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DERMATOLOGICA SINICA 29 (2011) 63e66

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Dermatologica Sinica

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CASE REPORT

Myocarditis in dapsone-induced drug reaction with eosinophilia and systemicsymptomsda case report and review of the literature

Wei-Hsuan Li, Han-Nan Liu, Ding-Dar Lee*

Department of Dermatology, National Yang-Ming University & Taipei Veterans General Hospital, Taipei, Taiwan

a r t i c l e i n f o

Article history:Received: Mar 30, 2010Revised: Jun 29, 2010Accepted: Sep 13, 2010

Keywords:DapsoneDrug hypersensitivityMyocarditis

* Corresponding author. Department of DermatoloHospital, No. 201, Section 2, Shih-Pai Road, Taipei 112

E-mail address: ddlee@vghtpe.gov.tw (D.-D. Lee).

1027-8117/$ e see front matter Copyright � 2011, Tadoi:10.1016/j.dsi.2011.05.005

a b s t r a c t

Dapsone (4,40-diaminodiphenylsulfone) has been used for a variety of dermatological conditions.Dapsone-induced drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but severedrug reaction characterized by fever, cutaneous eruption, and systemic involvement. We present a case ofdapsone-induced DRESS, which resulted in fever, maculopapular eruptions progressing to exfoliativedermatitis, cervical lymphadenopathy, transaminitis, and hypersensitivity myocarditis resulting incongestive heart failure. This patient was withdrawn from dapsone and treated with systemic cortico-steroids, but he finally passed away despite aggressive intensive care. We report this rare case and reviewthe literature concerning DRESS with cardiac involvement.

Copyright � 2011, Taiwanese Dermatological Association.Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) isa rare but severe drug reaction characterized by fever, skin erup-tion, and systemic involvement, including lymphadenopathy,abnormal liver function, renal impairment, pulmonary or pericar-dial infiltrates, and hematologic abnormalities, mainly hyper-eosinophilia and lymphocytosis. Symptoms typically beginbetween 2 weeks and 6 weeks after initiation of drug therapy andmostly subside after discontinuing the drug.1 However, potentiallylife-threatening events have been reported. The 10% mortality rateassociated with DRESS is usually secondary to hepatotoxicity ormyocarditis.2

Dapsone is the drug of choice for treatment of leprosy anddermatitis herpetiformis and can be used for various kinds ofinflammatory skin diseases. Dapsone-induced DRESS withmyocarditis is a rare but potentially fatal complication. In thisarticle, we present a case of dapsone-induced DRESS with hyper-sensitivity myocarditis and review previous reports of dapsone-induced DRESS with cardiac involvement.

Case report

A 33-year-old man presented with fever, malaise, multiple oralulcers, and generalized itchy erythematous maculopapular rash

gy, Taipei Veterans General, Taiwan.

iwanese Dermatological Associatio

with scaling on the face, trunk, and limbs for 3 weeks (Figure 1). Hehad received dapsone 100 mg daily for 6 weeks because of chronicrefractory urticaria. Dapsone-related drug eruption was suspected,and dapsone was therefore discontinued. Topical clobetasol creamand oral prednisolone (30 mg/d) were given in another medicalsetting but did not alleviate his symptoms. Then, hewas transferredto our hospital.

On admission, his body temperature was 38.7�C, blood pressure86/52 mmHg, and heart rate 135 beats/min. Other physical exam-inations of cardiovascular and respiratory system were unremark-able. Bilateral cervical lymphadenopathy was palpable. His skinbiopsy showed spongiosis, necrotic keratinocytes, and a denseperivascular inflammatory infiltrate of lymphohistiocytes andeosinophils (Figure 2). Laboratory investigations revealed hemo-globin, 13.9 g/dL (normal range: 14e18 g/dL); platelet count,495,000/mL (normal range: 150,000e450,000/mL); leukocyte count,17,700/mL (eosinophil,10%); total serum bilirubin, 0.3 mg/dL (normalrange: 0.2e1.6 mg/dL); aspartate aminotransferase, 226 U/L(normal range: 0e40 U/L); and alanine aminotransferase, 252 U/L(normal range: 5e45 U/L). Hepatitis B surface antigen, hepatitis Cvirus antibody, anti-dsDNA, antimitochondrial antibody, anti-Jo-1antibody, and extractable nuclear antigen were tested to rule outviral and autoimmune hepatitis. The workup was all negative.Subsequent laboratory studies for systemic infection, includingcytomegalovirus (CMV), Epstein-Barr virus (EBV), toxoplasma,herpes simplex virus, and HIV, were all negative. Intravascularhydrocortisone 150 mg daily was then given under the impressionof DRESS. However, the patient developed chest pain and dyspnea1 week after admission. Cardiac ischemic change was detected by

n. Published by Elsevier Taiwan LLC. All rights reserved.

