Core Dermatology Diagnoses / CategoriesInflammatory

Drug-induced hypersensitivity syndrome (DIHS) and Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

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Publish date: Posted on
Last updated: August 17, 2022

Keywords #

drug-induced hypersensitivity
DIHS
drug reaction with eosinophilia and systemic symptoms
DRESS

Diagnosis #

Drug-induced hypersensitivity syndrome (DIHS)—also known as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome—is a complex drug eruption associated with morbidity and potentially life-threatening organ dysfunction. Many potential causative medications have been identified, but the most frequently reported are anticonvulsants, allopurinol, sulfonamides, and antibiotics.[1] The pathophysiology of DIHS is incompletely understood, but several contributing factors have been identified, including defective drug metabolism, mutations in drug detoxification enzymes, and expression of certain HLA haplotypes.[2-5] Reactivation of herpesviruses, including EBV, CMV, HHV6, and HHV7, is also frequently identified in cases of DIHS.[6-7] Diagnosis can be challenging as the classic clinical features—fever, rash and organ dysfunction—can be seen in a variety of inflammatory and infectious disorders.

Key Concepts #
  • DIHS is characterized by a morbilliform rash associated with systemic symptoms following drug exposure.
  • The most frequent causative agents of DIHS are anticonvulsants, allopurinol, sulfonamides, and antibiotics though several other medications have been implicated.
  • Cutaneous and systemic manifestations of DIHS have a longer latency than other drug eruptions, occurring two to six weeks following initial drug administration.
  • While controversy exists surrounding optimal management, prompt identification and cessation of the offending drug is essential.
Epidemiology #

The risk of DIHS has been estimated between 1 in 1000 to 1 in 10,000 drug exposures, though the true incidence of the syndrome is unknown.[8]

Clinical Features #
  • Classically patients develop a morbilliform cutaneous eruption with facial edema, associated fever, lymphadenopathy, and organ dysfunction that can result in some combination of hematologic (most commonly leukocytosis, peripheral eosinophilia, and abnormal lymphocytes), hepatic, renal, pulmonary, cardiac, neurologic, gastrointestinal, and/or endocrine abnormalities.
  • These manifestations occur two to six weeks following initial drug administration (up to 8 weeks for anticonvulsants), and may persist several weeks to months after cessation of drug therapy.
  • Severe organ failure can occur including hepatic necrosis, myocarditis, and septic shock.
  • The estimated mortality of DIHS is reported to be 10% resulting from systemic involvement and complications from therapy.[9]
  • Delayed autoimmune phenomenon may also occur.[10]
Differential Diagnoses #
  • Simple drug eruptions
  • Stevens-Johnson syndrome
  • Acute generalized exanthematous pustulosis
  • Hypereosinophilic syndrome
  • Angioimmunoblastic T cell lymphoma
  • Acute graft-versus-host disease (in the correct clinical context)
  • Lymphoma or infectious conditions such as mononucleosis are also considered as prominent lymphadenopathy can be seen
Diagnostic Workup #

Diagnosis requires a careful physical examination, complete drug history and laboratory evaluation, including a complete blood count with differential, hepatic and renal function studies and a urinalysis in most cases. Additional studies may also be considered based on presentation. Alternative etiologies must be excluded. Several criteria for diagnosis have been proposed, first by Bocquet et al in 1996 and subsequently by a Japanese consensus group in 2006 (which highlighted the lack of peripheral eosinophilia seen in some cases and focused on the role of HHV-6 reactivation) and the RegiSCAR multinational group in 2007.[11-13] Consensus regarding these guidelines are lacking as are specific tests to improve diagnostic accuracy.

Treatment #

Currently, controversy exists regarding ideal management; however, studies have shown that delays in diagnosis and cessation of the offending agent are associated with poorer patient outcomes, emphasizing the importance of recognition. Given systemic symptoms, patients may be hospitalized and supportive measures pursued. While mild cases may benefit from skin-directed therapy alone, systemic agents are frequently utilized for more severe cases. While there is significant practice heterogeneity, the most common treatment used is systemic corticosteroids with a prolonged taper to prevent recrudescence. Outcomes can vary from little-to-no long-term morbidity to lifelong systemic complications.[14-15]

Slide Viewer #
https://utahderm.med.utah.edu/image-viewer/
References #
  1. Kardaun, S.H., et al., Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol, 2013. 169(5): p. 1071-80
  2. Santiago F, Gonçalo M, Vieira R, et al. Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS). Contact Dermatitis. 2010;62:47–53.
  3. Tas S, Simonart T. Drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Int J Clin Lab Med. 1999;54:197–200.
  4. Kashiwagi M, Aihara M, Takahashi Y, et al. Human leukocyte antigen genotypes in carbamazepine-induced severe cutaneous adverse drug response in Japanese patients. J Dermatol. 2008;35:683–5.
  5. Pirmohamed M, Lin K, Chadwick D, et al. TNFα promoter region gene polymorphisms in carbamazepine-hypersensitive patients. Neurology. 2001;56:890–6.<
  6. Seishima M, Yamanaka S, Fujisawa T, et al. Reactivation of human herpesvirus (HHV) family members other than HHV-6 in drug-induced hypersensitivity syndrome. Br J Dermatol. 2006;155:344–9.
  7. Hirahara K, Kano Y, Mitsuyama Y, et al. Differences in immunological alterations and underlying viral infections in two well-defined severe drug eruptions. Clin Exp Dermatol. 2010;35:863–8.
  8. Gomes ER, Demoly P. Epidemiology of hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol. 2005;5(4):309–16.
  9. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part I. Clinical perspectives. J Am Acad Dermatol. 2013;68(5):693.
  10. Chen, Y.C., et al., Long-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan. J Am Acad Dermatol, 2013. 68(3): p. 459-65
  11. Bocquet, H., M. Bagot, and J.C. Roujeau, Drug-induced pseudolymphoma and drug hypersensitivity syndrome (Drug Rash with Eosinophilia and Systemic Symptoms: DRESS). Semin Cutan Med Surg, 1996. 15(4): p. 250-7
  12. Shiohara, T., et al., The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations. Br J Dermatol, 2007. 156(5): p. 1083-4
  13. Kardaun, S.H., et al., Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol, 2007. 156(3): p. 609-11
  14. Tas S, Simonart T. Management of drug rash with eosinophilia and systemic symptoms (DRESS syndrome): An update. Dermatology. 2003;206:353–6.
  15. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: Part II. Management and therapeutics. J Am Acad Dermatol. 2013;68(5):718–9.
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