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The DRESS Syndrome: A Literature Review

      Abstract

      The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. We used the RegiSCAR scoring system that grades DRESS cases as “no,” “possible,” “probable,” or “definite” to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as “probable/definite” DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with “probable/definite” DRESS cases, whereas skin rash was described in almost all of the cases, including “possible cases.” Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice.

      Keywords

      The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. The estimated incidence of this syndrome ranges from 1 in 1000 to 1 in 10,000 drug exposures.
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      • Auzerie V.
      • Mahe E.
      • et al.
      A 6-month prospective survey of cutaneous drug reactions in a hospital setting.
      The acronym designated by Bocquet et al
      • Bocquet H.
      • Bagot M.
      • Roujeau J.C.
      Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS).
      describes a potentially life-threatening syndrome including a severe skin eruption, fever, hematologic abnormalities (eosinophilia or atypical lymphocytes), and internal organ involvement. The other noteworthy features are a delayed onset, usually 2-6 weeks after the initiation of drug therapy, and the possible persistence or aggravation of symptoms despite the discontinuation of the culprit drug.
      • Bocquet H.
      • Bagot M.
      • Roujeau J.C.
      Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS).
      • Roujeau J.C.
      • Stern R.S.
      Severe adverse cutaneous reactions to drugs.
      • Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a potentially life-threatening syndrome including severe eruption, fever, hypereosinophilia, and internal organ involvement.
      • The main culprit drugs are carbamazepine and allopurinol, even though 50 drugs can induce DRESS.
      • DRESS can be associated with human herpesvirus 4, 6, and 7 infections; thus, serology of these viruses should be checked.
      • The main treatments of DRESS are withdrawal of culprit drug and corticosteroid treatment.
      The pathogenesis of DRESS syndrome is partially understood. Different mechanisms have been implicated in its development, including detoxification defects leading to reactive metabolite formation and subsequent immunological reactions,
      • Shear N.H.
      • Spielberg S.P.
      Anticonvulsant hypersensitivity syndrome In vitro assessment of risk.
      slow acetylation, and reactivation of human herpes, including Epstein-Barr virus and human herpesvirus (HHV)-6 and -7.
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      • Edlinger C.
      • et al.
      Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.
      • Ichiche M.
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      DRESS syndrome associated with HHV-6 reactivation.
      • Picard D.
      • Janela B.
      • Descamps V.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response.
      The detection of HHV-6 reactivation has even been recently proposed as a diagnostic marker for DRESS.
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      • Yasukawa M.
      • et al.
      Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome.
      The diagnosis of DRESS is challenging because the pattern of cutaneous eruption and the types of organs involved are various. In addition, the multitude of denominations for this syndrome, such as drug hypersensitivity, drug-induced delayed multiorgan hypersensitivity syndrome,
      • Sontheimer R.D.
      • Houpt K.R.
      DIDMOHS: a proposed consensus nomenclature for the drug-induced delayed multiorgan hypersensitivity syndrome.
      and recently, drug-induced hypersensitivity syndrome (DIHS),
      • Shiohara T.
      • Iijima M.
      • Ikezawa Z.
      • et al.
      The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations.
      is confusing. However, recognizing this syndrome is of particular importance, as the mortality rate is up to 10%.
      In an effort to define more accurately the DRESS syndrome, a scoring system has been recently developed: the RegiSCAR scoring system.
      • Kardaun S.H.
      • Sidoroff A.
      • Valeyrie-Allanore L.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      RegiSCAR constitutes a European registry of severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and DRESS. One of the aims of this registry is to delineate each of these SCARs as distinct entities. In this line, the RegiSCAR's scoring system has been designed to grade DRESS cases as “no,” “possible,” “probable,” or “definite” case. The aim of this review was to classify cases reported as DRESS or drug hypersensitivity syndrome in the literature by using the RegiSCAR scoring system.
      • Kardaun S.H.
      • Sidoroff A.
      • Valeyrie-Allanore L.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      We also analyzed the clinical course and treatments of the reported cases. A better knowledge of DRESS may contribute to improving the diagnosis and management of this syndrome in clinical practice.
      With this scoring system, cases could be classified as definite DRESS without fulfilling all 7 criteria, while diagnosis of DIHS requires that all 7 criteria be present.

      Materials and Methods

      A systematic review of DRESS cases reported in the literature was carried out by searching PubMed-MEDLINE between January 1997 and May 2009. Search terms were “DRESS syndrome,” “drug reaction with eosinophilia and systemic symptoms,” “drug rash with eosinophilia and systemic symptoms,” “drug hypersensitivity and eosinophilia,” and “drug-induced hypersensitivity syndrome.” Publications were limited to the English and French languages.
      We used the RegiSCAR's scoring system recently published to classify the cases reported in the literature.
      • Kardaun S.H.
      • Sidoroff A.
      • Valeyrie-Allanore L.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      The scoring system is shown in Table 1 and includes the following items: fever, eosinophilia, enlarged lymph nodes, atypical lymphocytes, skin involvement, organ involvement, time of resolution, and the evaluation of other potential causes. Skin rash suggestive of DRESS encompasses maculopapular rash and erythematous skin eruption, often progressing to exfoliative dermatitis associated with facial edema.
      Table 1Scoring System for Classifying DRESS Cases as Definite, Probable, Possible, or No Case, from Kardaun et al
      • Kardaun S.H.
      • Sidoroff A.
