Abstract.: We describe a patient with a drug-induced hypersensitivity syndrome to carbamazepine and a concomitant active infection with human herpes virus 6 (HHV-6). The potential role of HHV-6 regarding the drug-induced hypersensitivity syndrome is discussed and the main clinical features of this potentially fatal adverse drug reaction are highlighte

Battegay, E.

Bircher, A.

Hirsch, H.

Schaub, N.

Steffen, I.

Zeller, A.

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254 Infection 31 · 2001 · No. 4 © URBAN & VOGELInfection Case ReportDrug Hypersensitivity Syndrome to Carbamazepineand Human Herpes Virus 6 Infection: Case Reportand Literature Review A. Zeller, N. Schaub, I. Steffen, E. Battegay, H.H. Hirsch, A.J. BircherAbstractWe describe a patient with a drug-induced hypersensitivitysyndrome to carbamazepine and a concomitant activeinfection with human herpes virus 6 (HHV-6). The potentialrole of HHV-6 regarding the drug-induced hypersensitivitysyndrome is discussed and the main clinical features of thispotentially fatal adverse drug reaction are highlighted.Infection 2003; 31: 254–256DOI 10.1007/s15010-002-3099-5IntroductionThe drug-induced hypersensitivity syndrome is an adversedrug reaction with high morbidity and rare mortality. Theincidence of this syndrome is low (1 in 1,000 to 10,000 drugexposures) [1]. Viral infections may contribute to the oc-currence of drug-induced exanthemas. Well-known exam-ples occur in patients with acute Epstein-Barr virus (EBV)infection treated with amoxicillin who develop skin erup-tions in 95–100% of cases. More recently, an association be-tween human herpes virus 6 (HHV-6) and the drug-inducedhypersensitivity syndrome has been reported [2]. PrimaryHHV-6 infection in adults is rare. The seroprevalence inolder children and adults is more than 95%.To our knowledge, 12 cases of drug-induced hypersen-sitivity syndrome in association with HHV-6 infection havebeen described so far [2, 3–6].We report the case of a drug-induced hypersensitivity syndrome due to cabamazepineand systemic HHV-6 infection.Case ReportA 24-year-old white woman with a history of oligosymptomaticpartial-complex seizures since childhood presented with fever,maculopapular rash and generalized lymphadenopathy. The pa-tient had no previous history of atopic diseases or drug hypersen-sitivity. Six weeks previously anticonvulsant treatment (carba-mazepine 200 mg once daily) had been administered for the firsttime because she had two seizures within 1 month. Four weeks ear-lier she suffered from a flu-like syndrome with fever, malaise,myalgia and enlarged bilateral cervical lymph nodes, which spon-taneously resolved after some days. Two weeks previously, whileon holiday abroad, she developed high fever with chills, swellingof the large joints and severe malaise. Assuming streptococcal in-fection, she received a single shot of penicillin intramuscularlyfrom a local physician. Subsequently, she decided to discontinuecarbamazepine. After returning home she asked for further eval-uation.Physical examination showed a febrile patient (38.6 °C) withgeneralized lymphadenopathy and a maculopapular exanthemaof the trunk and the perioral region. The oral cavity was normal.The edge of the liver was palpable 1–2 cm below the right costalmargin.There was no splenomegaly. Neurological, cardial and pul-monary examination showed no abnormalities.Abnormal labora-tory findings included a WBC count of 9.1  109/l (19.7% atypicallymphocytes and 8.1% eosinophils) and a liver dysfunction withelevated -glutamyl transferase (160 U/l, normal 49 U/l), alanineaminotransferase (50 U/l, normal 37 U/l) and alkaline phosphatase(114 U/l, normal 108 U/l).The flu-like syndrome and the presenceof atypical lymphocytes were suggestive of a viral infection. Sero-logical testing for HHV-6 IgG or IgM was done by indirect im-munofluorescence as