under 16 years of age prescribed GH by the Paediatric Endocrinology Department. Exclusion criteria were: absence of fundus examination prior to or at 3-4 months from starting treatment; severe optic disc atrophy where optic disc swelling would not develop; and cases where GH was prescribed by the Paediatric Nephrology Department. Predisposing pathology for intracranial hypertension was not considered an exclusion criterion, as fundus examinations were conducted before initiating treatment to rule out prior pathology of the optic nerve. The following variables were recorded: previous medical history; anthropometric data; and compliance with treatment.
Fundus was explored prior to and after 3-4 months of starting treatment or at any time when severe constant headache, vomiting or other presenting symptoms suggestive of intracranial hypertension arose. Prior fundus examination identified possible cases of pseudopapilledema and avoided possible confusion between this entity and newly developed papilledema in subsequent fundus follow-up examinations.
Fundus examination was carried out with indirect ophthalmoscopy and retinography was taken in cases of pseudopapilledema to facilitate follow up. In cases when papilledema was detected, GH was stopped and fundus examination was repeated four weeks later. If papilledema persisted, the patient was referred for neurological assessment, lumbar puncture and possible medical treatment with acetazolamide. Once papilledema resolved, if GH treatment was still considered necessary, treatment was re-initiated at a lower dose and progressively increased until the objective dose was achieved, with monthly ophthalmology visits until four months were completed at the target GH dose.
Cerebral magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis was performed in all patients with GH deficiency, prior to treatment. Initial GH doses were as indicated: 0.028-0.035 mg/kg/day for patients with GH deficiency and small for gestational age (SGA), 0.042 mg/kg/day for those with mutations in the SHOX gene and 1 mg/m2/day for patients with Prader-Willi syndrome (PWS).
Ethics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383). All subjects (or their parents or guardians) gave their written informed consent.
Statistical Analysis
In this case series, simple descriptive statistics were sufficient to delineate our populations. Variables are expressed as number, mean and percent (%) or range, as appropriate.
Results
There were 306 patients to whom GH was prescribed by the Paediatric Endocrinology Department between February 2013 and September 2017. Only 289 patients were enrolled in this study, 17 were excluded because of loss of ophthalmological follow up.
The mean age was nine years (range 1-16) and 53% of the patients were male. The patients were categorized according to their indication for GH treatment: 244 patients (84.4%) with GH deficiency; 36 patients (12.5%) with short stature associated with SGA; six patients (2%) with a mutation in the SHOX gene; and three (1%) with PWS. Patients diagnosed with chronic kidney disease were not included in the study as their indication for GH treatment and follow up was made by the Paediatric Nephrology Department.
In the first visit, prior to starting GH treatment, there were 546 eyes with normal optic discs, 16 eyes with pale optic discs, 11 eyes with pseudopapilledema, two eyes with optic disc and chorioretinal coloboma and one eye with dysplastic optic disc. Pale optic discs and optic disc and chorioretinal coloboma were secondary to the patient background pathology, suprasellar cerebral tumours and CHARGE anomaly respectively. In the follow up visit, five patients had optic disc swelling, suggesting papilledema, despite there being no symptoms of intracranial hypertension. None of the patients who presented with headache, who were visited urgently, presented with papilledema on fundus examination.
Table 1 outlines the characteristics of the five patients with papilledema. All these patients had GH deficiency: three had hypothalamic-pituitary axis abnormalities on brain MRI; two were congenital cases; and one was secondary to a suprasellar tumour. The patient with a suprasellar tumour had a ventriculoperitoneal shunt and was treated with external radiotherapy. The only patient with an isolated GH deficiency with normal MRI, had developed primary PTCS five years before and he was obese. The incidence of obesity in children without PTCS in our population is 10.3%.
The papilledema resolved on discontinuing GH treatment in four patients, whereas in the remaining patient, a lumbar puncture confirmed the diagnosis and was also therapeutic. The opening pressure was 25 cm H2O. The glucose was 61 mg/dL (38-82); protein 20 mg/dL (15-45) and there were neither leukocytes nor red blood cells present in the cerebrospinal fluid (CSF). Medical treatment was not required. In four cases GH treatment was reintroduced at a lower dose with progressive incremental doses, without the reappearance of papilledema.
Discussion
GH treatment is a risk factor for developing secondary PTCS although the mechanism is little understood. Two hypotheses have been proposed. The first is that GH could have a physiological antidiuretic effect, causing retention of sodium and water and expansion in blood volume, and reducing CSF resorption by the arachnoid villi. The second hypothesis proposes that GH would cross the blood-brain barrier, resulting in raised cerebral levels of GH and its mediator, insulin-like growth factor 1, and finally increasing CSF production (11,12,13,14).
GH was initially obtained from human pituitary gland, and was given at lower doses and frequency, and prescribed in fewer clinical situations. Since 1985, when recombinant human GH became commercially available, more patients were treated with larger doses and more often. Since then, indications for GH treatment have increased, as well as the potential adverse effects (15).
In our study, there were five patients with papilledema (1.7%), a higher incidence compared with the expected incidence in the general paediatric population (8,9,11,13). All of them had GH deficiency. Other indications for GH treatment did not appear to cause papilledema in this series, although these results may be biased due the small populations with these other indications.
As all the patients with papilledema were found to have GH deficiency, we analysed this group, classifying patients into three subgroups (Table 2):
1. Isolated GH deficiency (no other associated hormone deficiencies) with normal hypothalamic-pituitary axis anatomy on MRI.
2. Isolated GH deficiency or associated with other hormone deficiencies with altered hypothalamic-pituitary axis anatomy on MRI and/or past history of cerebral radiotherapy.
3. GH deficiency in patients with genetic or chromosomal diseases.
When considering patients who presented with papilledema, three completed criteria for subgroup 2, presenting with hypothalamic-pituitary axis abnormalities and external radiotherapy treatment in one case for a suprasellar tumour. These three patients in subgroup 2 had an intracranial hypertension, but not technically a PTCS, because the brain MRI was not normal. One other patient was classified as subgroup 3 for a non-specific genetic disease. Only one patient presented with an isolated GH deficiency with normal cerebral MRI, however this patient had had primary PTCS five years earlier. The patient with a suprasellar tumour also had a ventriculoperitoneal shunt, suggesting that the presence of a shunt is not protective against a rise in ICP induced by GH therapy.
For each GH indication, the incidence of this adverse effect can vary. Reeves and Doyle (8), reported higher incidences in patients with renal failure and Turner syndrome. Souza and Collet-Solberg (11), also detected a higher incidence in patients with chronic kidney disease. Darendeliler et al (16) proposed that patients with Turner syndrome, organic GH deficiency, PWS and chronic renal insufficiency might be more prone to develop papilledema when receiving GH. In our study, patients with renal disease were excluded, as the GH was not prescribed by the Paediatric Endocrinology Department. However, we have conducted a retrospective study of these patients with renal disease on GH treatment during the same time period and have also detected a higher incidence of papilledema, as described in the literature.
The association between the dose of GH and the risk of PTCS is not clearly established. Malozowski et al (15) reported that higher doses and increased frequency of administration since the introduction of recombinant human GH in 1985 may be contributing to the development of PTCS in some patients. However, Reeves and Doyle found no relationship between the GH dose and PTCS development (8). One of our patients received GH at the usual dose without complications, later on it was withdrawn due to lack of therapeutic effect. Interestingly, papilledema appeared three months after restarting GH at a higher dose. Patients with PWS and mutations in the SHOX gene, who received higher doses of GH did not present with papilledema, although these subgroups were small in this study. Even though there is no evidence that the GH dose is directly related with this complication, we recommend starting at lower dose and increasing it progressively, in order to minimize this complication.
Patients with a previous history of PTCS may experience recurrence at rates reported to vary between 6-22% (4,17,18,19). There is usually a triggering factor, such as weight gain or the introduction of known medications associated with secondary PTCS (20). In our series, the only patient with a previous history of PTCS, presented with papilledema. This patient was obese, which could have been a further risk factor for primary PTCS recurrence, however his weight had remained stable prior to starting GH treatment, at one month and at two months of treatment, when papilledema was diagnosed. For this reason, we believe it is important to identify patients initiating GH therapy with a previous history of PTCS because of the risk of recurrence. Also, consideration should be taken for starting treatment at a lower dose with progressive increases, accompanied by with careful follow-up including fundus examination during the first months of treatment.
Headache is a common symptom in the general paediatric population, and is also relatively frequent in patients on GH therapy, being the third most prevalent side effect described in KIGS (Pfizer International Growth study database) (16). On the other hand, headache is the main manifestation of intracranial hypertension at any age. However, in the paediatric population, headache is less common and 33% of children with PTCS may be totally asymptomatic (21,22), and diagnosis is only made on the observation of papilledema on fundus examination. It is important to highlight that papilledema is a cause of visual morbidity, including irreversible vision loss, independent of the patient symptoms. In our series, all patients with papilledema were asymptomatic, whereas no patients examined urgently for headache presented with papilledema.
Stopping GH is usually enough to treat this complication. Once papilledema has resolved GH can be reintroduced at a lower dose and progressively increased until the required dose is achieved to prevent recurrence and optimum growth. In the four patients where GH was reintroduced there were no recurrences of papilledema.
Study Limitations
The strengths of our study are the prospective design and the number of patients included in it. As children may be asymptomatic, prospective studies are the only way to establish the real incidence of this complication. The main limitation of our study is that patients with kidney diseases were not included and this group of patients has been reported to be at greatest risk of this complication in a different series.
Conclusion
In this study, we have shown that GH therapy is a risk factor for intracranial hypertension and the at-risk group were patients with GH deficiency and hypothalamic-pituitary axis abnormalities on MRI or genetic or chromosomal diseases. Patients may be totally asymptomatic, so fundus examination should be systematically implemented in this at-risk group, irrespective of the presence or absence of symptoms.
We thank Dr. Susana Noval for her valuable contribution in the analysis and interpretation of data and Dr. Silvia Muñoz for critical review of the manuscript.
Table 1 Characteristics of patients treated with growth hormone who developed papilledema
Table 2 Distribution of patients with growth hormone deficiency according to our classification in subgroups
Ethics
Ethics Committee Approval: Ethics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383, date: 17.05.2019).
Informed Consent: All subjects (or their parents or guardians) gave their written informed consent.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Concept/Design: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Data Collection or Processing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Analysis or Interpretation: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Literature Search: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Writing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste.
Financial Disclosure: The authors declared that this study received no financial support.
|
SOMATROPIN
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33006547
| 19,423,694
|
2021-06-02
|
What was the outcome of reaction 'Papilloedema'?
|
Growth Hormone Treatment and Papilledema: A Prospective Pilot Study
To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication.
Prospective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later.
Two hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before.
GH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.
What is already known on this topic?
Growth hormone (GH) replacement therapy is a risk factor for secondary pseudotumor cerebri. The incidence of this complication can vary depending on different GH indications.
What this study adds?
Children with intracranial hypertension could be asymptomatic, so the diagnosis should be based on fundus examination and not on patient’s symptoms. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. A previous history of pseudotumor cerebri should be investigated.
Introduction
Pseudotumor cerebri syndrome (PTCS) is a condition defined by elevated intracranial pressure (ICP) in the absence of clinical, laboratory or radiologic evidence of infection, vascular abnormality, intracranial space-occupying lesion or hydrocephalus (1,2). It can be primary, or secondary if there are any identifiable risk factors. Primary PTCS most commonly occurs in obese adult women of childbearing age (12-32/100,000). However, it is a rare condition in childhood (0.5-0.9/100,000) with an identifiable risk factor in 53-77% of paediatric cases (3,4,5). Papilledema is a hallmark in PTCS, which is not a benign disorder; there is a risk of severe and permanent visual loss. Even patients with mild visual loss experience reduction in quality of life (6).
Growth hormone (GH) replacement therapy was first associated with PTCS by The Food and Drug Administration in 1993 (7). Since then, multiple publications have described this association. Reeves and Doyle (8) found that the prevalence in the GH treated population was approximately 100 times greater than in the general paediatric population. This complication usually occurs in the first weeks after initiating treatment (approximately 2-12 weeks) and the papilledema (optic disc swelling from raised ICP) resolves on stopping treatment (8,9).
Pseudopapilledema is an elevated optic disc with obscured margins that may occur in hyperopic eyes and in the presence of buried optic disc drusen, rather than from raised ICP. Optic disc drusen are acellular deposits located within the optic disc. Sometimes it can be very difficult to differentiate between pseudopapilledema and papilledema, requiring the opinion of a suitably experienced ophthalmologist and complementary tests (10).
The aim of this study was to investigate the incidence of PTCS in children treated with GH in a paediatric hospital and to identify risk factors for this complication. A secondary aim was to identify which children really need fundus examination during GH treatment in order to detect this complication.
Methods
A prospective pilot study was conducted in paediatric patients who started GH treatment from February 2013 to September 2017. Inclusion criteria were patients under 16 years of age prescribed GH by the Paediatric Endocrinology Department. Exclusion criteria were: absence of fundus examination prior to or at 3-4 months from starting treatment; severe optic disc atrophy where optic disc swelling would not develop; and cases where GH was prescribed by the Paediatric Nephrology Department. Predisposing pathology for intracranial hypertension was not considered an exclusion criterion, as fundus examinations were conducted before initiating treatment to rule out prior pathology of the optic nerve. The following variables were recorded: previous medical history; anthropometric data; and compliance with treatment.
Fundus was explored prior to and after 3-4 months of starting treatment or at any time when severe constant headache, vomiting or other presenting symptoms suggestive of intracranial hypertension arose. Prior fundus examination identified possible cases of pseudopapilledema and avoided possible confusion between this entity and newly developed papilledema in subsequent fundus follow-up examinations.
Fundus examination was carried out with indirect ophthalmoscopy and retinography was taken in cases of pseudopapilledema to facilitate follow up. In cases when papilledema was detected, GH was stopped and fundus examination was repeated four weeks later. If papilledema persisted, the patient was referred for neurological assessment, lumbar puncture and possible medical treatment with acetazolamide. Once papilledema resolved, if GH treatment was still considered necessary, treatment was re-initiated at a lower dose and progressively increased until the objective dose was achieved, with monthly ophthalmology visits until four months were completed at the target GH dose.
Cerebral magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis was performed in all patients with GH deficiency, prior to treatment. Initial GH doses were as indicated: 0.028-0.035 mg/kg/day for patients with GH deficiency and small for gestational age (SGA), 0.042 mg/kg/day for those with mutations in the SHOX gene and 1 mg/m2/day for patients with Prader-Willi syndrome (PWS).
Ethics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383). All subjects (or their parents or guardians) gave their written informed consent.
Statistical Analysis
In this case series, simple descriptive statistics were sufficient to delineate our populations. Variables are expressed as number, mean and percent (%) or range, as appropriate.
Results
There were 306 patients to whom GH was prescribed by the Paediatric Endocrinology Department between February 2013 and September 2017. Only 289 patients were enrolled in this study, 17 were excluded because of loss of ophthalmological follow up.
The mean age was nine years (range 1-16) and 53% of the patients were male. The patients were categorized according to their indication for GH treatment: 244 patients (84.4%) with GH deficiency; 36 patients (12.5%) with short stature associated with SGA; six patients (2%) with a mutation in the SHOX gene; and three (1%) with PWS. Patients diagnosed with chronic kidney disease were not included in the study as their indication for GH treatment and follow up was made by the Paediatric Nephrology Department.
In the first visit, prior to starting GH treatment, there were 546 eyes with normal optic discs, 16 eyes with pale optic discs, 11 eyes with pseudopapilledema, two eyes with optic disc and chorioretinal coloboma and one eye with dysplastic optic disc. Pale optic discs and optic disc and chorioretinal coloboma were secondary to the patient background pathology, suprasellar cerebral tumours and CHARGE anomaly respectively. In the follow up visit, five patients had optic disc swelling, suggesting papilledema, despite there being no symptoms of intracranial hypertension. None of the patients who presented with headache, who were visited urgently, presented with papilledema on fundus examination.
Table 1 outlines the characteristics of the five patients with papilledema. All these patients had GH deficiency: three had hypothalamic-pituitary axis abnormalities on brain MRI; two were congenital cases; and one was secondary to a suprasellar tumour. The patient with a suprasellar tumour had a ventriculoperitoneal shunt and was treated with external radiotherapy. The only patient with an isolated GH deficiency with normal MRI, had developed primary PTCS five years before and he was obese. The incidence of obesity in children without PTCS in our population is 10.3%.
The papilledema resolved on discontinuing GH treatment in four patients, whereas in the remaining patient, a lumbar puncture confirmed the diagnosis and was also therapeutic. The opening pressure was 25 cm H2O. The glucose was 61 mg/dL (38-82); protein 20 mg/dL (15-45) and there were neither leukocytes nor red blood cells present in the cerebrospinal fluid (CSF). Medical treatment was not required. In four cases GH treatment was reintroduced at a lower dose with progressive incremental doses, without the reappearance of papilledema.
Discussion
GH treatment is a risk factor for developing secondary PTCS although the mechanism is little understood. Two hypotheses have been proposed. The first is that GH could have a physiological antidiuretic effect, causing retention of sodium and water and expansion in blood volume, and reducing CSF resorption by the arachnoid villi. The second hypothesis proposes that GH would cross the blood-brain barrier, resulting in raised cerebral levels of GH and its mediator, insulin-like growth factor 1, and finally increasing CSF production (11,12,13,14).
GH was initially obtained from human pituitary gland, and was given at lower doses and frequency, and prescribed in fewer clinical situations. Since 1985, when recombinant human GH became commercially available, more patients were treated with larger doses and more often. Since then, indications for GH treatment have increased, as well as the potential adverse effects (15).
In our study, there were five patients with papilledema (1.7%), a higher incidence compared with the expected incidence in the general paediatric population (8,9,11,13). All of them had GH deficiency. Other indications for GH treatment did not appear to cause papilledema in this series, although these results may be biased due the small populations with these other indications.
As all the patients with papilledema were found to have GH deficiency, we analysed this group, classifying patients into three subgroups (Table 2):
1. Isolated GH deficiency (no other associated hormone deficiencies) with normal hypothalamic-pituitary axis anatomy on MRI.
2. Isolated GH deficiency or associated with other hormone deficiencies with altered hypothalamic-pituitary axis anatomy on MRI and/or past history of cerebral radiotherapy.
3. GH deficiency in patients with genetic or chromosomal diseases.
When considering patients who presented with papilledema, three completed criteria for subgroup 2, presenting with hypothalamic-pituitary axis abnormalities and external radiotherapy treatment in one case for a suprasellar tumour. These three patients in subgroup 2 had an intracranial hypertension, but not technically a PTCS, because the brain MRI was not normal. One other patient was classified as subgroup 3 for a non-specific genetic disease. Only one patient presented with an isolated GH deficiency with normal cerebral MRI, however this patient had had primary PTCS five years earlier. The patient with a suprasellar tumour also had a ventriculoperitoneal shunt, suggesting that the presence of a shunt is not protective against a rise in ICP induced by GH therapy.
