In the original publication [...].

BACKGROUND AND OBJECTIVES:Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main triggers of drug hypersensitivity reactions (HSRs). NSAID-induced HSRs constitute a significant health problem owing to their prevalence, phenotypes, mechanisms of action, and complex diagnosis. However, in around 60% of individuals attending for suggestive NSAID-induced HSRs, this diagnosis is ruled out. Patients labeled as being hypersensitive to NSAIDs unnecessarily avoid NSAIDs, leading to increased waiting lists, diagnostic delay, and associated costs. Objective: To develop a machine learning (ML) based model for discriminating NSAID hypersensitive patients from non-NSAID hypersensitive individuals by assessing populations with suspected NSAID-induced HSRs. METHODS:We recruited a retrospective population and a prospective population of individuals attending the Allergy Unit of Malaga Regional University Hospital, Malaga, Spain for suggestive NSAID-induced HSRs in whom a diagnosis had been confirmed. One logistic regression analysis and 6 ML-based models were developed using retrospective data, and the most efficient was applied to the prospective population. In addition, 3 prospective populations from Madrid, Barcelona, and Salamanca were included for external validation. RESULTS:All the models classified at least 85% of individuals correctly, and, considering discrimination by chance, agreement was almost perfect for all of them (k>0.81). However, the light gradient-boosting machine (LGBM) model showed the highest sensitivity (99%), accuracy (97%), and k value (0.94). The final validated LGBM model achieved 91.76% accuracy, a 95.19% area under the curve, and a k of 0.83. Accuracy was >95% in all prospective populations. CONCLUSION:Our LGBM model efficiently differentiated NSAID-hypersensitive patients from individuals who can safely receive NSAIDs, despite suggestive NSAID-induced HSRs. Such a model could easily be incorporated into clinical settings, thus improving diagnosis, reducing waiting lists, and optimizing health care resources.

BACKGROUND:A label of betalactam (BL) allergy is estimated in around 10% of the population in their medical records. Second-line choices carry significant negative consequences, including reduced efficacy, effectiveness, and safety. This study aimed to develop a new highly specific score constructed by selecting variables assisted by artificial intelligence to identify low-risk BL-allergic patients. METHODS:In this study, derivation and validation of the BL-predictor score were performed on a retrospective cohort of 2207 patients who underwent penicillin allergy testing at Málaga University Hospital (Spain). The development of the BL-predictor encompassed expert drafting and a two-step variable selection process consisting of univariate analysis and variable filtering, followed by stepwise logistic regression with resampling. To assess the efficiency, a multicentric retrospective external validation was performed in 4261 patients from six populations: Salamanca and Madrid, Spain; Nashville, United States of America; Verona, Italy; Paris, France; and Copenhagen, Denmark. RESULTS:The definitive questionnaire consisted of eight items and risk points were computed from the logistic regression model as follows: +1 for reactions after first dose or in less than 1 h (ITEM-1), +2 for anaphylaxis (ITEM-2); +1 for previous reaction with the culprit (ITEM-3); -1 for resolution in > 24 h (ITEM-4); +2 for spontaneous resolution (ITEM-5); -2 for unknown symptoms (ITEM-6); -2 for reaction occurred > 5 years (ITEM-7), and -1 for another reported drug allergy (ITEM-8). After establishing a threshold of ≤ 0 points to classify individuals with low risk, internal validation showed a specificity of 86% and a negative predictive value (NPV) of 83%. Overall multicenter external validation showed a specificity of 93%, which implies a 25% increase in specificity compared to the previously published BL decision tool. CONCLUSION:This score would simplify diagnostic procedures in low-risk patients, enabling rapid delabeling, potentially in non-specialty settings, and reducing diagnostic costs and the negative consequences associated with incorrect antibiotic allergy labels.

