HLA-A*31:01
and Oxcarbazepine-DCX Hyun Kim, PharmD,a,b,c Laura Chadwick, PharmD,a,b Yasir Alzaidi,c Jonathan Picker, MBChB, PhD,a,d,e AnnapurnaInduced Poduri, MD, MPH, DRESSf,g Shannon Manzi, PharmDin a,ab Patient With Seizures and Complete Deletion abstract
Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy. Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with aClinical Pharmacogenomics Service, dDivision of – Genetics and Genomics, and Departments of bPharmacy eosinophilia and systemic symptoms, Stevens-Johnson syndrome, or and fNeurology, Boston Children’s Hospital, Boston, toxic epidermal necrolysis. The Food and Drug Administration approved Massachusetts; cSchool of Pharmacy, Massachusetts HLA-B*15:02 College of Pharmacy and Health Sciences University, label for oxcarbazepine currently presents information regarding a Boston, Massachusetts; and Departments of ePediatrics pharmacogenomic association with the HLA antigen allele and gNeurology, Harvard Medical School, Harvard University, Boston, Massachusetts and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele. However, unlike carbamazepine, screening for the Dr Kim interpreted the pharmacogenomics testing data and drafted the case report; Dr Chadwick presence of this allele is not routinely recommended before administration interpreted the pharmacogenomics testing data of oxcarbazepine. In practice, even with carbamazepine, HLA antigen and assisted in the drafting of the case report; testing is not always performed before initiating treatment because of Mr Alzaidi assisted in gathering clinical data for the case report and assisted in the drafting of the lack of physician awareness of the recommendations and because of the case report; Dr Picker was the attending geneticist desire to initiate treatment without delay. We present the clinical course for this patient, assisted in the interpretation of of a pediatric patient with focal epilepsy refractory to several AEDs who the pharmacogenomics testing data, and assisted developed drug reaction with eosinophilia and systemic symptoms after in the drafting of the case report; Dr Poduri was the attending neurologist for this patient and oxcarbazepine administration. The pharmacogenomic testing for various assisted in the drafting of the case report; Dr Manzi HLA antigen alleles was performed post hoc, and results were evaluated oversaw all aspects of the pharmacogenomic for structural similarities between AEDs and their molecular associations testing process and assisted in the drafting of the case report; and all authors approved the with HLA antigen proteins. In addition, we review the population-wide final manuscript as submitted and agree to be prevalence of various hypersensitivity reactions to AEDs and associated accountable for all aspects of the work. HLA antigen alleles. Finally, we discuss the potential utility of preemptive DOI: https://doi.org/10.1542/peds.2017-1361 pharmacogenomic screening of patients before pharmacological treatment Accepted for publication Dec 13, 2017 of epilepsy to assess the risk of developing hypersensitivity reactions. Address correspondence to Shannon Manzi, PharmD, Clinical Pharmacogenomics Service, Boston Children’s Hospital, 300 Longwood Ave, Enders 322, Boston, MA 02115. E-mail: shannon. Drug reaction with eosinophilia and drug interactions with major [email protected] systemic symptoms (DRESS) is a histocompatibility complex (MHC)3 PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, delayed hypersensitivity response, proteins of the immune system. 1098-4275). characterized by leukocytosis with MHC proteins are encoded by highly eosinophilia, rash, fever, malaise, polymorphic HLA antigen genes, and Copyright © 2018 by the American Academy of Pediatrics lymphadenopathy, and laboratory allele frequencies vary4,5 greatly between abnormalities depending on different ethnicities. 1 – To cite: Kim H, Chadwick L, Alzaidi Y, et al. HLA-A*31:01 specific organ involvement. DRESS and Oxcarbazepine-Induced DRESS in a Patient has been associated with several The Food and Drug Administration With Seizures and Complete DCX Deletion. Pedi antiepileptic drugs (AEDs) including approved labeling for some AEDs atrics. 