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Adverse drug reactions are a significant cause of morbidity and mortality and represent a major burden on the healthcare system. Some of those reactions are immunologically mediated (hypersensitivity reactions) and can be clinically subdivided into two categories: immediate reactions (IgE-related) and delayed reactions (T-cell-mediated). Delayed hypersensitivity reactions include both systemic syndromes and organ-specific toxicities and can be triggered by a wide range of chemically diverse drugs. Recent studies have demonstrated a strong genetic association between human leukocyte antigen alleles and susceptibility to delayed drug hypersensitivity. Most notable examples include human leukocyte antigen (HLA)-B*57:01 allele and abacavir hypersensitivity syndrome or HLA-B*15:02 and HLA-B*58:01 alleles related to severe cutaneous reactions induced by carbamazepine and allopurinol, respectively. This review aims to explore our current understanding in the field of pharmacogenomics of HLA-associated drug hypersensitivities and its translation into clinical practice for predicting adverse drug reactions.

Purpose of review An update of the pharmacogenetic risk factors associated with T-cell-mediated delayed hypersensitivity reactions. Recent findings Recent HLA associations relevant to our understanding of immunopathogenesis and clinical practice include HLA-B∗13:01 with co-trimoxazole-induced SCAR, and HLA-A∗32:01 with vancomycin-DRESS, for which an extended HLA class II haplotype is implicated in glycopeptide antibiotic cross-reactivity. Hypoactive variants of ERAP1, an enzyme-trimming peptide prior to HLA loading, are now associated with protection from abacavir-hypersensitivity in HLA-B∗57:01+ patients, and single-cell sequencing has defined the skin-restricted expansion of a single, public and drug-reactive dominant TCR across patients with HLA-B∗15:02-restricted carbamazepine-induced SJS/TEN. More recent strategies for the use of HLA and other risk factors may include risk-stratification, early diagnosis, and diagnosis in addition to screening. Summary HLA is necessary but insufficient as a risk factor for the development of most T-cell-mediated reactions. Newly emerged genetic and ecological risk factors, combined with HLA-restricted response, align with underlying immunopathogenesis and drive towards enhanced strategies to improve positive-predictive and negative-predictive values. With large population-matched cohorts, genetic studies typically focus on populations that have been readily accessible to research studies, but it is now imperative to address similar risk in globally relevant and understudied populations.

Epidemiologic drug allergy data from Latin America are scarce, and there are no studies on specific procedures focusing on this topic in Latin America.To assess the clinical characteristics and management of hypersensitivity drug reactions in different Latin American countries.An European Network of Drug Allergy questionnaire survey was implemented in 22 allergy units in 11 Latin American countries to report on consecutive patients who presented with a suspected hypersensitivity drug reaction. Each unit used its own protocols to investigate patients.Included were 868 hypersensitivity drug reactions in 862 patients (71% of adults and elderly patients were women and 51% of children were girls, P = .0001). Children presented with less severe reactions than adults and elderly patients (P.0001). Urticaria and angioedema accounted for the most frequent clinical presentations (71%), whereas anaphylaxis was present in 27.3% of cases. There were no deaths reported. Nonsteroidal anti-inflammatory drugs (52.3%), β-lactam antibiotics (13.8%), and other antibiotics (10.1%) were the drugs used most frequently. Skin prick tests (16.7%) and provocation tests (34.2%) were the study procedures most commonly used. A large proportion of patients were treated in the emergency department (62%) with antihistamines (68%) and/or corticosteroids (53%). Only 22.8% of patients presenting with anaphylaxis received epinephrine.Nonsteroidal anti-inflammatory drugs and antibiotics were the drugs used in at least 75% of patients. More than half the reactions were treated in the emergency department, whereas epinephrine was administered in fewer than 25% of patients with anaphylaxis. Dissemination of guidelines for anaphylaxis among primary and emergency department physicians should be encouraged.

Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug-induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive.

Drug provocation test (DPT) is necessary to diagnose most drug hypersensitivity reactions (HSRs) due to decreased sensitivity of skin testing even when combined with in-vitro tests in immunonologic drug HSR and limited availability of these tests in nonimmunologic reaction. We review the principles and controversial issues of DPT, and recent studies using DPT as a diagnostic tool.DPT is recommended in the diagnosis of HSR to β-lactams, as well as other drug classes [such as acetylsalicylic acid-NSAIDs (ASA-NSAIDs), non-β-lactams antibiotics, heparin, glucocorticoids, and local anesthetic agents]. In view of the decreased sensitivity of skin testing, limited accessibility to new benzylpenicillin polylysine (PPL)/mixture of minor determinant (MDM) test reagents and limited availability of validated sensitive in-vitro tests, individuals who require DPT to β-lactams are increasing. The negative predictive value of allergologic work-up is very high, ranging from 94 to 98% for β-lactams and those reactions after negative tests are mostly nonimmediate and mild. Finally, DPT is recommended to ascertain tolerability of alternative compound when evaluating cross-reactivity among different classes of β-lactams, NSAIDs and glucocorticoids, and possibly iodinated contrast media.DPT is often needed when evaluating patients with suspected drug HSR. More studies regarding standardization of the various protocols are needed in order to increase its acceptance and adoption as a standard practice in the diagnostic algorithm for drug HSR.