For each GH indication, the incidence of this adverse effect can vary. Reeves and Doyle (8), reported higher incidences in patients with renal failure and Turner syndrome. Souza and Collet-Solberg (11), also detected a higher incidence in patients with chronic kidney disease. Darendeliler et al (16) proposed that patients with Turner syndrome, organic GH deficiency, PWS and chronic renal insufficiency might be more prone to develop papilledema when receiving GH. In our study, patients with renal disease were excluded, as the GH was not prescribed by the Paediatric Endocrinology Department. However, we have conducted a retrospective study of these patients with renal disease on GH treatment during the same time period and have also detected a higher incidence of papilledema, as described in the literature.
The association between the dose of GH and the risk of PTCS is not clearly established. Malozowski et al (15) reported that higher doses and increased frequency of administration since the introduction of recombinant human GH in 1985 may be contributing to the development of PTCS in some patients. However, Reeves and Doyle found no relationship between the GH dose and PTCS development (8). One of our patients received GH at the usual dose without complications, later on it was withdrawn due to lack of therapeutic effect. Interestingly, papilledema appeared three months after restarting GH at a higher dose. Patients with PWS and mutations in the SHOX gene, who received higher doses of GH did not present with papilledema, although these subgroups were small in this study. Even though there is no evidence that the GH dose is directly related with this complication, we recommend starting at lower dose and increasing it progressively, in order to minimize this complication.
Patients with a previous history of PTCS may experience recurrence at rates reported to vary between 6-22% (4,17,18,19). There is usually a triggering factor, such as weight gain or the introduction of known medications associated with secondary PTCS (20). In our series, the only patient with a previous history of PTCS, presented with papilledema. This patient was obese, which could have been a further risk factor for primary PTCS recurrence, however his weight had remained stable prior to starting GH treatment, at one month and at two months of treatment, when papilledema was diagnosed. For this reason, we believe it is important to identify patients initiating GH therapy with a previous history of PTCS because of the risk of recurrence. Also, consideration should be taken for starting treatment at a lower dose with progressive increases, accompanied by with careful follow-up including fundus examination during the first months of treatment.
Headache is a common symptom in the general paediatric population, and is also relatively frequent in patients on GH therapy, being the third most prevalent side effect described in KIGS (Pfizer International Growth study database) (16). On the other hand, headache is the main manifestation of intracranial hypertension at any age. However, in the paediatric population, headache is less common and 33% of children with PTCS may be totally asymptomatic (21,22), and diagnosis is only made on the observation of papilledema on fundus examination. It is important to highlight that papilledema is a cause of visual morbidity, including irreversible vision loss, independent of the patient symptoms. In our series, all patients with papilledema were asymptomatic, whereas no patients examined urgently for headache presented with papilledema.
Stopping GH is usually enough to treat this complication. Once papilledema has resolved GH can be reintroduced at a lower dose and progressively increased until the required dose is achieved to prevent recurrence and optimum growth. In the four patients where GH was reintroduced there were no recurrences of papilledema.
Study Limitations
The strengths of our study are the prospective design and the number of patients included in it. As children may be asymptomatic, prospective studies are the only way to establish the real incidence of this complication. The main limitation of our study is that patients with kidney diseases were not included and this group of patients has been reported to be at greatest risk of this complication in a different series.
Conclusion
In this study, we have shown that GH therapy is a risk factor for intracranial hypertension and the at-risk group were patients with GH deficiency and hypothalamic-pituitary axis abnormalities on MRI or genetic or chromosomal diseases. Patients may be totally asymptomatic, so fundus examination should be systematically implemented in this at-risk group, irrespective of the presence or absence of symptoms.
We thank Dr. Susana Noval for her valuable contribution in the analysis and interpretation of data and Dr. Silvia Muñoz for critical review of the manuscript.
Table 1 Characteristics of patients treated with growth hormone who developed papilledema
Table 2 Distribution of patients with growth hormone deficiency according to our classification in subgroups
Ethics
Ethics Committee Approval: Ethics approval was obtained from the Ethic Review Committee of the Hospital Universitario Vall d’Hebron (approval number: 383, date: 17.05.2019).
Informed Consent: All subjects (or their parents or guardians) gave their written informed consent.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Concept/Design: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Data Collection or Processing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Analysis or Interpretation: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Literature Search: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste, Writing: Nieves Martín-Begué, Eduard Mogas, Charlotte Wolley Dod, Silvia Alarcón, María Clemente, Ariadna Campos-Martorell, Ana Fábregas, Diego Yeste.
Financial Disclosure: The authors declared that this study received no financial support.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33006547
| 19,423,694
|
2021-06-02
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Gastrointestinal haemorrhage'.
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
|
AMIKACIN, AMOXICILLIN\CLAVULANIC ACID, CYCLOSERINE, DEXAMETHASONE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LINEZOLID, MANNITOL, MEROPENEM, MOXIFLOXACIN, PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, RIFAMPIN, VANCOMYCIN
|
DrugsGivenReaction
|
CC BY
|
33012077
| 19,514,344
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancytopenia'.
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
|
AMIKACIN, AMOXICILLIN\CLAVULANIC ACID, CYCLOSERINE, ETHAMBUTOL HYDROCHLORIDE, ISONIAZID, LINEZOLID, MEROPENEM, MOXIFLOXACIN, RIFAMPIN
|
DrugsGivenReaction
|
CC BY
|
33012077
| 19,606,016
|
2021-04
|
What was the administration route of drug 'AMIKACIN'?
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY
|
33012077
| 19,514,344
|
2021-04
|
What was the administration route of drug 'ETHAMBUTOL HYDROCHLORIDE'?
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33012077
| 19,514,344
|
2021-04
|
What was the administration route of drug 'ISONIAZID'?
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33012077
| 19,514,344
|
2021-04
|
What was the administration route of drug 'LINEZOLID'?
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY
|
33012077
| 19,514,344
|
2021-04
|
What was the administration route of drug 'MOXIFLOXACIN'?
|
A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
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Intravenous (not otherwise specified)
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DrugAdministrationRoute
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CC BY
|
33012077
| 19,514,344
|
2021-04
|
What was the outcome of reaction 'Gastrointestinal haemorrhage'?
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A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia.
We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52-year-old woman who had relapsed leukemia with a remission duration of 7 months, and she received re-induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti-TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.
1 INTRODUCTION
Central nervous system (CNS) involvement of tuberculosis (TB) is quite infrequent but can cause serious neurologic damage and even death. Management of TB after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging as a result of severely compromised cell‐mediated immunity in transplant recipients, drug‐drug interactions with immunosuppressants, and hepatotoxicity of anti‐tuberculosis medications. We report an interesting case of TB meningo‐encephalitis with pulmonary TB that developed early after allogeneic HSCT in a patient with acute myeloid leukemia (AML) in the second complete remission (CR).
2 CASE DESCRIPTION
A 52‐year‐old female patient was diagnosed with AML during treatment for hypothyroidism. The peripheral blood blast count was 77%, bone marrow biopsy showed normocellular marrow with increased blasts (45.4%), and a CEBPA gene double allelic mutation was detected (c.158del [p.Gly53Alafs*107] and c.917_934del [p.Arg306_Gln311del]). Immunophenotype of the blasts was cMPO + CD117+CD13 + CD33+CD7+. Cytogenetics was normal (46,XX), and FLT3‐ITD and NPM1 mutations were not found. The patient achieved complete remission after idarubicin plus cytarabine induction, and she received three cycles of high‐dose cytarabine plus idarubicin consolidation. However, AML relapsed without clonal evolution after 7 months. In June 2019, she received re‐induction with CLAG‐M (cladribine, cytarabine and mitoxantrone) with granulocyte‐colony stimulating factor (G‐CSF) and achieved the second CR. After one cycle of high‐dose cytarabine consolidation, she received allogeneic stem cell transplantation from her HLA 8/8 matched brother. As a screening test before stem cell transplantation, she underwent Quantiferon‐TB Gold Plus (IGRA Qiagen). The result was positive (TB1 Ag minus Nil: 1.370iu/ml, TB2 Ag minus Nil: 1.78IU/mL), but as the chest x‐ray was normal, HSCT proceeded as scheduled without treatment of the latent tuberculosis infection (LTBI). After fludarabine combined with busulfan and antithymocyte globulin (ATG) conditioning 3.87 × 106/kg CD34(+) cells were infused on the 15th of October 2019, engraftment was verified 2 weeks later.
Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti‐fungal agent was added. Chest PA continued to show no active lung lesion. However, the high fever persisted despite resolution of candidemia. On the 2nd of November 2019, 25 days after HSCT, she complained of a severe headache, so a cerebrospinal fluid (CSF) study was performed by lumbar puncture. Opening pressure was 44 mmH2O (normal range: 5‐20 mmH2O), white blood cell (WBC) 8/μL (normal range: <5/μL; while WBC from peripheral blood was 350/μL), neutrophils 89%, glucose 71 mg/dL (normal range: 45‐60 mg/dL), protein 44.2 mg/dL (normal range: 20‐40 mg/dL), and adenosine deaminase (ADA) was 3.4 IU/L (normal range: 0‐10 IU/L). Brain non‐contrast computed tomography (CT) grossly showed no newly developed significant focal lesion, but contrast magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement with microabscesses scattered in the brain, suggesting a tuberculosis infection (Figure 1).
FIGURE 1 Axial diffusion‐weighted magnetic resonance imaging of this patient showed diffuse abnormal leptomeningeal enhancement and scattered, tiny diffusion restricted foci in both cerebral hemispheres and the cerebellar vermis. Black and white arrows indicate tiny, scattered enhancing lesions, which suggested tuberculosis infection
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty‐eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x‐ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs (Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo‐encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. She had not been treated for TB before and had no history of exposure to TB, but she received Bacillus Calmette‐Guérin (BCG) vaccination in childhood according to national immunization program.
TABLE 1 Drug‐susceptibility test result of M. tuberculosis isolate from cerebrospinal fluid culture
Drug Test concentration (μg/ml) Absolute concentration method Result
Isoniazid 0.2 — a S b
Isoniazid 1.0 — S
Rifampin 40 — S
Streptomycin 10 — S
Ethambutol 2.0 — S
Kanamycin 30 — S
Capreomycin 40 — S
Prothionamide 40 — S
Cycloserine 30 — S
Para‐amino salicylic acid 1.0 — S
Ofloxacin 4.0 — S
Moxifloxacin 1.0 — S
Amikacin 30 — S
Levofloxacin 2.0 — S
Rifabutin 20 — S
Linezolid 2.0 — S
Pyrazinamidase test — S
a No growth
b S: Susceptible; Drug‐susceptibility test using absolute concentration method with Löwenstein‐Jensen medium was performed to M tuberculosis isolated from cerebrospinal fluid.
John Wiley & Sons, Ltd
FIGURE 2 Chest non‐contrast computed tomography showed tiny nodules in both lungs. Arrows indicate tiny nodules in the right middle lobe and left upper lobe of the lungs, suggestive of disseminated tuberculosis infection
She received combination anti‐TB medications of isoniazid (INH) 300 mg PO once daily, linezolid (LZD) 600 mg IV q24hr, moxifloxacin (MXF) 400mg IV q24hr, ethambutol (EMB) 1200 mg PO once daily, and amikacin (AMK) 900 mg IV q24hr. Rifampin (RIF) was not used because of the patient's abnormal liver function (total bilirubin 4.8 mg/dL, AST 163 U/L, and ALT 37 U/L) and, in many studies, it seldom reached CSF concentrations exceeding minimum inhibitory concentration (MIC) of TB 1 so we selected INH which had excellent CNS penetration. Also she was immunocompromised patient and had severe infection so rapid bacteriocidal effect of INH against mycobacterium was needed. We excluded pyrazinamide (PZA) for the first‐line regimen because liver toxicity of PZA is higher than INH or RIF. Also in principle, (a) 9 months of INH, RIF with EMB or (b) prolonged treatment duration of RIF, EMB with FQ are the first‐choice options in pre‐existing liver disease. 2 But in this case, we chose the regimen conservatively because of two reasons: hyperbilirubinemia was getting worse and the risk of drug‐drug interaction should have been minimized right after transplantation.
Two days after starting anti‐TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti‐TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti‐TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV (Figure 3).
FIGURE 3 Transition of anti‐tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected.
Brain MRI on day 20 of anti‐TB medication showed decreased abnormal leptomeningeal enhancement, but it also demonstrated an increased number of enhancing lesions scattered in both cerebral hemispheres with multifocal hemorrhage. Chest CT showed patchy consolidation along the central bronchovascular bundles in both lungs. However, the radiologists suggested that these findings were more suggestive of fungal or other bacterial infection rather than TB. A follow‐up CSF analysis was not performed.
Therefore, according to the second‐line regimen of the WHO anti‐TB medication guideline, we decided to maintain INH, EMB, MXF, and AMK, which would have been continued until 20 months after negative conversion of the AFB stain.
For management of TB meningo‐encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo‐encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.
3 DISCUSSION
In 2018, the incidence of new TB cases in South Korea was 51.5 per 100 000 population, quite high compared to the global incidence of TB of 132 per 100 000 according to the WHO global tuberculosis report from 2019. 3 However, even in countries where TB is common, the incidence of TB after HSCT is extremely low. In previously reported data from our HSCT cohort from 1996 to 2003, 4 the incidence of TB after HSCT was 3.1% (9 of 295 allo‐ and auto‐HSCT). Among the nine cases of TB after HSCT, there were 7 cases of pulmonary, 1 case of pericardium, and 1 case of pulmonary with spine. No cases of meningitis were identified. In Pakistan, where the TB prevalence is higher than our country, the incidence of TB after HSCT was 2.6% (4 of 154 all HSCT) from 2001 to 2006. 5
TB meningo‐encephalitis accounts for 1% of all tuberculosis infections. In one study of solid organ transplantation, TB occurred in 0.48% (21 of 4388) of patients, and there was only 1 case of TB meningo‐encephalitis and 2 cases of disseminated TB. 6 Another study showed that TB developed in 1.58% after solid organ transplantation (SOT) and 1.02% after HSCT. 7 Considering the lower number of transplantations of SCT compared to solid organ, it is very rare to experience TB CNS infection after HSCT. However, transplant recipients with TB CNS infections have a high mortality and can suffer serious neurologic sequelae, so early diagnosis and treatment of TB meningitis are clinically very important.
The definitive diagnosis of TB meningitis depends on detecting mycobacterium in cerebrospinal fluid by culture. MTB PCR and radiologic methods are useful to differentiate TB from other infections and to determine the extent of the disease. Detecting the evidence of TB in other organs is also helpful because TB CNS as a form of disseminated tuberculosis infection is common. In the CSF analysis, increased WBC (100‐1000 cells/mL), elevated lymphocyte count, low glucose (<50 or 30 mg/dL or ratio of CSF to blood glucose < 0.4‐0.5), increased protein levels (150‐500 mg/dL), and elevated ADA level (more than 15.5 U/L9) are common features of TB meningo‐encephalitis. Although the burden of mycobacterium in the CSF is usually relatively small, repetition of lumbar punctures and sufficient volume of CSF are important to document mycobacterial involvement by culture and molecular study.
The principles of treatment for TB meningitis are the same as those for pulmonary TB, but the duration of medication is longer. In the first 2 months, a combination of INH, RIF, PZA, and EMB is recommended, and if there is no resistance, a combination of INH and RIF is administered for 7 to 10 months after induction treatment. However, if second‐line regimens are needed because of resistance or intolerance, cycloserine, streptomycin, AMK/kanamycin, and levofloxacin/MXF can be used. Among them, MXF was reported to have an excellent penetration rate through the blood‐brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8 In HSCT, the Center of International Blood and Marrow Transplant Research and Centers for Disease Control and Prevention recommend LTBI treatment in transplant recipients (a) who have been exposed to an individual with active, infectious pulmonary or laryngeal TB, (b) having a positive TST result regardless of prior BCG vaccination without previous treatment and no evidence of active TB disease, and (c) with a positive IGRA result without previous treatment and no evidence of active TB. 9
Clinicians must also consider drug‐drug interactions of anti‐TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol. Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%. The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224 (16.4%) HSCT recipients, 10 and the authors reported that only one patient developed active TB (2.5%). As the prevalence of LTBI and the reactivation rate of TB are not low, IGRA should be a routine screening test before stem cell transplantation in endemic countries.
Therefore, our experience supports that LTBI treatment before or concurrent with HSCT should be recommended for patients who test positive for IGRA.
AUTHOR CONTRIBUTIONS
Investigation: Yang JY, Moon SH. Supervision: Kwon MS, Huh KM, Jung CW. Writing – original draft: Yang JY. Writing – review & editing: Yang JY, Kwon MS, Huh KM, Jung CW.
DISCLOSURE
The authors have no potential conflicts of interest to disclose.
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Recovered
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ReactionOutcome
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CC BY
|
33012077
| 19,514,344
|
2021-04
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cholangitis acute'.
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Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
ASPIRIN, LENVATINIB, RABEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Duodenal ulcer'.
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
ASPIRIN, LENVATINIB, RABEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Enterobacter bacteraemia'.
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
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ASPIRIN, LENVATINIB, RABEPRAZOLE
|
DrugsGivenReaction
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CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Impaired healing'.
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
ASPIRIN, LENVATINIB, RABEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Jaundice cholestatic'.
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
ASPIRIN, LENVATINIB, RABEPRAZOLE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What is the weight of the patient?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
59 kg.
|
Weight
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What was the administration route of drug 'LENVATINIB'?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What was the administration route of drug 'RABEPRAZOLE'?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
Oral
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DrugAdministrationRoute
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What was the dosage of drug 'ASPIRIN'?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
DOSE AND FREQUENCY NOT PROVIDED
|
DrugDosageText
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What was the dosage of drug 'LENVATINIB'?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
8 mg (milligrams).
|
DrugDosage
|
CC BY-NC-ND
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33028766
| 18,412,747
|
2021-02-15
|
What was the dosage of drug 'RABEPRAZOLE'?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
DOSE AND FREQUENCY NOT PROVIDED
|
DrugDosageText
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What was the outcome of reaction 'Duodenal ulcer'?
|
Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
Recovered
|
ReactionOutcome
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
What was the outcome of reaction 'Enterobacter bacteraemia'?
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Obstructive Jaundice Due to Duodenal Ulcer Induced by Lenvatinib Therapy for Hepatocellular Carcinoma.
An 82-year-old man with hepatocellular carcinoma presented with upper abdominal pain, vomiting, and jaundice. He had been taking a standard lenvatinib dose for three months. Although acute cholangitis was suggested, imaging studies failed to detect the biliary obstruction site. An endoscopic examination following discontinuation of lenvatinib and aspirin revealed multiple duodenal ulcers, one of which was formed on the ampulla of Vater and causing cholestasis. Endoscopic biliary drainage and antibiotics improved concomitant Enterobacter cloacae bacteremia. Ulcer healing was confirmed after rabeprazole was replaced with vonoprazan and misoprostol. Our case shows that lenvatinib can induce duodenal ulcers resulting in obstructive jaundice.
Introduction
Lenvatinib is a potent antiangiogenic tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor-α, RET, and KIT (1). Based on the results of phase 3 trials focusing on radioiodine-refractory differentiated thyroid cancer (the SELECT trial) (2) and unresectable hepatocellular carcinoma (HCC) (the REFLECT trial) (3), lenvatinib is indicated as the first-line systemic therapy for these cancers (4-6). Although the prescribing information of lenvatinib warns that gastrointestinal perforation is a serious adverse reaction, the incidence of gastric or duodenal ulcer was 0.2-0.6% in those clinical trials (7). Furthermore, our literature search did not find any other publication describing upper gastrointestinal ulcer as an adverse event of lenvatinib. Thus, gastroduodenal ulcer is only rarely associated with lenvatinib therapy.