2018;141(s5):e20171361 carbamazepine,2 lamotrigine, and describes associations between phenytoin. The pathophysiology specific HLA antigen alleles of DRESS is believed to involve and hypersensitivity reactions. Downloaded from www.aappublications.org/news by guest on September 28, 2021 CASE REPORT PEDIATRICS Volume 141, number s5, April 2018:e20171361 Carbamazepine is the only AED that at 10 mg twice daily, clonazepam Infective etiology was ruled out with carries a black box warningHLA- that at 0.5 mg as needed, and rectally- negative results from blood, urine, stronglyB*15:02 recommends preemptive administered diazepam at 10 mg and pharyngeal cultures for aerobic genetic screening for the as needed. The patient reported no and anaerobic pathogens. Viral allele in patients of Asian known allergies or adverse reactions. screens were also negative, with the ancestry, a population in which6 Both parents are of classic Turkish exception of an increased Epstein- this allele is fairly common. No descent and are nonconsanguineous. Barr virus capsid IgG antibody level such recommendations– are given Of note, the patient had been living of 373 U/mL and human herpesvirus for oxcarbazepine,7 9 phenytoin, or in Hong Kong for most of her life, 6 IgG antibody index value of 9.73. lamotrigine. with frequent return medical visits Oxcarbazepine was discontinued on to the United States. She moved to suspicion of DRESS and supportive We present a case of a patient with the United States with her family a care was provided. ’ refractory epilepsy who experienced few days before presentation. The DRESS after oxcarbazepine Over the next few days, the patient s patient denied exposures to any new administration, scored as a definite rash gradually improved, and her foods or exotic animals while in Hong case according to European Registry aspartate aminotransferase, alanine Kong or travel through Japan. She ’ of Severe Cutaneous Adverse transaminase, and eosinophilia 10 received a second measles, mumps, Reactions criteria. Because the normalized. The patient s adjusted and rubella vaccination 1 month patient was not of known Asian AED regimen now included clobazam before presentation. A Chem-10 ancestry, she was not preemptively at 10 mg daily, zonisamide at 200 panel revealed no abnormal values. screened for HLA antigen alleles mg daily, and lorazepam at 3 mg A rapid group A streptococcal test, associated with hypersensitivity intravenously as needed for seizures measles and rubeola immunoglobulin reactions to medications. We will Streptococcus lasting more than 5 minutes. The (Ig) M titers, and cultures for discuss the potential for cross- patient was discharged 9 days after group A and measles reactivity of similarly structured admission. had negative results. The serum AEDs as well as the utility of μ – concentration of oxcarbazepine was Over the next 2 years, the patient preemptive pharmacogenomic μ 19.1 g/mL (reference: 15.0 35.0 experienced increased seizure testing to guide safe and effective g/mL). The patient was discharged frequency from 2 to 3 episodes per drug selection. from the hospital after receiving 1 week to several times every day. PATIENT PRESENTATION oral 500-mg dose of acetaminophen, Multiple medications were trialed, with instructions to return if her including perampanel, valproic condition worsened. acid, levetiracetam, rufinamide, ’ An 11-year-old girl presented to and lacosamide. Lamotrigine and The following day, the patient the Boston Children s Hospital phenytoin were withheld out of returned to the emergency Emergency Department with a 2-day concern of cross-reactivity with department with persistence of history of morbilliform eruptions oxcarbazepine-induced DRESS. All rash, fever, and emesis. The patient on the trunk and arms that evolved resulted in intolerable side effects described the rash as burning and into a diffuse, erythematous or were ineffective at controlling ° itching and reported emesis 3 hours maculopapular rash, facial erythema, the seizures. There were no further after the last dose of oxcarbazepine a temperature of 39 C, chills, incidences of hypersensitivity that morning, as well as during decreased appetite, mild cough, and reactions. A vagus nerve stimulator the previous night after being congestion. Pertinent medical history was implanted, leading to some discharged. The patient was admitted reduction in