Clinical and Molecular Characteristics of X-linked Agammaglobulinemia Patients 55 Years or Older

Aaron T Chin; Hans D Ochs; Roger Kobayashi; Hassan Abolhassani; Hana Alachkar; Sara Barmettler; Helen Baxendale; Kristina Boiling; Jason Cantanzaro; Ignastius Chua; Tanya Coulter; Charlotte Cunningham-Rundles; Suzanne E Elcombe; Alain Fischer; Bodo Grimbacher; Sudhir Gupta; Richard Herriot; Archana Herwadkar; Kohsuke Imai; Shota Inoue; Charles Kirkpatrick; Alan P Knutsen; Dinakantha Kumararatne; Edward Lea; Ming-Wei Lin; Jiri Litzman; Nizar Mahlaoui; Kunihiko Moriya; Shigeaki Nonoyama; Smita Patel; Elena Perez; Isabella Quinti; Robert W Hostoffer; Simon Rothenfusser; Ravishankar Sargur; Adrian Shields; Georgios Sogkas; Dan Suan; Tyng Tan; Moira Thomas; Klaus Warnatz; Elizabeth M Younger; Caroline Y Kuo

doi:10.1016/j.jaip.2025.06.025

Clinical and Molecular Characteristics of X-linked Agammaglobulinemia Patients 55 Years or Older

J Allergy Clin Immunol Pract. 2025 Jun 24:S2213-2198(25)00606-3. doi: 10.1016/j.jaip.2025.06.025. Online ahead of print.

Authors

Aaron T Chin¹, Hans D Ochs², Roger Kobayashi³, Hassan Abolhassani⁴, Hana Alachkar⁵, Sara Barmettler⁶, Helen Baxendale⁷, Kristina Boiling⁸, Jason Cantanzaro⁹, Ignastius Chua¹⁰, Tanya Coulter¹¹, Charlotte Cunningham-Rundles¹², Suzanne E Elcombe¹³, Alain Fischer¹⁴, Bodo Grimbacher¹⁵, Sudhir Gupta¹⁶, Richard Herriot¹⁷, Archana Herwadkar¹⁸, Kohsuke Imai¹⁹, Shota Inoue¹⁹, Charles Kirkpatrick²⁰, Alan P Knutsen²¹, Dinakantha Kumararatne²², Edward Lea²³, Ming-Wei Lin²⁴, Jiri Litzman²⁵, Nizar Mahlaoui¹⁴, Kunihiko Moriya¹⁹, Shigeaki Nonoyama¹⁹, Smita Patel²⁶, Elena Perez²⁷, Isabella Quinti²⁸, Robert W Hostoffer²⁹, Simon Rothenfusser³⁰, Ravishankar Sargur³¹, Adrian Shields³², Georgios Sogkas³³, Dan Suan³⁴, Tyng Tan³⁵, Moira Thomas³⁶, Klaus Warnatz¹⁵, Elizabeth M Younger³⁷, Caroline Y Kuo³