Duodenal ulcers have been sporadically complicated with obstructive jaundice (8-14). The first case in the American literature was described in 1853 (8) and similar reports have been published since then (9-14). When inflammation of the duodenal ulcer extends to the surrounding structures, including the ampulla of Vater, pancreas, and hepatoduodenal ligament, it can lead to external compression of the biliary tract and subsequent cholestasis (8, 9). Under these conditions, obstructive jaundice results from not only peptic ulcer (8, 9, 11) but also duodenal injuries associated with medical procedures, such as endoscopic hemostasis for bleeding ulcer (10, 12), percutaneous endoscopic gastrostomy (13), and transarterial radioembolization for HCC (14). Nevertheless, this condition has never been reported as a complication of systemic therapy.
Using the radiological criteria of modified RECIST (mRECIST) (15), the REFLECT trial showed that lenvatinib led to more favorable progression-free survival and objective response rate than sorafenib (3), another first-line multitargeted antiangiogenic TKI for HCC (5, 6). RECIST version 1.1 is used to assess the size of solid tumors in general (16), whereas mRECIST is specifically designed for HCC to evaluate intratumoral arterial enhancement on contrast-enhanced computed tomography (CT) or magnetic resonance imaging under the assumption that it reflects tumor viability (15). However, because of its study design as a non-inferior trial regarding the overall survival, the REFLECT trial did not fully elucidate the clinical relevance of a better objective response with lenvatinib therapy.
We herein report a case of HCC in which lenvatinib induced a duodenal ulcer, resulting in obstructive jaundice and subsequent bacteremia. Drastic HCC radiological changes in response to lenvatinib therapy were revealed in a series of contrast-enhanced CT scans.
Case Report
An 82-year-old man with HCC presented with upper abdominal pain and vomiting. He had achieved hepatitis C virus eradication with sofosbuvir and ledipasvir two years previously, but the background liver was cirrhotic. Despite two courses of transcatheter arterial chemoembolization followed by local ablation during the previous year, the patient developed recurrence of HCC. The tumor in the right lobe exhibited ill-defined heterogeneous arterial phase hyperenhancement (Fig. 1A) and washout on portal phase (Fig. 1B). The inferior side of the lesion had invaded the main right portal vein (Fig. 1C, D). The baseline serum levels of α-fetoprotein and des-γ-carboxy prothrombin were markedly elevated to 9,276 ng/mL (normal range 0-20 ng/mL) and 7,619 mAU/mL (normal range 0-39 mAU/mL), respectively. He had been continuously receiving a standard dose of lenvatinib (8 mg/day based on body weight of 59 kg) without any adverse events for 3 months.
Figure 1. Contrast-enhanced computed tomography before initiating lenvatinib. An ill-defined heterogenous arterial phase hyperenhancement (A) and washout on portal phase (B) in the right lobe of the liver indicated hepatocellular carcinoma. The inferior side of the hypervascular tumor invaded the main right portal vein (C), which was depicted as a perfusion defect on portal phase (D) (arrow).
His medical history included coronary stent placement for angina pectoris performed three years previously. He was taking low-dose aspirin as antiplatelet therapy, in addition to rabeprazole and several oral medications for hypertension, type 2 diabetes mellitus, and dyslipidemia. The results of routine esophagogastroduodenoscopy conducted one month before introducing lenvatinib were normal except for a small esophageal varix and mild chronic gastritis.
On admission, the patient complained of abdominal discomfort in the epigastrium and right upper quadrant. The vital signs were notable for a low-grade fever (37.5 °C) and hypertension (184/94 mmHg). A physical examination revealed mild icterus but otherwise unremarkable findings, including in the abdomen. Laboratory tests were significant for increases in the white blood cell count (13,600 /μL) and serum levels of total bilirubin (5.0 mg/dL), direct bilirubin (3.3 mg/dL), aspartate aminotransferase (278 U/L), alanine aminotransferase (125 U/L), alkaline phosphatase (654 U/L), γ-glutamyl transpeptidase (332 U/L), and C-reactive protein (2.68 mg/dL).
Contrast-enhanced CT revealed dilatation of the common bile duct (Fig. 2A, B). There was no wall thickening of the small or large intestine that suggested intestinal inflammation in the scanned abdominal area. Compared to pre-treatment CT, the tumor lacked arterial enhancement (Fig. 2C) but had grown by 10% in the longest diameter on the axial section (Fig. 2D). Magnetic resonance cholangiopancreatography demonstrated the absence of any defect in the diffusely dilated common bile duct (Fig. 3A). Duodenal wall thickening was noted on T2-weighted imaging (Fig. 3B).
Figure 2. Axial section (A) and coronal reconstruction (B) of the portal phase revealed diffuse dilatation of the common bile duct (arrow). The hepatocellular carcinoma lesion lacked arterial enhancement (C), but its hypodense area on portal phase had increased by 10% in diameter on the axial section (D).
Although the findings on admission suggested acute cholangitis (17), imaging studies were unable to determine the cause of biliary obstruction. After discontinuing lenvatinib and aspirin, we performed endoscopic retrograde cholangiopancreatography (ERCP). The endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (Fig. 4A-C), whereas no mucosal damage was observed in the stomach. Remarkably, one of the duodenal ulcers had formed on the swollen ampulla of Vater, from which infective bile was leaking (Fig. 4C). Cholangiography showed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (Fig. 4D). Taken together, these findings indicated that edematous papilla as a result of the duodenal ulcer located above was responsible for the cholestasis.
Figure 3. Magnetic resonance imaging on admission. Magnetic resonance cholangiopancreatography demonstrated the absence of a defect in the diffusely dilated common bile duct (A). Duodenal wall thickening was noted on T2-weighted imaging (B) (arrowheads).
Because the blood culture on admission turned positive for Gram-negative rod bacteria, we performed endoscopic biliary drainage by endoscopic sphincterotomy (EST) (Fig. 4E) and balloon sweeping (Fig. 4F). A biopsy of the duodenal ulcers was not obtained due to the prescribing information of lenvatinib warning about delayed wound healing (7).
Figure 4. Endoscopic retrograde cholangiopancreatography after admission. An endoscopic examination revealed multiple ulcers in the bulb and descending portion of the duodenum (A-C). One of the duodenal ulcers formed on the swollen ampulla of Vater, from which infective bile was leaking (C). Cholangiography revealed several inhomogeneous unfilled areas, compatible with pus accumulation, in the common bile duct without stricture (D). Endoscopic sphincterotomy (E) and balloon sweeping of the common bile duct (F) were subsequently performed.
Blood and bile cultures identified Enterobacter cloacae bacteremia, which improved with the biliary drainage and administration of cefepime and metronidazole. The patient's serum Helicobacter pylori antibody was negative. For the treatment of duodenal ulcers, rabeprazole was replaced with vonoprazan in combination with the temporal use of misoprostol. Duodenoscopy performed 12 days after ERCP confirmed healing of the ulcers (Fig. 5A, B), and antiplatelet therapy was resumed with clopidogrel rather than aspirin.
To determine the objective response of HCC and thereby assess the benefit of resuming lenvatinib despite the serious consequence of duodenal ulcers, we performed contrast-enhanced CT again on admission day 17. In contrast to the results on admission (Fig. 2C, D), the HCC lesion exhibited restored arterial enhancement (Fig. 6A). Although the increase in tumor size did not meet the threshold for progressive disease according to RECIST version 1.1 (Fig. 6B) (16), the confirmation of aggravating tumor burden resulted in the termination of lenvatinib therapy.
Figure 5. Follow-up duodenoscopy performed 12 days after endoscopic retrograde cholangiopancreatography revealed healing of the duodenal ulcers (A, B).
Figure 6. Contrast-enhanced computed tomography on admission day 17. The tumor exhibited restored arterial enhancement (A) with washout on portal phase (B).
Discussion
In this report, lenvatinib therapy induced a sequence of unusual conditions, namely duodenal ulcers and resulting obstructive jaundice, in a patient with HCC taking aspirin. We carefully adapted the treatment to this unique adverse event and incidentally observed radiological changes in HCC that provided insight into how to assess the treatment response to lenvatinib.
Gastrointestinal ulceration and eventual perforation are possible adverse events of antiangiogenic therapies, including monoclonal antibodies (18-24) and TKIs (25, 26), although the reported incidences are generally less than 2% in large-scale studies (18-26). The risk factors for gastrointestinal perforation are well-investigated in studies of bevacizumab, a monoclonal antibody against VEGF (18-23). One risk factor is the presence of a tumor in the gastrointestinal tract (18, 21-23), which can become necrotic following the chemotherapy. This finding is consistent with reports describing perforated intestinal metastasis of thyroid cancer (27) and HCC (28) during lenvatinib therapy. However, the duodenal ulcerations in our patient appeared and healed with the initiation and discontinuation of lenvatinib, respectively, suggesting a causal relationship to the treatment but a benign nature of these lesions.
Concomitant non-steroidal anti-inflammatory drugs (NSAIDs) during antiangiogenic therapy can also predispose patients to gastrointestinal perforation, as shown in a post-marketing study of bevacizumab in Japanese patients with colorectal cancer (23). In our patient, however, aspirin, which itself is a risk factor for gastroduodenal mucosal damage (29, 30), was unlikely to be the primary cause of the duodenal ulcers because these lesions had been absent despite the regular intake of the drug. Notably, because antiplatelet therapy was prohibited in the REFLECT trial (31) and no other study has addressed this issue, the safety profile of lenvatinib has not been established in patients with HCC who are taking aspirin. Hence, our report also provides safety information on the combined use of lenvatinib and aspirin.
Pharmacological perturbation of multiple molecular pathways may have contributed to the duodenal ulcers in our patient. In a rat study, lenvatinib caused chronic duodenal inflammation initiated upon damage to the Brunner's gland, and the authors attributed this phenomenon to disrupted VEGF signaling (32). Furthermore, blockade of the VEGF-VEGFR system reduced the intestinal blood flow by decreasing the number of intestinal capillaries in mouse models (18, 33, 34). Although one study reported that this reduction was insufficient to impair the intestinal function (18, 33), further mucosal damage may have been induced by inhibiting other target pathways of lenvatinib, particularly fibroblast growth factor (FGF) signaling. FGFR1-4 are differentially expressed in each layer of the duodenal wall and microvessels (35). In addition to proangiogenesis (36), the FGF-FGFR system plays various physiological roles in the adult intestine, such as promoting the proliferation and differentiation of intestinal cells, maintaining intestinal stem cell homeostasis, and triggering tissue repair (37). Furthermore, aspirin is classically known to exert damaging effects on the gastroduodenal mucosa through cyclooxygenase inhibition (29, 30). Thus, the net result of molecular suppression by lenvatinib and aspirin is speculated to be involved in the development of duodenal ulcers.
The endoscopic features of duodenal ulcers related to antiangiogenic agents have been described only in a few case reports (38-42). This may be because duodenal injury with these chemotherapy regimens is not only rare but also likely to manifest as perforation and require emergent management, such as surgery (22). Typically, peptic duodenal ulcers, including those induced by aspirin or NSAIDs, are either single or multiple lesions located in the duodenal bulb (29). Indeed, previous reports described deep and often penetrating ulcers in the bulb caused by bevacizumab (38, 40, 41) or pazopanib, a multiple TKI indicated for renal cell carcinoma and malignant soft tissue tumor (42). However, compared with these cases, the endoscopic findings of our patient differed in that the ulcerations were rather superficial and extended to the descending portion, including the ampulla of Vater. Of note, similar multiple ulcers in the descending portion, but sparing the major duodenal papilla, were reported in a case of HCC treated with sorafenib (39). Therefore, despite the limited and inconsistent information available at present, we can speculate that duodenal mucosal damage affecting the descending portion may be associated with multitargeted antiangiogenic TKIs.
The treatment strategy for obstructive jaundice secondary to duodenal ulcer should be determined based on each particular situation. Successful endoscopic biliary drainage has been reported in this setting (13, 14), whereas surgical intervention was selected in older studies (8, 9) or for cases suspected of having malignant biliary obstruction (11, 12). In our patient, an endoscopic examination was the first-choice approach for identifying the cause of cholestasis, and bacteremia resulting from cholangitis necessitated urgent biliary drainage (43). The rationale for selecting EST is to resolve biliary obstruction caused by edematous papilla and promptly remove pus from the common bile by balloon sweeping. While endoscopic biliary stenting and nasobiliary drainage would have been safer than EST, these approaches are associated with risks of tube obstruction or displacement (44). Although endoscopic treatment can be completed in a single procedure via EST without stent insertion (44), potential serious complications include bleeding and perforation (45). While EST under aspirin monotherapy is acceptable in patients at a high risk of thromboembolism (45, 46), perforation was a concern in the present study because of the incision to the ulcer and delayed wound healing related to lenvatinib (7). Therefore, in addition to the withdrawal of lenvatinib and aspirin, we modified the antiulcer medications to facilitate the recovery of duodenal ulcers and EST incision. Both vonoprazan (potassium-competitive acid blocker) (47) and misoprostol (prostaglandin E1 analogue) (48) are effective for treating aspirin-induced gastroduodenal ulcer via different mechanisms of action. As the ulcers healed successfully, our case suggests that a transpapillary endoscopic procedure is feasible for managing obstructive jaundice caused by an ampullary ulcer when combined with appropriate antiulcer therapy.
The radiological changes of HCC in our patient represent a pitfall in the interpretation of the treatment response during lenvatinib therapy. The tumor exhibited paradoxical CT findings during lenvatinib therapy, showing an increase in size but a lack of arterial enhancement. The rapid recovery of intratumoral perfusion suggested that the remaining hypodense lesion was still a viable tumor, not necrotic tissue. This, in turn, implies that arterial enhancement does not always correlate with tumor viability during lenvatinib therapy. It should be emphasized that our patient received the maximal dose intensity of lenvatinib until the initial radiological assessment, while a reduced relative dose intensity can negatively affect the objective response of HCC (49, 50). Therefore, it is essential to clarify whether or not the objective response of HCC based on mRECIST during lenvatinib therapy has a meaningful impact on the clinical outcomes, particularly the prognosis. Real-world studies have shown that patients with HCC who had a favorable response to lenvatinib based on mRECIST achieved a better overall survival than those who did not (50, 51). However, considering the discrepancy between the viable tumor size and arterial enhancement observed in this report, we warn against relying only on mRECIST when assessing the objective response during lenvatinib therapy for HCC.
In conclusion, we encountered a case of obstructive jaundice due to duodenal ulcer induced by lenvatinib therapy for HCC. The endoscopic features are characterized by multiple ulcerations in the bulb and descending portion of the duodenum, including the ampulla of Vater. The pathogenesis of the duodenal ulcers may be attributable to the inhibition of various molecular pathways by lenvatinib and aspirin. Prompt endoscopic treatment and antiulcer therapy were successful in managing this case of cholangitis with bacteremia. Further research is warranted to investigate the role of an objective response to lenvatinib therapy in patients with HCC.
The patient provided his written informed consent for publication of this article and the accompanying images.
Author's disclosure of potential Conflicts of Interest (COI).
Yasuhiro Fujiwara: Honoraria, EA Pharma and Takeda. Norifumi Kawada: Honoraria, Gilead Sciences and MSD; Research funding, Gilead Sciences.
|
Recovering
|
ReactionOutcome
|
CC BY-NC-ND
|
33028766
| 18,412,747
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung squamous cell carcinoma stage I'.
|
Regression of Lung Squamous Cell Carcinoma after the Withdrawal of Cyclosporin A Combined with Pirfenidone Treatment in a Patient with Idiopathic Pulmonary Fibrosis.
A 72-year-old man was treated with prednisolone and cyclosporine A for idiopathic pulmonary fibrosis. A nodule with a diameter of 19 mm was found in the right lung and diagnosed as lung squamous cell carcinoma. Anti-cancer treatments were not performed because of the presence of advanced interstitial pneumonia and chronic respiratory failure. Cyclosporine A was tapered to avoid suppression of anti-tumor immunity, and pirfenidone was initiated. Within 2 months, the tumor had shrunk to 10 mm in diameter and remained regressed for 9 months. This is the first report of a non-hematologic solid organ tumor responding to the discontinuation of immunosuppressants.
Introduction
Idiopathic pulmonary fibrosis (IPF) and other chronic fibroproliferative lung diseases can often be complicated with lung cancer (1), which is the third leading cause of death among IPF patients in Japan (2). A number of risk factors, such as cigarette smoking, age, and genetic factors, are shared between the pathogenesis of IPF and lung cancer (3). Immunosuppressants, including calcineurin inhibitors such as cyclosporine A (CyA) used for the treatment of IPF or other interstitial lung diseases, might be another predisposing factor for carcinogenesis and promote tumor growth (4-6).
Iatrogenic immunosuppression is associated with an increased risk of lymphoproliferative disorders (7) and also cancers in the solid organs or skin, as demonstrated in organ transplant recipients (8, 9) or patients with collagen-vascular diseases (10, 11). The causative relationship between immunosuppression and tumorigenesis has been further confirmed by the observation that spontaneous regression of lymphoproliferative disorders occurs following the withdrawal of immunosuppressants (12, 13). However, there have been no reports showing that non-hematologic solid tumors regress after the discontinuation of immunosuppressants.
We herein report an IPF case with squamous cell carcinoma in the lung where the primary tumor spontaneously regressed when CyA was tapered and discontinued.
Case Report
A 72-year-old man who was a former smoker (40 pack-years) with type 2 diabetes had been diagnosed with IPF 8 years ago based on typical images on thoracic computed tomography (CT), including honeycombing and traction bronchiectasis. Prednisolone, 30 mg per day, was started 3 years ago due to the subacute progression of dyspnea on exertion and appearance of ground-glass opacities in the bilateral lungs. CyA (200 mg/day) was added while the dose of prednisolone was reduced due to the worsened control of diabetes mellitus.
When he was referred to our hospital, he was receiving prednisolone (10 mg/day) and CyA (200 mg/day) (Fig. 1). Fine crackles in the lower lung fields were present, as well as an enhanced pulmonary component of the second heart sounds. Blood tests revealed increased levels of lactate dehydrogenase (320 U/L), Krebs-von-Lungen-6 (2,259 U/mL), and surfactant protein-D (326 ng/mL). An arterial blood gas analysis showed mild hypoxemia at rest with an arterial O2 partial pressure of 57.9 Torr and difference alveolar-arterial O2 partial pressure of 39.5. The vital capacity and diffusion capacity of the lungs for carbon monoxide were 63% and 42% of the predicted values, respectively. The six-minute walk distance was 170 m under 4 L/min O2 supplementation. In addition to honeycombing and traction bronchiectasis in the lower lung fields (Fig. 2A), a nodule with a diameter of 19 mm, which was 5 mm in diameter in a retrospective review of the previous CT scan taken 9 months before the referral (Fig. 2B), was identified in the right upper lobe on thoracic CT (Fig. 2C). A transbronchial biopsy of the nodule was performed, leading to a diagnosis of squamous cell carcinoma in the lung (Fig. 3A), with a clinical stage of IA2 (cT1bN0M0).