described previously [7]. Anti-HHV-6 IgMtiter was positive, an initial anti-HHV-6 IgG titer of 1 : 320 in-creased fourfold to 1 : 1,280 on the 25th day after initial evalua-tion; this was considered significant. HHV-6 DNA was detected inthe serum by nested PCR using the outer primers M852 5'-ACAACTGTCTGACTGGCA-3' and M853 5'-GCTAGAACGTATTTGCTG-3’ (yielding a 251 bp fragment) and the innerprimers M849 5'-CTCAAGATCAACAAGTTG-3' and M850 5'-TCACGGACATCGGTATAT-3' (yielding a 124 bp fragmentidentified by agarose gel electrophoresis). HHV-6-infected HSB-2 cells and cloned plasmid targets served as positive controls, un-infected HSB-2 as negative controls [H.H. Hirsch, unpublished re-sults].A. Zeller, E. BattegayOutpatient Dept. of Internal Medicine, University Hospital Basel, Switzer-landN. Schaub, A.J. Bircher (corresponding author)Allergy Unit, Dept. of Dermatology, University Hospital Basel, Peters-graben 4, CH-4031 Basel, Switzerland; Phone: (+41/61) 265-2525,Fax: -4885, e-mail: andreas.bircher@unibas.chI. SteffenInstitute for Medical Microbiology, University of Basel, SwitzerlandH.H. HirschDept. of Internal Medicine, Division of Infectious Diseases, UniversityHospital Basel, SwitzerlandReceived: June 27, 2002  • Revision accepted: November 4, 2002A. Zeller et al. Drug Hypersensitivity and HHV-6 InfectionInfection 31 · 2003 · No. 4 © URBAN & VOGEL 255Additional serological testing showed no signs of active in-fection with EBV (EBV VCA IgG positive, IgM negative, EBNApositive), HIV (antibodies negative), cytomegalovirus (CMV IgGpositive, IgM negative), hepatitis B virus (HBs antigen and anti-HBc negative) and hepatitis C virus (antibodies negative), Toxo-plasma gondii (IgG and IgM negative) and Borrelia burgdorferi(IgG and IgM negative).All symptoms and signs resolved spontaneously after 4 weeks.After complete resolution, an allergologic evaluation was per-formed. Patch tests were positive on day 2 and 3 for carba-mazepine (++/++) and phenytoin (+/+) respectively, the lympho-cyte transformation test stimulation index [8] was increased forcarbamazepine (twofold), and for phenytoin (2.5-fold).DiscussionOur patient fulfilled the clinical criteria for a drug-inducedhypersensitivity syndrome to carbamazepine [1].The aller-gologic investigation demonstrated a delayed-type hyper-sensitivity to carbamazepine supporting its etiologic role,and cross-reactivity to phenytoin, although the patient hasnever been exposed to this drug.The differential diagnosisof drug-induced hypersensitivity syndrome includes viralinfections, e. g. EBV, CMV and primary HIV infection. Inour patient, active HHV-6 infection was present as evi-denced by the presence of HHV-6-specific IgM, signifi-cantly increasing titers of HHV-6 specific IgG (4-fold) andthe detection of HHV-6 DNA in serum [9].The clinical pre-sentation of our patient corresponds to a infectiousmononucleosis syndrome (fever, rash, lymph nodes,pharyngitis, abnormal liver function tests, atypical lympho-cytes) which are typical for a primary infection with EBV,CMV or HHV-6. However, symptomatic reactivation ofHHV-6 infection can not be excluded. Taken together, ac-tive HHV-6 infection may have a role as cofactor of the hy-persensitivity syndrome to carbamazepine.In the literature HHV-6 reactivation has been impli-cated in 12 patients with a drug hypersensitivity (Table 1)[2, 3–6]. Descamps et al. [2] recently described seven pa-tients with evidence of HHV-6 infection and drug rash (tocarbamazepine, ibuprofen and sulfasalazine, respectively)with eosinophilia and systemic symptoms. Its pathogeneticrole for drug hypersensitivity syndrome is not clear, al-though polyclonal T-cell activation or increases in proin-flammatory cytokines may play a role [10]. In patients witha suspected drug-induced hypersensitivity syndrome the in-criminated drug must be stopped immediately. The cuta-neous lesions