This Executive Summary is intended to provide a concise overview of the key concepts and recommendations of the 2025 World Allergy Organization Guidelines for Hereditary Angioedema. It should be read and cited in conjunction with the full guideline, which remains the primary source for the complete recommendations, supporting evidence, and methodological framework.1
Introduction
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent subcutaneous and submucosal swelling involving the skin, gastrointestinal tract, upper airways, and other tissues. Bradykinin is currently considered the primary mediator of HAE, although advances in genetics and pathophysiology have expanded our understanding of the mechanisms underlying the disease. HAE causes substantial morbidity, impaired quality of life, and potentially fatal upper airway complications.1
Major advances in genetic characterization, diagnostic strategies, and targeted therapies have transformed HAE care. Nevertheless, delayed diagnosis and disparities in access to reliable testing, specialized care, and effective treatment remain important challenges. Since the previous international World Allergy Organization (WAO) HAE guidelines and subsequent updates,2 new evidence has prompted further refinement of disease classification, diagnosis, and management.
The 2025 WAO HAE Guidelines1 provide an updated, evidence-informed, and globally applicable framework for HAE. They introduce an endotype-oriented classification of recurrent angioedema encompassing bradykinin-mediated, vascular endothelial growth factor (VEGF)-mediated, mast cell-mediated, and idiopathic forms. Within HAE, the guidelines address HAE with C1 inhibitor deficiency (HAE-C1INH) and HAE with normal C1 inhibitor (HAE-nC1INH), including currently recognized genetic subtypes.
Early recognition is essential to reduce diagnostic delay and prevent potentially fatal complications. Clinical features that should raise suspicion include recurrent angioedema without urticaria, recurrent abdominal attacks, upper airway involvement, early disease onset, a family history of angioedema, and lack of response to conventional treatment directed at mast cell-mediated angioedema. Diagnosis prioritizes reliable assessment of C1 inhibitor function, complemented, when appropriate, by antigenic C1 inhibitor and C4 measurements, repeat testing to confirm abnormal results, and selective genetic evaluation.
Management encompasses effective on-demand treatment of acute attacks, short-term prophylaxis before procedures or other interventions that may trigger attacks, and individualized long-term prophylaxis. All patients should have access to effective on-demand therapy. Long-term treatment should be individualized according to disease burden, treatment efficacy and safety, patient preferences, and treatment availability, within a treat-to-target approach aimed at achieving optimal disease control and minimizing the impact of HAE on quality of life.
The 2025 WAO HAE Guidelines also recognize substantial regional disparities in diagnostic capacity, access to specialized care, and availability of effective therapies. Accordingly, their recommendations incorporate considerations of healthcare resources and treatment availability alongside the available evidence and patient-centered care.3
This Executive Summary synthesizes the key concepts of the 2025 WAO HAE Guidelines relevant to clinical recognition, disease classification, diagnosis, and management. It is intended to facilitate dissemination and implementation across different healthcare settings and should be read and cited in conjunction with the full guidelines, which remain the primary source for complete recommendations, evidence, methodology, and clinical guidance.1
Clinical recognition
Early recognition of HAE is essential to reduce diagnostic delay and unnecessary procedures, minimize disease-related morbidity, and prevent potentially life-threatening complications. HAE should be suspected in patients with recurrent angioedema without urticaria, especially with gastrointestinal or upper airway involvement, early onset, family history, or lack of response to conventional treatment for mast cell-mediated angioedema. The HA4E2 concept (Fig.
1) summarizes key clues: Hereditary, recurrent Angioedema, Abdominal angioedema or pain, Absence of urticaria, Absence of response to antihistamines, Early onset, and Estrogen association.4 Prodromal symptoms, such as erythema marginatum, may precede attacks and may help patients recognize and anticipate an impending attack.Fig. 1HA4E2: Red Flags for Hereditary Angioedema.Abbreviations: HAE: hereditary angioedema. Adapted from: Giavina-Bianchi P et al.4
Family history supports the diagnosis but is not required, and manifestations vary among patients and subtypes. Recurrent abdominal symptoms may mimic acute abdominal or surgical emergencies, while upper airway attacks carry a risk of asphyxiation. Recognition of these warning signs and timely access to appropriate testing are therefore essential for early diagnosis and appropriate HAE care.