Figure 1. Clinical course. When referred to our hospital (year X), the patient was being treated with prednisolone (10 mg/day) and cyclosporine A (CyA; 200 mg/day). A nodule with a diameter of 19 mm that was diagnosed as squamous cell carcinoma was observed in the right upper lobe of the lung. CyA was tapered and withdrawn, and pirfenidone (1,200 mg/day) was started. The nodule regressed to 10 mm in diameter for 9 months before it started to re-grow. The patient died of acute exacerbation of idiopathic pulmonary fibrosis (IPF) 17 months after he was diagnosed with lung cancer.
Figure 2. Thoracic computed tomography (CT). Honeycombing and traction bronchiectasis were observed in the bilateral lower lobes (A). A nodule that was eventually diagnosed as squamous cell carcinoma was observed nine months before the referral (B), at referral (C), and two (D) and six (E) months after the tapering of CyA with the concomitant initiation of pirfenidone.
The patient was not indicated for surgical treatment or thoracic irradiation due to the presence of advanced interstitial pneumonia and chronic respiratory failure. CyA was gradually tapered to avoid suppression of anti-tumor immunity, and pirfenidone was started. Two months later, after CyA had been reduced to 50 mg/day, the tumor had shrunk to 10 mm in diameter (Fig. 1, Fig. 2D). CyA was eventually discontinued, and the tumor remained regressed without any additional anti-cancer treatments for nine months (Fig. 1, Fig. 2E). The patient ultimately died of respiratory failure due to acute exacerbation of IPF 17 months after being diagnosed with lung cancer.
Figure 3. Histopathology of the lung tumor. Hematoxylin and Eosin staining (A) of the lung tumor obtained by a transbronchial biopsy demonstrated cancer cells with a high N/C ratio and eosinophilic cytoplasm as well as keratinization compatible with squamous cell carcinoma. Infiltration of lymphocytes or other inflammatory cells was absent in the interstitium. There was no expression of epithelial-mesenchymal transition markers in the cancer cells, such as N-cadherin (B) and vimentin (C).
Discussion
We present a case of a spontaneous regression of lung squamous cell carcinoma after the withdrawal of CyA. To our knowledge, this is the first report describing a non-hematologic solid organ tumor that responded to the discontinuation of immunosuppressants.
CyA suppresses T cell-mediated immune systems by binding to cyclophilin and forming a complex with calcineurin in T cells, which inhibits the nuclear translocation of a transcription factor, nuclear factor of activated T cells. CyA also promotes the vascular endothelial growth factor expression and neovascularization (4,6,14) and induces the release of transforming growth factor (TGF)-β, which increases tumor cell motility, invasiveness, and metastasis (5). A single-center study (15) demonstrated that the incidence of malignancy in 43 patients treated with CyA for interstitial pneumonia was 14% including 4 cases with lung cancer, with more rapid tumor doubling rates of 40-70 days than previously reported: 220 days for lung adenocarcinoma and 110 days for lung squamous cell carcinoma (16). In our case, the tumor doubling rate prior to the tapering of CyA was 100 days, which was prolonged to 390 days after CyA withdrawal. The physical stimulus during the transbronchial biopsy may have enhanced the release of new antigens and further activated the anti-tumor immune response (17).
Treatment with pirfenidone might have been another factor that contributed to the regression of lung cancer in our case. Pirfenidone suppresses the production of inflammatory cytokines, enhances the release of anti-inflammatory interleukin-10, and inhibits TGF-β-induced epithelial-mesenchymal transition (18), which might enhance the motility and invasiveness of carcinoma cells (19). The suppression of the TGF-β protein expression in tumor cells by pirfenidone also reduces the levels of matrix metalloproteinase-11, which is related to tumor invasiveness (20,21). It has been demonstrated that pirfenidone exerts in vivo anti-tumor activity synergistically with cisplatinum in a mouse transplanted with human lung or breast cancer cells (22,23). Although the expression of epithelial-mesenchymal transition markers, such as N-cadherin and vimentin, was not evident in this case (Fig. 3B, C), the introduction of pirfenidone might have affected the tumor regression in combination with the withdrawal of CyA.
Conclusion
Lung squamous cell carcinoma in a patient with IPF was regressed by the withdrawal of CyA and initiation of pirfenidone. When lung cancer develops in the presence of IPF or other chronic fibrotic lung diseases, physicians should consider reducing the dose of immunosuppressive medications as much as possible and starting anti-fibrotic agents in order to enhance anti-tumor immunity and minimize the risk of acute exacerbation accompanied by the tapering of immunosuppressants.
The authors state that they have no Conflict of Interest (COI).
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CYCLOSPORINE, PIRFENIDONE, PREDNISOLONE
|
DrugsGivenReaction
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CC BY-NC-ND
|
33028767
| 19,200,217
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'.
|
Regression of Lung Squamous Cell Carcinoma after the Withdrawal of Cyclosporin A Combined with Pirfenidone Treatment in a Patient with Idiopathic Pulmonary Fibrosis.
A 72-year-old man was treated with prednisolone and cyclosporine A for idiopathic pulmonary fibrosis. A nodule with a diameter of 19 mm was found in the right lung and diagnosed as lung squamous cell carcinoma. Anti-cancer treatments were not performed because of the presence of advanced interstitial pneumonia and chronic respiratory failure. Cyclosporine A was tapered to avoid suppression of anti-tumor immunity, and pirfenidone was initiated. Within 2 months, the tumor had shrunk to 10 mm in diameter and remained regressed for 9 months. This is the first report of a non-hematologic solid organ tumor responding to the discontinuation of immunosuppressants.
Introduction
Idiopathic pulmonary fibrosis (IPF) and other chronic fibroproliferative lung diseases can often be complicated with lung cancer (1), which is the third leading cause of death among IPF patients in Japan (2). A number of risk factors, such as cigarette smoking, age, and genetic factors, are shared between the pathogenesis of IPF and lung cancer (3). Immunosuppressants, including calcineurin inhibitors such as cyclosporine A (CyA) used for the treatment of IPF or other interstitial lung diseases, might be another predisposing factor for carcinogenesis and promote tumor growth (4-6).
Iatrogenic immunosuppression is associated with an increased risk of lymphoproliferative disorders (7) and also cancers in the solid organs or skin, as demonstrated in organ transplant recipients (8, 9) or patients with collagen-vascular diseases (10, 11). The causative relationship between immunosuppression and tumorigenesis has been further confirmed by the observation that spontaneous regression of lymphoproliferative disorders occurs following the withdrawal of immunosuppressants (12, 13). However, there have been no reports showing that non-hematologic solid tumors regress after the discontinuation of immunosuppressants.
We herein report an IPF case with squamous cell carcinoma in the lung where the primary tumor spontaneously regressed when CyA was tapered and discontinued.
Case Report
A 72-year-old man who was a former smoker (40 pack-years) with type 2 diabetes had been diagnosed with IPF 8 years ago based on typical images on thoracic computed tomography (CT), including honeycombing and traction bronchiectasis. Prednisolone, 30 mg per day, was started 3 years ago due to the subacute progression of dyspnea on exertion and appearance of ground-glass opacities in the bilateral lungs. CyA (200 mg/day) was added while the dose of prednisolone was reduced due to the worsened control of diabetes mellitus.
When he was referred to our hospital, he was receiving prednisolone (10 mg/day) and CyA (200 mg/day) (Fig. 1). Fine crackles in the lower lung fields were present, as well as an enhanced pulmonary component of the second heart sounds. Blood tests revealed increased levels of lactate dehydrogenase (320 U/L), Krebs-von-Lungen-6 (2,259 U/mL), and surfactant protein-D (326 ng/mL). An arterial blood gas analysis showed mild hypoxemia at rest with an arterial O2 partial pressure of 57.9 Torr and difference alveolar-arterial O2 partial pressure of 39.5. The vital capacity and diffusion capacity of the lungs for carbon monoxide were 63% and 42% of the predicted values, respectively. The six-minute walk distance was 170 m under 4 L/min O2 supplementation. In addition to honeycombing and traction bronchiectasis in the lower lung fields (Fig. 2A), a nodule with a diameter of 19 mm, which was 5 mm in diameter in a retrospective review of the previous CT scan taken 9 months before the referral (Fig. 2B), was identified in the right upper lobe on thoracic CT (Fig. 2C). A transbronchial biopsy of the nodule was performed, leading to a diagnosis of squamous cell carcinoma in the lung (Fig. 3A), with a clinical stage of IA2 (cT1bN0M0).
Figure 1. Clinical course. When referred to our hospital (year X), the patient was being treated with prednisolone (10 mg/day) and cyclosporine A (CyA; 200 mg/day). A nodule with a diameter of 19 mm that was diagnosed as squamous cell carcinoma was observed in the right upper lobe of the lung. CyA was tapered and withdrawn, and pirfenidone (1,200 mg/day) was started. The nodule regressed to 10 mm in diameter for 9 months before it started to re-grow. The patient died of acute exacerbation of idiopathic pulmonary fibrosis (IPF) 17 months after he was diagnosed with lung cancer.
Figure 2. Thoracic computed tomography (CT). Honeycombing and traction bronchiectasis were observed in the bilateral lower lobes (A). A nodule that was eventually diagnosed as squamous cell carcinoma was observed nine months before the referral (B), at referral (C), and two (D) and six (E) months after the tapering of CyA with the concomitant initiation of pirfenidone.
The patient was not indicated for surgical treatment or thoracic irradiation due to the presence of advanced interstitial pneumonia and chronic respiratory failure. CyA was gradually tapered to avoid suppression of anti-tumor immunity, and pirfenidone was started. Two months later, after CyA had been reduced to 50 mg/day, the tumor had shrunk to 10 mm in diameter (Fig. 1, Fig. 2D). CyA was eventually discontinued, and the tumor remained regressed without any additional anti-cancer treatments for nine months (Fig. 1, Fig. 2E). The patient ultimately died of respiratory failure due to acute exacerbation of IPF 17 months after being diagnosed with lung cancer.
Figure 3. Histopathology of the lung tumor. Hematoxylin and Eosin staining (A) of the lung tumor obtained by a transbronchial biopsy demonstrated cancer cells with a high N/C ratio and eosinophilic cytoplasm as well as keratinization compatible with squamous cell carcinoma. Infiltration of lymphocytes or other inflammatory cells was absent in the interstitium. There was no expression of epithelial-mesenchymal transition markers in the cancer cells, such as N-cadherin (B) and vimentin (C).
Discussion
We present a case of a spontaneous regression of lung squamous cell carcinoma after the withdrawal of CyA. To our knowledge, this is the first report describing a non-hematologic solid organ tumor that responded to the discontinuation of immunosuppressants.
CyA suppresses T cell-mediated immune systems by binding to cyclophilin and forming a complex with calcineurin in T cells, which inhibits the nuclear translocation of a transcription factor, nuclear factor of activated T cells. CyA also promotes the vascular endothelial growth factor expression and neovascularization (4,6,14) and induces the release of transforming growth factor (TGF)-β, which increases tumor cell motility, invasiveness, and metastasis (5). A single-center study (15) demonstrated that the incidence of malignancy in 43 patients treated with CyA for interstitial pneumonia was 14% including 4 cases with lung cancer, with more rapid tumor doubling rates of 40-70 days than previously reported: 220 days for lung adenocarcinoma and 110 days for lung squamous cell carcinoma (16). In our case, the tumor doubling rate prior to the tapering of CyA was 100 days, which was prolonged to 390 days after CyA withdrawal. The physical stimulus during the transbronchial biopsy may have enhanced the release of new antigens and further activated the anti-tumor immune response (17).
Treatment with pirfenidone might have been another factor that contributed to the regression of lung cancer in our case. Pirfenidone suppresses the production of inflammatory cytokines, enhances the release of anti-inflammatory interleukin-10, and inhibits TGF-β-induced epithelial-mesenchymal transition (18), which might enhance the motility and invasiveness of carcinoma cells (19). The suppression of the TGF-β protein expression in tumor cells by pirfenidone also reduces the levels of matrix metalloproteinase-11, which is related to tumor invasiveness (20,21). It has been demonstrated that pirfenidone exerts in vivo anti-tumor activity synergistically with cisplatinum in a mouse transplanted with human lung or breast cancer cells (22,23). Although the expression of epithelial-mesenchymal transition markers, such as N-cadherin and vimentin, was not evident in this case (Fig. 3B, C), the introduction of pirfenidone might have affected the tumor regression in combination with the withdrawal of CyA.
Conclusion
Lung squamous cell carcinoma in a patient with IPF was regressed by the withdrawal of CyA and initiation of pirfenidone. When lung cancer develops in the presence of IPF or other chronic fibrotic lung diseases, physicians should consider reducing the dose of immunosuppressive medications as much as possible and starting anti-fibrotic agents in order to enhance anti-tumor immunity and minimize the risk of acute exacerbation accompanied by the tapering of immunosuppressants.
The authors state that they have no Conflict of Interest (COI).
|
CYCLOSPORINE, PIRFENIDONE, PREDNISOLONE
|
DrugsGivenReaction
|
CC BY-NC-ND
|
33028767
| 19,200,217
|
2021-02-15
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'.
|
Intravenous immunoglobulin therapy in COVID-19-related encephalopathy.
OBJECTIVE
To report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy.
METHODS
We retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg.
RESULTS
Five patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19-55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1-10 days). No adverse events related to IVIg were observed.
CONCLUSIONS
Our preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.
Introduction
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19). While many individuals with SARS-CoV-2 infection are asymptomatic or develop only mild respiratory and constitutional symptoms, a subgroup of patients present with complications, including acute respiratory distress syndrome, disseminated intravascular coagulation and multiorgan dysfunction syndrome [1, 2].
Cytokine release syndrome (CRS) is a systemic hyperinflammatory condition presenting secondary to monocyte, macrophage and dendritic cell activation in severe COVID-19 infection and has been implicated in disease pathophysiology [3].
Neuropsychiatric manifestations are increasingly being reported in association with COVID-19, including encephalopathy [4]. The pathophysiology underlying this presentation remains unclear; however, a role of cytokine-mediated neuroinflammation has been suggested [5−10]. COVID-19-associated encephalopathy has been described responsive to high-dose steroids and plasmapheresis, consistent with an immune-mediated pathogenesis [5, 11, 12].
Intravenous immunoglobulin (IVIg) therapy has shown efficacy in treating systemic COVID-[13, 19] yet its role in the management of associated CNS manifestations remains to be determined.
We report five patients with COVID-19-related encephalopathy successfully treated with IVIg.
Methods
We retrospectively collected data on all patients with COVID-19 hospitalized at Bellaria Hospital, Bologna, and Infermi Hospital, Rimini, Italy, from March 13, 2020, to May 27, 2020, who developed encephalopathy during disease course and were treated with IVIg. COVID-19 diagnosis was made on the basis of at least one positive SARS-CoV-2 real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasopharyngeal swab specimens and consistent clinical and/or radiological findings. IVIg therapy was prescribed by the treating neurologist based on the patient’s clinical profile and suspected immune-mediated/inflammatory encephalopathy, in accordance with institutional and international guidelines.
Results
Five patients (two females) with a mean age of 66.8 years (range: 54–75 years) were included in this retrospective study. Demographics, comorbidities, disease course, timing of IVIg and other immunotherapies are summarized in Table 1. Clinical, neuroradiological, EEG and CSF findings are summarized in Table 2. The illustrative case of the first patient is shown in Fig. 1.Table 1 Demographics, comorbidities and disease course
Pt Age (y),
Sex Comorbidities COVID-19 onset (day)a,b Worst P/F (day)a IVIg treatment
(0.4 g/kg/d)
(start, end)a Clinical Response (initial, complete)a Other immunotherapies
(start, end)a Last f.up (day)a
1 54, F None − 5 130 (+ 3) + 18, + 21 + 19, + 21 Tocilizumab 400 mg (+ 0)
Low-dose steroids (+ 3, + 17)
+ 90
2 75, M Type 2 DM, hypertension, ischemic heart disease,
previous stroke
0 114 (+ 12) + 26, + 30 + 28, + 34 Tocilizumab 400 mg (+ 33)
Low-dose steroids (+ 21, + 36)
+ 115
3 69, F Bipolar disorder, MCI, iatrogenic parkinsonism, type 2 DM − 15 345 (+ 14) + 28, + 32 + 30, + 38 MP 1 g/die (+ 13, + 17) + 86
4 69, M Hypertensive cardiopathy − 23 81
(− 14)
+ 22, + 27 + 24, + 28 + 70
5 67, M Type 2 DM,
hypertension
− 20 79
(− 8)
+ 55, + 60 + 65, + 75 Tocilizumab 400 mg (− 8) + 105
DM diabetes mellitus, MCI mild cognitive impairment, MP methylprednysolone
aWe referred to encephalopathy onset as day “0”, and to all events occurred previously or subsequently as minus or plus “day”, respectively
bOnset of constitutional or respiratory symptoms such as fever, cough, dyspnea
Table 2 Neurological clinical and investigative findings
Pt Neurological manifestations EEG (D) MRI (D) CSF (D)
1 Irritability, quadriparesis with pyramidal signs, akinetic mutism, agitated delirium, frontal release reflexes Diffuse slowing at 6–7 Hz
(+ 15)
Fronto-parietal white matter hyperintensity
(+ 16)
Cells: 0/μL
Proteins: 26 mg/dL
Qalb: 4
(+ 17)
2 Confusion, disorientation, global memory deficits Diffuse slowing at 4–5 Hz
(+ 21)
Previous right fronto-parietal stroke
(+ 22)
Cells: 1 WBC/μL
Proteins: 60 mg/dL
Qalb: 17.8
(+ 25)
3 Apraxia, mixed delirium, pyramidal signs, frontal release reflexes, extrapyramidal signs (rigidity and bradykinesia)a Diffuse slowing at 6–7 Hz, frontal sharp waves
(+ 13)
Parietal white matter hyperintensity, cerebral atrophy
(+ 13)
Cells: 1 WBC/μL
Proteins: 32 mg/dL
Qalb: 3.8
(+ 9)
4 Decreased level of consciousness, agitation, tonic muscle spasms Diffuse slowing at 5–6 Hz, FIRDA
(+ 0)
Cerebral small vessel disease (chronic)
(+ 2)
Cells: 6 WBC/μL
Proteins 35 mg/dL
(+ 1)
5 Decreased level of consciousness, agitation, hemiparesis with pyramidal signs, extrapyramidal signs (rigidity and tremor), frontal release reflexes Diffuse slowing at 5–6 Hz
(+ 2)
Cerebral small vessel disease (chronic)
(+ 45)
Cells: 1 WBC/μL
Proteins: 29 mg/dL
(+ 2)
D number of days after encephalopathy onset, FIRDA frontal intermittent rhythmic delta activity, Qalb CSF/serum albumin quotient, WBC white blood cell
aExtrapyramidal signs were already present before COVID-19 due to drug-induced parkinsonism
Fig. 1 Disease course in patient 1. Neurological manifestations, respiratory distress, temperature, IL-6 levels, timing of immunomodulatory treatments and diagnostic investigations during disease course. Neurological status severity was evaluated by treating neurologists. On the 15th day after disease onset, neurological evaluation was performed during temporary weaning of sedatives (red dot). Temperature and SpO2/FiO2 ratio were measured at least daily during hospitalization. Crosses on the IL-6 line represent the actual measurements. EEG electroencephalography, EMG electromyography, ICU intensive care unit, IVIg intravenous immunoglobulin treatment, LP lumbar puncture, MRI magnetic resonance imaging, S/F SpO2/FiO2 ratio
Three patients (1, 4, 5) were placed on invasive mechanical ventilation due to respiratory distress, while patient 2 was treated with non-invasive mechanical ventilation. Patient 3 had prior hospitalization in another facility for mild respiratory distress, where she was treated with low-flow oxygen therapy. She was subsequently re-admitted to our facility due to the subacute onset of neuropsychiatric symptoms. All patients developed encephalopathy, with a mean onset of 12.6 days (range 0–23 days) after the presentation of respiratory/constitutional symptoms related to SARS-CoV-2 infection. In patients 4 and 5, encephalopathy presented following sedation weaning as persisting impaired consciousness, whereas CNS symptoms developed in the other patients independently. Neurological manifestations were heterogeneous, including confusion, agitation, delirium, akinetic mutism, apraxia, pyramidal, extrapyramidal and frontal release signs. EEG demonstrated diffuse slowing in all patients, with frontal predominance in two cases. Brain MRI showed non-specific diffuse white-matter hyperintensities in two patients, while the others displayed chronic cerebrovascular findings. CSF analysis revealed ≤ 6 WBC and normal protein levels in each patient. In all subjects, RT-PCR for SARS-CoV-2 and for common neurotropic viruses in CSF, as well as a panel of CSF and serologic antibodies against neuronal intracellular and cell surface antigens, tested negative. Blood tests revealed elevated inflammatory markers, including IL-6 (Supplementary Appendix). Patient 3 developed hypernatremia (up to 164 mEq/L) and prerenal acute kidney injury during hospitalization, but their correction did not result in mental status improvement. With this exception, common causes of encephalopathy such as renal or hepatic failure, electrolyte imbalances, and hypoxemia were excluded in all cases. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range 19–55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range 1–10 days). No further neurological symptoms were observed at the last follow-up visit, which was performed after a mean of 54.8 days (range 30–81) since clinical recovery. In patient 1, a marked reduction of serum IL-6 levels was evident on the fourth IVIg infusion day (from 218 to 28 pg/mL), coinciding with clinical response. No adverse events related to IVIg were observed.
