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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.

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.

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.

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.

Los antiinflamatorios no esteroides (AINEs) son los fármacos más frecuentemente prescritos en todo el mundo para el tratamiento del dolor y patologías inflamatorias. Las reacciones de hipersensibilidad (RHS) a fármacos se incluyen dentro del tipo B, o no predecibles, las cuales se caracterizan por la liberación de mediadores inflamatorios que inducen una gran variedad de manifestaciones clínicas, entre las que se incluyen reacciones leves como la urticaria y el angioedema, y reacciones graves como el broncoespasmo o la anafilaxia. Según estudios recientes, los AINEs son hoy día los medicamentos más frecuentemente implicados en las RHS, las cuales pueden estar mediadas por un mecanismo inmunológico específico, en concreto por anticuerpos IgE o células T, y conocidas como reacciones alérgicas selectivas (RS), o por un mecanismo no inmunológico, relacionado con la capacidad que tienen estos fármacos de inhibir la enzima ciclooxigenasa (COX-1) y con la subsecuente liberación de mediadores inflamatorios procedentes de la vía del ácido araquidónico, conocidas como reacciones de intolerancia cruzada (IC). Actualmente las reacciones de IC son el modelo mejor estudiado, sin embargo, las RS juegan un papel fundamental en las RHS a AINES siendo el principal desencadenante de cuadros graves de anafilaxia, llegando a representar en algunos países el tipo más frecuente de RHS a AINEs..., Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs and widely prescribed for treating pain and inflammatory conditions. Hypersensitivity drug reactions (HDRs) are classified as a type B reaction, or not predictable, which are triggered by the release of anti-inflammatory mediators eliciting a variety of clinical entities ranging from urticaria and angioedema to anaphylactic shock and bronchial asthma. Recent data shows that NSAIDs are the most frequent triggers of hypersensitivity drug reactions (HDR), which may be induced by both specific immunological mechanisms mediated by IgE antibodies or T cells (allergic or selective reactions SR) and mechanisms not based on immunological recognition related to the inhibition of the cyclooxygenase (COX)-1 enzyme and subsequent release of inflammatory mediators from arachidonic acid pathway (cross-hypersensitivity reactions [CRs]). Currently, CRs mediated clinical entities are the best studied models. However, SR are also play a fundamental role in HDRs to NSAIDs, being the main trigger of drug-induced anaphylaxis and it has recently been reported that in some countries they represent the most frequent type of NSAID hypersensitivity.

Los antiinflamatorios no esteroides (AINEs) son los fármacos más frecuentemente prescritos en todo el mundo para el tratamiento del dolor y patologías inflamatorias. Las reacciones de hipersensibilidad (RHS) a fármacos se incluyen dentro del tipo B, o no predecibles, las cuales se caracterizan por la liberación de mediadores inflamatorios que inducen una gran variedad de manifestaciones clínicas, entre las que se incluyen reacciones leves como la urticaria y el angioedema, y reacciones graves como el broncoespasmo o la anafilaxia. Según estudios recientes, los AINEs son hoy día los medicamentos más frecuentemente implicados en las RHS, las cuales pueden estar mediadas por un mecanismo inmunológico específico, en concreto por anticuerpos IgE o células T, y conocidas como reacciones alérgicas selectivas (RS), o por un mecanismo no inmunológico, relacionado con la capacidad que tienen estos fármacos de inhibir la enzima ciclooxigenasa (COX-1) y con la subsecuente liberación de mediadores inflamatorios procedentes de la vía del ácido araquidónico, conocidas como reacciones de intolerancia cruzada (IC). Actualmente las reacciones de IC son el modelo mejor estudiado, sin embargo, las RS juegan un papel fundamental en las RHS a AINES siendo el principal desencadenante de cuadros graves de anafilaxia, llegando a representar en algunos países el tipo más frecuente de RHS a AINEs..., Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used drugs and widely prescribed for treating pain and inflammatory conditions. Hypersensitivity drug reactions (HDRs) are classified as a type B reaction, or not predictable, which are triggered by the release of anti-inflammatory mediators eliciting a variety of clinical entities ranging from urticaria and angioedema to anaphylactic shock and bronchial asthma. Recent data shows that NSAIDs are the most frequent triggers of hypersensitivity drug reactions (HDR), which may be induced by both specific immunological mechanisms mediated by IgE antibodies or T cells (allergic or selective reactions SR) and mechanisms not based on immunological recognition related to the inhibition of the cyclooxygenase (COX)-1 enzyme and subsequent release of inflammatory mediators from arachidonic acid pathway (cross-hypersensitivity reactions [CRs]). Currently, CRs mediated clinical entities are the best studied models. However, SR are also play a fundamental role in HDRs to NSAIDs, being the main trigger of drug-induced anaphylaxis and it has recently been reported that in some countries they represent the most frequent type of NSAID hypersensitivity.

