Unifying Global Drug Allergy: Clarifying Concepts and Defining Low‐Risk Penicillin Allergy

At the inaugural EAACI Hong Kong Allergy School (August 27–29, 2025), more than 340 participants from 37 countries gathered under the theme “East Meets West.” As one of the main themes, a landmark roundtable united drug allergy experts from Africa, America, Asia, Australasia, and Europe, fostered an unprecedented global exchange and a unified call for international consensus. Two priorities emerged: establishing universal drug “allergy” nomenclature and definitions of “low-risk” penicillin allergy. Drug allergy (or “hypersensitivity”) remains a global health concern, but progress has been hindered by the lack of a unified nomenclature. Notably, even the distinction between “allergy” and “hypersensitivity” remains actively debated worldwide. The term “allergy” (derived from the Greek allos [other] and ergon [reaction]) was originally coined as a neutral descriptor for altered immune reactivity to a substance [1]. In this context, “hypersensitivity” was intended to denote a harmful response of such reactivity. However, various disputes and the parallel evolution of definitions for related conditions (e.g., anaphylaxis) over time have contributed to inconsistent interpretations of the terms “allergy” and “hypersensitivity”. Gell and Coombs introduced the four classic types of immune-mediated reactions which became the cornerstone of immunopathology and clinical immunology [2]. In 2001 and 2003, EAACI and the World Allergy Organization, respectively, proposed defining “hypersensitivity” as “objectively reproducible symptoms or signs triggered by a stimulus tolerated by normal individuals” [3, 4]. In this system, “hypersensitivity reactions” refer to adverse responses initiated by specific immunologic mechanisms (as defined by Gell and Coombs' classification), whereas “nonallergic hypersensitivity” describes reactions that occur without evidence of an immunologic basis. More specifically for drug reactions, the International CONsensus (ICON) on drug allergy defines drug hypersensitivity as “adverse effects of pharmaceuticals that clinically resemble allergy,” while the US Joint Task Force Drug Allergy Practice Parameters acknowledges variable usage in the literature and treats the terms “allergy” and “hypersensitivity” as interchangeable [5, 6]. Figure 1 illustrates various examples of how drug “allergy” versus “hypersensitivity” may currently be defined, highlighting discrepancies in nomenclature. However, several considerations complicate the approach to drug allergy/hypersensitivity. Reactions traditionally labeled as “immune-mediated” and those termed “nonimmune mediated” often involve overlapping adaptive and other inflammatory pathways, challenging historical distinctions. Clinical phenotypes frequently do not correlate with underlying mechanisms: a single drug may trigger reactions via haptenization, direct receptor activation (e.g., MRGPRX2 or HLA/TCR-p-i), or enzyme inhibition (e.g., cyclooxygenase), mechanisms not fully captured by Gell and Coombs' classification. Diagnostic tools for IgE- or T-cell-mediated reactions lack consistent sensitivity across culprit drugs, rendering positive provocation testing insufficient for mechanistic diagnosis. For directly drug-driven reactions, validated biomarkers or confirmatory assays are generally absent, leaving mechanistic assignments largely speculative. Discussions in Hong Kong underscored the urgent need for a harmonized nomenclature that reflects current clinical and mechanistic understanding and remains adaptable to future advances. Chronomorphologic criterion, based on reaction timing and clinical phenotype, may provide a pragmatic entry point to infer underlying pathways while avoiding misleading labels like “nonallergic hypersensitivity,” often misinterpreted as denoting milder or nonimmune side effects. For example, immediate reactions (within 1–6 h) include urticaria or anaphylaxis; delayed reactions (may occur at any time > 1 h) include maculopapular exanthema (MPE) or severe cutaneous adverse reactions. Timing and phenotype are inseparable; upon rechallenge, MPE could variably appear within 1–6 h. Through East–West collaboration, an EAACI Task Force is now actively working toward consensus, with recommendations expected soon. Recognizing that standardized definitions are essential to advancing drug allergy research, expert representatives unanimously identified a top global priority: reducing the burden of mislabelled antibiotic allergies, especially to penicillins. Penicillins remain the most widely prescribed and most mislabeled class of antibiotics worldwide. Globally, penicillin allergies may account for up to half of all drug allergy labels in some populations, yet approximately 90% of these labels are incorrect [7]. This widespread mislabeling leads to the unnecessary avoidance of first-line antibiotics and exacerbates the global crisis of antimicrobial resistance. Beyond preventing mislabeling, removing incorrect penicillin allergies (“delabel(l)ing”) stands as a cornerstone in the global effort against antimicrobial resistance. Given the overwhelming demand, scalable, safe, and efficient delabeling solutions and awareness are urgently needed. Emerging strategies, including direct drug provocation tests (without prior allergy testing), have proven to be effective and safe [8, 9]. Novel initiatives leveraging direct provocation tests from the East have been particularly impactful, with multidisciplinary models empowering nonspecialists (including trained nonallergist physicians, nurses, and pharmacists) to independently delabel low-risk penicillin allergy patients in the ambulatory setting [9]. However, these strategies depend on accurate identification of suitable “low-risk” patients, and clear recommendations regarding the training of nonspecialists undertaking “low-risk” delabeling are also urgently needed [8, 9]. While significant similarities exist between risk stratification strategies and recommendations from the East and West, there is currently no universal consensus on how to define low-risk penicillin allergy patients (Table 1). Definitions vary across regions, shaped by local experience, healthcare capacity, and cultural norms, as well as the need to tailor guidelines to local constraints. While such adaptation remains essential, the lack of harmonized criteria creates confusion, especially for frontline healthcare providers, who are the primary users of these guidelines. Moreover, inconsistent recommendations discourage uptake and dissuade clinicians due to concerns over legal liability or perceived clinical risk. Despite regional differences in practice and perspectives, experts from every continent shared a common foundation in the core principles for defining drug allergy and identifying patients at low risk for penicillin allergy. At the Hong Kong roundtable, global leaders unanimously urged standardized international definitions and approaches. Among the key areas of consensus, all agreed that benign childhood exanthema and historical MPE would be universally recognized as low-risk phenotypes and could serve as cornerstones of universal low-risk criteria for penicillin allergy. Additionally, all global representatives strongly recommended against pre-emptive skin testing in patients with no prior reaction, a practice still common in many countries despite its high false-positive rate and risk of perpetuating mislabelling [7]. All agreed that East–West collaboration is essential to equip frontline providers for safe, effective delabeling, strengthening antimicrobial stewardship and accelerating global drug allergy research. V.S. is a Senior Investigator of the Flemish Research Council (FWO, Grant 1804523N). The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.