Daniel Vázquez, Pedro Giavina-Bianchi, Darío Josviack, Allen P. Kaplan, Pablo A.S. Martinez, Claudio Fantini, J. Bernstein, Shahid Abbas, Nancy Agmon‐Levin, Mona Al-Ahmad, Sultan Alandijani, Hani Abdullah Alhashmi, R. Mohammed Ali, Ines Allam, Maryam Al-Nesf Al-Mansouri, Salem Al-Tamemi, S. Altrichter, Mirta Álvarez Castelló, Hilary D. Andoh, Marcelo Vívolo Aun, Kassim Babu Mapondela, Aleena Banerji, Noémi‐Anna Bara, Olga Melcina Barrera, Paulo Barrera Perigault, Manuel Branco Ferreira, Oscar Manuel Calderón-Llosa, Giorgio Walter Canonica, Raúl Castro Almarales, Lorenzo Cecchi, Y. J. Chang, Hiroshi Chantaphakul, Tinatin Chikovani, Herberto Jose Chong-Neto, Francisco Alberto Contreras-Verduzco, Federica Defendi, Vilbrun Dorsainvil, Motohiro Ebisawa, Zeinab A. El-Sayed, Mary Beth Fasano, Mohammad Reza Fazlollahi, Euguens Femine, Fátima Rodrigues Fernandes, Alessandro Fiocchi, Luz Fonacier, Claudia Gallego, Jose Luis García Abujeta, José Enrique Gereda, Erminia Giordano, Nihal Mete Gökmen, R. Maximiliano Gómez, Mónica González, Sandra González Díaz, Masumi Grau, Roman Hakl, Michihiro Hide, Elham Hossny, Laura Huilaja, Syed Rezaul Huq, Carla Irani, A Ishchanka, Zhanat Ispayeva, Kristina R. Jamalyan, Igor Kaidashev, George Kamkamidze, Luciana Kase Tanno, P. C. Kathuria, Aharon Kessel, Sorena Kiani-Alikhan, Nagendra Prasad Komarla, Violeta Kvedarienė, D. M. Lang, Y. H. Lee, Michael Levin, P. H. Li, Henry Li, William R. Lumry, Ketevan Machavariani, Inmaculada Martinez-Sager, Juan Pablo Maselli, Nikolaos Mikos, Nunu Mitskevich, Hassan M.S. Mobayed, Olga Patricia Monge-Ortega, Hideaki Morita, Sonomjamts Munkhbayarlakh, Mohammad Nabavi, Muhammad Raza Naqvi, Jaime Ocampo, Margarita Olivares, José Antonio Ortega-Martell, Batsaikhan Oyuntsatsral, Nikos Papadopoulos, Vincenzo Patella, R. Pawankar, Jonny Peter, Fotis Psarros, Frederico S. Regateiro, Marc Reidl, Ann Michelle Rigalt
The 2025 World Allergy Organization (WAO) Guidelines for the Classification, Diagnosis, and Treatment of Hereditary Angioedema (HAE) with Consideration of Worldwide Disparities provide a comprehensive, evidence-informed, and globally applicable framework for the care of this rare and potentially life-threatening disorder. HAE is a genetic disease characterized by recurrent episodes of subcutaneous and submucosal swelling, most commonly mediated by bradykinin, and is associated with substantial morbidity, impaired quality of life, and a lifelong risk of fatal laryngeal edema. The Guidelines were developed by an international panel of 40 experts from 22 countries, with representation from all world regions, reflecting the commitment of WAO to geographic diversity, inclusiveness, and global relevance. The development process for these guidelines followed a structured and transparent methodology that integrated systematic literature review, appraisal of real-world evidence, and application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework adapted for rare diseases, complemented by a formal Delphi consensus process. This approach was specifically designed to address the limitations of conventional evidence hierarchies in rare disorders, while ensuring clinical applicability across heterogeneous healthcare systems and resource settings. A central element of the guidelines is an updated classification of HAE based on underlying pathophysiology and disease endotypes. The traditional distinction between HAE types 1 and 2 is unified under the term HAE with C1 inhibitor deficiency (HAE-C1-INH), reflecting shared biological mechanisms and management principles. The guidelines also recognize an expanding spectrum of HAE with normal C1 inhibitor (HAE-nC1-INH), including forms associated with pathogenic variants in F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, and DAB2IP, as well as cases with currently unidentified genetic causes. The diagnostic strategy emphasizes early clinical recognition based on characteristic features, including recurrent angioedema without urticaria, abdominal or laryngeal involvement, early symptom onset, and family history. A simplified diagnostic algorithm is proposed, prioritizing the C1 inhibitor functional assay as the preferred initial test when performed in a reliable specialized laboratory. Alternative diagnostic pathways are outlined for settings with limited access to specialized testing, including pragmatic combinations of biochemical assays and selective use of genetic testing, particularly relevant for HAE-nC1-INH and family screening. Management recommendations address on-demand treatment of acute attacks, short-term prophylaxis, and individualized long-term prophylaxis. Universal access to on-demand therapy is emphasized for all patients with confirmed HAE, including those who are asymptomatic, given the unpredictable nature of attacks and lifelong risk. Long-term prophylaxis is addressed within a treat-to-target framework aimed at achieving complete disease control and sustained improvement in health-related quality of life, with regular reassessment and shared decision-making. Empowering patients and caregivers through structured education, access to appropriate medications, and integration with specialized referral centers is associated with earlier treatment, reduced healthcare utilization, and improved equity of care and reduced avoidable morbidity and mortality worldwide. The 2025 WAO Guidelines for Hereditary Angioedema establish an evidence-informed, patient-centered, and forward-looking framework for the classification, diagnosis, and management of HAE. By integrating advances in pathophysiology, diagnostics, and therapeutics with global expert consensus and real-world considerations, the guidelines aim to support consistent, equitable, and high-quality care for patients with HAE across regions and healthcare systems.