Affiliations

¹ Division of Immunology, Allergy and Rheumatology, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: atchin@mednet.ucla.edu.
² University of Washington School of Medicine, and Seattle Children's Research Institute, Seattle, WA, USA.
³ Division of Immunology, Allergy and Rheumatology, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
⁵ Liverpool University Hospitals, Immunology Department, Liverpool, UK.
⁶ Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Royal Papworth NHS Trust, Cambridge, UK.
⁸ Asthma/Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
⁹ Kaiser Permanente Department of Allergy, Asthma and Immunology, Denver, CO, USA.
¹⁰ Canterbury Health Laboratories, Te Whatu Ora, Christchurch, New Zealand.
¹¹ Northern Ireland Regional Immunology Service, Belfast Health and Social Care Trust, Belfast, UK.
¹² Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mt. Sinai, New York City, NY, USA.
¹³ Department of Immunology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals, UK.
¹⁴ Pediatric ImmunoHematology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris, Paris, France.
¹⁵ Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Freiburg, Germany.
¹⁶ Division of Basic & Clinical Immunology, University of California, Irvine, Irvine, CA, USA.
¹⁷ Immunology Department, Aberdeen Royal Infirmary, Aberdeen, UK.
¹⁸ Salford Care Organization, Northern Care Alliance NHS Trust, Salford, UK.
¹⁹ Department of Pediatrics, National Defense Medical College, Saitama, Japan.
²⁰ Division of Allergy and Clinical Immunology, University of Colorado Health Sciences Center, Aurora, CO, USA.
²¹ Division of Allergy and Immunology, Cardinal Glennon Children's Hospital, Saint Louis University, St. Louis, MO, USA.
²² Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²³ Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand.
²⁴ Westmead Hospital, ICPMR, Department of Clinical Immunology and Immunopathology, Sydney, Australia.
²⁵ Department of Clinical Immunology and Allergology, St Anne´s University Hospital, Masaryk University, Brno, Czech Republic.
²⁶ Department of Clinical Immunology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
²⁷ Allergy Associates of the Palm Beaches, North Palm Beach, FL, USA.
²⁸ Department of Molecular Medicine, PID Reference Centre, Sapienza University of Rome, Rome, Italy.
²⁹ University Hospitals, Cleveland Medical Centers, Cleveland, OH, USA.
³⁰ Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany.
³¹ Clinical Immunology and Allergy Unit, Northern General Hospital, Sheffield Teaching Hospitals NHS FT, Dept Infection & Immunity, University of Sheffield, Sheffield, UK.
³² Clinical Immunology Service, College of Medicine and Health, University of Birmingham; Department of Clinical Immunology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
³³ Department of Rheumatology and Immunology, Hannover Medical University, and Hannover Medical School, Hannover, Germany.
³⁴ Garvan Institute for Medical Research, Darlinghurst, NSW, Australia.
³⁵ Department of Clinical Immunology, NHS, Lothian, UK.
³⁶ NHS Greater Glasgow & Clyde, Glasgow, UK.
³⁷ Johns Hopkins School of Medicine, Baltimore, MD, USA.

PMID: 40571245
DOI: 10.1016/j.jaip.2025.06.025

Abstract

Background: X-linked Agammaglobulinemia (XLA), caused by mutations in the BTK gene, leads to defective B-cell development and low or absent serum immunoglobulins. Advances in diagnosis and treatment have improved outcomes, allowing some patients to live beyond their fifth decade.

Objective: To describe clinical, genetic, treatment, and functional status of XLA patients aged 55 years or older.

Methods: Immunologists provided anonymized, physician-reported clinical and molecular details of XLA patients aged 55 years or older. Patients were categorized as having missense mutations (BTK missense) or non-missense mutations (BTK non-missense).

Results: Fifty-seven patients were submitted. Forty-eight considered for final analysis, including forty-three with molecularly confirmed XLA and five with a strong clinical history. Persistent respiratory infections were common: 64.6% (upper respiratory tract) and 83.3% (lower respiratory tract). Chronic lung disease (72.9%) and gastrointestinal/hepatic disorders (47.9%) were amongst the most prevalent complications. Most living patients (80.5%) reported good functional status (Karnofsky scores >80). Missense variants accounted for 62.8% (n=27), non-missense variants for 37.2% (n=16); five patients lacked classifiable mutation details. Among 34 patients with BTK expression data, 70.6% had detectable BTK protein, significantly more common in the missense group (83.3% vs. 30%, p=0.005). The non-missense group had higher mortality, more infections, greater antibiotic use, worse pulmonary function, and lower functional status.

Conclusion: Chronic respiratory complications are common in older XLA patients, though most maintain good functional status. Genetic testing aids prognostication; BTK missense mutations are linked to better outcomes. Further research is needed to address the unique challenges of aging in XLA.

Keywords: Bruton Tyrosine Kinase (BTK); X-linked agammaglobulinemia (XLA); agammaglobulinemia; antibody deficiency; inborn error of immunity (IEI).