Ricardo Madrigal-Burgaleta

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.

The term “allergy” is often used ambiguously, frequently applied to a broad spectrum of immune and non-immune reactions, which can create confusion in clinical practice. Whilst there is some controversy, the term “allergy” is now primarily reserved for describing immunoglobulin E (IgE)-mediated (Type I) hypersensitivity. Accurate diagnosis requires distinguishing Type I reactions from their mimics, especially given the clinical overlap with non-IgE-mediated conditions. This review focuses on Type I hypersensitivity, detailing its immunopathogenesis, clinical features, and diagnostic strategies, with particular emphasis on the role of serum tryptase in confirming mast cell activation. A comprehensive clinical history is crucial to distinguishing IgE-mediated allergy from its mimics, focusing on timing, symptom reproducibility, and the identification of potential triggers. Cofactors like non-steroidal anti-inflammatory drugs, alcohol, and exercise may exacerbate reactions, complicating diagnosis. Prompt intramuscular adrenaline administration is essential in cases of anaphylaxis, while patient education and specialist referral are key to long-term management. The review also examines conditions that may mimic Type I reactions, such as chronic spontaneous urticaria or isolated angioedema. In addition to classical allergy, clinicians must consider conditions such as hereditary angioedema, neuroendocrine tumours, and drug-induced pseudoallergic reactions. Recognising these mimics is vital to prevent misdiagnosis, ensuring patient safety, and avoiding unnecessary allergy labels or suboptimal management. This article provides a structured framework for evaluating suspected allergy, enhancing diagnostic accuracy, and guiding appropriate, patient-centred care across allergy and related clinical disciplines.

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.

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.