drug rash with eosinophilia and systemic symptoms drug rash with eosinophilia and systemic symptoms drug rash with eosinophilia and systemic symptoms or 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, swollen lymph nodes, and characteristic blood abnormalities such as an abnormally high level of eosinophils, low number of platelets, and increased number of atypical white blood cells (lymphocytes). however, dress is often complicated by potentially life-threatening inflammation of internal organs and the syndrome has about a 10% mortality rate. treatment consists of stopping the offending medication and providing supportive care. systemic corticosteroids are commonly used as well but no controlled clinical trials have assessed the efficacy of this treatment. not to be confused with dressler syndrome. drug rash with eosinophilia and systemic symptomsother namesdrug reaction with eosinophilia and systemic symptoms, dress, dress syndrome, drug-induced hypersensitivity syndrome, dihs, drug hypersensitivity syndrome, dhs, drug-induced delayed multiorgan hypersensitivity syndrome, didmohs, (formerly) drug-induced pseudolymphomaspecialtyimmunology, dermatology dress is classified as one form of severe cutaneous adverse reactions (scars). in addition to dress, 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 disease mechanisms. new strategies are in use or development to screen individuals at risk for dress to aid them in avoiding medications that increase the risk of dress. alternative medications are used in all individuals testing positive for these predispositions. 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 medication evoking it, e.g. the anticonvulsant hypersensitivity syndrome, allopurinol hypersensitivity 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. signs and symptoms 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 of greater than 5), cholestatic (high alp, low alt/alp ratio of less than 2), and mixed (elevated alt and alp, alt/alp ratio between 2 and 5, the cutoff values for cholestatic and hepatocellular injury, respectively). 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 kidney 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. organpercentage involvementcommentblood abnormalitypercentage involvementcomment liver59-100%>90% if based on high blood levels of alteosinophilia30-95%usually seen in >66% of cases kidney8-40%>40% if based on high levels of bun or creatinineatypical blood lymphocytosis27-67%- lung5-33%usually resolveslymphocytosis~3%- heart (hypersensitivity reaction)2-15%generally not life-threateningleukocytosisup to 100%due to eosinophilia and/or lymphocytosis heart (necrotizing eosinophilic myocarditis)2-15%mortality> 50%thrombocytopenia3%thrombocytopenia may precede and not be due to dress syndrome nervous system~5%usually resolveselevated esr~60-70%marker of systemic inflammation pancreas~5%may result in diabeteselevated c-reactive protein~60%marker of systemic inflammation 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. regiscar inclusion criteria for dress syndrome: 3 of the 4 starred criteria are required for diagnosisjapanese consensus group diagnostic criteria for dihs: 7 criteria are needed for diagnosis of dihs or the first 5 criteria required for diagnosis of atypical dihs. hospitalizationpruritic, macular erythema containing papules, pustules or vesicles (generally a maculopapular rash), developing >3 weeks after starting suspected drug reaction suspected to be drug-relatedprolonged clinical symptoms 2 weeks after discontinuation of the suspected drug acute rash*fever > 38 °c fever > 38 °c*liver abnormalities (alt > 100 u/l) or other organ involvement lymphadenopathy in at least two sites*leukocyte abnormalities involvement of at least one internal organ*leukocytosis ( > 11 x 109/l) blood count abnormalities (lymphopenia or lymphocytosis*, eosinophilia*, thrombocytopenia*)atypical lymphocytosis (>5%) severe nerve painlymphadenopathy human herpesvirus 6 reactivation causes medications drugs that commonly induce dress syndrome arranged according to intended clinical action include the following: anticonvulsants: carbamazepine, lamotrigine, phenobarbital, phenytoin, oxcarbazepine, gabapentin, primidone antibacterial: amoxicillin, ampicillin, azithromycin, levofloxacin, minocycline, piperacillin/tazobactam combination, vancomycin, streptomycin anti-tubercular: ethambutol, isoniazid, pyrazinamide, rifampin anti-retroviral: abacavir, nevirapine anti-hepatitis c: boceprevir, telaprevir anti-inflammatory: acetaminophen, diclofenac, celecoxib, ibuprofen sulfa drugs: dapsone, sulfamethoxazole-trimethoprim combination, sulfasalazine anticancer drugs: sorafenib, vismodegib, vemurafenib, imatinib, other drugs: allopurinol (inhibits uric acid production; treatment for gout), mexiletine (treatment for heart arrhythmias), omeprazole (treatment for gastroesophageal reflux and peptic ulcer), strontium ranelate (osteoporosis treatment), chinese herbal medicine. medications associated with the development of dress are often popular, widely used, and/or clinically important for the control of certain diseases. this is evident in the most commonly cited medications that cause the dress 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). genetics 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: carbamazepine: chinese, koreans, japanese, and european individuals who express the hla serotype (i.e. allele) termed hla-a31:01 have a low (~1%) but