Hypersensitivity drug reactions (HDRs) vary over time in frequency, drugs involved, and clinical entities. Specific reactions are mediated by IgE, other antibody isotypes (IgG or IgM), and T cells. Nonspecific HDRs include those caused by nonsteroidal anti-inflammatory drugs (NSAIDs). beta-Lactams--the most important of which are amoxicillin and clavulanic acid--are involved in specific immunological mechanisms. Fluoroquinolones (mainly moxifloxacin, followed by ciprofloxacin and levofloxacin) can also induce HDRs mediated by IgE and T cells. In the case of radio contrast media, immediate reactions have decreased, while nonimmediate reactions, mediated by T cells, have increased. There has been a substantial rise in hypersensitivity reactions to antibiotics and latex in perioperative allergic reactions to anesthetics. NSAIDs are the most frequent drugs involved in HDRs. Five well-defined clinical entities, the most common of which is NSAID-induced urticaria/angioedema, have been proposed in a new consensus classification. Biological agents are proteins including antibodies that have been humanized in order to avoid adverse reactions. Reactions can be mediated by IgE or T cells or they may be due to an immunological imbalance. Chimeric antibodies are still in use and may have epitopes that are recognized by the immune system, resulting in allergic reactions.

Nonimmune hypersensitivity reactions are unpredictable adverse drug reactions that are clinically similar to allergic reactions for which no drug-specific antibodies or T lymphocytes are identified. Few tools allow a definite diagnosis, and most of the available ones need to be validated. True epidemiologic data are limited, and most of the available information on the incidence, mortality, and socioeconomic impact should be discussed with caution.

Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug-induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive. Refereed/Peer-reviewed

Hypersensitivity drug reactions (HDRs) represent a large and important health problem, affecting many patients and leading to a variety of clinical entities, some of which can be life-threatening. The culprit drugs include commonly used medications including antibiotics and NSAIDs. Nontherapeutical agents, such as contrast media, are also involved. Because the pathophysiological mechanisms are not well known and the current diagnostic procedures are somewhat insufficient, new approaches are needed for understanding the complexity of HDRs. Histochemical and molecular biology studies have enabled us to classify these reactions more precisely. Pharmacogenetics has led to the identification of several genes, involved mainly in T-cell-dependent responses, with a number of markers being replicated in different studies. These markers are now being considered as potential targets for reducing the number of HDRs. Transcriptomic approaches have also been used to investigate HDRs by identifying genes that show different patterns of expression in a number of clinical entities. This information can be of value for further elucidation of the mechanisms involved. Although first studies were performed using RT-PCR analysis to monitor the acute phase of the reaction, nowadays high-density expression platforms represent a more integrative way for providing a complete view of gene expression. By combining a detailed and precise clinical description with information obtained by these approaches, we will obtain a better understanding and management of patients with HDRs.

International audience; Non-steroidal anti-inflammatory drugs (NSAIDs) are the medications most frequently involved in hypersensitivity drug reactions. Because NSAIDs are prescribed for many conditions, this is a world-wide problem affecting patients of all ages. Various hypersensitivity reactions have been reported, mainly affecting the skin and/or the respiratory airways. The most frequent of these is acute urticaria, which can be induced by several different NSAIDs. Both specific and non-specific immunological pathways have been proposed as underlying mechanisms. This review presents the clinical phenotypes and the drugs involved in NSAID hypersensitivity. Five major clinical syndromes can be distinguished: aspirin-exacerbated respiratory disease (AERD), aspirin-exacerbated cutaneous disease (AECD), multiple NSAID-induced urticaria/angioedema (MNSAID-UA), single NSAID-IgE reactions and single NSAID T cell responses. However, further classification is possible within these five major entities, by detailed descriptions of the clinical characteristics enabling more phenotypes to be defined. This detailed differentiation now seems required in order to undertake appropriate pharmacogenetic studies.

In this new issue of Current Opinion in Allergy and Clinical Immunology, five major areas of research in the field of hypersensitivity reactions to drugs in the past year are reviewed. The manuscript of Blanca-Lopez et al.[1] is devoted to hypersensitivity reactions to NSAIDs. NSAIDs are the drugs most frequently involved in hypersensitivity drug reactions [2,3]. In a study published recently, it has been shown that almost 50% of the cases had confirmed NSAIDs hypersensitivity followed by 20% with beta-lactam hypersensitivity. Both groups of drugs together contributed to more than the 70% of drug hypersensitivity reactions [2]. These results are consistent with data published by other groups [3]. There has been increasing interest in the nonpulmonary manifestations of NSAID hypersensitivity, which have not been studied in detail. An expert group from the European Academy of Allergy Asthma and Clinical Immunology has provided a consensus document, carefully defining these reactions [4]. Five major clinical entities are now recognized, and it is expected that in the future major subgroups will be identified making genome-wide association studies more specific to each clinical entity [5–7].