The impact of anaphylaxis extends well beyond the acute allergic episode, imposing a substantial burden on patients, clinicians, and healthcare systems. From patients' perspective, anaphylaxis is not defined solely as an acute reaction, but also as a persistent fear of recurrence and the uncertainty surrounding future exposure. Consequently, anaphylaxis greatly impacts quality of life, shaping dietary choices, social interactions, travel, employment, or schooling, and psychological wellbeing (Martino et al, 2025). The burden is particularly significant when the causative factor cannot be clearly identified, cannot be reliably avoided, or when multiple interacting cofactors such as exercise, infections, medications, or stress contribute to disease expression leaving patients and their family in a continuous state of vigilance and lifelong dependence on adrenaline auto-injectors (Knibb et al, 2025).These patient-level challenges are mirrored in daily clinical practice. In many cases of anaphylaxis, the inability to confirm a final diagnosis following extensive investigation makes anaphylaxis one of the most challenging conditions encountered in allergy practice. Physicians are frequently confronted with diagnostic uncertainty arising from heterogeneous clinical presentations, limited availability and/or access to sensitive biomarkers, and in some clinical scenarios overlap with other acute medical conditions. These difficulties are further amplified in idiopathic anaphylaxis, cofactor-dependent reactions, , and reactions triggered by rare or unconventional allergens, where classical IgE-mediated mechanisms do not fully explain disease expression.Real-world insights into uncommon presentations, diagnostic pitfalls, and emerging management strategies provided the foundation for the Research Topic "Anaphylaxis Challenges: Idiopathic and Rare Causes." By focusing on Idiopathic reactions, unusual triggers, and atypical phenotypes, this collection aims to advance understanding, support clinical decision-making, inform future research, and subsequently improve outcomes for patients living with this high-risk condition. This topic also aimed to investigate geographical diversity, cultural dietary habits, environmental exposures, and healthcare inequalities that may further contribute to variability in anaphylaxis recognition and management.The resulting collection comprises twelve peer-reviewed contributions, including case reports, mini-reviews, and original research articles, offering complementary perspectives on idiopathic anaphylaxis, rare allergens, pediatric disease evolution, biologic therapies, desensitization strategies, and life-threatening refractory reactions.Anaphylaxis continues to represent the most severe spectrum of allergic reactions and may be lifethreatening if not recognized or treated early (Motosue et al. 2022, Abunada et al. 2018). The burden of anaphylaxis is increasing worldwide, affecting patients across all age groups. Idiopathic anaphylaxis remains a diagnosis of exclusion and continues to pose significant challenges for clinicians, patients and health systems. Idiopathic reactions may be driven by underrecognized cofactors rather than the absence of a trigger. These include physical exertion, infections, medications, hormonal influences, emotional stress, and environmental conditions. Within this Research Topic, contemporary perspectives emphasize that idiopathic anaphylaxis should be viewed as a dynamic condition, requiring repeated clinical reassessment rather than a static diagnosis. Recognition of cofactors is essential for improving prevention strategies, patient education, and long-term outcomes. Elkhalifa et al. discussed idiopathic anaphylaxis describing it as unpredictable, reported more frequently in women, and with a wide age range of onset. Female sex in general has been well established as a risk for anaphylaxis particularly from puberty through middle age. This is likely due to estrogen increasing nitric oxide production, augmenting vascular leakage ( Venom immunotherapy can cause anaphylaxis during treatment course, yet severe systemic with particular cardiovascular manifestations are not common. Brunetto S. et al described a case of anaphylaxis after administration of a maintenance dose of Hymenoptera venom immunotherapy, with preeminent cardiac involvement evidenced by ECG alterations disappearing after the patient's recovery from the anaphylactic reaction. A possible underlying mast-cell disorder was suggested to trigger such unexpected anaphylactic reaction. At the extreme end of the clinical spectrum lies refractory anaphylaxis, which remains associated with significant mortality. Grafeneder et al. presented a very unusual case report of a multi-phasic life-threatening anaphylaxis refractory to epinephrine treatment who responded to extracorporeal membrane oxygenation (ECMO) illustrating the potential role of advanced life-support modalities when conventional treatment fails, prompt escalation of care, and integration between allergy specialists, emergency physicians, and intensive care teams.Conclusively, this Research Topic brings together diverse yet interconnected perspectives on idiopathic and rare causes of anaphylaxis. By integrating case-based observations with broader conceptual insights, the collection advances understanding of anaphylaxis as a multifactorial, dynamic, and highly individualized condition.
Al-Nesf et al. (Fri,) studied this question.