Jean Christoph Caubet

These updated EAACI guidelines aim to standardize skin testing methodologies for both immediate and non‐immediate drug hypersensitivity reactions. For immediate reactions, the optimal testing window is 4–6 weeks post‐reaction; whereas beyond 6 months, false‐negative results increase. For chemotherapy‐related reactions, earlier testing (within 2 weeks) remains necessary due to treatment urgency. The previously published multicenter ENDA study established the international reference method for positive immediate intradermal test reading: injection of exactly 0.02 mL with a wheal at 20 min measuring ≥ initial wheal +3 mm, representing a major standardization achievement. For patch testing, exact active ingredient concentrations must be systematically documented. When tablets are crushed and diluted at 30% in petrolatum, significant variability in final concentrations has been observed. The guidelines present validated nonirritant concentrations for major drug classes including antibiotics, contrast media, anesthetics, proton pump inhibitors, chemotherapies, and biologicals. Specific recommendations are based on negative controls demonstrating specificity, while conditional recommendations are provided when few or no negative controls are available. Risk stratification algorithms now allow direct drug provocation testing for mild maculopapular exanthema, bypassing preliminary skin tests. However, more severe reactions such as anaphylaxis require skin testing before considering drug provocation tests. For DRESS/AGEP/SJS/TEN, skin tests are useful and safe for identifying culprit drugs. These harmonized methods enable safe drug allergy delabeling while preserving diagnostic accuracy and patient safety. Strict adherence to these standardized protocols is essential to ensure reproducible results and safe clinical practice in drug hypersensitivity evaluation.

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.

In drug hypersensitivity, drug provocation testing (DPT), also called drug challenge, is the gold standard for investigation. In recent years, risk stratification has become an important tool for adjusting the diagnostic strategy to the perceived risk, whilst still maintaining a high level of safety for the patient. Skin tests are recommended before DPT but may be omitted in low‐risk patients. The task force suggests a strict definition of such low‐risk patients in children and adults. Based on experience and evidence from studies of allergy to beta‐lactam antibiotics, an algorithm on how to adjust DPT to the risk, and when to omit skin tests before DPT, is presented. For other antibiotics, non‐steroidal anti‐inflammatory drugs and other drugs, skin tests are poorly validated and DPT is frequently necessary. We recommend performing DPT with chemotherapeutics and biologicals to avoid unnecessary desensitization procedures and DPT with skin tests negative contrast media. We suggest DPT with anesthetics only in highly specialized centers. Specifics of DPT to proton pump inhibitors, anticonvulsants and corticosteroids are discussed. This position paper provides general recommendations and guidance on optimizing use of DPT, whilst balancing benefits with patient safety and optimizing the use of the limited available resources.

Diagnosing immediate drug hypersensitivity reactions (IDHRs) can pose a significant challenge and there is an urgent need for safe and reliable tests. Evidence has emerged that the basophil activation test (BAT), an in vitro assay that mirrors the in vivo response, can be a complementary test for many drugs. In this position paper, members of Task Force (TF) “Basophil activation test in the evaluation of Drug Hypersensitivity Reactions” from the European Academy of Allergy and Clinical Immunology (EAACI) present the data from a survey about the use and utility of BAT in IDHRs in Europe. The survey results indicate that there is a great interest for using BAT especially for diagnosing IDHRs. However, there are still main needs, mainly in the standardization of the protocols. Subsequently consensus‐based recommendations were formulated for: (i) Technical aspects of BAT in IDHRs including type of sample, management of drugs, flow cytometry protocols, interpretation of the results; and (ii) Drug‐specific aspects that should be taken into account when performing BAT in relation to betalactams, neuromuscular blocking agents, fluoroquinolones, chlorhexidine, opioids, radio contrast media, chemotherapeutics, biological agents, nonsteroidal anti‐inflammatory drugs, COVID vaccine, and excipients. Moreover, aspects in the evaluation of pediatric population have also been considered. All this indicates that BAT offers the clinician and laboratory a complementary tool for a safe diagnostic for IDHRs, although its place in the diagnostic algorithm depends on the drug class and patient population (phenotype, geography, and age). The standardization of BAT is important for generalizing this method beyond the individual laboratory.