Over the past several decades, there have been significant advances in our understanding of both immunological and pharmacological mechanisms of adverse drug reactions (ADRs). Immune-mediated drug reactions (IMDRs) represent a small proportion of ADRs and are caused by a pathological activation of the immune system or inflammatory pathways. Drugs can act as an antigen or may directly interact with the immune system or inflammatory pathways, making immune-mediated drug reactions observed in contemporary practice not sufficiently explained by the Gell and Coombs (G&C) framework. Moreover, the phenotype alone is neither pathognomonic nor sufficient to infer the endotype. The proposed nomenclature integrates chrono-morphological phenotypes, mechanistic endotypes and characteristics of the involved drug. In this nomenclature, IMDRs are classified, according to the nature of interaction with the immune system, in: (i) drug allergy that encompasses antigen-driven reactions-diagnosed by tests detecting sensitisation-and (ii) drug hypersensitivity that includes the heterogeneous broad group of drug-directly-driven reactions. This framework supports precision medicine, aligns terminology with mechanisms, and provides a common language for interdisciplinary communication, pharmacovigilance, and drug development. It accommodates emerging therapeutic classes and remains adaptable to future discoveries in immunopathogenesis and biomarker development.

Background/Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed drugs worldwide and the main cause of drug hypersensitivity reactions (HSRs). The most common NSAID-HSR class is cross-hypersensitivity (CR), with patients reacting to NSAIDs from different chemical groups without specific immunological recognition, with NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype. Although CR-HSRs are triggered by arachidonic acid (AA) alterations following cyclooxygenase (COX)-1 inhibition and cysteinyl-leukotrienes synthesis by 5-lypoxygenase (5-LO), current evidence supports the participation of additional mechanisms. As COX-1 and 5-LO head oxidative pathways, it is conceivable that enzymes participating in antioxidant control are involved in these mechanisms. In addition, as the CR-HSR susceptibility seems to be influenced by genetic factors, the possibility of genetic variants playing a role in such enzymes should not be excluded. Methods: In this observational case-control study, we analysed for the first time in NIUA the overall genetic variability in key antioxidant defence enzymes genes, including catalase (CAT), glutathione peroxidase (GPX)-1 and 3, and superoxide dismutase (SOD)-1. We selected a set of tagging single nucleotide polymorphisms (tSNPs) in these genes using data from Europeans in the 1000 Genomes Project. Two independent Spanish populations (discovery and replication) of NIUA patients and NSAID-tolerant individuals were included. Results: Twenty-six tSNPs were genotyped in the discovery population, with three that were significantly associated with NIUA: rs3448 (GPX-1), rs3792798 (GPX-3), and rs10432782 (SOD-1). They were then genotyped in the replication group, with rs3792798 being protective and rs10432782 being associated with an increased NIUA risk. Conclusions: Our results suggest that a role for antioxidant enzyme polymorphisms in NIUA is required. Nevertheless, further research is needed to replicate our findings in other populations and their meaning at the molecular level and to investigate the role of such variants in other CR-HSR-induced phenotypes.

BACKGROUND:Diagnostic strategies for cephalosporin allergy are not well defined due to differences in inclusion criteria among studies and a lack of standardised diagnostic tests. Our aim was to describe the characteristics of patients with a suspicion of cephalosporin allergy and to analyse the role of in vivo tests. METHODS:Patients with suspected cephalosporin allergy were prospectively evaluated (2019-2023). Diagnosis was achieved using clinical history, skin tests (STs) and, if negative, drug provocation tests (DPTs). A randomised group of patients who tolerated DPT were retested by STs at 2-8 weeks. RESULTS:211 patients were evaluated, with 55.4% reporting IRs and 44.5% NIRs. Skin was involved in half of the patients reporting IRs and in all reporting NIRs (p < 0.0001). Anaphylaxis was experienced by 18% and shock by 7.1%. The cephalosporin most commonly involved was cefuroxime (63.6%) (p < 0.0001) in the Spanish cohort and cefazolin (51%) (p < 0.0001) in the Italian one. Allergy was confirmed in 57.2% of patients reporting IRs (47% by STs and 9.4% by DPT) and 14.9% of NIRs (5.3% by STs and 8.5% by DPT). In the positive-ST group, the percentage of grade II and III reactions was higher (p = 0.02) and the interval reaction-study shorter (p = 0.0007) than in negative-ST. Of the 48 patients retested, 1 (2.9%) who reported an IR and 1 (7.1%) who reported NIR resulted positive. CONCLUSIONS:The patterns of cephalosporin allergy may differ across different regions, being STs and DPT useful for diagnosis. Further studies are needed to confirm the role of retesting, as well as to identify which patients would benefit most from this procedure.