      • Valeyrie-Allanore L.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      Score−1012
      Fever ≥38.5°CNo/UYes
      Enlarged lymph nodesNo/UYes
      EosinophiliaNo/U
       Eosinophils0.7-1.499 × 109 L−1≥1.5 × 109 L−1
       Eosinophils, if leukocytes <4.0 × 109 L−110%-19.9%≥20%
      Atypical lymphocytesNo/UYes
      Skin involvement
       Skin rash extent (% body surface area)No/U>50%
       Skin rash suggesting DRESSNoUYes
       Biopsy suggesting DRESSNoYes/U
      Organ involvement
      After exclusion of other explanations: 1, one organ; 2, two or more organs. Final score<2, no case; final score 2-3; possible case; final score 4-5, probable case; final score>5, definite case.
       LiverNo/UYes
       KidneyNo/UYes
       Muscle/heartNo/UYes
       PancreasNo/UYes
       Other organNo/UYes
      Resolution ≥15 daysNo/UYes
      Evaluation of other potential causes
       Antinuclear antibody
       Blood culture
       Serology for HAV/HBV/HCV
       Chlamydia/mycoplasma
       If none positive and ≥3 of above negativeYes
      DRESS = Drug Reaction with Eosinophilia and Systemic Symptom; U = unknown/unclassifiable; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C virus.
      low asterisk After exclusion of other explanations: 1, one organ; 2, two or more organs. Final score < 2, no case; final score 2-3; possible case; final score 4-5, probable case; final score > 5, definite case.
      The times of both onset and resolution of symptoms were recorded, as well as the detection of HHV-6 infection.
      Data were extracted and recorded in a Microsoft Excel spreadsheet (Microsoft Corporation, Redmond, Wash). For each case report, a final score was calculated allowing the cases to be classified as “no case,” “possible case,” “probable case,” and “definite case” of DRESS. Then, 2 groups were defined as the “no/possible cases” group and the “probable/definite” cases group. The characteristics of the 2 groups of patients were compared using the chi-squared or Wilcoxon test. Multivariate logistic regression was performed to define factors associated with “probable/definite cases.”
      The impacts of using DRESS in the title of the publication and of the year of the publication on the classification of DRESS also were assessed. Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, NC).

      Results

      From a total of 131 independent published reports, 172 cases of DRESS were analyzed. Publications were excluded from analysis when they displayed data group summaries in which data could not be fully analyzed because the results were not assigned to a specific patient (Figure).
      Figure thumbnail gr1
      FigureFlow diagram of literature selection process. DRESS = Drug Reaction with Eosinophilia and Systemic Symptom.
      The drugs associated with DRESS and the distribution of the cases after RegiSCAR's score assignment are displayed in Table 2.
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      Abacavir hypersensitivity reaction after switching from the twice-daily to the once-daily formulation.
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      Agranulocytosis and fever seven weeks after starting abacavir.
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      Drug-induced hypersensitivity syndrome: drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome induced by aspirin treatment of Kawasaki disease.
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      Fever, eosinophilia, and a rash.
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      DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy.
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      DRESS syndrome associated with nevirapine therapy.
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      Oxcarbazepine and DRESS syndrome: a paediatric cause of acute liver failure [French].
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      • Barbara G.
      • et al.
      Drug rash with eosinophilia and systemic symptoms secondary to phenobarbitone.
      • Sakuma K.
      • Kano Y.
      • Fukuhara M.
      • et al.
      Syndrome of inappropriate secretion of antidiuretic hormone associated with limbic encephalitis in a patient with drug-induced hypersensitivity syndrome.
      • Descamps V.
      • Bouscarat F.
      • Laglenne S.
      • et al.
      Human herpesvirus 6 infection associated with anticonvulsant hypersensitivity syndrome and reactive haemophagocytic syndrome.
      • Scheuerman O.
      • Nofech-Moses Y.
      • Rachmel A.
      • et al.
      Successful treatment of antiepileptic drug hypersensitivity syndrome with intravenous immune globulin.
      • Lachgar T.
      • Touil Y.
      The drug hypersensitivity syndrome or DRESS syndrome to Phenobarbital [French].
      • Bavdekar S.B.
      • Muranjan M.N.
      • Gogtay N.J.
      • et al.
      Anticonvulsant hypersensitivity syndrome: lymphocyte toxicity assay for the confirmation of diagnosis and risk assessment.
      • Autret-Leca E.
      • Norbert K.
      • Bensouda-Grimaldi L.
      • et al.
      DRESS syndrome, a drug reaction which remains bad known from paediatricians [French].
      • Valade S.
      • Toledano C.
      • Tiev K.
      • et al.
      DRESS syndrome caused by phenylbutazone [French].
      • Yigit S.
      • Korkmaz A.
      • Sekerel B.
      Drug-induced hypersensitivity syndrome in a premature infant.
      • Brown C.E.
      • Smith G.D.
      • Coniglione T.
      Anticonvulsant hypersensitivity: an unfortunate case of triple exposure to phenytoin.
      • Criado P.R.
      • Criado R.F.
      • Vasconcellos C.
      • et al.
      Drug-induced hypersensitivity syndrome due to anticonvulsants in a two-year-old boy.
      • Fujino Y.
      • Nakajima M.
      • Inoue H.
      • et al.
      Human herpesvirus 6 encephalitis associated with hypersensitivity syndrome.
      • Greco M.
      • Dupre-Goetghebeur D.
      • Leroy J.P.
      • et al.
      DRESS syndrome related to Hexaquine (quinine and thiamine) [French].
      • Kunisaki Y.
      • Goto H.
      • Kitagawa K.
      • et al.
      Salazosulfapyridine induced hypersensitivity syndrome associated with reactivation of humanherpes virus 6.
      • Belhadjali H.
      • Bouzgarrou L.
      • Youssef M.
      • et al.
