Drug rash with eosinophilia and systemic symptoms

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"DRESS" redirects here. For other uses, see Dress (disambiguation).
Not to be confused with Dressler syndrome.
Drug rash with eosinophilia and systemic symptoms
Other 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 pseudolymphoma
SpecialtyImmunology, dermatology Edit this on Wikidata

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.[1] 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.[2]

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.[3]

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.[4] 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.[5][6]

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

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.[4][8]

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.[9][4][10][11][12]

Organ Percentage involvement Comment Blood abnormality Percentage involvement Comment
Liver 59-100% >90% if based on high blood levels of
ALT
 Eosinophilia 30-95% usually seen in >66% of cases
Kidney 8-40% >40% if based on high levels of BUN or creatinine Atypical blood lymphocytosis 27-67% -
Lung 5-33% usually resolves Lymphocytosis ~3% -
Heart (hypersensitivity reaction) 2-15% generally not life-threatening Leukocytosis up to 100% due to eosinophilia and/or lymphocytosis
Heart (necrotizing eosinophilic myocarditis) 2-15% mortality> 50% Thrombocytopenia 3% Thrombocytopenia may precede and not be due to DRESS syndrome[13]
Nervous system ~5% usually resolves Elevated ESR ~60-70% marker of systemic inflammation
Pancreas ~5% may result in diabetes Elevated 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 [14] and the Japanese consensus group criteria.[15] 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 diagnosis Japanese 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.
Hospitalization pruritic, macular erythema containing papules, pustules or vesicles (generally a Maculopapular rash), developing >3 weeks after starting suspected drug
Reaction suspected to be drug-related Prolonged 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 pain Lymphadenopathy
Human herpesvirus 6 reactivation

Causes

Medications

Drugs that commonly induce DRESS syndrome arranged according to intended clinical action include the following:[4][16][17][18][19][20][21]

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.,

nonsteroidal anti-inflammatory drugs (diclofenac, celecoxib, ibuprofen, and phenylbutazone).[9]

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:[4][22]

Pathophysiology

Main article: Severe cutaneous adverse reactions § Pathophysiology

Human leukocyte antigens

Like other drug-induced SCARs disorders, the DRESS syndrome is a

TNFα which promotes inflammation but also has cell-killing actions.[26][27][28]

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

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.[28][29] Thus, only rare individuals are predisposed to develop SCARs in response to a particular drug on the basis of their expression of HLA serotypes.[30] 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.[26][31]

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.[28][22] Thus, only rare individuals are predisposed to develop a SCARs disorder in response to a particular drug on the basis of their expression of specific cell receptor types.[30] While the evidence supporting these ideas is limited, one study identified the preferential presence of the TCR-V-b and complementarity-determining region 3 in T-cell receptors found on the T cells in the blisters of patients with allopurinol-induced DRESS syndrome. This finding is compatible with the notion that specific types of T-cell receptors are involved in the development of specific drug-induced SCARs.[31]

ADME

Variations in

anti-inflammatory drug.[9] None-genetic ADME factors are also associated with increased risks of developing the DRESS syndrome. Allopurinol is metabolized to oxipurinol, a product with a far slower renal excretion rate than its parent compound. Renal impairment is associated with abnormally high blood levels of oxipurinol and an increased risk of developing the DRESS syndrome, particularly the more severe forms of this disorder. Dysfunction of the kidney and liver are also suggested to promote this disorder in response to other drugs due to the accumulation of SCARs-inducing drugs or metabolites in blood and tissues.[3][32][33] Currently, it is suspected that the expression of particular HLA proteins and T-cell receptors interact with ADME factors to promote SCARs particularly in their more serious forms.[3]

Viral reactivation

During the progression of the DRESS syndrome certain viruses that previously infected an individual and then became

type 1 diabetes mellitus. While these viral reactivations, particularly of human herpes virus 6, have been suggested to be an important factor in the pathogenesis of the DRESS syndrome, studies to date have not clearly determined if they are a cause or merely a consequence of T cell-mediated tissue injury.[3][4]

Preventative

Currently, screening individuals for the expression of certain HLA

alleles before initiating treatment of patients with DRESS-inducing drugs is recommended. These recommendations typically apply only to specific populations that have a significant chance of expressing the indicated allele since screening of populations with extremely low incidences of expressing an allele is considered cost-ineffective.[34] Individuals expressing the HLA allele associated with sensitivity to an indicated drug should not be treated with the drug. These recommendations include:[3][35]

Current trials are underway to evaluate the ability of genetic screening to prevent the DRESS syndrome for dapsone and HLA-B*13:01 in China and Indonesia. Similar trials are underway in Taiwan to prevent phenytoin-induced DRESS syndrome in individuals expressing the CYP2C9*3 allele of CYP2C9 as well as a series of HLA alleles.[35]

Treatment

Immediate discontinuance of the offending drug or drug(s) is the first and critical step in treating any SCARs disorder. In the past, the mainstay treatment of severe cases of DRESS syndrome was the use, often at high-dosage, of systemic

randomized control trials reporting on the systemic use of these drugs. Rather, there are suggestions that treatment with systemic glucocorticoids is associated with a higher incidence of relapse compared to topical glucocorticoid treatment and may be associated with a higher rate of opportunistic infection. Accordingly, less severe cases of this disorder may be better treated conservatively with general support and, where needed, topical glucocorticoids. Severer cases, particularly those involving significant internal organ involvement, may require systemic corticosteroids and efforts to support heart, kidney, lung, or other organ dysfunctions.[4][28]

Terminology

DRESS syndrome is one of several terms that have been used to describe a severe idiosyncratic reaction to a drug that is characterized by a long latency of onset after exposure to the offending medication, a rash, involvement of internal organs, hematologic abnormalities, and systemic illness. Other synonymous names and acronyms include drug-induced hypersensitivity syndrome (DIHS or DHiS), anticonvulsant hypersensitivity syndrome, drug-induced delayed multiorgan hypersensitivity syndrome, drug-induced pseudolymphoma, anticonvulsant hypersensitivity syndrome, allopurinol hypersensitivity syndrome, dapsone syndrome, and dapsone hypersensitivity syndrome.[1][4][5][6]

See also

References

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Further reading
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