Discussion
Encephalopathy is emerging as a recurrent complication of COVID-19, yet the best approach to management and treatment remains unknown. We described five patients with COVID-19-related encephalopathy, all of whom recovered following IVIg.
IVIg is an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological disorders; however, its mode of action is complex and not yet fully understood [15]. The pathophysiology underlying the diseases which respond to IVIg is highly heterogeneous, thus it is likely that IVIg acts on various disease-specific pathways.
In patients with COVID-19 and severe pulmonary involvement, treatment with IVIg led to a significant clinical improvement and concomitant reduction of serum inflammatory markers, observed as early as the first infusion day [13]. Correspondingly, our patients showed a prompt and dramatic improvement of neurological manifestations following IVIg. Similar results have been achieved in six other patients with COVID-19-related encephalopathy treated with high-dose corticosteroids [5, 11]. In our third case, steroid pulse therapy was ineffective, where subsequent IVIg was concomitant with clinical recovery. In support of our preliminary findings, IVIg led to improved neuropsychiatric symptoms in four COVID-19 patients with mixed central and peripheral neurological manifestations and to clinico-radiological recovery in a further patient with frontal status epilepticus and encephalopathy [16, 17].
Clinical course and investigative findings observed in the present case series, including negative RT-PCR for SARS-CoV-2 in CSF, absence of significant elevation of CSF cells and protein levels, non-specific MRI findings, and the dramatic response to immunotherapy, suggest an inflammatory/immune-mediated pathogenesis rather than CNS viral invasion. An autoantibody-mediated mechanism is unlikely to explain CNS involvement, based on the brief temporal interval between CNS and infection-related symptom onset, negative testing for anti-neuronal antibodies, and the prompt and sustained response to IVIg [15]. Cytokine-mediated neuroinflammation has been implicated in the underlying pathogenic mechanism of COVID-19-associated encephalopathy, and may have contributed to disease course in our patients [5–10]. Except the third case, all patients suffered acute respiratory distress secondary to CRS induced by SARS-CoV-2. Interestingly, case 3 is the only patient with previous cognitive impairment, a condition that possibly made her more susceptible to develop encephalopathy despite mild systemic inflammation, as in other reported geriatric patients [10]. In patient 1 and 4, we observed a delay between the rise of inflammatory markers in serum and the onset/peak of neurological manifestations, possibly due to a delayed rise of CSF cytokines with respect to serum levels. Unfortunately, we were not able to measure CSF cytokines.
IVIg has anti-cytokine qualities, which appear important for its anti-inflammatory action. This may be related to the presence of anti-cytokine autoantibodies found in natural human immunoglobulin, including anti-TNF-α, anti-IL-1 and anti IL-8 [18]. Additionally, the natural IgG fraction inhibits the production of proinflammatory cytokines in a dose-dependent manner via the Fc portion [18]. Accordingly, IVIg therapy has been shown to significantly reduce circulating proinflammatory cytokines within 3 days [19], as observed in patient 1.
Cytokines may drive neuroinflammation even without severe CRS, possibly as a consequence of local CNS production [5, 6, 20]. The IVIg anti-cytokine effects documented peripherally may independently and directly act on the CNS. IVIg can cross an intact blood–brain-barrier and is bioavailable in sufficient concentrations to interact with the therapeutic targets, with the maximum concentration reached in the CNS 24 h after administration in a murine model [1, 2].
None of our patients experienced adverse events related to IVIg. Adverse reactions to IVIg therapy are usually minor and occur in less than 10% of patients [15]. However, as both COVID-19 and IVIg may predispose to thromboembolic events such as stroke and pulmonary embolism [2, 15], prophylactic anticoagulation should be considered. In patients with evidence of coagulopathy, an alternate immunotherapy such as high-dose corticosteroids should be preferred. However, since the likelihood of thromboembolic disease in COVID-19 might be secondary to CRS, the global thromboembolic risk may be partially compensated by the anti-inflammatory action of IVIg [1, 16].
Conclusions
IVIg was a safe and effective treatment for COVID-19-related encephalopathy in our case series. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities. Our preliminary observation needs to be confirmed with larger clinical studies. However, considering the emerging evidence supporting an inflammatory-mediated pathogenesis in a subgroup of patients with COVID-19-related encephalopathy, we believe that immunotherapy with IVIg or other agents might be considered to hasten clinical recovery and prevent potential long-term neurological sequelae.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (DOCX 22 kb)
Acknowledgements
We thank all the colleagues working at the COVID-19 units of Bellaria and Infermi hospitals, especially L. Guerra, S. Zaccaroni, L.L. Gramegna, P. Riguzzi, C. Calabrò, E. Fileccia, G. Fornaro, F. Volpato, L. Bussini. We also thank Prof. R. Lodi, Prof. P. Affanni, Prof. M.C. Re, G. Bordin, I. Bon, G. Rossini.
Author contributions
LM, UP, GB and FB contributed to conception and design of the study; all authors contributed to the acquisition and/or analysis of data; LM and UP drafted the manuscript; IC prepared the figure; FB supervised the study.
Funding
Open access funding provided by Alma Mater Studiorum - Università di Bologna within the CRUI-CARE Agreement.
Compliance with ethical standards
Conflicts of interest
Nothing to report.
Ethical approval
All investigations were carried out according to the Declaration of Helsinki.
Lorenzo Muccioli and Umberto Pensato have contributed equally to this work.
|
METHYLPREDNISOLONE
|
DrugsGivenReaction
|
CC BY
|
33030607
| 20,053,014
|
2021-08
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'.
|
Intravenous immunoglobulin therapy in COVID-19-related encephalopathy.
OBJECTIVE
To report on efficacy and safety of intravenous immunoglobulin (IVIg) therapy in a case series of patients with COVID-19-related encephalopathy.
METHODS
We retrospectively collected data on all patients with COVID-19 hospitalized at two Italian hospitals who developed encephalopathy during disease course and were treated with IVIg.
RESULTS
Five patients (two females, mean age 66.8 years) developed encephalopathy after a mean of 12.6 days, since the onset of respiratory/constitutional symptoms related to COVID-19. Four patients suffered severe respiratory distress, three of which required invasive mechanical ventilation. Neurological manifestations included impaired consciousness, agitation, delirium, pyramidal and extrapyramidal signs. EEG demonstrated diffuse slowing in all patients. Brain MRI showed non-specific findings. CSF analysis revealed normal cell count and protein levels. In all subjects, RT-PCR for SARS-CoV-2 in CSF tested negative. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range: 19-55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range: 1-10 days). No adverse events related to IVIg were observed.
CONCLUSIONS
Our preliminary findings suggest that IVIg may represent a safe and effective treatment for COVID-19-associated encephalopathy. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities.
Introduction
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of coronavirus disease-2019 (COVID-19). While many individuals with SARS-CoV-2 infection are asymptomatic or develop only mild respiratory and constitutional symptoms, a subgroup of patients present with complications, including acute respiratory distress syndrome, disseminated intravascular coagulation and multiorgan dysfunction syndrome [1, 2].
Cytokine release syndrome (CRS) is a systemic hyperinflammatory condition presenting secondary to monocyte, macrophage and dendritic cell activation in severe COVID-19 infection and has been implicated in disease pathophysiology [3].
Neuropsychiatric manifestations are increasingly being reported in association with COVID-19, including encephalopathy [4]. The pathophysiology underlying this presentation remains unclear; however, a role of cytokine-mediated neuroinflammation has been suggested [5−10]. COVID-19-associated encephalopathy has been described responsive to high-dose steroids and plasmapheresis, consistent with an immune-mediated pathogenesis [5, 11, 12].
Intravenous immunoglobulin (IVIg) therapy has shown efficacy in treating systemic COVID-[13, 19] yet its role in the management of associated CNS manifestations remains to be determined.
We report five patients with COVID-19-related encephalopathy successfully treated with IVIg.
Methods
We retrospectively collected data on all patients with COVID-19 hospitalized at Bellaria Hospital, Bologna, and Infermi Hospital, Rimini, Italy, from March 13, 2020, to May 27, 2020, who developed encephalopathy during disease course and were treated with IVIg. COVID-19 diagnosis was made on the basis of at least one positive SARS-CoV-2 real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasopharyngeal swab specimens and consistent clinical and/or radiological findings. IVIg therapy was prescribed by the treating neurologist based on the patient’s clinical profile and suspected immune-mediated/inflammatory encephalopathy, in accordance with institutional and international guidelines.
Results
Five patients (two females) with a mean age of 66.8 years (range: 54–75 years) were included in this retrospective study. Demographics, comorbidities, disease course, timing of IVIg and other immunotherapies are summarized in Table 1. Clinical, neuroradiological, EEG and CSF findings are summarized in Table 2. The illustrative case of the first patient is shown in Fig. 1.Table 1 Demographics, comorbidities and disease course
Pt Age (y),
Sex Comorbidities COVID-19 onset (day)a,b Worst P/F (day)a IVIg treatment
(0.4 g/kg/d)
(start, end)a Clinical Response (initial, complete)a Other immunotherapies
(start, end)a Last f.up (day)a
1 54, F None − 5 130 (+ 3) + 18, + 21 + 19, + 21 Tocilizumab 400 mg (+ 0)
Low-dose steroids (+ 3, + 17)
+ 90
2 75, M Type 2 DM, hypertension, ischemic heart disease,
previous stroke
0 114 (+ 12) + 26, + 30 + 28, + 34 Tocilizumab 400 mg (+ 33)
Low-dose steroids (+ 21, + 36)
+ 115
3 69, F Bipolar disorder, MCI, iatrogenic parkinsonism, type 2 DM − 15 345 (+ 14) + 28, + 32 + 30, + 38 MP 1 g/die (+ 13, + 17) + 86
4 69, M Hypertensive cardiopathy − 23 81
(− 14)
+ 22, + 27 + 24, + 28 + 70
5 67, M Type 2 DM,
hypertension
− 20 79
(− 8)
+ 55, + 60 + 65, + 75 Tocilizumab 400 mg (− 8) + 105
DM diabetes mellitus, MCI mild cognitive impairment, MP methylprednysolone
aWe referred to encephalopathy onset as day “0”, and to all events occurred previously or subsequently as minus or plus “day”, respectively
bOnset of constitutional or respiratory symptoms such as fever, cough, dyspnea
Table 2 Neurological clinical and investigative findings
Pt Neurological manifestations EEG (D) MRI (D) CSF (D)
1 Irritability, quadriparesis with pyramidal signs, akinetic mutism, agitated delirium, frontal release reflexes Diffuse slowing at 6–7 Hz
(+ 15)
Fronto-parietal white matter hyperintensity
(+ 16)
Cells: 0/μL
Proteins: 26 mg/dL
Qalb: 4
(+ 17)
2 Confusion, disorientation, global memory deficits Diffuse slowing at 4–5 Hz
(+ 21)
Previous right fronto-parietal stroke
(+ 22)
Cells: 1 WBC/μL
Proteins: 60 mg/dL
Qalb: 17.8
(+ 25)
3 Apraxia, mixed delirium, pyramidal signs, frontal release reflexes, extrapyramidal signs (rigidity and bradykinesia)a Diffuse slowing at 6–7 Hz, frontal sharp waves
(+ 13)
Parietal white matter hyperintensity, cerebral atrophy
(+ 13)
Cells: 1 WBC/μL
Proteins: 32 mg/dL
Qalb: 3.8
(+ 9)
4 Decreased level of consciousness, agitation, tonic muscle spasms Diffuse slowing at 5–6 Hz, FIRDA
(+ 0)
Cerebral small vessel disease (chronic)
(+ 2)
Cells: 6 WBC/μL
Proteins 35 mg/dL
(+ 1)
5 Decreased level of consciousness, agitation, hemiparesis with pyramidal signs, extrapyramidal signs (rigidity and tremor), frontal release reflexes Diffuse slowing at 5–6 Hz
(+ 2)
Cerebral small vessel disease (chronic)
(+ 45)
Cells: 1 WBC/μL
Proteins: 29 mg/dL
(+ 2)
D number of days after encephalopathy onset, FIRDA frontal intermittent rhythmic delta activity, Qalb CSF/serum albumin quotient, WBC white blood cell
aExtrapyramidal signs were already present before COVID-19 due to drug-induced parkinsonism
Fig. 1 Disease course in patient 1. Neurological manifestations, respiratory distress, temperature, IL-6 levels, timing of immunomodulatory treatments and diagnostic investigations during disease course. Neurological status severity was evaluated by treating neurologists. On the 15th day after disease onset, neurological evaluation was performed during temporary weaning of sedatives (red dot). Temperature and SpO2/FiO2 ratio were measured at least daily during hospitalization. Crosses on the IL-6 line represent the actual measurements. EEG electroencephalography, EMG electromyography, ICU intensive care unit, IVIg intravenous immunoglobulin treatment, LP lumbar puncture, MRI magnetic resonance imaging, S/F SpO2/FiO2 ratio
Three patients (1, 4, 5) were placed on invasive mechanical ventilation due to respiratory distress, while patient 2 was treated with non-invasive mechanical ventilation. Patient 3 had prior hospitalization in another facility for mild respiratory distress, where she was treated with low-flow oxygen therapy. She was subsequently re-admitted to our facility due to the subacute onset of neuropsychiatric symptoms. All patients developed encephalopathy, with a mean onset of 12.6 days (range 0–23 days) after the presentation of respiratory/constitutional symptoms related to SARS-CoV-2 infection. In patients 4 and 5, encephalopathy presented following sedation weaning as persisting impaired consciousness, whereas CNS symptoms developed in the other patients independently. Neurological manifestations were heterogeneous, including confusion, agitation, delirium, akinetic mutism, apraxia, pyramidal, extrapyramidal and frontal release signs. EEG demonstrated diffuse slowing in all patients, with frontal predominance in two cases. Brain MRI showed non-specific diffuse white-matter hyperintensities in two patients, while the others displayed chronic cerebrovascular findings. CSF analysis revealed ≤ 6 WBC and normal protein levels in each patient. In all subjects, RT-PCR for SARS-CoV-2 and for common neurotropic viruses in CSF, as well as a panel of CSF and serologic antibodies against neuronal intracellular and cell surface antigens, tested negative. Blood tests revealed elevated inflammatory markers, including IL-6 (Supplementary Appendix). Patient 3 developed hypernatremia (up to 164 mEq/L) and prerenal acute kidney injury during hospitalization, but their correction did not result in mental status improvement. With this exception, common causes of encephalopathy such as renal or hepatic failure, electrolyte imbalances, and hypoxemia were excluded in all cases. IVIg at 0.4 g/kg/die was commenced 29.8 days (mean, range 19–55 days) after encephalopathy onset, leading to complete electroclinical recovery in all patients, with an initial improvement of neuropsychiatric symptoms observed in 3.4 days (mean, range 1–10 days). No further neurological symptoms were observed at the last follow-up visit, which was performed after a mean of 54.8 days (range 30–81) since clinical recovery. In patient 1, a marked reduction of serum IL-6 levels was evident on the fourth IVIg infusion day (from 218 to 28 pg/mL), coinciding with clinical response. No adverse events related to IVIg were observed.
Discussion
Encephalopathy is emerging as a recurrent complication of COVID-19, yet the best approach to management and treatment remains unknown. We described five patients with COVID-19-related encephalopathy, all of whom recovered following IVIg.
IVIg is an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological disorders; however, its mode of action is complex and not yet fully understood [15]. The pathophysiology underlying the diseases which respond to IVIg is highly heterogeneous, thus it is likely that IVIg acts on various disease-specific pathways.
In patients with COVID-19 and severe pulmonary involvement, treatment with IVIg led to a significant clinical improvement and concomitant reduction of serum inflammatory markers, observed as early as the first infusion day [13]. Correspondingly, our patients showed a prompt and dramatic improvement of neurological manifestations following IVIg. Similar results have been achieved in six other patients with COVID-19-related encephalopathy treated with high-dose corticosteroids [5, 11]. In our third case, steroid pulse therapy was ineffective, where subsequent IVIg was concomitant with clinical recovery. In support of our preliminary findings, IVIg led to improved neuropsychiatric symptoms in four COVID-19 patients with mixed central and peripheral neurological manifestations and to clinico-radiological recovery in a further patient with frontal status epilepticus and encephalopathy [16, 17].
Clinical course and investigative findings observed in the present case series, including negative RT-PCR for SARS-CoV-2 in CSF, absence of significant elevation of CSF cells and protein levels, non-specific MRI findings, and the dramatic response to immunotherapy, suggest an inflammatory/immune-mediated pathogenesis rather than CNS viral invasion. An autoantibody-mediated mechanism is unlikely to explain CNS involvement, based on the brief temporal interval between CNS and infection-related symptom onset, negative testing for anti-neuronal antibodies, and the prompt and sustained response to IVIg [15]. Cytokine-mediated neuroinflammation has been implicated in the underlying pathogenic mechanism of COVID-19-associated encephalopathy, and may have contributed to disease course in our patients [5–10]. Except the third case, all patients suffered acute respiratory distress secondary to CRS induced by SARS-CoV-2. Interestingly, case 3 is the only patient with previous cognitive impairment, a condition that possibly made her more susceptible to develop encephalopathy despite mild systemic inflammation, as in other reported geriatric patients [10]. In patient 1 and 4, we observed a delay between the rise of inflammatory markers in serum and the onset/peak of neurological manifestations, possibly due to a delayed rise of CSF cytokines with respect to serum levels. Unfortunately, we were not able to measure CSF cytokines.