      DRESS syndrome induced by sodium meglumine ioxitalamate.
      • Conilleau V.
      • Dompmartin A.
      • Verneuil L.
      • et al.
      Hypersensitivity syndrome due to 2 anticonvulsant drugs.
      • Ghislain P.D.
      • Bodarwe A.D.
      • Vanderdonckt O.
      • et al.
      Drug-induced eosinophilia and multisystemic failure with positive patch-test reaction to spironolactone: DRESS syndrome.
      • Passeron T.
      • Ndir M.C.
      • Aubron C.
      • et al.
      Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin.
      • Jonville-Bera A.P.
      • Crickx B.
      • Aaron L.
      • et al.
      Strontium ranelate-induced DRESS syndrome: first two case reports.
      • de Aquino R.T.
      • Vergueiro C.S.
      • Magliari M.E.
      • et al.
      Sulfasalazine-induced DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms).
      • Descloux E.
      • Argaud L.
      • Dumortier J.
      • et al.
      Favourable issue of a fulminant hepatitis associated with sulfasalazine DRESS syndrome without liver transplantation.
      • Bejia I.
      • Ben Hammouda S.
      • Riahi K.
      • et al.
      DRESS syndrome induced by sulphasalazine in rheumatoid arthritis.
      • Komatsuda A.
      • Okamoto Y.
      • Hatakeyama T.
      • et al.
      Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus.
      • Komura K.
      • Hasegawa M.
      • Hamaguchi Y.
      • et al.
      Drug-induced hypersensitivity syndrome associated with human herpesvirus 6 and cytomegalovirus reactivation.
      • Michel F.
      • Navellou J.C.
      • Ferraud D.
      • et al.
      DRESS syndrome in a patient on sulfasalazine for rheumatoid arthritis.
      • Teo R.Y.
      • Tay Y.K.
      • Tan C.H.
      • et al.
      Presumed dapsone-induced drug hypersensitivity syndrome causing reversible hypersensitivity myocarditis and thyrotoxicosis.
      • Condat B.
      • Zanditenas D.
      • Collot V.
      • et al.
      A new cause of intra and extrahepatic cholangitis: the drug hypersensitivity syndrome or DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) [French].
      • Mainra R.R.
      • Card S.E.
      Trimethoprim-sulfamethoxazole-associated hepatotoxicity - part of a hypersensitivity syndrome.
      • Zuliani E.
      • Zwahlen H.
      • Gilliet F.
      • et al.
      Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment.
      • Vauthey L.
      • Uckay I.
      • Abrassart S.
      • et al.
      Vancomycin-induced DRESS syndrome in a female patient.
      • Tamagawa-Mineoka R.
      • Katoh N.
      • Nara T.
      • et al.
      DRESS syndrome caused by teicoplanin and vancomycin, associated with reactivation of human herpesvirus-6.
      • Marik P.E.
      • Ferris N.
      Delayed hypersensitivity reaction to vancomycin.
      A total of 44 drugs were described to be associated with DRESS. Of these, the most frequently reported drugs were carbamazepine, allopurinol, sulfasalazine, phenobarbital, lamotrigine, and nevirapine. However, more than half of the drugs were associated with only one case of DRESS.
      Table 2Classification of Published DRESS Cases According to the RegiSCAR's Score
      • Kardaun S.H.
      • Sidoroff A.
      • Valeyrie-Allanore L.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      DrugsClassification of DRESS cases n = 172Nb of Cases n (%)
      No case n = 13 (8%)Possible n = 35 (20%)Probable n = 77 (45%)Definite n = 47 (27%)
      Abacavir
      • Bonta P.I.
      • Vermeulen J.N.
      • Speelman P.
      • et al.
      Severe abacavir hypersensitivity reaction in a patient tested HLA-B*5701 negative.
      • Calza L.
      • Rosseti N.
      • Biagetti C.
      • et al.
      Abacavir-induced reaction with fever and severe skin rash in a patient tested human leukocyte antigen-B*5701 negative.
      • Fox J.
      • Newton P.
      • Daly R.
      • et al.
      An unusual abacavir reaction.
      • Gervasoni C.
      • Vigano O.
      • Grinelli E.
      • et al.
      Abacavir hypersensitivity reaction after switching from the twice-daily to the once-daily formulation.
      • Sankatsing S.U.
      • Prins J.M.
      Agranulocytosis and fever seven weeks after starting abacavir.
      415 (3)
      Allopurinol
      • Sackesen C.
      • Dut R.
      • Gucer S.
      • et al.
      Allopurinol-induced DRESS syndrome in a 13-year-old girl.
      • Seishima M.
      • Yamanaka S.
      • Fujisawa T.
      • et al.
      Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced hypersensitivity syndrome.
      • Suzuki Y.
      • Inagi R.
      • Aono T.
      • et al.
      Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome.
      • Chan Y.C.
      • Tay Y.K.
      • Ng S.K.
      Allopurinol hypersensitivity syndrome and acute myocardial infarction—two case reports.
      • Masaki T.
      • Fukunaga A.
      • Tohyama M.
      • et al.
      Human herpes virus 6 encephalitis in allopurinol-induced hypersensitivity syndrome.
      • Hamanaka H.
      • Mizutani H.
      • Nouchi N.
      • et al.
      Allopurinol hypersensitivity syndrome: hypersensitivity to oxypurinol but not allopurinol.
      • Gutierrez-Macias A.
      • Lizarralde-Palacios E.
      • Martinez-Odriozola P.
      • et al.
      Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia.
      • Yoshikawa T.
      • Fujita A.
      • Yagami A.
      • et al.
