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HLA-A*31:01 and Oxcarbazepine- Induced DRESS in a Patient With

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HLA-A*31:01 and Oxcarbazepine- Induced DRESS in a Patient With 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 InducedAnnapurna Poduri, MD, MPH, DRESS f, g Shannon Manzi, PharmDin a,a b 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, B*15:02strongly 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)
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