Natalia Blanca-Lopez,1 Victor Soriano,2 Elena Garcia-Martin,3 Gabriela Canto,1 Miguel Blanca11Infanta Leonor University Hospital, Madrid, Spain; 2General University Hospital of Alicante-ISABIAL, Alicante, Madrid, Spain; 3Medical and Surgery Therapy Department, University of Extremadura, Caceres, SpainAbstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24–48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.Keywords: NSAIDs

Natalia Blanca-Lopez,1 Victor Soriano,2 Elena Garcia-Martin,3 Gabriela Canto,1 Miguel Blanca11Infanta Leonor University Hospital, Madrid, Spain; 2General University Hospital of Alicante-ISABIAL, Alicante, Madrid, Spain; 3Medical and Surgery Therapy Department, University of Extremadura, Caceres, SpainAbstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24–48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required.Keywords: NSAIDs

[EN] Background: Although ibuprofen and other arylpropionic acid derivatives (APs) are the most common medicines involved in hypersensitivity drug reactions (HDRs) to NSAIDs, no patient series studies have been performed regarding immediate selective reactions (SRs) to these drugs. Objective: To characterize patients with immediate selective HDRs to ibuprofen and other APs through clinical history and challenge. Methods: Subjects who developed an HDR to APs less than 1 h after drug intake were included. Tolerance to aspirin was assessed and challenge was performed with ibuprofen in all cases, and additionally with the culprit drug (if different) in those patients that tolerated ibuprofen. Serum tryptase levels and tryptase immunohistochemical staining in skin biopsies were also assessed in some patients with a positive DPT to ibuprofen. Results: From a total of 245 patients with a confirmed history of HDRs to APs, 17% were classified as selective immediate hypersensitivity reactors by both clinical history and challenge. A selective response to naproxen and dexketoprofen with tolerance to ibuprofen was found in 16 of 20 cases. Significant differences in serum tryptase levels were observed between 2 and 24 h in the 11 cases that were studied further. Conclusions: Within the group of patients with HDRs to NSAIDs, APs can induce immediate SRs. Within this group, selective responses to a single drug or responders to several APs may exist, suggesting potential immunological crossreactivit

[EN] Background: Although ibuprofen and other arylpropionic acid derivatives (APs) are the most common medicines involved in hypersensitivity drug reactions (HDRs) to NSAIDs, no patient series studies have been performed regarding immediate selective reactions (SRs) to these drugs. Objective: To characterize patients with immediate selective HDRs to ibuprofen and other APs through clinical history and challenge. Methods: Subjects who developed an HDR to APs less than 1 h after drug intake were included. Tolerance to aspirin was assessed and challenge was performed with ibuprofen in all cases, and additionally with the culprit drug (if different) in those patients that tolerated ibuprofen. Serum tryptase levels and tryptase immunohistochemical staining in skin biopsies were also assessed in some patients with a positive DPT to ibuprofen. Results: From a total of 245 patients with a confirmed history of HDRs to APs, 17% were classified as selective immediate hypersensitivity reactors by both clinical history and challenge. A selective response to naproxen and dexketoprofen with tolerance to ibuprofen was found in 16 of 20 cases. Significant differences in serum tryptase levels were observed between 2 and 24 h in the 11 cases that were studied further. Conclusions: Within the group of patients with HDRs to NSAIDs, APs can induce immediate SRs. Within this group, selective responses to a single drug or responders to several APs may exist, suggesting potential immunological crossreactivit