IVIg has anti-cytokine qualities, which appear important for its anti-inflammatory action. This may be related to the presence of anti-cytokine autoantibodies found in natural human immunoglobulin, including anti-TNF-α, anti-IL-1 and anti IL-8 [18]. Additionally, the natural IgG fraction inhibits the production of proinflammatory cytokines in a dose-dependent manner via the Fc portion [18]. Accordingly, IVIg therapy has been shown to significantly reduce circulating proinflammatory cytokines within 3 days [19], as observed in patient 1.
Cytokines may drive neuroinflammation even without severe CRS, possibly as a consequence of local CNS production [5, 6, 20]. The IVIg anti-cytokine effects documented peripherally may independently and directly act on the CNS. IVIg can cross an intact blood–brain-barrier and is bioavailable in sufficient concentrations to interact with the therapeutic targets, with the maximum concentration reached in the CNS 24 h after administration in a murine model [1, 2].
None of our patients experienced adverse events related to IVIg. Adverse reactions to IVIg therapy are usually minor and occur in less than 10% of patients [15]. However, as both COVID-19 and IVIg may predispose to thromboembolic events such as stroke and pulmonary embolism [2, 15], prophylactic anticoagulation should be considered. In patients with evidence of coagulopathy, an alternate immunotherapy such as high-dose corticosteroids should be preferred. However, since the likelihood of thromboembolic disease in COVID-19 might be secondary to CRS, the global thromboembolic risk may be partially compensated by the anti-inflammatory action of IVIg [1, 16].
Conclusions
IVIg was a safe and effective treatment for COVID-19-related encephalopathy in our case series. Clinical efficacy may be driven by the anti-inflammatory action of IVIg, associated with its anti-cytokine qualities. Our preliminary observation needs to be confirmed with larger clinical studies. However, considering the emerging evidence supporting an inflammatory-mediated pathogenesis in a subgroup of patients with COVID-19-related encephalopathy, we believe that immunotherapy with IVIg or other agents might be considered to hasten clinical recovery and prevent potential long-term neurological sequelae.
Electronic supplementary material
Below is the link to the electronic supplementary material.Supplementary material 1 (DOCX 22 kb)
Acknowledgements
We thank all the colleagues working at the COVID-19 units of Bellaria and Infermi hospitals, especially L. Guerra, S. Zaccaroni, L.L. Gramegna, P. Riguzzi, C. Calabrò, E. Fileccia, G. Fornaro, F. Volpato, L. Bussini. We also thank Prof. R. Lodi, Prof. P. Affanni, Prof. M.C. Re, G. Bordin, I. Bon, G. Rossini.
Author contributions
LM, UP, GB and FB contributed to conception and design of the study; all authors contributed to the acquisition and/or analysis of data; LM and UP drafted the manuscript; IC prepared the figure; FB supervised the study.
Funding
Open access funding provided by Alma Mater Studiorum - Università di Bologna within the CRUI-CARE Agreement.
Compliance with ethical standards
Conflicts of interest
Nothing to report.
Ethical approval
All investigations were carried out according to the Declaration of Helsinki.
Lorenzo Muccioli and Umberto Pensato have contributed equally to this work.
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METHYLPREDNISOLONE
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DrugsGivenReaction
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CC BY
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33030607
| 20,053,014
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2021-08
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'.
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Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
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CARBOPLATIN, CETIRIZINE HYDROCHLORIDE, CHLORPHENIRAMINE HYDROCHLORIDE, CROMOLYN SODIUM, DEXAMETHASONE, FEXOFENADINE HYDROCHLORIDE, KETOTIFEN, MONTELUKAST SODIUM, ONDANSETRON, PACLITAXEL, RANITIDINE
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DrugsGivenReaction
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CC BY
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33032491
| 18,450,575
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Back pain'.
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
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CARBOPLATIN, CETIRIZINE HYDROCHLORIDE, CHLORPHENIRAMINE HYDROCHLORIDE, CROMOLYN SODIUM, DEXAMETHASONE, FEXOFENADINE HYDROCHLORIDE, KETOTIFEN, MONTELUKAST SODIUM, ONDANSETRON, PACLITAXEL, RANITIDINE
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DrugsGivenReaction
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CC BY
|
33032491
| 18,450,575
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2021-06
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Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'.
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Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
CARBOPLATIN, CETIRIZINE HYDROCHLORIDE, CHLORPHENIRAMINE HYDROCHLORIDE, CROMOLYN SODIUM, DEXAMETHASONE, FEXOFENADINE HYDROCHLORIDE, KETOTIFEN, MONTELUKAST SODIUM, ONDANSETRON, PACLITAXEL, RANITIDINE
|
DrugsGivenReaction
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dry skin'.
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
CARBOPLATIN, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33032491
| 18,523,491
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'.
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
CARBOPLATIN, PACLITAXEL
|
DrugsGivenReaction
|
CC BY
|
33032491
| 18,523,491
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Flushing'.
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
CARBOPLATIN, CETIRIZINE HYDROCHLORIDE, CHLORPHENIRAMINE HYDROCHLORIDE, CROMOLYN SODIUM, DEXAMETHASONE, FEXOFENADINE HYDROCHLORIDE, KETOTIFEN, MONTELUKAST SODIUM, ONDANSETRON, PACLITAXEL, RANITIDINE
|
DrugsGivenReaction
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the administration route of drug 'CARBOPLATIN'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the administration route of drug 'CETIRIZINE HYDROCHLORIDE'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Oral
|
DrugAdministrationRoute
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the administration route of drug 'CHLORPHENIRAMINE HYDROCHLORIDE'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Intravenous (not otherwise specified)
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DrugAdministrationRoute
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CC BY
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33032491
| 18,450,575
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2021-06
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What was the administration route of drug 'ONDANSETRON'?
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Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the administration route of drug 'PACLITAXEL'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Intravenous (not otherwise specified)
|
DrugAdministrationRoute
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the dosage of drug 'CETIRIZINE HYDROCHLORIDE'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
10 MILLIGRAM, CYCLE 1, 2, 3 + 4
|
DrugDosageText
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the dosage of drug 'CHLORPHENIRAMINE HYDROCHLORIDE'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
10 MG, CYCLE 1, 2, 3, 4 (30 MIN BEFORE)
|
DrugDosageText
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the dosage of drug 'ONDANSETRON'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
8 MG, CYCLE 1, 2, 3 + 4 (30 MIN BEFORE)
|
DrugDosageText
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the outcome of reaction 'Back pain'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Recovered
|
ReactionOutcome
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the outcome of reaction 'Dry skin'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Recovered
|
ReactionOutcome
|
CC BY
|
33032491
| 18,523,491
|
2021-06
|
What was the outcome of reaction 'Fatigue'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Recovered
|
ReactionOutcome
|
CC BY
|
33032491
| 18,523,491
|
2021-06
|
What was the outcome of reaction 'Flushing'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Recovered
|
ReactionOutcome
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
What was the outcome of reaction 'Hypersensitivity'?
|
Safe administration of chemotherapy in mast cell activation syndrome.
BACKGROUND
Mast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.
METHODS
We present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.
Introduction
Mast cell activation disorders (MCAS) are a heterogeneous group of conditions associated with mast cell hyperreactivity and/or proliferation. 1 Patients experience signs and symptoms attributable to inappropriate mast cell activation and pro-inflammatory mediator release. Symptoms range from mild, self-limiting allergic symptoms to potentially life-threatening recurrent anaphylaxis.
Mechanistically, MCAS can be classified as primary, secondary or idiopathic based on biochemical, molecular and clinical factors. 2 , 3 In primary MCAS genetic abnormalities, such as mutations in the tyrosine kinase receptor KIT, results in a monoclonal proliferation of mast cells. 4 Secondary MCAS occurs as an indirect result of another disease and/or inflammatory process, most commonly IgE-dependent allergic disease. Idiopathic MCAS is diagnosed when no primary or secondary causes are identified, despite extensive investigation. Many different drugs including chemotherapeutic agents (including carboplatin and paclitaxel) are known to be potent mast cell stimulators, therefore careful consideration is required before initiating any new procedure or treatment. 5 , 6
Endometrial cancer (EC) is the fourth most common female cancer and the 8th leading cause of cancer-related deaths. 7 Over 70% of endometrial cancers are detected at an early stage (stage 1 or 2) with the remainder being advanced disease with regional (stage 3) or distant (stage 4) metastasis. 8 Surgery is the initial mainstay of management of EC. However, patients with advanced disease (stage 3 or 4) or those with high risk features (clear cell, serous adenocarcinoma or grade 3 invasive endometroid carcinoma) have a greater risk of disease re-occurrence with surgical management alone. 9 , 10 Thus, adjuvant treatment to reduce the risk of re-occurrence and extend relapse-free survival is indicated. Chemotherapy and radiotherapy (pelvic and brachytherapy) are the two modalities of treatment which are given in the adjuvant setting. 11 , 12 At the time of treatment (January 2018) the standard of care at our institution was a combination of chemotherapy (carboplatin and paclitaxel) followed by radiotherapy (pelvic and/or brachytherapy).
We present a case of how chemotherapy can be pragmatically administered safely to a patient with MCAS at high risk of serious allergic sequalae. There are currently no case reports to guide management in this situation and we hope this may provide a safe framework for other to follow in this unusual circumstance.
Case report
A 59-year old lady presented to her primary care physician (September 2017) with a 4-week history of vaginal bleeding and weight loss. She was referred urgently to a tertiary gynaecology-oncology centre for further investigations. Initial evaluation consisted of blood tests, hysteroscopy and CT imaging of the chest, abdomen and pelvis. Her case was evaluated at the gynaecology oncology multi-disciplinary team (MDT) meeting and a provisional diagnosis of endometroid EC (likely stage 3) was agreed. It was recommended to proceed initially for surgical management.
The patient had a past medical history of hypertension, type 2 diabetes mellitus and most significantly, idiopathic mast cell activation disorder (MCAS) with a persistently raised tryptase. This condition initially presented 7 years ago with recurrent anaphylaxis. A plethora of different triggers have been established including foods (such as chicken, various nuts and seeds) and mast cell triggering drugs such as penicillin and macrolide antibiotics, experiencing both immediate and delayed reactions (up to 48 hours later). This condition was managed at a specialist allergy centre and she took a number of mast cell stabilising/allergy medications including sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine. She also took intermittent short courses of corticosteroid (two courses in past year) following severe reactions. However, despite these measures she continued to experience recurrent anaphylaxis with between two to four life-threatening episodes annually. Patch testing of potential triggers proved inconsistent and unreliable, failing to delineate any definitive triggers.
Recommended surgery consisted of a hysterectomy and salpingo-oophorectomy. Due to her diagnosis of MCAS her operation required meticulous planning, avoiding drugs with proven or theoretical high risk of mast cell activation such as muscle relaxants (e.g. atracurium), anaesthetic drugs (e.g. thiopental) and opioid analgesics (e.g. morphine). The operation proceeded and had no significant complications. She made an excellent recovery and was discharged five days after admission. Following surgery her case was re-discussed at the gynaecology oncology MDT with definitive histology from the operation. Her diagnosis was confirmed as a fully resected (R0 resection) stage IIIA grade 2 endometroid EC with lymphovascular space infiltration. Due to these high risk features she was referred to the oncology team for consideration of adjuvant chemotherapy and radiotherapy.
Currently guidelines for adjuvant treatment in EC recommend between four and six cycles of chemotherapy with carboplatin and paclitaxel followed by radiotherapy. 11 , 12 However, in the context of administering chemotherapy in MCAS there are currently no guidelines or case reports to guide management. This patient was reviewed in the oncology clinic and these issues were explored. Due to her higher risk of reoccurrence she wished to attempt adjuvant chemotherapy to minimise the disease reoccurrence risk.
Liaising with her allergy team, consideration was given to patch test for both carboplatin and paclitaxel, however given the previous unreliability of this test, time scale and the lack of utility for predicting sensitivity to taxanes, this was not deemed appropriate. Taking into account her risk factors for hypersensitivity (MCAS, postmenopausal) it was agreed to proceed cautiously with a staged approach (Table 1) of 4 cycles every 3 weeks of adjuvant chemotherapy (carboplatin and paclitaxel).
Table 1. Schedule of Treatment (3-week interval between treatments).
Drug Route Dose
Cycle 1
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via Desensitization regimen IV 560 mg
Cycle 2
Day -1: pre-medications (12hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via Desensitization regimen IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 3
Day -1: pre-medications (12 hours before) Dexamethasone PO 8 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 8 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5)Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 6-hour infusion IV 378 mg
Cycle 4
Day -1: pre-medications (12hours before) Dexamethasone PO 20 mg
Ranitidine PO 150 mg
Cetirizine PO 10 mg
Day 1: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Ranitidine IV 50 mg
Ondansetron IV 8 mg
Chlorpheniramine IV 10 mg
Day 1: chemotherapy Carboplatin (AUC 5) Via 1-hour infusion IV 560 mg
Day 2: pre-medications (30 minutes before) Dexamethasone IV 20 mg
Day 2: chemotherapy Paclitaxel (175 mg/m2)Via 3-hour infusion IV 378 mg
Note: Patient continued with regular medicines throughout treatment (sodium cromoglicate, fexofenadine, ketotifen, montelukast and cetirizine).
The first step to ensure accurate dosing of her chemotherapy (particularly carboplatin) was to estimate her renal function. Therefore, a glomerular filtration rate (GFR) analysis with 51Cr- ethylenediamine tetra-acetic acid (EDTA) was performed. Mild allergic phenomenon has been reported with administration of 51Cr-EDTA, however the incidence has not been quantified but is believed to be low. 13 Therefore, as a precautionary measure she was pre-treated with an intravenous antihistamine (chlorpheniramine 10 mg) thirty minutes before proceeding. This investigation was completed satisfactorily without incident.
The preferred chemotherapy regimen is currently carboplatin and paclitaxel given every 3 weeks. No trials exist comparing the efficacy of either single agent in the adjuvant setting. However, when evaluating the single agent response rate in metastatic EC chemotherapy naïve patients and the hypersensitivity risk of each drug, it was agreed to initially commence with carboplatin, adding paclitaxel in later cycles if no allergic sequalae or other problems had been encountered.
Traditionally this chemotherapy regimen is given as an outpatient. However, due to her risk of hypersensitivity reactions and having previously experienced both immediate and late-onset severe hypersensitivity reactions to drugs, it was agreed she should receive chemotherapy as an inpatient. To minimise her risk of hypersensitivity sequalae she would also receive pre-medication enhancement drugs and carboplatin as part of a phased 4-step regimen (see Table 2). Phased carboplatin desensitization regimes have been developed to induce short-lived tolerance to facilitate administration in patients who initially developed significant carboplatin hypersensitivity and was deemed appropriate for use in this setting to enhance safety. 14
Table 2. Carboplatin desensitization protocol.
Concentration of infusion Infusion rate
Infusion 1 0.1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 2 1% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 3 10% of total carboplatin dose a IV in 100 mls of glucose over 30 minutes
Infusion 4 Remainder of carboplatin dose a IV in 100 mls of glucose over 1 hour
Note: Patients should receive pre-medication schedule as outlined in Table 1 (cycle 1).
aCarboplatin total dose is calculated based on Calvert formula: 5 x (Glomerular Filtration Rate* + 25).
*Glomerular Filtration Rate (GFR) as calculated by 51Cr-EDTA GFR scan (alternative would be Creatinine Clearance based on Cockcroft-Gault Equation).
The night before her chemotherapy she took oral corticosteroid, antihistamine and H2 receptor antagonist (in addition to her normal mast cell stabilising medications) before being admitted to hospital on the morning of planned treatment. On admission she had her bloods re-checked for suitability and a physician safety assessment to confirm fitness for treatment. She received pre-medication with intravenous corticosteroid, antihistamine, 5HT3 receptor antagonist and H2 receptor antagonist thirty minutes before chemotherapy. The patient’s total dose of carboplatin (560 mg) was calculated based on the Calvert formula (see Table 2) with an area-under the curve (AUC) of 5. 15 This was prepared in four increasing concentrations of the total dose: 0.1%, 1%, 10% and standard infusion concentration following a predefined protocol. 15 , 16 Each infusion was administered over 30 minutes, except for the highest concentration which was given over 1 hour. Prior to proceeding to the next concentration level, she was examined for signs of hypersensitivity. She completed the treatment without any complications and was observed overnight as an extra-precaution before being discharged.
Following successful treatment without any hypersensitivity sequalae she was reviewed in clinic and consideration given to the stage of her treatment. She reported some constitutional symptoms such as fatigue and dry skin, however overall tolerated the treatment well. After careful consideration it was agreed for her next treatment cycle to continue with the carboplatin desensitization regimen and if she continued to tolerate this without complication, to receive paclitaxel the following day. Paclitaxel has a higher risk of immediate hypersensitivity reaction, therefore was given at a slower infusion rate (normally 3 hours) of 6 hours. As per the standard protocol the pre-medication corticosteroid dose (dexamethasone 20 mg) was also increased. She attended for cycle 2, three weeks after her first and received her chemotherapy without incident and was discharged after completing the second infusion.
For the third cycle as she had tolerated both drugs without incident, it was agreed she should continue to receive the drugs as an inpatient on consecutive days. However, as she had not experienced any problems with carboplatin, she should receive this normally (over 1 hours), not via the desensitization protocol and the paclitaxel infusion at the normal rate the next day. This cycle was again completed without any significant adverse events.
For her final cycle she was given carboplatin and paclitaxel on consecutive days as an outpatient but continuing with the enhanced pre-medication. Unfortunately, on the second day during the paclitaxel infusion, she developed a minor hypersensitivity reaction (flushing, back pain). Her infusion was immediately stopped, and she was treated with intravenous hydrocortisone and chlorpheniramine. She responded well to this management and her symptoms stopped within 30 minutes and was able to complete the infusion at a slower (6 hours) infusion rate.
Management & outcome
Following successful completion of 4 cycles of adjuvant chemotherapy she moved onto the next phase of her treatment. She completed adjuvant radiotherapy in the form of 45 Grey external beam radiotherapy (in 25 fractions) and 8 Grey high dose rate brachytherapy (in 2 fractions).
This was completed without incident. She has continued on regular follow-up since this time and at the time of censoring (May 2020) has had no evidence of disease re-occurrence.
Discussion
Currently there are no recognised protocols to guide safe administration of chemotherapy in patients with MCAS. The combination of carboplatin and paclitaxel chemotherapy agents is an established regime for the adjuvant treatment of endometrial cancer in women with high risk disease. 12 The hypersensitivity profiles of paclitaxel and carboplatin differ considerably. Paclitaxel is associated with a higher incidence of hypersensitivity (8-45%). 17 , 18 Reactions typically occurs immediately (within 10 minutes) and only 1.3% are severe (grade 3 or 4 reaction). 17 Carboplatin has a lower incidence of hypersensitivity; reactions become more frequent with cumulative exposure. In patients receiving up to 6 cycles of chemotherapy the reported incidence is <1%, making this ideal in the adjuvant treatment setting. 17 , 19 However, beyond 6 cycles this rises to 27% and half are classed as moderate or severe reactions. 17 Factors pre-disposing patients to hypersensitivity for both agents include any prior history of drug allergies or pre-existing hypersensitivity disorder (including mast cell disorders). Reactions in patients with pre-existing allergic conditions are characteristically more severe in nature and less responsive to pre-medication and treatment strategies. Recent evidence has also demonstrated than concomitant carboplatin and paclitaxel is associated with a higher hypersensitivity risk than alternative carboplatin combination regimens. 20
Currently there are no trials evaluating use of single agent chemotherapy in the adjuvant setting for EC. However, information can be gleaned from single agent chemotherapy naïve metastatic EC trials. The most active single agent drugs are platinum agents, taxanes and anthracyclines all producing similar response rates of 20–30%. 21 Therefore, when considering a treatment paradigm for this patient, evaluating the hypersensitivity safety profile of carboplatin for 4 cycles and the similar response rates of both drugs, carboplatin was selected as the initial drug of choice.
Desensitization is an allergological procedure primarily utilised to induce a state of temporary tolerance to facilitate essential drug administration. Drug desensitization regimens are typically used when no alternative drug is available and the benefits of such as treatment outweigh potential risks. In this case we utilized a carboplatin desensitization regimen to facilitate safer chemotherapy administration to a patient deemed to be at extremely high risk of developing both immediate and delayed life threatening allergic sequalae. This is the first reported use of this methodology and we hope this may be suitable in other high-risk cases. This approach did allow successful administration, however required significant additional healthcare resources (inpatient admission, special pharmacy chemotherapy preparation) to facilitate treatment.
Systemic mast cell activation diseases (such as systemic mastocytosis) have an associated increased risk of solid cancers including melanoma and non-melanoma skin cancers. 22 In MCAS the cancer association risk is less well-defined, however registry studies have identified significantly increased prevalence of melanoma and cancers of the breast, ovary, cervix uteri, thyroid and lung. 23 Taking account of the increasing utility of anti-cancer treatments including chemotherapy and the higher risk of malignancy in patient with mast cell disorders, this is likely to be a situation encountered more frequently in the future, therefore appropriate strategies are required.
Conclusion
Administering chemotherapy in any setting to patients with a history of severe hypersensitivity reactions and anaphylaxis can be challenging. This case demonstrates a framework to allow cautious chemotherapy administration in patients at high risk of serious allergic sequalae. We have presented this case in the hope that this can be used in similar setting to facilitate patients with a history of hypersensitivity to receive chemotherapy safely and pragmatically.
Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.L. has received an educational grant from Bayer; L.T. has received honoraria from Tesaro and AstraZeneca, outside the submitted work; I.M. has received honoraria from Clovis Oncology, Tesaro, AstraZeneca and Takeda, and has also received grants from AstraZeneca, outside the submitted work; J.K. has received honoraria from Clovis Oncology, Tesaro and AstraZeneca, outside the submitted work.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Informed consent: Informed consent was obtained from the patient included in the case report.
ORCID iD: MP Lythgoe https://orcid.org/0000-0002-8952-7639
|
Recovered
|
ReactionOutcome
|
CC BY
|
33032491
| 18,450,575
|
2021-06
|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia'.
|
Development of donepezil-induced hypokalemia following treatment of cognitive impairment.
Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.
Introduction
Hypokalemia is a common electrolyte disturbance in clinical practice. The major causes of hypokalemia include gastrointestinal loss and medications such as diuretics [1,2]. Most cases are asymptomatic and mild, but some patients develop severe hypokalemia resulting in arrhythmias and patient death. About 20% of inpatients experience hypokalemia during hospitalization [3], and among these cases, severe hypokalemia was sometimes associated with prolonged hospitalization and increased mortality [4].
Donepezil is the second approved acetylcholinesterase inhibitor for the treatment of mild to moderate Alzheimer disease by the United States Food and Drug Administration (FDA), extensively used worldwide [5]. As donepezil is generally tolerated, most adverse events are gastrointestinal symptoms, including vomiting and diarrhea [6]. However, rare adverse events such as lupus, psychosis, and arrhythmia have been reported in a few patients [7,8]. According to the FDA, hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients [9,10].
Notably, hypokalemia exhibits non-specific symptoms such as general weakness, fatigue, dyspepsia, myalgia, tingling sensation, muscle cramps, and spasms; hence, it can be difficult to diagnose without laboratory investigations. Therefore, clinicians sometimes fail to recognize the signs and symptoms of hypokalemia. Accordingly, a rare case of hypokalemia induced by medication is significant. Herein, we report a case of hypokalemia developed after initiating donepezil as a treatment for cognitive impairment.
Case
The study was approved by the Institutional Review Board of the Catholic University of Korea (IRB No: PC20ZASI0046) with waiver of informed consent.
An 87-year-old man visited the outpatient clinic owing to poor oral intake. According to his medical history, he had undergone surgery for benign prostatic hyperplasia 6 years ago and had discontinued the medication for benign prostatic hyperplasia 4 months before hospitalization. Recently, he was diagnosed with cognitive dysfunction based on a mini-mental status examination score of 22, and a global deterioration scale of 3. And was started on appropriate medication. At the time of admission, he was prescribed choline alfoscerate 400 mg twice daily and donepezil 5 mg for the control of Alzheimer disease.
A review of systems did not reveal abnormal findings. His vital signs were as follows: blood pressure (BP), 180/70 mmHg; pulse rate, 72 beats/min; respiratory rate, 20 breaths/min; body temperate, 36.7℃. To determine the cause of poor oral intake, routine investigations were performed, including complete blood count, blood chemistry, urine analysis, electrocardiogram, and chest X-ray. The presence of subtle pneumonia on the chest X-ray and hypokalemia (serum potassium 2.6 mmol/L) was detected. Initial serum inflammatory markers showed the following results: plasma leukocyte count, 7,500/mm3; serum c-reactive protein, 0.74 mg/dL (range, 0.01–0.5 mg/dL). Except for potassium, blood chemistry revealed the following: serum albumin, 4.0 g/dL (range, 3.5–5.2 g/dL); blood urea nitrogen, 10.9 mg/dL; serum creatinine, 0.72 mg/dL (range, 0.61–1.20 mg/dL); serum sodium, 140 mmol/L; serum chloride, 91 mmol/L; serum magnesium, 2.4 mg/dL; serum osmolality, 290 mOsm/kg. Urinalysis and urine sediment examination presented the following: urine pH, 7.5; urine specific gravity, 1.011; urine white blood cells, 0–2/high power field; urine red blood cells, 0–2/high power field. Blood gas analysis revealed compensated metabolic alkalosis as follows: arterial blood pH, 7.52; arterial blood pCO2, 46.6 mmHg; arterial blood pO2, 73.7 mmHg; arterial blood HCO3¯, 36.8 mmol/L. Chest X-ray and inflammatory markers suggested that the pneumonia was not severe. Therefore, hypokalemia could be the cause of underlying poor oral intake.
The patient was admitted to treat pneumonia and hypokalemia. For pneumonia treatment, he received ceftriaxone and clarithromycin as antibiotic agents. To determine the cause of hypokalemia, further investigations were performed. No clues indicating hypokalemia were detected in the medical history and review of systems. Next, his renal potassium excretion was measured to determine the potassium/creatinine ratio, fractional excretion of potassium, and transtubular potassium gradient (TTKG), using blood chemistry and spot urine chemistry. The results of spot urine chemistry were as follows: urea nitrogen, 392.8 mg/dL; creatinine, 90.8 mg/dL; total protein, 29.9 mg/dL; sodium, 35 mEq/L; potassium, 29.2 mEq/L; chloride, 45 mEq/L; osmolality, 309 mOsm/kg. Additionally, the following values were determined and suggested renal potassium wasting: urine potassium/creatinine ratio, 32.2 mEq/g; fractional excretion of potassium, 8.9%; TTKG, 10.5. Those findings suggested renal potassium wasting. Next, computed tomography demonstrated no abnormalities in the bilateral adrenal glands and both kidneys (Fig. 1). A hormone study was conducted to evaluate the cause of high BP. The thyroid function test was in the normal range. The adrenocorticotropic hormone (ACTH) level was 36.02 pg/mL (range, 10.0–60.0 pg/mL) and the cortisol level was 10.51 µg/dL (range, 9.41–26.06 µg/dL), which were within the normal range, revealing no mineral corticoid excess. Plasma renin activity was determined as 0.19 ng/mL/hr (range, 0.3–2.9 ng/mL/hr), aldosterone concentration was 14.93 pg/mL (range, 29.9–158.8 pg/mL), and the aldosterone/renin ratio was 7.86, indicating hyporeninemic hypoaldosteronism. However, unlike Liddle syndrome, the serum sodium level was normal at 140 mmol/L. The serum magnesium level was normal at 2.4 mg/dL, which was far from that observed in Gitelman syndrome. Hence, no obvious cause of hypokalemia was determined.
During investigations analyzing the possible cause of hypokalemia, he underwent potassium supplementation using intravenous and oral formulations. Until the fourth day of hospitalization, his serum potassium level demonstrated difficulty increasing beyond 3.0 mmol/L despite sufficient potassium administration (Fig. 2). As the hypokalemia was poorly corrected, clinicians suspected other causes of hypokalemia. A thorough review of the therapeutic agents prescribed for cognitive dysfunction was conducted. On examining possible adverse effects, we identified evidence suggesting that donepezil causes hypokalemia as a rare adverse event [9,10]. Therefore, donepezil was immediately discontinued. Thereafter, his potassium demand, supplemented intravenously, gradually decreased and was modified to oral potassium agents. On the third day after donepezil cessation, his serum potassium level recovered to 3.5 mmol/L under oral potassium supplementation of 32 mEq/day (Fig. 2). During hypokalemia evaluation and correction, pneumonia was properly controlled. Finally, he was able to maintain serum potassium of 3.3 mmol/L under oral potassium supplementation of 32 mEq/day and was discharged on the ninth day of hospitalization. At the time of discharge, the results of blood chemistry and spot urine chemistry were as follows: serum creatinine, 0.73 mg/dL; serum potassium, 3.5 mmol/L; serum magnesium, 2.3 mg/dL; serum osmolality, 295 mOsm/kg; urine creatinine, 120.6 mg/dL; potassium, 46.7 mEq/L; osmolality, 330 mOsm/kg. Additionally, the following values were determined: urine potassium/creatinine ratio, 38.7 mEq/g; fractional excretion of potassium, 8.1%; TTKG, 11.9.
Conversely, in the past, he had presented a systolic BP of less than 130 mmHg and diastolic BP of 80 mmHg during several visits to the outpatient clinic, with no history of medication-related hypertension. However, for 24 hours after hospitalization, BP was continuously confirmed as 160/90 mmHg or more, including a maximum of 185/105 mmHg, and amlodipine 5 mg was initiated. As BP measurements were above 140/90 mmHg on average after the addition of amlodipine 5 mg, the patient was additionally prescribed olmesartan 20 mg on the fifth day of hospitalization. Finally, in the outpatient clinic follow-ups, serum potassium was measured as 4.5 mmol/L, and oral potassium agents were withheld.
Discussion
This case report presents the rare development of hypokalemia with donepezil, an agent used to treat cognitive dysfunction. The most common cause of hypokalemia is gastrointestinal losses, followed by medications such as diuretics [1,2]. Additionally, various conditions lead to hypokalemia. For example, the following factors result in the development of renal potassium wasting: malignant hypertension, renal artery stenosis, renin-secreting tumors that can increase renin, adrenal hyperplasia, Cushing syndrome, medication including diuretics, magnesium deficiency, Gitelman syndrome, and chronic metabolic acidosis [3]. However, it is difficult to implicate donepezil, used for cognitive dysfunction therapy, as a causative agent. If this patient had multiple prescriptions, donepezil was probably not considered a major cause of hypokalemia.
Donepezil is a cholinesterase inhibitor, mainly prescribed for Alzheimer disease. By inhibiting acetylcholinesterase, donepezil improves behavioral and cognitive symptoms, including confusion, aggression, and psychosis [11,12]. In several studies, donepezil has demonstrated improved cognitive functions in patients with dementia, but it had some adverse effects [13]. The adverse effects were associated with increased cholinergic activity, and the gastrointestinal system was mainly affected. Therefore, nausea, vomiting, and diarrhea were the most common symptoms, as well as insomnia, abnormal dreams, hepatotoxicity, and cardiovascular adverse events [14]. Hypokalemia was one of the rare adverse effects.
The mechanism by which donepezil causes hypokalemia remains unclear. In this case, based on TTKG, potassium excretion continued under donepezil therapy. Therefore, we hypothesized the mechanism by which donepezil caused renal potassium wasting. This finding may be due to the action of donepezil on the ion channels in the renal tubule or Henle's loop. Donepezil could potentially inhibit the Na+-K+-2Cl- cotransporter in the thick ascending limb of Henle's loop, suppressing potassium reabsorption. Additionally, it could be postulated that donepezil stimulates the renal outer medullary potassium channel to excrete potassium. As another hypothesis, donepezil could affect the sodium channel epithelium in the principal cell of the collecting tubule. Thereafter, potassium appeared to be secreted into the lumen to maintain electrolyte balance. Although the mechanism by which donepezil induces hypokalemia remains unclear, we anticipated that renal potassium wasting would recover after its withdrawal. Unfortunately, the follow-up study did not achieve demonstrate an improvement in renal potassium wasting. Based on previous reports, we speculated the possible reasons by which recovery from renal potassium wasting may vary from 2 days to 3 months [15,16]. Therefore, the patient may require further time for recovery. Nonetheless, this case was significant as it confirmed the progression of hypokalemia recovery, necessitating a decrease in the daily amount of potassium supplementation after the withdrawal of donepezil.
A limitation of this case report is that we have not done additional research regarding how donepezil affects the renal ion channels. Further case reports and research would assist in determining the mechanism by which donepezil causes renal potassium wasting. Although donepezil demonstrates rare serious adverse events, symptoms during early therapy require a differential diagnosis for hypokalemia.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contributions
Conceptualization: all authors; Data curation: DK, THB, HSP; Formal analysis: DK, THB, HEY, BSC, BSK; Investigation: DK, THB, HEY, HSP; Methodology, Project administration: THB; Supervision: THB, BSC, BSK; Validation: THB, SJS, BSC, BSK; Writing-original draft: DK; Writing-review & editing: DK, THB, HEY, HSP, SJS.
Fig. 1. Abdominal computed tomography scan. (A) Both adrenal glands (arrows) show no abnormalities. (B) Both kidneys (arrows) show no abnormal findings.
Fig. 2. Summary of serum potassium level, potassium supplementation, total intake, and total output per day. IV, intravenous; PO, per oral.
|
CHOLINE ALFOSCERATE, DONEPEZIL
|
DrugsGivenReaction
|
CC BY-NC
|
33045804
| 18,742,345
|
2021-01
|
What was the administration route of drug 'DONEPEZIL'?
|
Development of donepezil-induced hypokalemia following treatment of cognitive impairment.
Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.
Introduction
Hypokalemia is a common electrolyte disturbance in clinical practice. The major causes of hypokalemia include gastrointestinal loss and medications such as diuretics [1,2]. Most cases are asymptomatic and mild, but some patients develop severe hypokalemia resulting in arrhythmias and patient death. About 20% of inpatients experience hypokalemia during hospitalization [3], and among these cases, severe hypokalemia was sometimes associated with prolonged hospitalization and increased mortality [4].
Donepezil is the second approved acetylcholinesterase inhibitor for the treatment of mild to moderate Alzheimer disease by the United States Food and Drug Administration (FDA), extensively used worldwide [5]. As donepezil is generally tolerated, most adverse events are gastrointestinal symptoms, including vomiting and diarrhea [6]. However, rare adverse events such as lupus, psychosis, and arrhythmia have been reported in a few patients [7,8]. According to the FDA, hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients [9,10].
Notably, hypokalemia exhibits non-specific symptoms such as general weakness, fatigue, dyspepsia, myalgia, tingling sensation, muscle cramps, and spasms; hence, it can be difficult to diagnose without laboratory investigations. Therefore, clinicians sometimes fail to recognize the signs and symptoms of hypokalemia. Accordingly, a rare case of hypokalemia induced by medication is significant. Herein, we report a case of hypokalemia developed after initiating donepezil as a treatment for cognitive impairment.
Case
The study was approved by the Institutional Review Board of the Catholic University of Korea (IRB No: PC20ZASI0046) with waiver of informed consent.
An 87-year-old man visited the outpatient clinic owing to poor oral intake. According to his medical history, he had undergone surgery for benign prostatic hyperplasia 6 years ago and had discontinued the medication for benign prostatic hyperplasia 4 months before hospitalization. Recently, he was diagnosed with cognitive dysfunction based on a mini-mental status examination score of 22, and a global deterioration scale of 3. And was started on appropriate medication. At the time of admission, he was prescribed choline alfoscerate 400 mg twice daily and donepezil 5 mg for the control of Alzheimer disease.
A review of systems did not reveal abnormal findings. His vital signs were as follows: blood pressure (BP), 180/70 mmHg; pulse rate, 72 beats/min; respiratory rate, 20 breaths/min; body temperate, 36.7℃. To determine the cause of poor oral intake, routine investigations were performed, including complete blood count, blood chemistry, urine analysis, electrocardiogram, and chest X-ray. The presence of subtle pneumonia on the chest X-ray and hypokalemia (serum potassium 2.6 mmol/L) was detected. Initial serum inflammatory markers showed the following results: plasma leukocyte count, 7,500/mm3; serum c-reactive protein, 0.74 mg/dL (range, 0.01–0.5 mg/dL). Except for potassium, blood chemistry revealed the following: serum albumin, 4.0 g/dL (range, 3.5–5.2 g/dL); blood urea nitrogen, 10.9 mg/dL; serum creatinine, 0.72 mg/dL (range, 0.61–1.20 mg/dL); serum sodium, 140 mmol/L; serum chloride, 91 mmol/L; serum magnesium, 2.4 mg/dL; serum osmolality, 290 mOsm/kg. Urinalysis and urine sediment examination presented the following: urine pH, 7.5; urine specific gravity, 1.011; urine white blood cells, 0–2/high power field; urine red blood cells, 0–2/high power field. Blood gas analysis revealed compensated metabolic alkalosis as follows: arterial blood pH, 7.52; arterial blood pCO2, 46.6 mmHg; arterial blood pO2, 73.7 mmHg; arterial blood HCO3¯, 36.8 mmol/L. Chest X-ray and inflammatory markers suggested that the pneumonia was not severe. Therefore, hypokalemia could be the cause of underlying poor oral intake.
