Fatal and refractory anaphylaxis: Immunopathogenesis, endotypes, and biomarkers

Fatal and near-fatal anaphylaxis remain among the most critical emergencies in clinical practice, despite improvements in the recognition and management of severe allergic reactions. While most episodes respond to timely intramuscular epinephrine, a subset of patients develop refractory anaphylaxis, characterized by persistent or worsening cardiovascular and/or respiratory compromise despite appropriate first-line treatment. These severe phenotypes raise essential questions about the underlying immune effector and non-immunological pathways that drive extreme systemic responses and resistance to standard therapy.This Research Topic aims to gather multidisciplinary evidence exploring the complexity of life‑threatening anaphylaxis by integrating clinical observations with cellular and systems immunology, molecular, and translational research. Emerging studies highlight the importance of heterogeneity in mast cell and basophil activation, the role of IgE-dependent and IgE-independent pathways (including complement- and receptor-mediated activation), the contribution of late-phase and secondary mediators, and the potential interplay between genetic susceptibility and environmental or pharmacologic triggers. In parallel, promising biomarkers - such as kinetic patterns of serum tryptase, lipid mediators, complement/activation markers, and advanced proteomic signatures - are opening new avenues for stratifying high‑risk immune endotypes and improving diagnostic accuracy.To gather further insights into the multidimensional aspects of severe anaphylaxis, this Research Topic encompasses translational, clinical, and basic science perspectives while focusing specifically on immune mechanisms driving severe, life-threatening, and therapy-resistant cases. We welcome articles addressing, but not limited to, the following themes:- Susceptibility: immunological, genetic, and environmental determinants of severe anaphylaxis- Immune endotypes and cellular mechanisms underlying refractory and biphasic reactions- Biomarkers and molecular signatures for risk stratification and immunomonitoring- Immunology-informed optimization of diagnostic and management algorithms for extreme presentations- Innovative therapeutic approaches and interventions for resistant cases, including mechanism-guided and targeted immunomodulatory strategiesFatal and refractory anaphylaxis continue to challenge both prehospital and hospital teams, underscoring the need for refined diagnostic algorithms, earlier recognition of severity predictors, and optimized therapeutic strategies informed by immunopathogenesis. By bringing together original research, mechanistic studies, clinical case series, and comprehensive reviews, this collection seeks to advance current understanding of the pathogenic mechanisms that lead to the most severe expressions of anaphylaxis.We invite clinicians, basic scientists, and translational researchers to contribute novel insights that may ultimately enhance prevention, diagnosis, and treatment of this potentially fatal condition. Topic editors: Miguel Angel Tejedor-Alonso, Rosa Muñoz Cano Source: https://www.frontiersin.org/research-topics/78999/fatal-and-refractory-anaphylaxis-immunopathogenesis-endotypes-and-biomarkers