seizure frequency at the time of presentation included ’ for inpatient observation with refractory focal epilepsy secondary and severity. Because of the highly diagnoses of fever and rash. refractory nature of the patient s to structural brain malformationDCX (subcortical band heterotopia due to Testing revealed significant aspartate epilepsy, pharmacogenomic testing a complete deletion of the gene, aminotransferase and alanine was performed to determine if which encodes for doublecortin, transaminase elevations (226 there was a genetic contribution to medication response. a microtubule-associated protein 11 U/L and 667 U/L, respectively), essential for cortical development) pronounced hyperbilirubinemia The presence of major HLA and celiac disease. Medications at without jaundice (total bilirubin = 1.8 antigen alleles associated with the time included oxcarbazepine mg/dL; direct bilirubin = 1.4 mg/dL), hypersensitivityHLA-A*31:01 reactions was at 300 mg twice daily initiated and hematologic abnormalities assayed by using the PG3101 × µ several weeks before presentation, including eosinophilia (absolute3 Detection Kit ( ; zonisamide at 200 mg daily, clobazam eosinophil count = 0.3 10 cells/ L). Pharmigene, Inc, Palo Alto, CA) and Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 141, number s5, April 2018 S435 HLA-B theHLA-B*15:02 TaqMan HLA-B*57:01 single-nucleotideHLA- constructs clinical guidelines based polymorphismB*58:01 genotyping panel on the strongest evidence. There ( , , and are 4 CPIC guidelinesHLA-B*15:02 regarding ; Thermo Fisher Scientific, HLA associations with drug “ ” Inc, Waltham, MA). In both assays, hypersensitivity:HLA-B*57:01 for25,26 a positive result indicates the carbamazepine and phenytoin, “ ” HLA-B*58:01 27 presence of 1 or more copies of FIGURE 1 for abacavir, and Chemical structures of carbamazepine and 28 the allele and a negative result oxcarbazepine. Note the presence of a ketone for HLA-A*31:01allopurinol. There indicates the absenceHLA-A*31:01 of any copies of moiety at the 10 position of the dibenzoazepine are currently no CPIC guidelines for ring of oxcarbazepine. N, nitrogen; NH , amide; the allele. The patientHLA-B was found to 2 the screening of before be positive for the allele O, oxygen. oxcarbazepine administration. DISCUSSIONand negative for all alleles. For most drug therapies that use haplotype screening to determine the populations, with notable genetic appropriateness of therapy, there is Oxcarbazepine is recommended contributions18 from East Asian typically a subset of patients positive as a first-line treatment option for populations. Although the label for the HLA antigen allele in question generalized tonic-clonic seizures 12 for carbamazepine also states a who would have otherwise been able and focal seizures. It is structurally HLA-A*31:01 moderate association between to tolerate and derive clinical benefit related to carbamazepine, and the allele and from the medication. For example, chemical differences are believed hypersensitivity reactions, there is in the Prospective Randomized to impart greater resistance to no recommendation for testing for Evaluation of DNA Screening in a hepatic conversion into toxic epoxide HLA-B*57:01 13,14 this particular allele. This association Clinical Trial study, the authors report metabolites (Fig 1). that 19 out of 49 carriers HLA-A*31:01between carbamazepine-induced DRESS secondary to AED exposure tolerated abacavir during a 6-week hypersensitivity reactions and is rare, ranging from 1 to 4.1 per observation period. Conceivably, has been validated for 10000 patients taking carbamazepine European, Han Chinese, Korean, these patients would likely be and 2.3 to 4.5 per 1510000 patients and Japanese populations, although deemed ineligible to receive abacavir- taking phenytoin. Relative to containing therapy in a clinical the prevalence of this allele– and the Stevens-Johnson syndrome and toxic strength of the association varies setting with29 preemptive haplotype 19 23 screening. epidermal necrolysis, DRESS has a among ethnic groups. long latency, usually not becoming There are 3 factors driving the apparent for 2 to 6 weeks after the 2,16 Oxcarbazepine and phenytoin carry need for preemptive screening initial exposure. The patient for HLA alleles associated