Evaluating penicillin allergy labels and expanding access to preferred treatment options safely is of critical public health importance. Most patients with penicillin allergy labels are not allergic, and even in those with verified allergy, sensitization wanes over time. However, sensitization is complex, and whereas a patient may have a negative penicillin allergy evaluation (including a drug challenge), resensitization can occur, raising a risk of a subsequent reaction on exposure. In this pro-con debate we deliberate on whether patients who have had negative penicillin allergy evaluations should undergo retesting for sensitization before subsequent administrations. The pro position is presented by Drs Inmaculada Do & ntilde;a, Maria Salas, and Maria Torres, whereas the con position is described by Drs Ami Belmont and Roland Solensky. (c) 2025 American Academy of 2025;13:1004-10)

Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) have been classified as immediate (or acute) and delayed. Immediate reactions can be further classified into 4 clinical types: NSAID-exacerbated respiratory disease (N-ERD), NSAID-exacerbated cutaneous disease (NECD), NSAID-induced urticaria/angioedema (NIUA), and single NSAID-induced urticaria/angioedema/anaphylaxis (SNIUAA). Specifically, the NIUA type references reactions to ≥2 NSAIDs belonging to different chemical groups, involving urticaria and/or angioedema in patients with no underlying chronic spontaneous urticaria. However, there are patients meeting cross-reactive criteria for NIUA phenotype who report reactions that involve 2 organ systems (eg, cutaneous and respiratory; cutaneous and gastrointestinal) and have been termed “blended”. In pediatrics, this type of reaction is recognized and has been termed NSAID-induced urticaria/angioedema/anaphylaxis (NIUAA), an acronym we suggest be extended now to adults. There are small subgroups of N-ERD patients who also report skin symptoms and, alternatively, NECD patients who report respiratory symptoms. These 2 subgroups could be diagnosed as having mixed N-ERD and mixed NECD, respectively. In fact, they are patients suffering from N-ERD or NECD who have had reactions consistent with anaphylaxis.In the current classifications of NSAID hypersensitivity, the reactions in which NSAIDs act as aggravating factors or cofactors in subjects with sensitization to foods are not included. Recently, this type of reactions has been defined as NSAID-exacerbated food allergy (NEFA) and NSAID-induced food allergy (NIFA), respectively.This Statement of the World Allergy Organization (WAO) aims to update both the classification of hypersensitivity reactions to NSAIDs and their diagnosis, addressing the novel issues.

BACKGROUND:Penicillins (PENs) are the most frequent drug-allergic reactions trigger. However, diagnostic work-up is complex and time-consuming: it requires skin testing (ST) and drug-provocation test (DPT), needing faster delabelling strategies. Although direct DPT without previous STs has shown to be safe, most of the studies are performed in children or in North American, Asian, or Oceanian adults, with few studies in the European adult population. We explored its safety in European adult patients with low-risk PEN allergy history and, additionally, analysed ST role and T-cell involvement by lymphocyte transformation test (LTT). METHODS:We prospectively evaluated > 16 years of PEN-allergic labelled patients referred to Málaga Regional University Hospital during 2023. They reported non-immediate reactions without alarm signs and unknown reactions. Direct-single-dose DPT was performed in all patients. If positive, ST and LTT were carried out after reaction resolution. RESULTS:We included 269 patients with the culprits being an unidentified PEN (36%), amoxicillin (AX) (32%), and AX-clavulanic acid (AX-CLV) (31%); and the symptoms maculopapular exanthema (MPE) (34%) and unknown reaction during childhood (23%). Only 16 (5.9%) had positive DPT, being 56% for AX and 44% for AX-CLV, 81% developing MPE, none severe. Most DPT-reacting patients reported cutaneous non-immediate reactions in the index reaction, and only one had an unknown childhood reaction. The mean day interval between drug administration and symptom development was lower (p = 0.002) in positive DPT than in the index reaction (2 vs 5 days). Moreover, ST was positive in only 19% and LTTs in 86.7% of positive DPT patients. CONCLUSIONS:Direct-single-dose DPT is safe for delabelling PEN allergy in non-immediate reactions without alarm signs and unknown reactions. ST had a poor diagnostic value and LTT had a high one, confirming a T-cell involvement.

