Antonino Romano

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.

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.

Background: Beta‐lactams (BLs) are the predominant cause of immediate allergic reactions to drugs. Immediate hypersensitivity reactions (IHR) with positive provocation tests and negative skin and in vitro tests have undetermined mechanisms. We evaluated whether biomarkers of IgG‐dependent neutrophil activation could help to assess this subgroup of BL IHRs. Methods: We evaluated biomarkers of neutrophil activation and neutrophil extracellular traps (NETs) in the serum of 26 BL IHR patients presenting with a positive provocation test, negative skin and serum specific IgE, and positive specific sIgG, and 8 perioperative BL IHR cases with positive skin tests and negative sIgE compared to 19 non‐allergic matched controls. Results: We observed increased levels of DNase activity, neutrophil elastase (NE), myeloperoxidase (MPO)‐DNA, IL8 and decreased IL4 and IL13 in patients, compared to matched controls, in the first 15 min of IHRs. DNAse activity, NE and MPO‐DNA were maintained at high levels 2 h later (T0 + 2), while cell‐free DNA and CXCR2 decreased significantly. IgG‐related activation of neutrophils was suggested by significant correlations between NE, IL8 and CXCR2 axis and a single cluster associating BL sIgG antibodies and NE at T0 + 2, in principal factor analysis of all biomarkers. Conclusion: Biomarkers of neutrophil activation and NETs were increased in BL IHRs with negative skin tests, positive sIgG and negative serum sIgE, and positive provocation test. We propose DNAse activity and NE as biomarkers for the biological assessment of BL IHRs and provocation tests and to consider IgG‐related neutrophil activation as one of the mechanisms involved in BL IHRs with undetermined cause.

Diagnosis of type I hypersensitivity reactions (IgE-mediated reactions) to penicillins is based on clinical history, skin tests (STs), and drug provocation tests (DPTs). Among in vitro complementary tests, the fluoro-enzyme immunoassay (FEIA) ImmunoCAP^® (Thermo-Fisher, Waltham, MA, USA) is the most widely used commercial method for detecting drug-specific IgE (sIgE). In this study, we aimed to analyze the utility of ImmunoCAP^® for detecting sIgE to penicillin G (PG) and amoxicillin (AX) in patients with confirmed penicillin allergy. The study includes 139 and 250 patients evaluated in Spain and Italy, respectively. All had experienced type I hypersensitivity reactions to penicillins confirmed by positive STs. Additionally, selective or cross-reactive reactions were confirmed by DPTs in a subgroup of patients for further analysis. Positive ImmunoCAP^® results were 39.6% for PG and/or AX in Spanish subjects and 52.4% in Italian subjects. When only PG or AX sIgE where analyzed, the percentages were 15.1% and 30.4%, respectively, in Spanish patients; and 38.9% and 46% in Italian ones. The analysis of positive STs showed a statistically significant higher percentage of positive STs to PG determinants in Italian patients. False-positive results to PG (16%) were detected in selective AX patients with confirmed PG tolerance. Low and variable sensitivity values observed in a well-defined population with confirmed allergy diagnosis, as well as false-positive results to PG, suggest that ImmunoCAP^® is a diagnostic tool with relevant limitations in the evaluation of subjects with type I hypersensitivity reactions to penicillins.

Background: Nonimmediate (delayed)‐allergic reactions to penicillins are common and some of them can be life‐threatening. The genetic factors influencing these reactions are unknown/poorly known/poorly understood. We assessed the genetic predictors of a delayed penicillin allergy that cover the HLA loci.Methods: Using next‐generation sequencing (NGS), we genotyped the MHC region in 24 patients with delayed hypersensitivity compared with 20 patients with documented immediate hypersensitivity to penicillins recruited in Italy. Subsequently, we analyzed in silico Illumina Immunochip genotyping data that covered the HLA loci in 98 Spanish patients with delayed hypersensitivity and 315 with immediate hypersensitivity compared to 1,308 controls.Results: The two alleles DRB3*02:02:01:02 and DRB3*02:02:01:01 were reported in twenty cases with delayed reactions (83%) and ten cases with immediate reactions (50%), but not in the Allele Frequency Net Database. Bearing at least one of the two alleles increased the risk of delayed reactions compared to immediate reactions, with an OR of 8.88 (95% CI, 3.37–23.32; p < .0001). The haplotype (ACAA) from rs9268835, rs6923504, rs6903608, and rs9268838 genetic variants of the HLA‐DRB3 genomic region was significantly associated with an increased risk of delayed hypersensitivity to penicillins (OR, 1.7; 95% CI: 1.06–1.92; p = .001), but not immediate hypersensitivity.Conclusion: We showed that the HLA‐DRB3 locus is strongly associated with an increased risk of delayed penicillin hypersensitivity, at least in Southwestern Europe. The determination of HLA‐DRB3*02:02 alleles in the risk management of severe delayed hypersensitivity to penicillins should be evaluated further in larger population samples of different origins.