Key clinical features and treatment-response patterns that may help distinguish angioedema subtypes are summarized in Table 1.Table 1Clinical features and treatment-response patterns of recurrent angioedema subtypes.CharacteristicHAE-C1INHHAE-nC1INHAAE-C1INHMast cell-mediated AngioedemaPrimary mediatorBradykininBradykininBradykininHistamineTypical clinical features•Family history (autosomal dominant)•Often trauma-triggered•Earlier onset (childhood/adolescence)•Non-pruritic, non-urticarial swelling•Erythema marginatum may occur as a prodrome•Family history•Often trauma-triggered•Later onset (often adulthood)•Phenotype varies depending on the endotype•Estrogen association may occur•Tongue involvement may occur•Local hematoma may occur•No family history•Underlying disease (e.g., lymphoproliferative or autoimmune disorder)•Often trauma-triggered•Later onset (usually >40 years)•More severe and frequent attacks•Exclude ACE inhibitor-induced angioedema (tongue involvement may occur)•No family history•Spontaneous onset•Can occur at any age•Often associated with urticaria•Commonly involves eyelids/lips•More pruritic•Shorter duration of episodes•Frequently induced or exacerbated by NSAIDsTreatment responsePatternAcute attacks (on-demand treatment)Good response to bradykinin-targetedTherapy.Good response to bradykinin-targeted therapy in bradykinin- mediated endotypes.Good response to bradykinin-targeted therapy; higher doses may be requiredin some cases.Responds to antihistamines; epinephrine and/or corticosteroids when clinically indicated (e.g., severe reactions).Long-term prophylaxisEffective with targeted HAEProphylaxis.Effective with targetedHAE prophylaxis in bradykinin-mediatedEndotypes.Control improves with treatment of the underlyingDisorder and HAE-directedProphylaxis when needed.Responds to antihistamines; omalizumab shows goodEfficacy in antihistamine- refractory disease.Abbreviations: AAE-C1INH, acquired angioedema with C1 inhibitor deficiency; C1INH, C1 inhibitor; HAE, hereditary angioedema; HAE-C1INH, hereditary angioedema with C1 inhibitor deficiency; HAE-nC1INH, hereditary angioedema with normal C1 inhibitor; NSAIDs, non-steroidal anti-inflammatory drugs.
Disease classification
The 2025 WAO HAE Guidelines use an endotype-oriented framework for recurrent angioedema that integrates clinical presentation, underlying mechanisms, and genetic characteristics.5, 6 HAE is broadly classified as HAE with C1 inhibitor deficiency (HAE-C1INH) or HAE with normal C1 inhibitor (HAE-nC1INH). HAE-C1INH encompasses the former types 1 and 2, which differ in quantitative and functional deficiency, respectively, but share the same fundamental mechanism and clinical management.
HAE-nC1INH is an expanding, heterogeneous group. Identified genetic variants involve pathways related to contact-system activation, bradykinin generation, and vascular endothelial regulation; other patients have a compatible hereditary phenotype without an identifiable pathogenic variant. Emerging evidence also supports hereditary forms associated with abnormalities in VEGF signaling.
The broader framework also includes mast cell-mediated and idiopathic recurrent angioedema, emphasizing the importance of distinguishing mechanistically distinct disorders with similar clinical presentations. Fig. 2 summarizes the proposed endotypes and current pathophysiological understanding; the framework should remain dynamic as new genetic and molecular mechanisms emerge.Fig.
2Proposed classification of recurrent angioedema based on underlying endotypes. This classification is based on current knowledge and existing scientific evidence and may evolve as understanding of HAE expands with new data. Adapted from: Giavina-Bianchi P et al.5, 6 ⁎ANGPT1 mutations impair the inhibitory effect of angiopoietin-1 on the increased vascular permeability induced by both bradykinin and VEGF.⁎⁎May not affect bradykinin pathway.⁎⁎⁎Familial clustering of NSAID-induced angioedema has been reported, suggesting a possible inherited predisposition; however, genetic susceptibility has not yet been established.