BACKGROUND:Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed medicines worldwide and the main drug hypersensitivity triggers. The most common type is bred by pharmacologic cyclooxygenase-1 (COX-1) inhibition, after chemically unrelated NSAID intake, and NSAID-induced acute urticaria/angioedema (NIUA) is the most frequent clinical phenotype, with patients being frequently sensitized (atopic) to Dermatophagoides pteronyssinus (DP). OBJECTIVE:Although NIUA and atopy hold a genetic basis, atopy-related genes have not been previously evaluated in NIUA. In this observational case-control study, we assessed genetic variants in atopy-related genes in NIUA. METHODS:Tagging single nucleotide polymorphisms in key atopy genes, including cytokines (IL3, IL5, IL9, and the IL4/IL13 region) and receptors (IL4RA and FCER1A), were evaluated in two independent populations of NIUA patients and NSAID-tolerant controls. RESULTS:One thousand two hundred forty individuals were included. Forty-eight tagging single nucleotide polymorphisms were successfully genotyped in the discovery population, with 4 being significantly associated (rs1805010 and rs1801275 in IL4RA, and rs2251746 and rs2494250 in FCER1A). They were further genotyped in the replication population; rs1805010 and rs2494250 remained associated with NIUA. Patients carrying the minor allele of rs1805010 and rs2494250 presented higher total IgE levels than noncarriers (P < .001) and controls (P = .001). NIUA carriers of the rs1805010 minor allele also showed higher levels of DP-specific IgE compared with noncarrier NIUA patients (P = .028) and controls (P < .001). Similar results were found when only atopic NIUA and controls were considered. CONCLUSIONS:IL4RA and FCER1A polymorphisms may display a role in NIUA, shedding new light on its relationship with DP sensitization at the molecular level.

Antiplatelet drug (APD) therapy is the cornerstone for the prevention of atherosclerotic cardiovascular disease. The main APDs are aspirin and thienopyridines, particularly clopidogrel. These drugs may induce hypersensitivity reactions (HSRs). The most common reported reactions to these drugs are cutaneous, such as exanthemas associated with thienopyridine and urticaria/angioedema by aspirin, which can also induce respiratory symptoms. APDs other than aspirin, particularly ticlopidine, can also cause hematologic reactions consisting mainly of isolated thrombocytopenia, agranulocytosis, and leukopenia. Immune-mediated reactions to aspirin are very rare. Few data suggest the usefulness of skin testing in patients with cutaneous reactions to APDs other than aspirin, particularly clopidogrel. Therefore, the drug provocation test is the gold standard for diagnosing hypersensitivity to APDs. Low-dose aspirin challenge (i.e., up to 150-180 mg) and aspirin desensitization have emerged as effective and safe approaches in patients with suspected or confirmed aspirin hypersensitivity who require aspirin therapy. Both, a short course of oral glucocorticoids without interruption of clopidogrel treatment and desensitization, appears to be effective and safe options in patients with cutaneous HSRs to clopidogrel. This position paper provides data and recommendations regarding the characteristics of HSRs to APDs and related diagnostic procedures in order to make them as safe and effective as possible. Management and treatment options, including desensitization protocols, are also provided.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main cause of drug hypersensitivity, being NSAID-induced urticaria/angioedema (NIUA) the most commun clinical entity. NIUA has been associated with an imbalance between prostaglandin and leukotriene (LT) biosynthesis in the arachidonic acid (AA) pathway due to COX-1 inhibition. LTB4 is an eicosanoid released in this pathway by the LTA4 hydrolase/aminopeptidase (LTA4H). Although some studies have reported associations between NIUA and single nucleotide polymorphisms (SNPs) in AA-related genes, there is no information concerning SNPs in the LTA4H gene and this clinical phenotype.

