Drug hypersensitivity: Past, present and future

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.