Editorial: Genetic and immunological insights into angioedema without wheals

Angioedema without wheals (AE) is a distinct clinical entity characterized by recurrent, selflimiting episodes of localized swelling occurring in the absence of urticaria. Attacks may affect the face, lips, tongue, larynx, gastrointestinal tract, genitalia, or extremities, and typically do not respond to antihistamines or corticosteroids, necessitating interventions that primarily target the bradykinin pathways. Despite a shared clinical phenotype, AE reflects diverse underlying molecular mechanisms, creating persistent diagnostic and therapeutic challenges across emergency medicine, allergy/immunology, internal medicine, and genetics settings.Misdiagnosis and delayed recognition remain common, prolonging avoidable morbidity and, in the case of laryngeal involvement, exposing patients to potentially fatal risk. This Research Topic brings together 12 contributions spanning mechanistic hypotheses, biomarker discovery, genetic insights, real-world treatment evidence, health-service delivery, and patient-centred outcomes. Taken together, these studies convey a clear unifying message: sustained progress in AE arises from aligning biology (genetics, inflammatory mediators, and pathway crosstalk) with measurement (robust, validated outcomes and emerging digital monitoring approaches) and implementation (pragmatic prophylaxis strategies and models of care).A central challenge in AE is understanding why clinically similar swelling phenotypes can arise from different upstream drivers (e.g., contact pathway dysregulation in hereditary angioedema (HAE) vs. mast-cell-mediated processes), and why triggers such as stress or intercurrent inflammation can precipitate attacks. Porebski and colleagues revisit one of the field's most compelling unresolved questions: whether, and by what mechanisms, mast cell degranulation might intersect with bradykinin-driven AE, proposing candidate mechanistic links and highlighting knowledge gaps that must be addressed experimentally. Two original research contributions add depth to the inflammation story. Gil-Serrano et al. examine systemic inflammation biomarkers during acute HAE attacks, leveraging a multi-marker approach that aims to distinguish baseline from attack-associated inflammatory signatures and to refine biomarker candidates for future validation, suggesting that inflammation extends beyond the localized edematous area. In a complementary direction, use a controlled stress paradigm, the socially evaluated cold pressor test, to quantify stress reactivity in HAE-C1INH. They report higher perceived stress and elevated cytokine levels (notably IL-6 and TNF-α patterns) in patients compared with controls, supporting a biologically plausible link between stress, inflammatory mediators, and disease vulnerability.As genetic testing becomes increasingly integrated into routine practice, the field faces a new dilemma: how to interpret and responsibly communicate results that are incidentally discovered, especially in HAE with normal C1 inhibitor (HAE-nC1INH), where genetic confirmation is often required for accurate diagnosis. Germenis and Sanoudou provide a timely practice-oriented framework for handling incidental findings and variants of uncertain significance in genes associated with HAE-nC1INH, arguing for restraint when evidence on penetrance and prevalence is insufficient, and for structured collaboration among clinicians, The evidence gathered in this Research Topic points to three immediate priorities. First, we need validated biomarkers that improve diagnosis and enable biologically meaningful stratification across AE phenotypes in both attack and remission states. Second, outcomes should be captured in a multi-dimensional way, combining disease activity, control, sleep and patient-reported burden, so that clinical trials and routine care reflect what patients experience.Third, advances must be translated through implementation-focused efforts, including scalable care pathways, equitable access to prophylaxis, and practical frameworks for switching, monitoring, and long-term follow-up in real-world settings. AE without wheals remains a highimpact diagnostic and therapeutic challenge, but the field is moving toward a more integrated, patient-centred model in which genetics, immunology, and patient-centred care delivery evolve together.