respond to topical corticosteroids.In conclusion, the drug hypersensitivity syndrome is anunderdiagnosed adverse drug reaction due to its wide rangeof clinical presentations. Early recognition can avoid po-tentially fatal outcomes or dangerous re-exposures. It maytake from 2 weeks to 3 months until clinical manifestationsoccur after initiating therapy with a new drug.Appropriatelaboratory studies should be performed to rule out othercontributing causes. Primary infections with EBV, CMV,HIV or viral hepatitis can mimic the clinical presentation.Our case and the data in the literature support the role ofHHV-6 as cofactor for sensitization and subsequent mani-festation of a drug hypersensitivity syndrome.References1. Vittorio CC, Muglia JJ: Anticonvulsant hypersensitivity syn-drome. Arch Intern Med 1995; 155: 2285–2290.2. Descamps V, Valance A, Edlinger C: Association of human herpesvirus 6 infection with drug reaction with eosinophilia and sys-temic symptoms. Arch Dermatol 2001; 137: 301–304.3. Conilleau V, Dompmartin A, Verneuil L, Michel M, LeroyD: Hyper-sensitivity syndrome due to 2 anticonvulsant drugs. ContactDermatitis 1999; 41: 141–144.Reference Responsible drug No. of cases Virological testing of HHV-6 infectionDescamps V et al. [2] Carbamazepine, 5 Anti-HHV-6 IgM positive in 1/7 casesibuprofen, 1 4-fold increase in anti-HHV-6 IgG titer in 4/7 casessulfasalazine 1 PCR for HHV-6 negative in all cases Conilleau V et al. [3] Sodium valproate and 1 Significant increase in HHV-6 antibodies ethosuximide measured by indirect immunofluorescenceDescamps V et al. [4] Phenobarbital 1 4-fold increase in anti-HHV-6 antibodiesPCR for HHV-6 negativeTohyama M et al. [5] Sulfasalazine 2 HHV-6 isolated from peripheral blood mononuclear cells in 1/2 cases> 4-fold increase in anti-HHV-6 IgG titersSuzuki Y et al. [6] Allopurinol 1 > 4-fold increase in anti-HHV-6 IgG titerPCR for HHV-6 positive in skin lesionsPresent case Carbamazepine 1 Anti-HHV-6 IgM positive 4-fold increase in anti-HHV-6 IgG titer PCR for HHV-6 positive in peripheral bloodTable 1Association of drug-induced hypersensitivity syndrome and HHV-6.A. Zeller et al. Drug Hypersensitivity and HHV-6 Infection256 Infection 31 · 2003 · No. 4 © URBAN & VOGEL4. Descamps V, Bouscarat F, Laglenne S, Aslangul E, Veber B,Descamps D, Saraux IL, Grange MS, Grossin M, Navratil E, CrickxB, Belaich S: Human herpes virus 6 associated with anticonvul-sant hypersensitivity syndrome and reactive hemophagocyticsyndrome. Br J Dermatol 1997; 137: 605–608.5. Tohyama M, Yohata Y, Yusukawa M, Inagi R, Urano Y, YamanishiK, Hashimoto K: Severe hypersensitivity syndrome due to sul-fasalazine associated with reactivation of human herpes virus6. Arch Dermatol 1998; 134: 1113–1117.6. Suzuki Y, Inagi R, Aono T, Yamanishi K, Shiohara T: Human herpesvirus 6 infection as a risk factor for the development of severedrug-induced hypersensitivity syndrome. Arch Dermatol 1998;134: 1108–1112.7. Rudin C, Hirsch HH: How often can the clinical diagnosis of ex-anthema subitum be confirmed with the HHV-6 serology test.Klin Pediatr 1991; 203: 109–112.8. Schaub N, Bircher AJ: Severe hypersensitivity syndrome to lam-otrigine confirmed by lymphocyte stimulation in vitro. Allergy2000; 55: 191–193.9. Huang LM, Kuo PF, Lee CY, Chen JY, Liu MY, Yang CS: Detection ofhuman herpes virus-6 DNA by polymerase chain reaction inserum or plasma. J Med Virol 1992; 38: 7–10.10. Le Cleach L, Fillet A, Agut H: Human Herpes Virus 6 and 7. Newroles yet to be discovered? Arch Dermatol 1998; 134: 1155–1157.

Drug Hypersensitivity Syndrome toCarbamazepine and Human Herpes Virus 6 Infection: Case Reportand Literature Review

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Drug Hypersensitivity Syndrome toCarbamazepine and Human Herpes Virus 6 Infection: Case Reportand Literature Review

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