The development of new drugs has contributed to increase the population's quality of life and life expectancy. However, it also increases the risk of drug hypersensitivity (DH). The incidence of DH in the general population remains largely unknown, due to the lack of harmonized definitions, classification and coding strategies. Despite this, evidence seems to indicate an increase in incidence over last decades, with a change on drugs involved over time in the same population and between countries, which is probably related to consumption patterns. In this issue, Doña et al.1 present relevant epidemiological data on DH and analyse in detail how new drug availability and prescription habits have a high impact in the type of reactions developed, therefore affecting our daily clinical practice. Two important examples are proton-pump inhibitors (PPIs) and COVID-19 vaccines. PPIs, whose increasing consumption facilitated in most countries by over-the-counter sales, have contributed to an increased DH incidence, which is expected to grow in the next few years. However, despite this increasing incidence, the management of PPI-DH is still a matter of debate. With an aim of harmonization, Bavbek et al.2 published a comprehensive position paper that provides clinicians with practical evidence-based recommendations for the diagnosis and management of patients reporting PPI-DH. Similarly, the use of vaccines has been growing over last decades with a sharp increase in 2020 when they were developed to treat COVID-19 infection. Yon et al.3 show in this issue how the cumulative number of reports on vaccine-associated anaphylaxis has gradually increased over time, with a strong increase after 2020, due to anaphylaxis associated to COVID-19 mRNA vaccines. Moreover, Shin et al.4 estimate the risk of anaphylaxis following COVID-19 vaccines in 1.45 cases per 1 million COVID-19 vaccine doses, being more frequent in younger females and recipients of vaccines based on non-mRNA platforms. All these data emphasize the need of careful monitoring, considering the life-threatening nature of anaphylaxis, especially for individuals at higher risk. The precise evaluation and monitoring of patients reporting DH are important as both under- and over-diagnosis are common, probably due to the lack of standardized definitions of DH, and diagnostic procedures such as skin tests and drug provocation tests (DPT), poorly identified biomarkers, and the complexity of the underlying mechanisms, which are not completely understood (Figure 1). Drugs can interact in different ways with the immunological system, and consequently, hypersensitivity reactions can be produced by very diverse mechanisms. Mechanisms may even vary over time in the same patient with the same drug, as reported by Jiménez et al.5 in oxaliplatin-reactive patients who initially presented a type-I reaction and switched to mixed reactions, cytokine release reactions or even non-immediate reactions during a desensitization protocol. Moreover, the clarification of mechanism is more complex when evaluating drugs not frequently prescribed, as with Glatiramer acetate, used for treating relapsing–remitting multiple sclerosis, or human albumin, used for its oncotic and plasma-expanding properties. Glatiramer acetate, when administered subcutaneously, causes injection-site reactions by a not-well understood mechanism, which can lead to treatment suspension. Chaki et al.6 has demonstrated that glatiramer acetate induces degranulation of skin-derived mast cells via MRGPRX2, which has important implications as MRGPRX2 inhibitors could be used to prevent treatment discontinuation. Regarding human albumin administration, immediate hypersensitivity reactions are rarely reported and diagnosis is difficult because human albumin is usually administered in circulatory instability conditions and if an anaphylaxis appears it can mimic worsening of patient's critical state, therefore not being diagnosed. Nguyen Basu et al.7 report a group of patients with hypersensitivity to human albumin confirmed by positive skin testing or DPT, indicating that a specific immunological mechanism involvement. As stated above, diagnosing DH can pose a significant challenge. Skin tests are poorly validated for many drugs, and the gold standard is DPT, a costly and risky test. Therefore, indication for DPT should be based on risk stratification including reaction-related (such as severity, suspected mechanism, suspected drug) and clinical characteristics. However, controversies exist regarding the risk stratification criteria. In this sense, Barbaud et al.8 published a comprehensive position paper with practical recommendations and guidance for selecting the best DPT strategy with a range of different drug groups. However, as DPT is not risk-free, might be contraindicated in patients with life-threatening reactions, and does not reflect the underlying mechanism, there is an urgent need for safe and reliable biomarkers able to discriminate patients within the same phenotype. This will allow us to tailor the medical interventions to each patient (Figure 2), moving towards an individuals' approach based on endotypes. For this, precise biomolecular and genome information leading to more detailed understanding of heterogeneous pathogenesis associated with specific phenotypes is needed. Currently, several endophenotypic categories and associated biomarkers have been proposed, being described in a complete review by Mayorga et al.9 published in this issue. Among them, a promising biomarker and tool for immediate DH diagnosis is basophil activation test (BAT), which determines basophil activation upon stimulation with the culprit drug by flow cytometry. However, BAT protocols are still not fully standardized in terms of cellular identification and activation markers, ideal timing, factors influencing activation, and drug concentrations and management. Mayorga et al.10 performed a practice survey about BAT use and utility in immediate DH and developed a position paper with detailed recommendations for the use of BAT for immediate DH diagnosis. A DH label represents not only a health problem but also a significant financial burden for affected individuals and health systems, as the main consequence is the interruption of first-line treatment and the switch to second-line alternatives, which may be less effective, and more toxic and costlier, usually affecting quality of life. To address both under- and over-diagnosis understanding the underlying mechanisms and identifying specific biomarkers for a precise endotyping is crucial. This knowledge could present almost unlimited avenues for the future, in both our basic understanding of the immune system, as well as in practical applications for diagnostic, avoiding risky DPT procedures, and therapeutic purposes. We thank Ms. Claudia Corazza for help with the English version of the manuscript. The authors declare that they do not have conflict of interests related to the contents of this editorial. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

