BACKGROUND: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features. METHODS: A survey instrument was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to collect both structured and semi-structured data on X-linked agammaglobulinemia. The survey was sent to 54 centers around the world chosen on the basis of World Allergy Organization participation and/or registration in the European Society for Immunodeficiencies. There were 40 centers that responded, comprising 32 countries. RESULTS: This study reports on 783 patients from 40 centers around the world. Problems with diagnosis are highlighted by the reported delays in diagnosis>24 months in 34% of patients and the lack of genetic studies in 39% of centers Two infections exhibited regional variation. Vaccine-associated paralytic poliomyelitis was seen only in countries with live polio vaccination and two centers reported mycobacteria. High rates of morbidity were reported. Acute and chronic lung diseases accounted for 41% of the deaths. Unusual complications such as inflammatory bowel disease and large granular lymphocyte disease, among others were specifically enumerated, and while individually uncommon, they were collectively seen in 20.3% of patients. These data suggest that a broad range of both inflammatory, infectious, and autoimmune conditions can occur in patients. The breadth of complications and lack of data on management subsequently appeared as a significant challenge reported by centers. Survival above 20 years of age was lowest in Africa (22%) and reached above 70% in Australia, Europe and the Americas. Centers were asked to report their challenges and responses (n = 116) emphasized the difficulties in access to immunoglobulin products (16%) and reflected the ongoing need for education of both patients and referring physicians. CONCLUSIONS: This is the largest study of patients with X-linked agammaglobulinemia and emphasizes the continued morbidity and mortality of XLA despite progress in diagnosis and treatment. It presents a world view of the successes and challenges for patients and physicians alike. A pivotal finding is the need for education of physicians regarding typical symptoms suggesting a possible diagnosis of X-linked agammaglobulinemia and sharing of best practices for the less common complications.

Ankara University School of Medicine Department of Pediatric Immunology and Allergy Ankara Turkey

Centre for Primary Immunodeficiency Department of Pediatric Pulmonology and Immunology Ghent University Hospital Belgium

Clinical Immunology Unit P1 Ibn Rushd Hospital Laboratoire d'Immunologie Clinique Inflammation et Allergie LICIA and Medicine and Pharmacy Faculty of Hassan 2 University Casablanca Morocco

Dalhousie University IWK Health Centre Halifax Nova Scotia Canada

Department of Allergy and Immunology The Royal Children's Hospital Melbourne Australia

Department of Child Health and Development Graduate School of Medical and Dental Sciences Tokyo Medical and Dental University Tokyo Japan

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Immunology Institut Pasteur d'Algérie Faculty of Medicine Algiers Algeria

Department of Immunology Institute of Biomedical Sciences University of Sao Paulo Sao Paulo Sp Brazil

Department of Immunology National Medical and Research Center for Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Medicine and Sciences of Aging University G d'Annunzio of Chieti Pescara Italy

Department of Microbiology Parasitology and Immunology Faculty of Medicine University of Khartoum Sudan

Department of Paediatrics and Adolescent Medicine Queen Mary Hospital The University of Hong Kong Hong Kong China

Department of Pediatric and Child Health Aga Khan University Hospital Karachi Pakistan

Department of Pediatric Hematology Oncology Super Speciality Pediatric Hospital and PG Teaching Institute Noida India

Department of Pediatric Infectious Diseases and Immunology Shupyk National Medical Academy of Postgraduate Education and Center for Clinical Immunology City Children's Hospital N1 Kiev Ukraine

Department of Pediatrics and Chief Allergy Immunology Unit Advanced Pediatrics Centre Post Graduate Institute of Medical Education and Research Chandigarh India

Department of Pediatrics Faculty of Medicine Cairo University Egypt

Department of Pediatrics Faculty of Medicine Kuwait University Allergy and Clinical Immunology Unit Al Sabah Hospital Kuwait City Kuwait

Department of Translational Medical Sciences Section of Pediatrics Federico 2 University Naples Italy

Division of Allergy and Clinical Immunology Department of Pediatrics Medical College of Wisconsin Milwaukee WI USA

Division of Allergy Immunology Department of Pediatrics The Children's Hospital of Philadelphia Philadelphia PA USA

Division of Pediatric Infectious Diseases and Center for Infectious Diseases Research Department of Pediatrics and Adolescent Medicine American University of Beirut Beirut Lebanon

Federal University of Parana Curitiba Brazil

Hospital HHA Universidad de la Frontera Temuco Chile

Immunology Unit Hospital de Niños Ricardo Gutiérrez and CIC CABA Buenos Aires Argentina

LSU Health Sciences Center New Orleans LA USA

Murdoch Children's Research Institute Melbourne Australia

Paediatric Infectious Diseases Unit Red Cross War Memorial Children's Hospital and the Department of Paediatrics and Child Health University of Cape Town Cape Town South Africa

Paediatric Institute Kuala Lumpur General Hospital Kuala Lumpur Malaysia

Pediatric Allergy and Immunology Unit Children's Hospital Ain Shams University Cairo Egypt

Pediatric Immuno hematology Unit Bone Marrow Transplantation Center University Tunis El Manar Faculty of Medicine Tunis Tunisia

Pediatric Immunopathology and Allergology Unit Tor Vergata University Hospital University of Rome Tor Vergata Rome Italy

Pediatrics Clinic and Institute for Molecular Medicine A Nocivelli Department of Clinical and Experimental Sciences University of Brescia and ASST Spedali Civili of Brescia Brescia Italy

Primary Immunodeficiencies Unit Hospital Dona Estefânia Centro Hospitalar de Lisboa Central and CEDOC Nova Medical School Lisboa Portugal

Primary Immunodeficiency Research Lab Ghent University Belgium

Primary Immunodeficiency Unit Allergy and Immunology Division Hospital Nacional Edgardo Rebagliati Martins Lima Peru

Rare Diseases Center Children's Hospital and Adult Immunodeficiency Unit Infectious Diseases Inflammation Center University of Helsinki and Helsinki University Hospital Helsinki Finland

Research Center for Immunodeficiencies Children's Medical Center Tehran University of Medical Sciences and Network of Immunity in Infection Malignancy and Autoimmunity Tehran Iran

Servicio de Inmunología Hospital Universitario Virgen del Rocío Seville Spain

The Immunodeficiencies Research Unit National Institute of Pediatrics Mexico City Mexico

The Royal Hospitals and Queen's University Belfast United Kingdom

The University of Melbourne Australia

University Department of Pediatrics Unit of Immune and Infectious Diseases Childrens' Hospital Bambino Gesù University of Rome Tor Vergata Rome Italy

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Self-reported Clinical Outcomes and Quality of Life in Agammaglobulinemia: the Importance of an Early Diagnosis