      Human herpesvirus 6 reactivation and inflammatory cytokine production in patients with drug-induced hypersensitivity syndrome.
      • Chao S.C.
      • Yang C.C.
      • Lee J.Y.
      Hypersensitivity syndrome and pure red cell aplasia following allopurinol therapy in a patient with chronic kidney disease.
      • Descamps V.
      • Mahe E.
      • Houhou N.
      • et al.
      Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.
      • Marrakchi C.
      • Kanoun F.
      • Kilani B.
      • et al.
      Allopurinol induced DRESS syndrome [French].
      • Shalom R.
      • Rimbroth S.
      • Rozenman D.
      • Markel A.
      Allopurinol-induced recurrent DRESS syndrome: pathophysiology and treatment.
      • Suzuki H.I.
      • Asai T.
      • Tamaki Z.
      • et al.
      Drug-induced hypersensitivity syndrome with rapid hematopoietic reconstitution during treatment for acute myeloid leukemia.
      168419 (11)
      Amoxicillin plus clavulanic acid
      • Yu M.K.
      • Yu M.C.
      • Lee F.
      Association of DRESS syndrome with chylous ascites.
      11 (0.6)
      Amitriptyline
      • Galindo Bonilla P.A.
      • Romero Aguilera G.
      • Feo Brito F.
      • et al.
      Phenytoin hypersensitivity syndrome with positive patch test A possible cross-reactivity with amitriptyline.
      • Milionis H.J.
      • Skopelitou A.
      • Elisaf M.S.
      Hypersensitivity syndrome caused by amitriptyline administration.
      22 (1)
      Atovarstatin
      • Gressier L.
      • Pruvost-Balland C.
      • Dubertret L.
      • Viguier M.
      Atorvastatin-induced drug reaction with eosinophilia and systemic symptoms (DRESS) [French].
      11 (0.6)
      Aspirin
      • Kawakami T.
      • Fujita A.
      • Takeuchi S.
      • et al.
      Drug-induced hypersensitivity syndrome: drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome induced by aspirin treatment of Kawasaki disease.
      11 (0.6)
      Captopril
      • Ichiche M.
      • Kiesch N.
      • De Bels D.
      DRESS syndrome associated with HHV-6 reactivation.
      11 (0.6)
      Carbamazepine5,18,24,35-63310201447 (27)
      Cefadroxil
      • Hernanto M.
      • Yudani B.A.
      • Pudjiati S.R.
      • et al.
      DRESS syndrome from cefadroxil confirmed by positive patch test.
      11 (0.6)
      Celecoxib
      • Lee J.H.
      • Park H.K.
      • Heo J.
      • et al.
      Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome induced by celecoxib and anti-tuberculosis drugs.
      11 (0.6)
      Chlorambucil
      • Vaida I.
      • Roszkiewicz F.
      • Gruson B.
      • et al.
      Drug rash with eosinophilia and systemic symptoms after chlorambucil treatment in chronic lymphocytic leukaemia.
      11 (0.6)
      Clomipramine
      • Nishimura Y.
      • Kitoh A.
      • Yoshida Y.
      • et al.
      Clomipramine-induced hypersensitivity syndrome with unusual clinical features.
      11 (0.6)
      Clopidogrel
      • Doogue M.P.
      • Begg E.J.
      • Bridgman P.
      Clopidogrel hypersensitivity syndrome with rash, fever, and neutropenia.
      11 (0.6)
      Codeine phosphate
      • Enomoto M.
      • Ochi M.
      • Teramae K.
      • et al.
      Codeine phosphate-induced hypersensitivity syndrome.
      11 (0.6)
      Cotrimoxazole/cefixime
      • Garnier A.
      • El Marabet el H.
      • Kwon T.
      • et al.
      Acute renal failure in a 3-year-old child as part of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome following hepatitis A.
      11 (0.6)
      Cyanamide
      • Mitani N.
      • Aihara M.
      • Yamakawa Y.
      • et al.
      Drug-induced hypersensitivity syndrome due to cyanamide associated with multiple reactivation of human herpesviruses.
      11 (0.6)
      Dapsone
      • Itha S.
      • Kumar A.
      • Dhingra S.
      • Choudhuri G.
      Dapsone induced cholangitis as a part of dapsone syndrome: a case report.
      • Sener O.
      • Doganci L.
      • Safali M.
      • et al.
      Severe dapsone hypersensitivity syndrome.
      • Teo L.
      • Tan E.
      Sulphasalazine-induced DRESS.
      • Takahashi H.
      • Tanaka M.
      • Tanikawa A.
      • et al.
      A case of drug-induced hypersensitivity syndrome showing transient immunosuppression before viral reactivation during treatment for pemphigus foliaceus.
      44 (2)
      Diaphenylsulfone
      • Higuchi M.
      • Agatsuma T.
      • Iizima M.
      • et al.
      A case of drug-induced hypersensitivity syndrome with multiple organ involvement treated with plasma exchange.
      11 (0.6)
      Efalizumab
      • White J.M.
      • Smith C.H.
      • Robson A.
      • et al.
      DRESS syndrome caused by efalizumab.
      11 (0.6)
      Esomeprazole
      • Caboni S.
      • Gunera-Saad N.
      • Ktiouet-Abassi S.
      • et al.
      Esomeprazole-induced DRESS syndrome Studies of cross-reactivity among proton-pump inhibitor drugs.
      11 (0.6)
      Hydroxychloroquine
      • Volpe A.
      • Marchetta A.
      • Caramaschi P.
      • et al.
      Hydroxychloroquine-induced DRESS syndrome.
      • Schmutz J.L.
      • Barbaud A.