far higher risk of developing the syndrome in response to carbamazepine than those not expressing it. japanese expressing the serotypes hla-a11 or hla-b51 also have increased risks of developing it in response to carbamazepine. phenytoin: han chinese individuals expressing hla-b13:01, hla-b51:01, hla-b15:02, hla-cw*08:01, or hla-drb1*16:02 serotypes have higher risks of developing the syndrome in response to phenytoin. dapsone: han chinese individuals expressing the hla-b13:01 serotype have a higher risk (7.8%) of developing the dress syndrome in response to dapsone. allopurinol: han chinese, korean, thai, and european individuals expressing the hla-b58:01 serotype have a higher incidence of developing the syndrome in response to allopurinol. nevirapine: africans, asians, and europeans expressing hla-drb1:01:01 or hla-drb1:01:02, or hla-cw4 serotypes, asians expressing the hla-b35 serotype and australians and europeans expressing the hla-c04 serotype have higher incidences of developing the syndrome in response to nevirapine. abacavir: european and african individuals expressing the hla-b57:01 serotype have a higher incidence (55%) of developing the syndrome in response to abacavir. vancomycin: european individuals carrying hla-a*32:01 have an approximately 20% chance of developing dress syndrome after ≥ 2 weeks of vancomycin pathophysiology main article: severe cutaneous adverse reactions § pathophysiology human leukocyte antigens like other drug-induced scars disorders, the dress syndrome is a type iv hypersensitivity reaction in which a drug or its metabolite stimulates cytotoxic t cells (i.e. cd8+ t cells) or t helper cells (i.e. cd4+ t cells) to initiate autoimmune reactions that attack self tissues. dress syndrome is a scars type iv, subtype ivb reaction. this contrasts with sjs, sjs/ten, and ten which are type iv, subtype ivc reactions and agep which is a type iv subtype ivd reaction. dress syndrome therefore differs from the other scars disorders in that it involves the tissue-injuring action of cd4+ cells and the cell- and tissue-injuring action of eosinophils as well as the release of the following cytokines: interleukins 5 and 13 which simulate the growth, longevity, and activation of eosinophils; interleukin 4 which promotes the differentiation of naive helper t cells into th2 helper cells that then serve to activate eosinophils as well as other types of pro-inflammatory cells; ifnγ which activates macrophages and induces the expression of class ii mhc molecules; and tnfα which promotes inflammation but also has cell-killing actions. like other scars-inducing drugs, dress syndrome-inducing drugs or their metabolites stimulate cd8+ t or cd4+ t cells to initiate autoimmune responses. studies indicate that the mechanism by which a drug or its metabolites accomplishes this stimulation involves subverting the antigen presentation pathways of the innate immune system. the drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. an antigen-presenting cell (apc) takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. hla) component of their major histocompatibility complex (i.e. mhc); and presents the mhc-associated peptides to the t-cell receptor on cd8+ t or cd4+ t cells. those peptides expressing a drug-related, non-self epitope on their hla-a, hla-b, hla-c, hla-dm, hla-do, hla-dp, hla-dq, or hla-dr proteins may bind to a t-cell receptor to stimulate the receptor-bearing parent t cell to initiate attacks on self tissues. alternatively, a drug or metabolite may stimulate these t cells by inserting into the groove on a hla protein to serve as a non-self epitope or bind outside of this groove to alter a hla protein so that it forms a non-self epitope. importantly, however, non-self epitopes must bind to specific hla serotypes in order to stimulate t cells. since the human population expresses some 13,000 different hla serotypes while an individual expresses only a fraction of them and since a dresss-inducing drug or metabolite interacts with only one or a few hla serotypes, a drug's ability to induce scars is limited to those individuals who express hla serotypes targeted by the drug or its metabolite. thus, only rare individuals are predisposed to develop scars in response to a particular drug on the basis of their expression of hla serotypes. studies have identified several hla serotypes associated with development of the dress syndrome in response to certain drugs, have developed tests to identify individuals who express some of these serotypes, and thereby have identified individuals who should avoid certain dress syndrome-inducing drugs. t-cell receptors a drug or its metabolite may also stimulate cd8+ t or cd4+ t cells to initiate autoimmune responses by directly binding to the t-cell receptors on these t cells. again, this binding appears to develop only on certain t-cell receptors. since the genes for these receptors are highly edited, i.e. altered to encode proteins with different amino acid sequences, and since the human population may express more than 100 trillion different (i.e. different amino acid sequences) t-cell receptors while an individual express only a fraction of these, a drug's or its metabolite's ability to induce the dress syndrome by interacting with a t-cell receptor is limited to those individuals whose t cells express a t-cell receptor(s) that can interact with drug or its metabolite. thus, only rare individuals are predisposed to develop a scars disorder in response