The patient was admitted to treat pneumonia and hypokalemia. For pneumonia treatment, he received ceftriaxone and clarithromycin as antibiotic agents. To determine the cause of hypokalemia, further investigations were performed. No clues indicating hypokalemia were detected in the medical history and review of systems. Next, his renal potassium excretion was measured to determine the potassium/creatinine ratio, fractional excretion of potassium, and transtubular potassium gradient (TTKG), using blood chemistry and spot urine chemistry. The results of spot urine chemistry were as follows: urea nitrogen, 392.8 mg/dL; creatinine, 90.8 mg/dL; total protein, 29.9 mg/dL; sodium, 35 mEq/L; potassium, 29.2 mEq/L; chloride, 45 mEq/L; osmolality, 309 mOsm/kg. Additionally, the following values were determined and suggested renal potassium wasting: urine potassium/creatinine ratio, 32.2 mEq/g; fractional excretion of potassium, 8.9%; TTKG, 10.5. Those findings suggested renal potassium wasting. Next, computed tomography demonstrated no abnormalities in the bilateral adrenal glands and both kidneys (Fig. 1). A hormone study was conducted to evaluate the cause of high BP. The thyroid function test was in the normal range. The adrenocorticotropic hormone (ACTH) level was 36.02 pg/mL (range, 10.0–60.0 pg/mL) and the cortisol level was 10.51 µg/dL (range, 9.41–26.06 µg/dL), which were within the normal range, revealing no mineral corticoid excess. Plasma renin activity was determined as 0.19 ng/mL/hr (range, 0.3–2.9 ng/mL/hr), aldosterone concentration was 14.93 pg/mL (range, 29.9–158.8 pg/mL), and the aldosterone/renin ratio was 7.86, indicating hyporeninemic hypoaldosteronism. However, unlike Liddle syndrome, the serum sodium level was normal at 140 mmol/L. The serum magnesium level was normal at 2.4 mg/dL, which was far from that observed in Gitelman syndrome. Hence, no obvious cause of hypokalemia was determined.
During investigations analyzing the possible cause of hypokalemia, he underwent potassium supplementation using intravenous and oral formulations. Until the fourth day of hospitalization, his serum potassium level demonstrated difficulty increasing beyond 3.0 mmol/L despite sufficient potassium administration (Fig. 2). As the hypokalemia was poorly corrected, clinicians suspected other causes of hypokalemia. A thorough review of the therapeutic agents prescribed for cognitive dysfunction was conducted. On examining possible adverse effects, we identified evidence suggesting that donepezil causes hypokalemia as a rare adverse event [9,10]. Therefore, donepezil was immediately discontinued. Thereafter, his potassium demand, supplemented intravenously, gradually decreased and was modified to oral potassium agents. On the third day after donepezil cessation, his serum potassium level recovered to 3.5 mmol/L under oral potassium supplementation of 32 mEq/day (Fig. 2). During hypokalemia evaluation and correction, pneumonia was properly controlled. Finally, he was able to maintain serum potassium of 3.3 mmol/L under oral potassium supplementation of 32 mEq/day and was discharged on the ninth day of hospitalization. At the time of discharge, the results of blood chemistry and spot urine chemistry were as follows: serum creatinine, 0.73 mg/dL; serum potassium, 3.5 mmol/L; serum magnesium, 2.3 mg/dL; serum osmolality, 295 mOsm/kg; urine creatinine, 120.6 mg/dL; potassium, 46.7 mEq/L; osmolality, 330 mOsm/kg. Additionally, the following values were determined: urine potassium/creatinine ratio, 38.7 mEq/g; fractional excretion of potassium, 8.1%; TTKG, 11.9.
Conversely, in the past, he had presented a systolic BP of less than 130 mmHg and diastolic BP of 80 mmHg during several visits to the outpatient clinic, with no history of medication-related hypertension. However, for 24 hours after hospitalization, BP was continuously confirmed as 160/90 mmHg or more, including a maximum of 185/105 mmHg, and amlodipine 5 mg was initiated. As BP measurements were above 140/90 mmHg on average after the addition of amlodipine 5 mg, the patient was additionally prescribed olmesartan 20 mg on the fifth day of hospitalization. Finally, in the outpatient clinic follow-ups, serum potassium was measured as 4.5 mmol/L, and oral potassium agents were withheld.
Discussion
This case report presents the rare development of hypokalemia with donepezil, an agent used to treat cognitive dysfunction. The most common cause of hypokalemia is gastrointestinal losses, followed by medications such as diuretics [1,2]. Additionally, various conditions lead to hypokalemia. For example, the following factors result in the development of renal potassium wasting: malignant hypertension, renal artery stenosis, renin-secreting tumors that can increase renin, adrenal hyperplasia, Cushing syndrome, medication including diuretics, magnesium deficiency, Gitelman syndrome, and chronic metabolic acidosis [3]. However, it is difficult to implicate donepezil, used for cognitive dysfunction therapy, as a causative agent. If this patient had multiple prescriptions, donepezil was probably not considered a major cause of hypokalemia.
Donepezil is a cholinesterase inhibitor, mainly prescribed for Alzheimer disease. By inhibiting acetylcholinesterase, donepezil improves behavioral and cognitive symptoms, including confusion, aggression, and psychosis [11,12]. In several studies, donepezil has demonstrated improved cognitive functions in patients with dementia, but it had some adverse effects [13]. The adverse effects were associated with increased cholinergic activity, and the gastrointestinal system was mainly affected. Therefore, nausea, vomiting, and diarrhea were the most common symptoms, as well as insomnia, abnormal dreams, hepatotoxicity, and cardiovascular adverse events [14]. Hypokalemia was one of the rare adverse effects.
The mechanism by which donepezil causes hypokalemia remains unclear. In this case, based on TTKG, potassium excretion continued under donepezil therapy. Therefore, we hypothesized the mechanism by which donepezil caused renal potassium wasting. This finding may be due to the action of donepezil on the ion channels in the renal tubule or Henle's loop. Donepezil could potentially inhibit the Na+-K+-2Cl- cotransporter in the thick ascending limb of Henle's loop, suppressing potassium reabsorption. Additionally, it could be postulated that donepezil stimulates the renal outer medullary potassium channel to excrete potassium. As another hypothesis, donepezil could affect the sodium channel epithelium in the principal cell of the collecting tubule. Thereafter, potassium appeared to be secreted into the lumen to maintain electrolyte balance. Although the mechanism by which donepezil induces hypokalemia remains unclear, we anticipated that renal potassium wasting would recover after its withdrawal. Unfortunately, the follow-up study did not achieve demonstrate an improvement in renal potassium wasting. Based on previous reports, we speculated the possible reasons by which recovery from renal potassium wasting may vary from 2 days to 3 months [15,16]. Therefore, the patient may require further time for recovery. Nonetheless, this case was significant as it confirmed the progression of hypokalemia recovery, necessitating a decrease in the daily amount of potassium supplementation after the withdrawal of donepezil.
A limitation of this case report is that we have not done additional research regarding how donepezil affects the renal ion channels. Further case reports and research would assist in determining the mechanism by which donepezil causes renal potassium wasting. Although donepezil demonstrates rare serious adverse events, symptoms during early therapy require a differential diagnosis for hypokalemia.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contributions
Conceptualization: all authors; Data curation: DK, THB, HSP; Formal analysis: DK, THB, HEY, BSC, BSK; Investigation: DK, THB, HEY, HSP; Methodology, Project administration: THB; Supervision: THB, BSC, BSK; Validation: THB, SJS, BSC, BSK; Writing-original draft: DK; Writing-review & editing: DK, THB, HEY, HSP, SJS.
Fig. 1. Abdominal computed tomography scan. (A) Both adrenal glands (arrows) show no abnormalities. (B) Both kidneys (arrows) show no abnormal findings.
Fig. 2. Summary of serum potassium level, potassium supplementation, total intake, and total output per day. IV, intravenous; PO, per oral.
|
Oral
|
DrugAdministrationRoute
|
CC BY-NC
|
33045804
| 18,742,345
|
2021-01
|
What was the dosage of drug 'CHOLINE ALFOSCERATE'?
|
Development of donepezil-induced hypokalemia following treatment of cognitive impairment.
Donepezil is a cholinesterase inhibitor used extensively to treat Alzheimer disease. The increased cholinergic activity is associated with adverse effects, therefore gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are common. Hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients. Although hypokalemia of mild and moderate grade does not present serious signs and symptoms, severe hypokalemia often results in prolonged hospitalization and mortality. Herein, we report a case of hypokalemia developed after the initiation of donepezil therapy for cognitive impairment.
Introduction
Hypokalemia is a common electrolyte disturbance in clinical practice. The major causes of hypokalemia include gastrointestinal loss and medications such as diuretics [1,2]. Most cases are asymptomatic and mild, but some patients develop severe hypokalemia resulting in arrhythmias and patient death. About 20% of inpatients experience hypokalemia during hospitalization [3], and among these cases, severe hypokalemia was sometimes associated with prolonged hospitalization and increased mortality [4].
Donepezil is the second approved acetylcholinesterase inhibitor for the treatment of mild to moderate Alzheimer disease by the United States Food and Drug Administration (FDA), extensively used worldwide [5]. As donepezil is generally tolerated, most adverse events are gastrointestinal symptoms, including vomiting and diarrhea [6]. However, rare adverse events such as lupus, psychosis, and arrhythmia have been reported in a few patients [7,8]. According to the FDA, hypokalemia is a rare adverse event that occurs in less than 1% of donepezil-treated patients [9,10].
Notably, hypokalemia exhibits non-specific symptoms such as general weakness, fatigue, dyspepsia, myalgia, tingling sensation, muscle cramps, and spasms; hence, it can be difficult to diagnose without laboratory investigations. Therefore, clinicians sometimes fail to recognize the signs and symptoms of hypokalemia. Accordingly, a rare case of hypokalemia induced by medication is significant. Herein, we report a case of hypokalemia developed after initiating donepezil as a treatment for cognitive impairment.
Case
The study was approved by the Institutional Review Board of the Catholic University of Korea (IRB No: PC20ZASI0046) with waiver of informed consent.
An 87-year-old man visited the outpatient clinic owing to poor oral intake. According to his medical history, he had undergone surgery for benign prostatic hyperplasia 6 years ago and had discontinued the medication for benign prostatic hyperplasia 4 months before hospitalization. Recently, he was diagnosed with cognitive dysfunction based on a mini-mental status examination score of 22, and a global deterioration scale of 3. And was started on appropriate medication. At the time of admission, he was prescribed choline alfoscerate 400 mg twice daily and donepezil 5 mg for the control of Alzheimer disease.
A review of systems did not reveal abnormal findings. His vital signs were as follows: blood pressure (BP), 180/70 mmHg; pulse rate, 72 beats/min; respiratory rate, 20 breaths/min; body temperate, 36.7℃. To determine the cause of poor oral intake, routine investigations were performed, including complete blood count, blood chemistry, urine analysis, electrocardiogram, and chest X-ray. The presence of subtle pneumonia on the chest X-ray and hypokalemia (serum potassium 2.6 mmol/L) was detected. Initial serum inflammatory markers showed the following results: plasma leukocyte count, 7,500/mm3; serum c-reactive protein, 0.74 mg/dL (range, 0.01–0.5 mg/dL). Except for potassium, blood chemistry revealed the following: serum albumin, 4.0 g/dL (range, 3.5–5.2 g/dL); blood urea nitrogen, 10.9 mg/dL; serum creatinine, 0.72 mg/dL (range, 0.61–1.20 mg/dL); serum sodium, 140 mmol/L; serum chloride, 91 mmol/L; serum magnesium, 2.4 mg/dL; serum osmolality, 290 mOsm/kg. Urinalysis and urine sediment examination presented the following: urine pH, 7.5; urine specific gravity, 1.011; urine white blood cells, 0–2/high power field; urine red blood cells, 0–2/high power field. Blood gas analysis revealed compensated metabolic alkalosis as follows: arterial blood pH, 7.52; arterial blood pCO2, 46.6 mmHg; arterial blood pO2, 73.7 mmHg; arterial blood HCO3¯, 36.8 mmol/L. Chest X-ray and inflammatory markers suggested that the pneumonia was not severe. Therefore, hypokalemia could be the cause of underlying poor oral intake.
The patient was admitted to treat pneumonia and hypokalemia. For pneumonia treatment, he received ceftriaxone and clarithromycin as antibiotic agents. To determine the cause of hypokalemia, further investigations were performed. No clues indicating hypokalemia were detected in the medical history and review of systems. Next, his renal potassium excretion was measured to determine the potassium/creatinine ratio, fractional excretion of potassium, and transtubular potassium gradient (TTKG), using blood chemistry and spot urine chemistry. The results of spot urine chemistry were as follows: urea nitrogen, 392.8 mg/dL; creatinine, 90.8 mg/dL; total protein, 29.9 mg/dL; sodium, 35 mEq/L; potassium, 29.2 mEq/L; chloride, 45 mEq/L; osmolality, 309 mOsm/kg. Additionally, the following values were determined and suggested renal potassium wasting: urine potassium/creatinine ratio, 32.2 mEq/g; fractional excretion of potassium, 8.9%; TTKG, 10.5. Those findings suggested renal potassium wasting. Next, computed tomography demonstrated no abnormalities in the bilateral adrenal glands and both kidneys (Fig. 1). A hormone study was conducted to evaluate the cause of high BP. The thyroid function test was in the normal range. The adrenocorticotropic hormone (ACTH) level was 36.02 pg/mL (range, 10.0–60.0 pg/mL) and the cortisol level was 10.51 µg/dL (range, 9.41–26.06 µg/dL), which were within the normal range, revealing no mineral corticoid excess. Plasma renin activity was determined as 0.19 ng/mL/hr (range, 0.3–2.9 ng/mL/hr), aldosterone concentration was 14.93 pg/mL (range, 29.9–158.8 pg/mL), and the aldosterone/renin ratio was 7.86, indicating hyporeninemic hypoaldosteronism. However, unlike Liddle syndrome, the serum sodium level was normal at 140 mmol/L. The serum magnesium level was normal at 2.4 mg/dL, which was far from that observed in Gitelman syndrome. Hence, no obvious cause of hypokalemia was determined.
During investigations analyzing the possible cause of hypokalemia, he underwent potassium supplementation using intravenous and oral formulations. Until the fourth day of hospitalization, his serum potassium level demonstrated difficulty increasing beyond 3.0 mmol/L despite sufficient potassium administration (Fig. 2). As the hypokalemia was poorly corrected, clinicians suspected other causes of hypokalemia. A thorough review of the therapeutic agents prescribed for cognitive dysfunction was conducted. On examining possible adverse effects, we identified evidence suggesting that donepezil causes hypokalemia as a rare adverse event [9,10]. Therefore, donepezil was immediately discontinued. Thereafter, his potassium demand, supplemented intravenously, gradually decreased and was modified to oral potassium agents. On the third day after donepezil cessation, his serum potassium level recovered to 3.5 mmol/L under oral potassium supplementation of 32 mEq/day (Fig. 2). During hypokalemia evaluation and correction, pneumonia was properly controlled. Finally, he was able to maintain serum potassium of 3.3 mmol/L under oral potassium supplementation of 32 mEq/day and was discharged on the ninth day of hospitalization. At the time of discharge, the results of blood chemistry and spot urine chemistry were as follows: serum creatinine, 0.73 mg/dL; serum potassium, 3.5 mmol/L; serum magnesium, 2.3 mg/dL; serum osmolality, 295 mOsm/kg; urine creatinine, 120.6 mg/dL; potassium, 46.7 mEq/L; osmolality, 330 mOsm/kg. Additionally, the following values were determined: urine potassium/creatinine ratio, 38.7 mEq/g; fractional excretion of potassium, 8.1%; TTKG, 11.9.
Conversely, in the past, he had presented a systolic BP of less than 130 mmHg and diastolic BP of 80 mmHg during several visits to the outpatient clinic, with no history of medication-related hypertension. However, for 24 hours after hospitalization, BP was continuously confirmed as 160/90 mmHg or more, including a maximum of 185/105 mmHg, and amlodipine 5 mg was initiated. As BP measurements were above 140/90 mmHg on average after the addition of amlodipine 5 mg, the patient was additionally prescribed olmesartan 20 mg on the fifth day of hospitalization. Finally, in the outpatient clinic follow-ups, serum potassium was measured as 4.5 mmol/L, and oral potassium agents were withheld.
Discussion
This case report presents the rare development of hypokalemia with donepezil, an agent used to treat cognitive dysfunction. The most common cause of hypokalemia is gastrointestinal losses, followed by medications such as diuretics [1,2]. Additionally, various conditions lead to hypokalemia. For example, the following factors result in the development of renal potassium wasting: malignant hypertension, renal artery stenosis, renin-secreting tumors that can increase renin, adrenal hyperplasia, Cushing syndrome, medication including diuretics, magnesium deficiency, Gitelman syndrome, and chronic metabolic acidosis [3]. However, it is difficult to implicate donepezil, used for cognitive dysfunction therapy, as a causative agent. If this patient had multiple prescriptions, donepezil was probably not considered a major cause of hypokalemia.
Donepezil is a cholinesterase inhibitor, mainly prescribed for Alzheimer disease. By inhibiting acetylcholinesterase, donepezil improves behavioral and cognitive symptoms, including confusion, aggression, and psychosis [11,12]. In several studies, donepezil has demonstrated improved cognitive functions in patients with dementia, but it had some adverse effects [13]. The adverse effects were associated with increased cholinergic activity, and the gastrointestinal system was mainly affected. Therefore, nausea, vomiting, and diarrhea were the most common symptoms, as well as insomnia, abnormal dreams, hepatotoxicity, and cardiovascular adverse events [14]. Hypokalemia was one of the rare adverse effects.
The mechanism by which donepezil causes hypokalemia remains unclear. In this case, based on TTKG, potassium excretion continued under donepezil therapy. Therefore, we hypothesized the mechanism by which donepezil caused renal potassium wasting. This finding may be due to the action of donepezil on the ion channels in the renal tubule or Henle's loop. Donepezil could potentially inhibit the Na+-K+-2Cl- cotransporter in the thick ascending limb of Henle's loop, suppressing potassium reabsorption. Additionally, it could be postulated that donepezil stimulates the renal outer medullary potassium channel to excrete potassium. As another hypothesis, donepezil could affect the sodium channel epithelium in the principal cell of the collecting tubule. Thereafter, potassium appeared to be secreted into the lumen to maintain electrolyte balance. Although the mechanism by which donepezil induces hypokalemia remains unclear, we anticipated that renal potassium wasting would recover after its withdrawal. Unfortunately, the follow-up study did not achieve demonstrate an improvement in renal potassium wasting. Based on previous reports, we speculated the possible reasons by which recovery from renal potassium wasting may vary from 2 days to 3 months [15,16]. Therefore, the patient may require further time for recovery. Nonetheless, this case was significant as it confirmed the progression of hypokalemia recovery, necessitating a decrease in the daily amount of potassium supplementation after the withdrawal of donepezil.
A limitation of this case report is that we have not done additional research regarding how donepezil affects the renal ion channels. Further case reports and research would assist in determining the mechanism by which donepezil causes renal potassium wasting. Although donepezil demonstrates rare serious adverse events, symptoms during early therapy require a differential diagnosis for hypokalemia.
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contributions
Conceptualization: all authors; Data curation: DK, THB, HSP; Formal analysis: DK, THB, HEY, BSC, BSK; Investigation: DK, THB, HEY, HSP; Methodology, Project administration: THB; Supervision: THB, BSC, BSK; Validation: THB, SJS, BSC, BSK; Writing-original draft: DK; Writing-review & editing: DK, THB, HEY, HSP, SJS.
Fig. 1. Abdominal computed tomography scan. (A) Both adrenal glands (arrows) show no abnormalities. (B) Both kidneys (arrows) show no abnormal findings.
Fig. 2. Summary of serum potassium level, potassium supplementation, total intake, and total output per day. IV, intravenous; PO, per oral.
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400 mg (milligrams).
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DrugDosage
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CC BY-NC
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33045804
| 18,430,605
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2021-01
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