      • Trechot P.
      Hydroxychloroquine and DRESS [French].
      22 (1)
      Ibruprofen
      • Descamps V.
      • Valance A.
      • Edlinger C.
      • et al.
      Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.
      • Chiou C.C.
      • Chung W.H.
      • Hung S.I.
      • et al.
      Fulminant type 1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection.
      22 (1)
      Imatinib
      • Le Nouail P.
      • Viseux V.
      • Chaby G.
      • Billet A.
      • Denoeux J.P.
      • Lok C.
      Drug reaction with eosinophilia and systemic symptoms (DRESS) following imatinib therapy [French].
      11 (0.6)
      Lamotrigine52,83-91332210 (6)
      Mexilletine24,92-95235 (3)
      Minocycline
      • Brown R.J.
      • Rother K.I.
      • Artman H.
      • et al.
      Minocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae.
      • Favrolt N.
      • Bonniaud P.
      • Collet E.
      • et al.
      Severe drug rash with eosinophilia and systemic symptoms after treatment with minocycline [French].
      • Descamps V.
      • Collot S.
      • Mahe E.
      • et al.
      Active human herpesvirus 6 infection in a patient with drug rash with eosinophilia and systemic symptoms.
      213 (2)
      Nevirapine
      • Bourezane Y.
      • Salard D.
      • Hoen B.
      • et al.
      DRESS (drug rash with eosinophilia and systemic symptoms) syndrome associated with nevirapine therapy.
      • Claudio G.A.
      • Martin A.F.
      • de Dios Perrino S.
      • et al.
      DRESS syndrome associated with nevirapine therapy.
      • Lanzafame M.
      • Rovere P.
      • De Checchi G.
      • et al.
      Hypersensitivity syndrome (DRESS) and meningoencephalitis associated with nevirapine therapy.
      • Santos R.P.
      • Ramilo O.
      • Barton T.
      Nevirapine-associated rash with eosinophilia and systemic symptoms in a child with human immunodeficiency virus infection.
      • Sissoko D.
      • Ajana F.
      • de la Tribonniere X.
      • Baclet V.
      • Mouton Y.
      Cutaneous, hepatic and hematologic manifestations due to nevirapine: DRESS syndrome? [French].
      • Fields K.S.
      • Petersen M.J.
      • Chiao E.
      • et al.
      Case reports: treatment of nevirapine-associated dress syndrome with intravenous immune globulin (IVIG).
      3328 (5)
      Olanzapine
      • Raz A.
      • Bergman R.
      • Eilam O.
      • et al.
      A case report of olanzapine-induced hypersensitivity syndrome.
      11 (0.6)
      Oxcarbazepine
      • Bosdure E.
      • Cano A.
      • Roquelaure B.
      • et al.
      Oxcarbazepine and DRESS syndrome: a paediatric cause of acute liver failure [French].
      • D'Orazio J.L.
      Oxcarbazepine-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).
      • Wyplosz B.
      • Vaghefi P.
      • Terki A.K.
      • et al.
      DRESS syndrome à l'oxcarbazepine et infection par le HHV6.
      123 (2)
      Phenobarbital18,37,47,109-11534310 (6)
      Phenylbutazone
      • Valade S.
      • Toledano C.
      • Tiev K.
      • et al.
      DRESS syndrome caused by phenylbutazone [French].
      11 (0.6)
      Phenytoin24,47,58,117-1201337 (4)
      Quinine and thiamine
      • Greco M.
      • Dupre-Goetghebeur D.
      • Leroy J.P.
      • et al.
      DRESS syndrome related to Hexaquine (quinine and thiamine) [French].
      11 (0.6)
      Salazosulfapyridine
      • Descamps V.
      • Valance A.
      • Edlinger C.
      • et al.
      Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.
      • Kunisaki Y.
      • Goto H.
      • Kitagawa K.
      • et al.
      Salazosulfapyridine induced hypersensitivity syndrome associated with reactivation of humanherpes virus 6.
      112 (1)
      Sodium meglumine ioxitalamate
      • Belhadjali H.
      • Bouzgarrou L.
      • Youssef M.
      • et al.
      DRESS syndrome induced by sodium meglumine ioxitalamate.
      11 (0.6)
      Sodium valproate/ethosuximide
      • Conilleau V.
      • Dompmartin A.
      • Verneuil L.
      • et al.
      Hypersensitivity syndrome due to 2 anticonvulsant drugs.
      11 (0.6)
      Spironolactone
      • Ghislain P.D.
      • Bodarwe A.D.
      • Vanderdonckt O.
      • et al.
      Drug-induced eosinophilia and multisystemic failure with positive patch-test reaction to spironolactone: DRESS syndrome.
      11 (0.6)
      Streptomycin
      • Passeron T.
      • Ndir M.C.
      • Aubron C.
      • et al.
      Drug rash with eosinophilia and systemic symptoms (DRESS) due to streptomycin.
      11 (0.6)
      Strontium ranelate
      • Jonville-Bera A.P.
      • Crickx B.
      • Aaron L.
      • et al.
      Strontium ranelate-induced DRESS syndrome: first two case reports.
      112 (1)
      Sulfalazine62,93,128-13532510 (6)
      Sulfamethoxazole
      • Fox J.
      • Newton P.
      • Daly R.
      • et al.
      An unusual abacavir reaction.
      • Mainra R.R.
      • Card S.E.
      Trimethoprim-sulfamethoxazole-associated hepatotoxicity - part of a hypersensitivity syndrome.
      22 (1)
      Tribenoside
      • Calza L.
      • Rosseti N.
      • Biagetti C.
      • et al.