Abbreviations: HAE: hereditary angioedema; C1INH: C1 inhibitor; AAE-C1INH: acquired angioedema; VEGF: vascular endothelial growth factor; HAE-C1INH: HAE with C1INH deficiency; HAE-nC1INH: HAE with normal C1INH; HAE-ANGPT1: HAE with angiopoietin-1 (ANGPT1) mutation; HAE-CPN1: HAE with carboxypeptidase N (CPN1) mutation; HAE-DAB2IP: HAE with DAB2-interacting protein (DAB2IP) mutation; HAE-FXII: HAE with factor 12 (F12) mutation; HAE-HS3ST6: HAE with heparan sulfate-3-O-sulfotransferase 6 (HS3ST6) mutation; HAE-KNG1: HAE with kininogen 1 (KNG1) mutation; HAE-MYOF: HAE with myoferlin (MYOF) mutation; HAE-PLG: HAE with plasminogen (PLG) mutation
Diagnostic strategy
Diagnosis of HAE integrates clinical suspicion with laboratory evaluation to confirm disease, distinguish HAE subtypes, and differentiate hereditary from acquired and other recurrent angioedema forms. C1 inhibitor function is central to HAE-C1INH diagnosis; when a reliable standardized assay is available, clearly reduced functional activity in a compatible clinical context may be sufficient. When reliable C1–INH functional testing is unavailable or limited, C4 may support the diagnosis, while a reduced C1–INH antigenic level may establish HAE-C1INH in patients with quantitative C1–INH deficiency, which accounts for approximately 85% of cases; the remaining cases are characterized by a functional C1–INH defect despite normal or elevated antigenic levels.
Results must be interpreted in the clinical context and repeated when they are inconsistent with the clinical suspicion, because preanalytical factors, sample handling, and methodological variability may affect complement and C1–INH functional measurements.
Patients with a suggestive phenotype but normal C1–INH parameters require further evaluation. Genetic testing may help establish the diagnosis of HAE-C1INH when C1–INH measurements are unavailable or unreliable and may identify HAE-nC1INH and defined genetic subtypes. However, the absence of an identified pathogenic variant does not exclude hereditary angioedema.
The differential diagnosis includes acquired C1–INH deficiency, ACE inhibitor-associated angioedema, mast cell-mediated angioedema, and other forms of recurrent angioedema. C1q, anti-C1-INH antibodies, and genetic testing for SERPING1 variants may help differentiate between acquired and hereditary C1–INH deficiency.
After diagnosis, family members should be evaluated to enable early recognition and appropriate management of affected relatives. Table 2 summarizes the characteristic laboratory patterns, and Fig. 3 presents the diagnostic algorithm.Table 2Laboratory and genetic characteristics of bradykinin-mediated angioedema.Angioedema endotypeC1INH antigenic levelC1INH functional activityC4C1qAnti-C1INHGenetic testingHAE-C1INH type 1<50%<50%Decreased(80–95% of time)NormalAbsentSERPING1HAE-C1INH type 2Normal orelevated<50%Decreased(80–95% of time)NormalAbsentSERPING1HAE-nC1INHNormalNormalNormalNormalAbsentFXII, PLG,ANGPT1,KNG1, MYOF,HS3ST6, CPN1,DAB2IPAAE-C1INHDecreasedDecreasedDecreasedDecreased(75% of time)Present(50% of time)NoneAAE-ACEiNormalNormalNormalNormalAbsentNoneAbbreviation: HAE: hereditary angioedema; C1INH: C1 inhibitor; HAE-C1INH: HAE with C1INH deficiency; HAE-nC1INH: HAE with normal C1INH; HAE-ANGPT1: HAE with angiopoietin-1 (ANGPT1) mutation; HAE-CPN1: HAE with carboxypeptidase N (CPN1) mutation; HAE-DAB2IP: HAE with DAB2-interacting protein (DAB2IP) mutation; HAE-FXII: HAE with factor 12 (F12) mutation; HAE-HS3ST6: HAE with heparan sulfate-3-O-sulfotransferase 6 (HS3ST6) mutation; HAE-KNG1: HAE with kininogen 1 (KNG1) mutation; HAE-MYOF: HAE with myoferlin (MYOF) mutation; HAE-PLG: HAE with plasminogen (PLG) mutation; AAE-C1INH: acquired angioedema; AAE-ACEi: angiotensin-converting enzyme inhibitor–associated angioedema.Fig.