BACKGROUND:Delabelling pathways offer confirmatory diagnosis and can prevent unnecessary second-line therapies or drug desensitization procedures after chemotherapeutic hypersensitivity reactions (CHT-HSRs). However, these pathways rely on risky in vivo tests. Data on whether in vitro tests could be helpful are scarce. We assessed the role of basophil activation test (BAT) in the diagnosis of HSRs to platin salts (PSs) and taxanes (TXs) in a well-defined population featuring varied endophenotypes and severities of HSRs. METHODS:We conducted a 3-year-long multicentric, prospective study with 121 suspected-immediate CHT-HSR patients. The allergy workup included clinical history (initial reaction based on Type I, cytokine release syndrome, and mixed phenotype's symptoms and if unable to fit in any of these, as "indeterminate"), skin testing (ST), and drug provocation testing (DPT), provided risk assessment was favorable. Final diagnosis classified patients as "hypersensitive," "non-hypersensitive," or "inconclusive." We performed BAT using CD63 and CD203c as activation markers in patients and controls. Patients underwent DPT regardless of BAT results to prevent bias. RESULTS:ST positivity significantly correlated with skin involvement, Type I phenotype, cancer recurrence, and lifetime exposures before reactions. DPTs were negative in all indeterminate phenotype patients (p = .02) and those considered low-risk, whereas they were negative in 62% moderate-risk patients. 55% were confirmed as hypersensitive (mainly Type I reactions, p < .0001), 24% as non-hypersensitive (mainly TXs and indeterminate phenotypes), and 21% as inconclusive. BAT showed 79% sensitivity in Type I IgE-mediated reactions to PSs with a high correlation to ST. CONCLUSIONS:BAT is a promising tool for delabelling and endotyping CHT-HSRs, especially Type I reactions to PSs, possibly identifying patients at risk of positive DPT. ST seems useful in confirming CHT-HSRs, especially PS-induced reactions, and DPT remains the gold standard, being essential even in moderate-risk patients.

Despite the relevance of hypersensitivity reactions to chemotherapeutics (CHT-HRs), diagnostic confirmation through drug provocation test (DPT) is insufficiently performed, leading to unnecessarily repeated desensitizations. We aimed to evaluate the DPT role in immediate-CHT-HRs