      Abacavir-induced reaction with fever and severe skin rash in a patient tested human leukocyte antigen-B*5701 negative.
      11 (0.6)
      Vancomycin
      • Zuliani E.
      • Zwahlen H.
      • Gilliet F.
      • et al.
      Vancomycin-induced hypersensitivity reaction with acute renal failure: resolution following cyclosporine treatment.
      • Vauthey L.
      • Uckay I.
      • Abrassart S.
      • et al.
      Vancomycin-induced DRESS syndrome in a female patient.
      • Tamagawa-Mineoka R.
      • Katoh N.
      • Nara T.
      • et al.
      DRESS syndrome caused by teicoplanin and vancomycin, associated with reactivation of human herpesvirus-6.
      • Marik P.E.
      • Ferris N.
      Delayed hypersensitivity reaction to vancomycin.
      1214 (2)
      Zonisamide
      • Seishima M.
      • Yamanaka S.
      • Fujisawa T.
      • et al.
      Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced hypersensitivity syndrome.
      11 (0.6)
      DRESS = Drug Reaction with Eosinophilia and Systemic Symptom.
      The vast majority of cases obtained through literature search were classified as either definite or probable cases of DRESS, whereas <10% of reported cases were not scored as DRESS according to the RegiSCAR system (Table 2).
      The main demographic, clinical, and treatment characteristics associated with DRESS are shown in Table 3. Skin rash was reported in almost all cases. The cutaneous eruption was mostly described as a maculopapular rash or a generalized erythematous rash.
      Table 3Demographic, Clinical, and Treatment Characteristics Associated with DRESS
      n%
      Age (years)
       Mean ± SD (range)40.7 ± 20.9 (0.1-84)
      Sex
       Male87/16553
       Female78/16547
      Onset (weeks)
      Time between the initiation of drug therapy and the occurrence of symptoms.
       Mean ± SD (range)3.9 ± 2.3 (0.5-16)
      Skin rash167/17297
       Maculopapular rash101/16760
       Generalized erythematous rash90/16754
       Facial edema65/16739
      Internal organ involvement151/17288
       Liver142/15194
        Elevation of liver function tests84/14259
        Hepatomegaly17/14212
       Kidney12/1518
       Lung7/1515
       Central nervous system3/1512
       Heart3/1512
      Hypereosinophilia (>0.7 × 109 L−1)114/17266
      Eosinophils (109 L−1)
       Mean ± SD (range)3.5 ± 4.1 (0.4-30)
      Fever >38.5°C111/17264
      Lymphadenopathy96/17256
      Atypical lymphocytes47/17227
      HHV-6 infection
       Detection70/17241
       Positive56/7080
      Treatment
       Corticosteroids134/17278
       Intravenous immunoglobulin16/1729
      DRESS = Drug Reaction with Eosinophilia and Systemic Symptom; HHV-6 = human herpesvirus 6.
      low asterisk Time between the initiation of drug therapy and the occurrence of symptoms.
      Internal organ involvement was mentioned in the vast majority of patients. The liver was the most frequently involved internal organ. Liver involvement was described by either the elevation of liver function tests or the presence of hepatomegaly. The levels of aspartate aminotransferase and alanine aminotransferase increased by approximately 9 fold (range 1.5-160) and 10 fold (range 1.5-54) above the normal limits, respectively. Affection of other organs was rarely reported. In addition, no relevant link could be established between internal organ impairment and the type of causative drug. Following skin rash and systemic symptoms, hypereosinophilia was the third most frequently reported sign in patients having a DRESS. Fever and peripheral lymphadenopathy occurred in approximately more than half of the patients.
      The mechanisms underlying DRESS development were not investigated in the vast majority of cases: detection of HHV-6 infection was performed in less than half of cases (Table 3). However, when HHV-6 infection was investigated, the results of the test (serology or polymerase chain reaction) were positive in 80% of cases. Of these cases, the positive diagnosis of HHV-6 infection was mostly based on an increase in the anti-HHV-6 immunoglobulin G titer, implicating an HHV-6 reactivation. Other potential causes of symptoms besides drugs were ruled out in 52 cases (30%) based on the following criteria: absence of antinuclear antibody, negative blood culture, and negative serology for hepatitis A, hepatitis B, and hepatitis C virus.
      In all cases, patients were hospitalized and the culprit drug was withheld within the first days of hospitalization. The main treatment was corticosteroids (Table 3). The doses and route of administration were, however, rarely mentioned. Corticosteroids were combined with intravenous immunoglobulin in 10 cases. Overall, the mean time for recovery was 6.4±9.4 weeks (range 0.5-90 weeks). However, DRESS syndrome resulted in death in 9 cases (5%). Characteristics of DRESS cases resulting in death are displayed in Table 4. The patients with severe DRESS cases tended to be older than those recovering from DRESS. Almost all of these cases were associated with liver involvement, and treatment with corticosteroids did not prevent a fatal outcome. The cause of death was cardiac or hepatic. In addition, no significant differences were found for demographic, clinical, and outcome parameters between cases resulting in death and those that resolved (data not shown).
      Table 4Characteristics of DRESS Cases Resulting in Death
      n = 9
      Age (years)
       Mean ± SD (range)49.0 ± 23.5 (13-80)
      Sex
       Male5
       Female4
      Onset (weeks)
      Time between the initiation of drug therapy and the occurrence of symptoms.
       Mean ± SD (range)3.6 ± 2.3 (0.5-8)
      Skin rash9
      Liver involvement8
      Time between onset of symptoms and death6.2 ± 5.2 (1-16)
      DRESS = Drug Reaction with Eosinophilia and Systemic Symptom.
      low asterisk Time between the initiation of drug therapy and the occurrence of symptoms.