3Diagnostic workup for patients suspected of having HAE.⁎ An adequate therapeutic trial to exclude mast cell-mediated angioedema should include high-dose antihistamines and, when appropriate, omalizumab, at doses up to 600 mg every 2 weeks. Lack of response to antihistamines alone should not by itself establish a diagnosis of HAE-nC1INH. Abbreviations: HAE: hereditary angioedema; C1–INH: C1 inhibitor; HAE-C1INH: HAE with C1INH deficiency; AAE-C1INH: acquired angioedema; HAE-nC1INH: HAE with normal C1INH
Management principles
HAE management should be individualized to achieve the highest possible level of disease control while minimizing the impact of HAE and its treatment. The overall approach to individualized HAE management is summarized in Fig. 4.
It comprises 3 complementary strategies: on-demand treatment, short-term prophylaxis, and long-term prophylaxis (Table 3). Decisions should consider attack frequency, severity, and location; airway risk; overall disease burden and quality of life; treatment efficacy and safety; patient preferences; and resource availability. All patients should have access to effective on-demand treatment.Fig.
4Treat-to-target management algorithm for hereditary angioedema. Abbreviations: HAE, hereditary angioedema; LTP, long-term prophylaxis; STP, short-term prophylaxisTable 3Recommended pharmacological management of hereditary angioedema.1. Treatment of attacks (ON-DEMAND therapy)Line of preferenceRecommended optionsKey considerations1st line•C1–INH concentrate (IV)•Icatibant (SC)•Sebetralstat (oral)•Treat attacks as early as possible.•All patients should have access to effective on-demand treatment (at least 2 doses of ODT).•Upper airway involvement requires immediate treatment, seeking emergency care and careful monitoring.2nd line•Ecallantide (SC)•Ecallantide is an alternative when first-line agents are unavailable, contraindicated or not tolerated.•Ecallantide is not approved in all countries and is associated with a risk of anaphylaxis; its use requires appropriate medical supervision.3rd line•Solvent/detergent treated plasma (IV)•Fresh frozen plasma (IV)•Plasma should be used only when other options are unavailable.2.
SHORT-TERM prophylaxis (before procedures/interventions)Line of preferenceRecommended optionsKey considerations1st line•C1–INH concentrate (IV)•Consider before procedures that carry an increased risk of triggering HAE attacks, depending on the patient's previous history.•Does not guarantee prevention of attacks.•On-demand treatment must be readily available.2nd line•Solvent/detergent treated plasma (IV)•Fresh frozen plasma (IV)•Attenuated androgens (oral)•Consider when first-line agents are unavailable, not tolerated, or inappropriate.3. LONG-TERM prophylaxisLine of preferenceRecommended optionsKey considerations1st line•Plasma-derived C1–INH (SC)•Lanadelumab (SC)•Berotralstat (oral)•Garadacimab (SC)•Donidalorsen (SC)•Choice should be individualized based on disease burden, attack pattern, patient preference, safety, feasibility and availability.•Reassess regularly using a treat-to-target approach.•On-demand treatment remains essential.2nd line•C1–INH concentrate (IV)•Attenuated androgens (oral)•Antifibrinolytics (tranexamic acid, oral)•Consider when first-line agents are unavailable, not tolerated, or inappropriate.⁎C1–INH concentrate includes both plasma-derived and recombinant C1–INH products.Abbreviations: C1–INH, C1 inhibitor; IV, intravenous; SC, subcutaneous; ODT, on-demand therapy; HAE, hereditary angioedema.
Shared decision-making, patient education, and an individualized action plan are fundamental. Patients and caregivers should understand how to recognize and treat attacks, when to seek emergency care, and when prophylaxis may be appropriate. Management should be reassessed as disease activity, life circumstances, therapeutic options, and patient priorities evolve.
Treatment of acute attacks
Acute HAE attacks are unpredictable and may cause substantial morbidity or life-threatening airway obstruction. Effective on-demand treatment should therefore be available to all patients and administered as early as possible; upper airway attacks require immediate treatment, close monitoring, and prompt transfer to emergency care. Therapy should be selected according to local availability and regulatory approval, patient characteristics and prior response, route and feasibility of administration, and patient preference.
