A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and <i>CTLA4</i>-Mediated Immune Dysregulation Syndrome in Greece
Androniki Kapousouzi,
Fani Kalala,
Styliani Sarrou,
Evangelia Farmaki,
Nikolaos Antonakos,
Ioannis Kakkas,
Alexandra Kourakli,
Vassiliki Labropoulou,
Charikleia Kelaidi,
Georgia Tsiouma,
Maria Dimou,
Theodoros P. Vassilakopoulos,
Michael Voulgarelis,
Ilias Onoufriadis,
Eleni Papadimitriou,
Sophia Polychronopoulou,
Evangelos J. Giamarellos-Bourboulis,
Argiris Symeonidis,
Christos Hadjichristodoulou,
Anastasios E. Germenis,
Matthaios Speletas
Affiliations
Androniki Kapousouzi
Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece
Fani Kalala
Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece
Styliani Sarrou
Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece
Evangelia Farmaki
Pediatric Immunology and Rheumatology Referral Center, First Department of Pediatrics, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
Nikolaos Antonakos
4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece
Ioannis Kakkas
Department of Immunology and Histocompatibility Department, “Evaggelismos” General Hospital, 10676 Athens, Greece
Alexandra Kourakli
Hematology Division, Department of Internal Medicine, University of Patras Medical School-University Hospital, 26504 Patras, Greece
Vassiliki Labropoulou
Hematology Division, Department of Internal Medicine, University of Patras Medical School-University Hospital, 26504 Patras, Greece
Charikleia Kelaidi
Department of Pediatric Hematology-Oncology (T.A.O.), “Aghia Sophia” Children’s Hospital, 11527 Athens, Greece
Georgia Tsiouma
ENT Department, General Hospital of Volos, 38222 Volos, Greece
Maria Dimou
Department of Haematology and Bone Marrow Transplantation, “Laikon” General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
Theodoros P. Vassilakopoulos
Department of Haematology and Bone Marrow Transplantation, “Laikon” General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece
Michael Voulgarelis
Department of Pathophysiology, “Laikon” General Hospital, Medical School, National University of Athens, 11527 Athens, Greece
Ilias Onoufriadis
Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece
Eleni Papadimitriou
Pediatric Immunology and Rheumatology Referral Center, First Department of Pediatrics, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
Sophia Polychronopoulou
Department of Pediatric Hematology-Oncology (T.A.O.), “Aghia Sophia” Children’s Hospital, 11527 Athens, Greece
Evangelos J. Giamarellos-Bourboulis
4th Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece
Argiris Symeonidis
Hematology Division, Department of Internal Medicine, University of Patras Medical School-University Hospital, 26504 Patras, Greece
Christos Hadjichristodoulou
Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, 41222 Larissa, Greece
Anastasios E. Germenis
Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece
Matthaios Speletas
Department of Immunology and Histocompatibility, Faculty of Medicine, University of Thessaly, 41500 Larissa, Greece
Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0–77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with “secondary” hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6–14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0–43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.