      When cases were classified into 2 groups based on the RegiSCAR's scoring system, that is, “no/possible cases” and “probable/definite cases,” the 2 groups differed significantly regarding the vast majority of clinical and outcome parameters (Table 5). The following were significantly most reported in the “probable/definite” cases group: the presence of skin rash, liver involvement, high grade fever, hypereosinophilia, lymphadenopathy, and atypical lymphocyte. Consistently, the multivariate logistic regression identified fever, hypereosinophilia, liver involvement, and lymphadenopathy as factors significantly associated with “probable/definite” cases of DRESS.
      Table 5Comparison of Clinical and Outcome Parameters between “No/Possible” Cases and “Probable/Definite” Cases of DRESS: Analysis of Factors Associated with “Probable/Definite” Cases of DRESS
      Univariate AnalysisLogistic Regression
      No/Possible Cases n = 48Probable/Definite Cases n = 124P ValueOdds Ratio95% Confidence IntervalP Value
      Age, mean ± SD42.2 ± 21.340.1 ± 20.8.535
      Sex.107
       Male30/48 (63)57/117 (49)
       Female18/48 (38)60/117 (51)
      Skin rash44 (92)123 (99).022
      Internal organ involvement
       Liver30 (63)112 (90)<.001113-41<.001
       Kidney1 (2)11 (9).183
       Lung1 (2)6 (5).675
      Hypereosinophilia (>0.7 × 109 L−1)12 (25)102 (82)<.001299-88<.001
      Fever >38.5°C23 (48)88 (71).00562-16.001
      Lymphadenopathy16 (33)80 (65)<.001103-28<.001
      Atypical lymphocytes4 (8)43 (35)<.001
      HHV-6 infection9/14 (64)47 (84).135
      Treatment (corticosteroids)38 (79)96 (77).804
      Onset (weeks), mean ± SD3.6 ± 2.04.1 ± 2.4.042
      Resolution (weeks), mean ± SD3.8 ± 2.87.3 ± 10.6.007
      “DRESS” in the title of the publication7 (15)53 (48)<.001
      Year of publication ≥200812 (25)25 (20).488
      DRESS = Drug Reaction with Eosinophilia and Systemic Symptom; HHV-6 = human herpesvirus 6.
      When DRESS appeared in the title of a publication, cases were more often classified as “probable/definite” (Table 5). In addition, because the RegiSCAR's scoring system was published in 2007, we assessed the impact of the year of the publication on cases classification. The proportion of cases defined as “probable/definite” was not statistically different when cases were published before 2008 (Table 5).

      Discussion

      In this review, we have done an extended analysis of 172 cases reported as DRESS or drug hypersensitivity syndrome in the literature by using the RegiSCAR scoring system.
      • Kardaun S.H.
      • Sidoroff A.
      • Valeyrie-Allanore L.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      This review shows that DRESS is challenging to diagnose. Patients defined by the scoring system as “no/possible” cases of DRESS accounted for approximately one quarter of all the DRESS cases reported in the literature. However, cases classified as “probable/definite” by the RegiSCAR scoring system represented the vast majority (88%) of cases published under the denomination of DRESS. Consistently, fewer cases (63%) published under another denomination were classified as “probable/definite” cases. This indicates that the denomination DRESS is accurately used in the literature.
      The presenting symptoms in almost all patients were skin rash, liver involvement, hypereosinophilia, and lymphadenopathy. Consistent with the fact that we have used a scoring system, the distribution of these clinical characteristics significantly differed between patients with “no/possible” DRESS cases and those with “probable/definite” DRESS cases. However, skin rash was the most frequently reported symptom in both groups, in accordance with the original signification of the DRESS acronym.
      • Bocquet H.
      • Bagot M.
      • Roujeau J.C.
      Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS).
      Here, only 5 of 172 cases were described with no skin involvement. Of these 5 cases, 3 were defined as “no DRESS.” Nevertheless, skin rash also has been described in almost all of the “possible cases” and was not significantly associated with “probable/definite” cases. No pathognomonic pattern of skin rash emerged from the literature. The presence of facial edema was reported in only one third of cases.
      In contrast to skin rash, hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with “probable/definite” DRESS cases. Liver involvement was described either as raised aminotransferase or hepatomegaly. Other organs such as the kidney or the central nervous system were rarely involved. Altogether, these results indicate that DRESS should be suspected, not on the sole presence of skin eruption, but also on the presence of hypereosinophilia, liver involvement, fever, and lymphadenopathy. However, these symptoms also are common to other diseases such as connective tissue diseases, idiopathic hypereosinophilia, and viral hepatitis. These differential diagnoses of DRESS have been ruled out in only 30% of reported cases, on the basis of the absence of antinuclear antibody, negative blood culture, and negative serology for hepatitis A, hepatitis B, and hepatitis C virus.
      A delayed onset of symptoms 2-6 weeks after the initiation of causative drug is a feature of DRESS. Consistently, the onset of symptoms appeared to be more delayed in patients with “probable/definite” cases. The resolution occurred after a longer time period in the “probable/definite” cases compared with the “no/possible” cases. This resolution also was characterized by several flare-ups of clinical symptoms despite the management of DRESS. The type of DRESS management recorded in this review included the discontinuation of the causative drug in all the DRESS cases and treatment with corticosteroids. The rates of patients treated with corticosteroids were similar in both groups. Unfortunately, the route of administration and dose of corticosteroid treatment were not reported in many case reports considered in this review, rendering it difficult to analyze these therapies. This highlights the lack of consensus guidelines on DRESS syndrome treatment and consequently the need for improving the management of DRESS.