Figure 1 A 33-year-old male patient presented with generalized exfoliative dermatitis involving most of the trunk and limbs. (A) Diffuse itchy scaly erythematous-to-brownishpapulosquamous eruptions on the trunk. (B) A closer view of the patient’s back showing confluent brownish papulosquamous lesions with moderate scaling.

W.-H. Li et al. / Dermatologica Sinica 29 (2011) 63e6664

abnormal electrocardiogram (ST elevation in leads V1, V2, andT-wave inversion in V3eV6) and elevated cardiac enzyme (creati-nine kinase,1074 U/L (normal range: 40e210 U/L)). Troponin-I levelwas 13.43 ng/mL (<1.5 ng/mL). The echocardiography revealedgeneralized hypokinesia and markedly declined left ventricularejection fraction (from 64% to 11%). The patient’s coronaryangiography demonstrated patent coronary arteries. The endo-myocardial biopsy revealed organizing endomyocarditis witheosinophilic infiltration (Figure 3). His condition deterioratedrapidly, and he passed away despite aggressive intensive care andextracorporeal membrane oxygenation support.

Figure 2 Biopsy specimens from the exfoliative lesions. (A) These specimens demonstrateinterstitial mixed inflammatory cell infiltrate composed of lymphohistiocytes and eosinophiDyskeratotic cells in the epidermis (H&E, original magnification �400).

Discussion

Dapsone (4,40-diaminodiphenylsulfone) is the parent compound ofthe sulfones. It has a history of more than a century and remainsa powerful therapeutic tool for many skin diseases, includingleprosy, dermatitis herpetiformis, erythema elevatum diutinum,3

linear immunoglobulin A dermatosis,4 and the bullous eruptionof systemic lupus erythematosus.5 It is an alternative treatment forchronic idiopathic urticaria.6

The anti-inflammatory effects of dapsone are mainly associ-ated with its interference with neutrophil chemotactic migration,

spongiosis, acanthosis with dyskeratotic cells in the epidermis, and a perivascular andls in the upper dermis [hematoxylin and eosin (H&E), original magnification �100]. (B)

Figure 3 Endomyocardial biopsy demonstrates endocardial fibrosis with infiltrate oflymphohistiocytes and eosinophils (hematoxylin and eosin, original magnification�400).

W.-H. Li et al. / Dermatologica Sinica 29 (2011) 63e66 65

adherence, and recruitment by inhibiting local production oftoxic respiratory/secretory products and oxidants.7 There havebeen reported dapsone-induced adverse effects, includinghemolysis, agranulocytosis, methemoglobinemia, hepatobiliarydamage, and cutaneous involvement (morbilliform eruptions,erythema multiforme, exfoliative dermatitis, or toxic epidermalnecrolysis).8

The definition of DRESS was proposed by Bocquet et al1 as feverwith eosinophilia, skin rash, and multisystemic involvement in1996. It is a rare but serious drug reaction with delayed onset,variable clinical presentation, and prolonged course. Various groupsof drugs are emerging as culprits of DRESS, including aromaticanticonvulsants, antidepressants, sulfones, sulfonamides, allopu-rinol, nonsteroidal anti-inflammatory drugs, anti-infective agents(minocycline, penicillin, metronidazole, terbinafine), angiotensin-converting enzyme inhibitors, and b-blockers. Aromatic anticon-vulsants and sulfonamides are the most common culprit drugsinducing DRESS.9,10 The interval between first drug exposureand symptoms is usually 2e4 weeks but has been reported inindividuals receiving anticonvulsants for 3 months.11 Cutaneousmanifestations in DRESS can be presented as facial edema, mac-ulopapular eruptions, or exfoliative dermatitis. Multivisceralinvolvement may be manifested as lymphadenopathy, hepatitis,cholangitis, renal toxicity, pneumonitis, myocarditis, pericardialeffusion, thyroiditis, and cerebral edema. Hematological abnor-malities include hypereosinophilia and lymphocytosis with large,activated, and sometimes atypical, circulating lymphocytes.12e14