Patients should have rapid access to treatment and, whenever feasible, be trained to self-administer it outside healthcare settings. Education and an individualized action plan should specify when to initiate treatment and when to seek emergency care.
Short-term prophylaxis
Short-term prophylaxis should be considered before medical, surgical, dental, or other procedures that may trigger an HAE attack, particularly those involving trauma or manipulation of the upper aerodigestive tract. Decisions should be individualized based on procedural risk, history of procedure-related or severe attacks, current disease activity, and access to effective on-demand treatment during the intervention.
Because prophylaxis does not guarantee prevention of an attack, effective on-demand treatment must remain immediately available. The choice of prophylactic therapy should consider efficacy, safety, feasibility, availability, and individual patient characteristics.
Long-term prophylaxis
Long-term prophylaxis should be considered according to overall disease burden rather than attack frequency alone. Assessment should consider the frequency, severity, duration, and location of attacks; the risk of upper airway involvement; the impact of HAE on daily activities, education, employment, social functioning, and quality of life; and treatment response, safety, feasibility, access, and patient preferences.
The need for and choice of long-term prophylaxis should be reassessed regularly through shared decision-making as disease activity, life circumstances, therapeutic options, and patient priorities change. Treatment selection should consider efficacy, safety, route and frequency of administration, and local availability. Long-term prophylaxis does not eliminate the need for effective on-demand treatment of breakthrough attacks.
Treat-to-Target
The goal of HAE management is to achieve optimal disease control while minimizing the impact of HAE on patients' lives. Treatment targets should extend beyond reducing attack frequency to include attack severity and unpredictability, the risk of life-threatening events, treatment burden, functional limitations, and health-related quality of life. Ideally, patients should be free from attacks and meaningful impairment, while goals remain individualized according to disease characteristics, patient priorities, treatment response, feasibility, and access.
Disease control should be assessed regularly using clinical outcomes and the patient's perspective. Changes in attack frequency or severity, breakthrough attacks, emergency healthcare use, limitations in daily activities, or patient-reported outcomes may indicate the need to reassess treatment.
When targets are not achieved, management should be adjusted when possible by optimizing on-demand therapy, reconsidering or modifying prophylaxis, and addressing barriers related to administration, adherence, availability, or patient preference. Treat-to-target is therefore a continuous, dynamic process supported by regular reassessment and shared decision-making.
Global disparities and implementation
Despite major advances, substantial worldwide disparities persist in access to HAE diagnosis, specialized care, and effective treatment, contributing to diagnostic delay, limited access to appropriate testing and therapy, and unequal clinical outcomes. Implementation of evidence-based recommendations must therefore reflect differences in healthcare systems, resources, reliability, affordability, and local availability while striving to maintain the highest achievable standard of care.
Improving outcomes requires more than access to new therapies: awareness, early recognition, reliable diagnostic testing, specialized care, timely treatment, and patient education and empowerment are all essential. Patients should be supported to recognize attacks, understand their treatment options, participate in shared decision-making, and, when appropriate, administer treatment outside healthcare settings.
Addressing global disparities is therefore an integral component of HAE management, not a separate implementation challenge.3
Conclusion
The 2025 WAO HAE Guidelines provide a contemporary, globally applicable framework for HAE care, integrating an evolving endotype-based classification with pragmatic diagnosis and individualized management. Early recognition, timely on-demand treatment, appropriate short- and long-term prophylaxis, and a treat-to-target strategy centered on achieving optimal disease control and minimizing the impact of HAE on quality of life are fundamental components of care.
Implementation must, however, reflect real-world differences in access to diagnostic testing, specialized care, and effective therapies. Addressing these disparities is essential to translating scientific and therapeutic advances into better outcomes worldwide and ensuring that HAE care continues to evolve with emerging evidence.
Contributions of authors
All authors participated in the design of the present study and wrote the manuscript.
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Declaration of Generative AI and AI-assisted technologies in the writing process
During the preparation of this work the authors used Chat GPT (OpenAI) in order to improve language and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. They also used ChatGPT to assist with the design, formatting, and visual organization of Fig.
1, Fig. 2, Fig. 4.
The scientific content and interpretation were developed and verified by the authors.
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Conflict of interest
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