Drug reaction with eosinophilia and systemic symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS), also termed drug-induced hypersensitivity syndrome (DIHS), is a rare reaction to certain medications. It involves primarily a widespread skin rash, fever, lymphadenopathy, and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia, and atypical lymphocytosis. However, it is often complicated by potentially life-threatening inflammation of internal organs: the syndrome has about a 10% mortality. Treatment consists of stopping the offending medication and providing supportive care. Systemic steroids are commonly used as well but no controlled clinical trials assess the efficacy of this treatment. Drug reaction with eosinophilia and systemic symptoms (DRESS), also termed drug-induced hypersensitivity syndrome (DIHS), is a rare reaction to certain medications. It involves primarily a widespread skin rash, fever, lymphadenopathy, and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia, and atypical lymphocytosis. However, it is often complicated by potentially life-threatening inflammation of internal organs: the syndrome has about a 10% mortality. Treatment consists of stopping the offending medication and providing supportive care. Systemic steroids are commonly used as well but no controlled clinical trials assess the efficacy of this treatment. DRESS syndrome is classified as one form of severe cutaneous adverse reactions (SCARs). In addition to DRESS syndrome, SCARs includes four other drug-induced skin reactions, the Stevens-Johnson syndrome (SJS); Toxic epidermal necrolysis (TEN), Stevens-Johnson/toxic epidermal necrolysis overlap syndrome (SJS/TEN); and Acute generalized exanthematous pustulosis (AGEP). The SCARs disorders have similar pathophysiologies, i.e. disease-causing mechanisms, for which new strategies are in use or development to identify individuals predisposed to experience the SCARs-inducing effects of specific drugs and thereby avoid treatment with them. In the overall strategy for handling the DRESS syndrome, then, individuals slated to receive certain DRESS syndrome-inducing drugs are first screened to identify those who are genetically or otherwise predisposed to develop the disorder in response to these drugs. Alternative drugs are used in all individuals testing positive for these predispositions. Drugs associated with the development of the DRESS disorder are often popular, widely used, and/or clinically important for the control of certain diseases. This is evident in the most commonly cited drugs that cause the DRESS syndrome viz., allopurinol, sulfasalazine, and minocycline, as well as in prominent but less commonly cited causes of the disorder such as strontium ranelate, leflunomide, dapsone, and nonsteroidal anti-inflammatory drugs (diclofenac, celecoxib, ibuprofen, and phenylbutazone). Prior to 1996, there were numerous reports on individuals presenting with a medication-induced disorder now recognized as the DRESS syndrome. For example, anticonvulsants in the 1930s, phenytoin in 1950, and other medications in the ensuing years were reported to do so. The reports often named the disorder based on the drug evoking it, e.g. the anticonvulsant hypersensitivity syndrome, anticonvulsant hypersensitivity syndrome, allopurinol hypersensitivity syndrome, dapsone syndrome, and dapsone hypersensitivity syndrome. In 1996, however, the term DRESS syndrome was coined in a report attempting to simplify the terminology and consolidate these various clearly related syndromes into a single underlying disorder. The symptoms of DRESS syndrome usually begin 2 to 6 weeks but uncommonly up to 8–16 weeks after exposure to an offending drug. Symptoms generally include fever, an often itchy rash which may be morbilliform or consist mainly of macules or plaques, facial edema (i.e. swelling, which is a hallmark of the disease), enlarged and sometimes painful lymph nodes, and other symptoms due to inflammation-based internal organ involvement, most commonly liver, less commonly kidney, lung, and heart, and rarely pancreas or other organs. laboratory findings include increased blood eosinophil and atypical lymphocyte counts, elevated blood markers for systemic inflammation (e.g. erythrocyte sedimentation rate, C-reactive protein), and evidence of internal organ involvement. Liver involvement is detected by measuring blood levels of alanine aminotransferase (ALT), a marker of hepatocyte injury, and alkaline phosphatase (ALP), a marker of bile duct injury, to define three types of injury: hepatocellular (elevated ALP, high ALT/ALP ratio), cholestatic (high ALP, low ALT/ALP ratio), and mixed (elevated ALT and ALP, ALT/ALP ratio between cutoff values for hepatocellular and bile duct injury). Renal involvement is more prone to occur in older individuals and in those with prior kidney or cardiovascular disease; it may take the form of severe interstitial nephritis, acute tubular necrosis, or vasculitis and may lead to renal failure and, uncommonly, be lethal. Lung involvement takes the form of interstitial pneumonitis, pleuritis, or the acute respiratory distress syndrome; minocycline and abacavir are the main culprit drugs causing severe lung involvement. However, lung involvement in this disorder typically resolves. Cardiac involvement usually presents with evidence of left ventricular dysfunction and ECG changes; it occurs more often in individuals taking minocycline, ampicillin, or sulfonamides, and is either a cardiac hypersensitivity reaction classified as an eosinophilic myocarditis which generally resolves or a far more serious acute necrotizing eosinophilic myocarditis which has a mortality rate of more than 50%. Neurological manifestations of the DRESS syndrome include headache seizure, coma, and motor dysfunction due to meningitis or encephalitis. Rare manifestations of the disorder include inflammation of the pancreas gastrointestinal tract, and spleen. The following table gives the percentages for organ involvement and blood abnormalities found in individuals with the DRESS syndrome based on various studies. There are large variations in the percentages found in different studies and populations. No gold standard exists for diagnosis, and at least two diagnostic criteria have been proposed viz., the RegiSCAR criteria and the Japanese consensus group criteria. These two sets of criteria are detailed in the following table. Drugs that commonly induce DRESS syndrome arranged according to intended clinical action include the following: Studies have found that certain populations that express particular serotypes (i.e. alleles) of HLA-A, HLA-B, and/or HLA-C have an increased risk of developing the DRESS syndrome in response to specific medications. These associations include the following: