Original Article
Drug-induced severe cutaneous adverse reactions: Determine the cause and prevention

https://doi.org/10.1016/j.anai.2019.08.004Get rights and content

Abstract

Background

Approximately 45% of all adverse drug reactions are manifested in the skin. Although most are mild, severe cutaneous adverse reactions (SCARs) are potentially lethal.

Objective

To review the etiology and clinical manifestations of severe cutaneous adverse reactions (SCARs) and the demographic characteristics of patients with SCARs.

Methods

This study is a retrospective review of electronic medical records for patients who developed drug-induced cutaneous reactions and were treated for initial or ongoing care at a university medical center from June 4, 2008, to August 10, 2018. Search terms included Stevens-Johnson syndrome(SJS) , drug rash with eosinophilia and systemic symptoms(DRESS), acute generalized exanthematous pustulosis(AGEP), toxic epidermal necrolysis (TEN), and TEN/SJS overlap.

Results

Of 596 cases of drug-induced rash, 35 cases (5.9%) of SCARs were encountered (male-to-female ratio, 1.06:1.0; mean age, 48.5 years). Of those 35 cases, 32 were in white patients (91.4%). The most common manifestations were DRESS (19 [54.3%]), SJS (8 [22.8%]), AGEP (6 [17.1%]), TEN (1 [2.9%]), and overlap (1 [2.9%]). Multiple causative drugs were implicated in 14 cases, whereas a single drug was responsible in 21 cases. The most common drugs implicated were antibiotics (88.1%). The most common causative antibiotics were cephalosporins (23.7%). Most of the patients with SCARs were given triamcinolone cream and prednisone alone (18 [51.4%]), methylprednisolone alone (1 [2.9%]), methylprednisolone and prednisone combined (4 [11.4%]), methylprednisolone and prednisolone (1 [2.9%]) or prednisone and prednisolone (1 [2.9%]).

Conclusion

The most common SCARs were, in order, DRESS, SJS, AGEP, TEN, and overlap. The most common causative drugs were, in order, cephalosporins, penicillins, trimethoprim-sulfamethoxazole, and fluoroquinolones.

Introduction

Drug-induced hypersensitivity reactions are of major medical concern. Approximately 45% of all adverse drug reactions are manifested in the skin, which occur in 2% to 3% hospitalized patients on drug administration.1 Drug hypersensitivity reactions can be categorized into immediate reactions and delayed reactions. Immediate reactions occur within minutes or hours of drug exposure.2 The manifestations of immediate-type reactions range from pruritus, urticaria, angioedema, to anaphylaxis. The delayed-type reactions are primarily T-cell–mediated type IV reactions that usually take several days or even weeks to manifest after drug exposure. The manifestations of delayed-type drug hypersensitivity range from mild maculopapular exanthema and fixed drug eruptions to severe cutaneous adverse reactions (SCARs).3 Most skin reactions are mild and self-limited and usually resolve after use of the drug is discontinued. However, SCARs are potentially lethal events. Despite the low incidence, SCARs account for a high mortality from 10% to 40% and may incur disability.4 The most frequent clinical subtypes include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).4 Patients with SCARs may also have fever, mucosal lesions, hematologic abnormalities, and, in some cases, multiple organ involvement.5, 6

The prevalence and patterns of SCARs differ greatly among different ethnic groups and geographic distributions. It is estimated that the incidence of TEN in Singapore is at least 1.4 cases per million population,7 whereas the incidence in the United States is 0.5 cases per million population.4 The rapid development of technologies and current advancements in pharmacogenomics studies have extended our understanding on the genetic basis of hypersensitivity. Numerous studies have found that there is a strong association between HLA alleles and drug-induced cutaneous reactions.8 For example, carbamazepine-induced hypersensitivity reactions were associated with HLA-B*15:02 allele among Han Chinese, Taiwanese, Vietnamese, and other Southeast Asian descendants. However, these CBZ-induced adverse reactions were found to be associated with HLA-A*31.01 in European and Japanese populations.8 Interestingly, allopurinol-induced SJS and TEN were found to be strongly linked with HLA-B*58:01 genotype, and this correlation was fairly universal because the study was successfully replicated in Southeast Asians, Japanese, and European patients.6, 8 Other HLA-drug associations that have been reported in SCARs include HLA-B*13:01 with dapsone, HLA-A*31:01 and HLA-B*15:11 with carbamazepine, HLA-B*15:02 with phenytoin, HLA-B*57:01 with abacavir, HLA-B*38 with sulfamethoxazole and lamotrigine, HLA-B*73 with oxicam, and HLA-B*59:01 with methazolamide.8 Another study found that genetic variants of CYP2C9 are strongly associated with phenytoin-induced SCARs.9 Currently, HLA screening, although recommended by US Food and Drug Administration for high-risk groups, is not required. The aim of this study was to retrospectively review the etiology and clinical manifestations of SCARs and the demographic characteristics of patients with SCARs at a university medical center to emphasize the importance of prevention, avoidance of unnecessary medications, early diagnosis to reduce morbidity and mortality, and treatment, especially removal of the offending agent.

Section snippets

Methods

This study is a retrospective review of electronic medical records for patients who developed drug-induced cutaneous reactions and were treated for initial or ongoing care at Penn State Hershey Medical Center from June 4, 2008, to August 10, 2018. Search terms included Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), TEN/SJS overlap, drug rash with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) (L27.0). Because currently there

Demographic Characteristics

A total of 1379 cases of drug reactions during the past 10 years were screened, and 596 cases (43%) of drug rash were confirmed by screening electronic medical records (Table 1). Of these 596 cases of drug-induced rash, a total of 35 cases (5.9%) of SCARs were encountered (Fig 1). Most patients with SCARs were white (32 [91.4%]), and no patients were Asian. There were 17 males (48.6%) and 18 females (51.4%), with ages ranging from 2 to 81 years. A female preponderance was seen in the SJS, TEN,

Discussion

SCARs are rare but potentially life-threatening, with broad clinical features. The estimated incidence of SCARs varies from 1 in 1000 to 1 in 10,000 drug exposures.4 Multiple factors have been discovered to be associated with drug-induced SCARs, including sex, age, HLA-related gene, and defect of drug detoxification.13

In terms of demographic characteristics in our study, most patients were white (32 [91.4%]); however, the referral area for the medical center according to data from the US Census

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Disclosures: The authors have no conflicts of interest to report.

Funding Sources: Funding for the project was from Dr Craig's research account and Penn State University work study program.work study program.

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