Drug-induced anaphylaxis: Molecular pathophysiology, diagnosis, and management

Drug-induced anaphylaxis is a severe, potentially fatal hypersensitivity reaction triggered by various pharmacologic agents, including antibiotics, nonsteroidal anti-inflammatory drugs, and biologics. It involves a spectrum of immunologic and nonimmunologic mechanisms, ranging from classical IgE-mediated pathways to complement activation and direct mast cell stimulation via receptors such as Mas-related G-protein-coupled receptor member X2 (MRGPRX2). The clinical heterogeneity of anaphylaxis presents significant diagnostic challenges, often requiring a combination of clinical evaluation, laboratory biomarkers (eg, serum tryptase and histamine), in vitro tests (eg, basophil activation test and specific IgE test), skin testing, and in some cases, a gold-standard drug provocation test, to establish a definitive diagnosis. Emerging insights into phenotypes and endotypes-such as cytokine-release reactions and bradykinin-mediated responses-enable a more complex understanding of pathophysiological mechanisms, facilitating precision diagnostics and targeted interventions. Accurate risk stratification considers both drug-related and patient-related factors, including genetic polymorphisms and comorbidities. Management hinges on the prompt administration of intramuscular epinephrine, with supportive therapies tailored to the underlying mechanism. In select patients, desensitization and delabeling strategies may allow continued treatment with essential medications. This review provides a comprehensive synthesis of the current knowledge on the pathogenesis, clinical features, diagnostic approaches, and management strategies for drug-induced anaphylaxis and highlights areas for future research aimed at improving patient safety and therapeutic outcomes.