Table 1 Cases of dapsone-induced DRESS syndrome with cardiac involvement in the lite

Case Age/sex Race Interval (wk) Clinical presentations

1 71/M Chinese 8 Fever, jaundice, hepatomegaly, transamifailure, pleural effusion, myocarditis, and

2 22/M Malaysian 12 Fever, rash, lymphadenopathy, hypereosserositis, hepatitis, hypersensitivity myoand congestive heart failure

3 45/F Chinese 5 High fever, generalized maculopapular ratrial-ventricular block, two episodes of

Our case 33/M Chinese 6 Fever, exfoliative dermatitis, lymphadenhypersensitivity myocarditis, and conges

DRESS has been associated with considerable morbidity andmortality, which is 10% if unrecognized and untreated.2

The pathogenesis of DRESS still remains unclear, but it is likelyto involve a complex interaction of many factors, includinggenetics, immunology, individual metabolic difference in theproduction and detoxification of reactive metabolites, and reac-tivation of latent viruses of the human herpes virus (HHV) family,including HHV-6, CMV, EBV, and HHV-7.15 Our patient had negativeserologies for CMV and EBV. HHV-6 and HHV-7 serologies were nottested.

DRESS with myocardial involvement has been induced byvarious drugs, such as antibiotics (sulfonamides and penicillins),anticonvulsants, diuretics, allopurinol, and antipsychotic agents.16

Cardiac involvement is an unusual presentation of dapsone-induced DRESS. To date, only three cases of DRESS with cardiacinvolvement were documented at the time of this literature review(Table 1).17e19 The total four cases, including our case, were Asians(3 Chinese and 1 Malaysian). Including our patient, there werethree cases manifested as hypersensitivity myocarditis combinedwith fever, skin rash, and transaminitis. The other one case pre-sented as complete atrial-ventricular block and had episodes ofsyncope. One case of myocarditis was diagnosed with postmortemhistological examination. Despite systemic corticosteroids treat-ment, intensive care, and immediate withdrawal of dapsone, two ofthem eventually died. Clinicians should be vigilant for the possi-bilities of hypersensitivity myocarditis when the signs and symp-toms of drug hypersensitivity coexist with nonspecific cardiacfindings, such as unexplained tachycardia, electrocardiographicchanges, and elevations of cardiac enzymes.20 An endomyocardialbiopsy remains the golden standard for diagnosis of myocarditis.16

Many factors, including delayed endomyocardial biopsy and inad-equate sampling, contributed to underestimation of hypersensi-tivity myocarditis.

DRESS must be promptly recognized and all potential culpritdrugs should be withdrawn. Although controlled clinical trialsregarding the effectiveness of corticosteroids in DRESS are lack-ing, it is recommended for patients with life-threatening visceralmanifestations. The recommended dose of corticosteroids is0.5e1 mg/kg/d.14 Because dapsone is found to persist in the bodyfor up to 35 days because of protein binding and enterohepaticrecirculation, slow tapering of corticosteroids over at least 1month with close monitoring of organ function is required. Whenthe skin rash results in exfoliative dermatitis, supportive careconsists of warming the environmental temperature and usinglocal antiseptics and topical corticosteroids.21 If the erythrodermais severe, clinicians should be vigilant to the development ofcardiac failure in elderly patients or those with prior cardiacdisease.

Dapsone-induced DRESS with hypersensitivity myocarditis isa rare but potentially fatal adverse reaction. Patients treated with

rature.

Management Outcomes Reference

nitis, acute renalhypereosinophilia

Withdraw dapsone, intensive care Expired Lau17

inophilia, thyroiditis,carditis,

Withdraw dapsone, prednisolone40 mg/d, intensive care

Recovery Teo et al18

ash, completesyncope

Methylprednisonlone 320 mg/d Recovery Zhu et al19

opathy, transaminitis,tive heart failure

Withdraw dapsone, prednisolone30 mg/d, then hydrocortisone150 mg/d, intensive care

Expired Presentstudy

W.-H. Li et al. / Dermatologica Sinica 29 (2011) 63e6666

dapsone for various indications are required to be monitoredcarefully for the development of DRESS.

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