      Improving the management of DRESS is closely linked to better knowledge of its pathogenesis, including identification of the culprit drugs and viral reactivation. DRESS has been initially described as the anticonvulsant hypersensitivity syndrome.
      • Shear N.H.
      • Spielberg S.P.
      Anticonvulsant hypersensitivity syndrome In vitro assessment of risk.
      Here, anticonvulsants including carbamazepine, lamotrigine, and phenobarbital accounted for one third of the drugs causing DRESS. In contrast, the vast majority of the other drugs were only associated with one case of DRESS. Some of these drugs even appeared not to be the causative drug of the DRESS syndrome. Indeed, of the 5 cases of drug hypersensitivity syndrome associated with the antiretroviral agent abacavir, 4 were scored as “no case.” Genetic susceptibility has been shown to influence abacavir hypersensitivity,
      • Mallal S.
      • Nolan D.
      • Witt C.
      • et al.
      Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.
      suggesting that abacavir hypersensitivity could be a distinct clinical entity of DRESS. This variety of drugs, together with the clinical course characterized by slow resolution and relapse, suggests that drugs cannot be the sole etiology of DRESS. In accordance with this hypothesis, HHV-6 reactivation has been defined in previous studies as a potential contributor to DRESS development.
      • Descamps V.
      • Valance A.
      • Edlinger C.
      • et al.
      Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms.
      • Ichiche M.
      • Kiesch N.
      • De Bels D.
      DRESS syndrome associated with HHV-6 reactivation.
      In this review, the detection of HHV-6 was performed in 41% of cases. This relatively low rate of detection may reflect the fact that the involvement of HHV-6 infection in DRESS development is a recent hypothesis. The majority of the cases reporting HHV-6 detection have been recently published. In the majority of these publications (52/70), HHV-6 infection was found to be reactivated. Consistently, the diagnosis of DIHS that represents the most recent proposal for DRESS denomination requires HHV-6 reactivation together with the presence of maculopapular rash, prolonged clinical symptom, fever, liver abnormalities, leukocyte abnormalities, and lymphadenopathy.
      • Shiohara T.
      • Iijima M.
      • Ikezawa Z.
      • et al.
      The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations.
      Because cases could be classified as definite DRESS without fulfilling all these criteria, DIHS has been regarded as a more severe form of DRESS.
      • Shiohara T.
      • Iijima M.
      • Ikezawa Z.
      • et al.
      The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations.
      For some of the remaining cases without HHV-6 reactivation, other types of viral infection were reported, such as cytomegalovirus reactivation
      • Hashizume H.
      • Takigawa M.
      Drug-induced hypersensitivity syndrome associated with cytomegalovirus reactivation: immunological characterization of pathogenic T cells.
      and paramyxovirus infection.
      • Naniwa T.
      • Maeda S.
      • Sawada H.
      • et al.
      Drug-induced hypersensitivity syndrome associated with a marked increase in anti-paramyxovirus antibody titers in a scleroderma patient.
      The high prevalence of viral infection, mostly HHV-6 infection, supports an emerging role of HHV-6 and other types of virus in the pathogenesis of DRESS. Recently, in a prospective study including 40 DRESS patients, Epstein-Barr virus, HHV-6, and HHV-7 reactivations were found in 76% of the cases. Interestingly, the culprit drugs were able to trigger viral reactivations that induce a pathogenic antiviral CD8+ immune response.
      • Picard D.
      • Janela B.
      • Descamps V.
      • et al.
      Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response.
      Because DRESS is a life-threatening syndrome, predictive factors for serious cases need to be defined. However, no differences for demographic and clinical variables were found between cases resulting in death and those that resolved, suggesting that recognizing serious DRESS cases remains an issue. The type of causative drug may influence the outcome of DRESS such as allopurinol. In this review, allopurinol was involved in 3 of 9 patients with serious DRESS. This finding is in accordance with previous studies showing that the death rate in patients with allopurinol-associated DRESS was higher than that described in DRESS cases due to other drugs.
      • Eshki M.
      • Allanore L.
      • Musette P.
      • et al.
      Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms: a cause of unpredictable multiorgan failure.
      • Peyriere H.
      • Dereure O.
      • Breton H.
      • et al.
      Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?.
      Our study has several limitations. The retrospective review is subject to publication bias. The conclusions we were able to draw are limited by data gaps in many reports. Details on clinical and outcome parameters or on therapy were often not described.
      In conclusion, the diagnosis of DRESS should be highly suspected with the presence of skin rash, liver involvement, fever, hypereosinophilia, and lymphadenopathy. The high rate of HHV-6 and other herpes viruses reactivation associated with DRESS implies that HHV-6 and other herpes viruses should be detected in routine clinical practice. Besides the prompt withdrawal of causative drug as standard of care, further studies are needed to recommend specific treatment guidelines.

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      Linked Article

      • Human Herpesvirus 6 Reactivation in Drug-induced Hypersensitivity Syndrome and DRESS Validation Score
        The American Journal of MedicineVol. 125Issue 7
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          We read with great interest the article entitled, “The DRESS Syndrome: A Literature Review” by Cacoub et al.1 The authors classified 172 cases reported as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in the literature by using the RegiSCAR scoring system.2 They concluded that the vast majority of cases could be defined as “probable/definite” DRESS cases. Among various terms to refer to this syndrome, the criteria for drug-induced hypersensitivity syndrome (DIHS) proposed by a Japanese severe cutaneous adverse reaction group includes human herpesvirus 6 (HHV-6) reactivation,3 different from that for DRESS reported by Bocquet et al.
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