Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice

Abstract

The majority of immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCAR) are an uncommon, potentially life-threatening and challenging sub-group of IM-ADRs with diverse clinical phenotypes, mechanisms and offending drugs. T-cell mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN); although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short and long-term morbidity/ mortality and the potential need to treat ongoing co-morbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive,diagnostic, treatment and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying co-morbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management.

Antibiotic Allergy in Pediatrics

“…6,33,87 Pseudoallergic reactions, also known as "anaphylactoid" reactions or non-IgE-mediated mast cell activation, can resemble type I hypersensitivity reactions (Table 2). 47,57,88,89 Delayed or nonimmediate reactions range from benign to severe and can be classified by timing and clinical features (Table 3). 47,88,89 Delayed urticaria that occurs several hours to days after drug exposure is often non-IgE mediated.…”

“…47,57,88,89 Delayed or nonimmediate reactions range from benign to severe and can be classified by timing and clinical features (Table 3). 47,88,89 Delayed urticaria that occurs several hours to days after drug exposure is often non-IgE mediated. The underlying cause of cutaneous drug reactions during viral infections may involve a viral-induced polyclonal activation of lymphocytes, an enhancement of cellular immunity, or changes in drug metabolism.…”

Severe Cutaneous Adverse Drug Reactions Associated with Allopurinol: An Analysis of Spontaneous Reporting System in Southern Italy

“…In conclusion, according to literature: cutaneous ADRs are responsible for about 2% of hospital admissions; SCARs are of major concern because of high mortality and morbidity rates; SCARs still represent a challenge for healthcare providers mainly due to absence of accurate and standardized biomarkers that delays the diagnosis; hypouricaemic drugs represent one of the drug classes most frequently associated with serious cutaneous ADRs (including SCARs) [24][25][26][27][28]. Based on that, we carried out a study evaluating the safety profile of allopurinol, with a focus on serious cutaneous ADRs (including SCARs), in real life conditions in the Campania Region using data from the Italian spontaneous reporting system.…”

Defining Regional Differences in Drug‐Induced Stevens–Johnson Syndrome/Toxic Epidermal Necrolysis: A Tool to Improve Drug Safety?

“…For type B or immunologically mediated reactions, the risk of such off-target reactions may lie in the population prevalence of the genetic risk factor that may be necessary, but not sufficient, for the development of the hypersensitivity reaction. 7 How might understanding the epidemiology of drug-induced SJS/TEN and other serious IMADRs across different regions improve drug safety globally? There are important insights to be gained that could potentially guide how drug use and drug formularies should be managed.…”

“…Immunologically mediated reactions related to abacavir, carbamazepine, and allopurinol have provided clear examples illustrating that racial differences in the epidemiology of the respective adverse drug reactions provided important clues that were springboards for the genetic discovery that explains these population differences (Figure 1). 7 In the case of abacavir, the story was simple in that HLA-B*57:01 to date has been the only HLA risk factor associated with AHS and HLA-B*57:01 has a high PPV (55%) for AHS compared with other drug HLA pairs, where the PPV has been consistently <5%. In addition, the structural, biochemical, and functional basis for AHS has now been defined through mechanistic studies that followed the original genetic association and genetic screening licensing studies.…”