with demonstrated the delayed appearance similarHLA-B*15:02 statements of associations hypersensitivity reactions. First, of the classic features of DRESS, with hypersensitivity reactions and the similar chemical structure which resolved on discontinuation the allele, but testing is of several AEDs may result in of oxcarbazepine and the provision only recommended for oxcarbazepine comparable MHC-binding properties of supportive care. According to the and no specific recommendation7,8 is 17 and, thus, potential shared risk Naranjo et al causality score, the made for phenytoin. The authors of for hypersensitivity reactions. Our probability that the DRESS was caused 1 previous cohort study demonstrated HLA-A*31:01 “ ” HLA-B*15:02 patient was found to have a positive by the oxcarbazepine was rated as a strong association between the allele carrier status, probable. allele and Stevens- which, because of its moderate Johnson syndrome development after Currently, carbamazepine is the HLA-A*31:0124 association with carbamazepine oxcarbazepine administration. There only AED that carries a black box hypersensitivity, results in a is no reference to in the warning strongly recommending 8 clinically significant risk of cross- oxcarbazepine drug label, as this drug- HLA-B*15:02preemptive testing for ethnicities reactivity that warrants further gene association has not previously that report higher frequencies of the study. Second, patients with seizure been reported. Further investigation allele,6 such as certain disorders historically report only Asian populations. Interestingly, into this association is required. 60% to 70% effectiveness with the these recommendations have not The Clinical Pharmacogenomics first AED and often require trials of specifically included patients of Implementation Consortium multiple different medications30 to Turkish ancestry, whose genetics (CPIC) reviews scientific literature attain optimal seizure control. If 1 have been found to be more closely pertaining to the genetic basis of the preferred AEDs for a patient aligned with Southern European of variable drug response and is associated with hypersensitivity Downloaded from www.aappublications.org/news by guest on September 28, 2021 S436 KIM et al ABBREVIATIONS reaction and current guidelines to advocate for implementation warrant the testing for specific of preemptive screening for HLA HLA antigen alleles, receiving antigen alleles associated with AED: antiepileptic drug that information proactively is hypersensitivity reactions for CPIC: Clinical Pharmacogenomics paramount to ensure that a patient any patient who is about to or Implementation does not experience lapses in is currently undergoing treatment Consortium treatment or prolonged use of with AEDs. DRESS: drug reaction with eosin- ineffective or dangerous therapy. ACKNOWLEDGMENTS ophilia and systemic Lastly, hypersensitivity reactions symptoms dramatically impact patient Ig: immunoglobulin morbidity and mortality and come The authors thank the patient and MHC: major histocompatibility at significant costs to the health her family for allowing us to present complex care system. Thus, it is feasible this case. FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: Dr Picker is a founding member of Global Gene Corporation, a genomic data company, and is paid a monthly consultancy fee for 20 hours per week to provide scientific support toward the company’s mission of characterizing genomics in India, which includes trying to define the pharmacogenomic profiles for the populations; the other authors have indicated they have no potential conflicts of interest to disclose.
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 S438 KIM et al HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion Hyun Kim, Laura Chadwick, Yasir Alzaidi, Jonathan Picker, Annapurna Poduri and Shannon Manzi Pediatrics 2018;141;S434 DOI: 10.1542/peds.2017-1361
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Downloaded from www.aappublications.org/news by guest on September 28, 2021 HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion Hyun Kim, Laura Chadwick, Yasir Alzaidi, Jonathan Picker, Annapurna Poduri and Shannon Manzi Pediatrics 2018;141;S434 DOI: 10.1542/peds.2017-1361
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