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Dress syndrome: drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DiHS)
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DiHS), is considered to result from complex interactions between genetic predisposition, exposure to drug, and viral reactivation. DRESS is characterized by multiorgan involvement with cutaneous, mucosal, hematological, and solid organ manifestations. The cutaneous involvement in DRESS is typically extensive and symptomatic. Delayed onset of 2–8 weeks after drug administration followed by a stepwise development of manifestations is characteristic. Two types of diagnostic criteria are available: the Japanese study group of severe cutaneous adverse reactions to drugs and the RegiSCAR network. Symptoms are usually present for several weeks even after discontinuation of the offending agent and appropriate treatment. Late complications, including mostly autoimmune diseases and end-organ failure, should be closely monitored. Mortality in DRESS has been estimated at 10%, with most patients dying from liver failure.
Management Strategy
DRESS/DiHS is a severe adverse drug reaction with multiorgan involvement that is potentially fatal. Hence, prompt diagnosis and management are essential.
Initial management of DRESS/DiHS requires withdrawal of the culprit drug and assessment of the extent and severity of cutaneous, mucosal, and systemic involvement (hematological and solid organs).
DRESS presents with a combination of fever, diffuse rash, and signs of systemic involvement (any internal organ can be affected) – this triad is often the key to diagnosis. Delayed onset of 2–8 weeks after drug administration followed by a stepwise development of manifestations is characteristic. Fever is the most common sign, followed by a skin rash. The cutaneous involvement in DRESS is typically extensive and symptomatic (pruritus, burning, and pain), with morbilliform eruption being most common. However, various dermatological features may appear. Facial edema and diffuse lymphadenopathy are observed in most patients and mucosal involvement, mainly of the lips and oral cavity, may be demonstrated.
DRESS is considered to occur as a result of complex interactions between genetic predisposition (such as HLA-B∗13:01 with dapsone hypersensitivity), exposure to drug, and viral reactivation.
According to the above, thorough investigations are to be conducted by history-taking, skin and full body exam (including assessment of mucous membranes and lymph nodes), blood work, and additional assessment for systemic involvement, viral reactivation, and to exclude alternative diagnosis.
Differential diagnosis must be done with other diseases that may present with skin rash, systemic symptoms, hematologic abnormalities, adenopathy, and fever. These include other severe drug reactions, viral and bacterial infections, autoimmune diseases, hypereosinophilic syndromes, Sézary syndrome, pseudolymphoma, and lymphomas.
Histological assessment is mandatory. Histopathology of cutaneous lesions in DRESS syndrome are variable. However, most commonly include perivascular dense lymphocytic infiltrate in the papillary dermis, with eosinophils, atypical lymphocytes, and spongiosis of the epidermis.
The RegiSCAR group developed a validated and practical scoring system for the diagnosis of DRESS. A severity score is an additional clinical tool to guide treatment options and assist in predicting outcomes.
Proper identification of the culprit drug is of utmost importance for avoiding it and all drugs that may cross-react with this agent and for providing the patient with reassurance to use other drugs that are safe.
The following methods are helpful to establish whether there is a causal relationship between the suspected drug and the clinical event: 1) patient history: the patient should be questioned about former drug eruptions and whether discontinuing the drug improved the eruption; 2) analysis of the literature: PubMed ( http://www.ncbi.nlm.nih.gov/pubmed/ ) and Litt’s D.E.R.M. Drug Eruptions and Reactions Manual and database ( http://www.drugeruptiondata.com/ ); and 3) in vitro and in vivo diagnostic assessments, including human leukocyte antigen (HLA) genetic tests.
Specific Investigations
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Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist?
Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Br J Dermatol 2007; 156: 609–11.
RegiSCAR DRESS validation score is presented.
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms severity score: a useful tool for assessing disease severity and predicting fatal cytomegalovirus disease
Mizukawa Y, Hirahara K, Kano Y, et al. J Am Acad Dermatol 2019; 80(3): 670–8.
DRESS severity score is presented with implications regarding treatment options and predicting outcomes, including CMV-related complications.
Sensitivity and specificity of the lymphocyte transformation test in drug reaction with eosinophilia and systemic symptoms causality assessment
Cabañas R, Calderón O, Ramírez E, et al. Clin Exp Allergy 2018; 48(3): 325–33.
An observational retrospective analysis was performed on 41 patients diagnosed with DRESS syndrome and 35 additional patients with non-immediate drug-induced reactions in which a re-exposition drug test was performed. Sensitivity and specificity of the lymphocyte transformation test (LTT) in the recovery phase of DRESS were 73% and 82%, respectively, whereas in the acute phase, they were only 40% and 30%, respectively. The data indicate that LTT has a good sensitivity and specificity and is a reliable tool for diagnosis of drug causality, mainly when performed in the recovery phase in DRESS syndrome.
A combined approach using a detailed case history, LTT, and skin tests is advised to identify the causative drug.
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