ORIGINAL PAPER
Frequency and clinical spectrum of immune dysregulation in primary immunodeficiencies: experience of a single Central European Adult Care Centre
1
Department of Rheumatology and Immunology, Medical School, University of Pécs, Hungary
Submission date: 2025-07-02
Final revision date: 2026-01-28
Acceptance date: 2026-02-06
Online publication date: 2026-10-09
Corresponding author
Gabor Kumanovics
Department of Rheumatology and Immunology, Medical School, University of Pécs, Hungary
Department of Rheumatology and Immunology, Medical School, University of Pécs, Hungary
KEYWORDS
inborn errors of immunityadult-onset primary immunodeficienciesimmune dys-regulationCVIDautoimmunity
ABSTRACT
Introduction:
Primary immunodeficiencies (PIDs) encompass not only recurrent infections but also a wide range of manifestations of immune dysregulation, including autoimmunity, lymphoproliferation, granulomatous disease, and malignancies. The aim of the study was to analyse the prevalence and clinical features of immune dysregulation among adult patients with PID, and to evaluate the relationship between age at diagnosis, diagnostic delay, and the development of non-infectious complications.
Material and Methods:
We retrospectively reviewed the records of 28 adult patients with PID receiving immunoglobulin replacement therapy. Features of immune dysregulation were analysed in relation to age at diagnosis and diagnostic delay.
Results:
We were able to diagnose PID in 28 patients (estimated prevalence of adult-onset PID in the area of our centre is 3.01/100.000), among these, the most common group was primary antibody deficiency (PAD: 25/28, 89%). Immune dysregulation was observed in 22 patients (79%), three of whom presented without any infectious manifestations. The prevalence of autoimmune disease was significantly higher among patients diagnosed after the age of 50 than among those diagnosed in childhood (58% vs. 0%, p = 0.0377). ROC analysis identified age ≥ 41 years at diagnosis as a significant discriminator of immune dysregulation-related complications (AUC = 0.724, p = 0.025). Malignancy accounted for half of all deaths (3/6, 50%), while no patient died of infection.
Conclusions:
Immune dysregulation represents a hallmark of adult-onset PID, often preceding or occurring independently of recurrent infections. Malignancy, rather than infection, emerged as the leading cause of death. The observed gap between expected and diagnosed prevalence highlights an unmet need for improved recognition of PID in adults and better transition pathways from paediatric to adult care in Central and Eastern Europe.
Primary immunodeficiencies (PIDs) encompass not only recurrent infections but also a wide range of manifestations of immune dysregulation, including autoimmunity, lymphoproliferation, granulomatous disease, and malignancies. The aim of the study was to analyse the prevalence and clinical features of immune dysregulation among adult patients with PID, and to evaluate the relationship between age at diagnosis, diagnostic delay, and the development of non-infectious complications.
Material and Methods:
We retrospectively reviewed the records of 28 adult patients with PID receiving immunoglobulin replacement therapy. Features of immune dysregulation were analysed in relation to age at diagnosis and diagnostic delay.
Results:
We were able to diagnose PID in 28 patients (estimated prevalence of adult-onset PID in the area of our centre is 3.01/100.000), among these, the most common group was primary antibody deficiency (PAD: 25/28, 89%). Immune dysregulation was observed in 22 patients (79%), three of whom presented without any infectious manifestations. The prevalence of autoimmune disease was significantly higher among patients diagnosed after the age of 50 than among those diagnosed in childhood (58% vs. 0%, p = 0.0377). ROC analysis identified age ≥ 41 years at diagnosis as a significant discriminator of immune dysregulation-related complications (AUC = 0.724, p = 0.025). Malignancy accounted for half of all deaths (3/6, 50%), while no patient died of infection.
Conclusions:
Immune dysregulation represents a hallmark of adult-onset PID, often preceding or occurring independently of recurrent infections. Malignancy, rather than infection, emerged as the leading cause of death. The observed gap between expected and diagnosed prevalence highlights an unmet need for improved recognition of PID in adults and better transition pathways from paediatric to adult care in Central and Eastern Europe.
REFERENCES (30)
1.
Seidel MG, Kindle G, Gathmann B, et al. (2019): The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract 7: 1763-1770.
2.
Bonilla FA, Khan DA, Ballas ZK, et al. (2015): Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol 136: 1186-1205.e78.
3.
De Wit, J, Brada RJK, Van Veldhuizen J, et al. (2019): Skin disorders are prominent features in primary immunodeficiency diseases: A systematic overview of current data. Allergy 74: 464-482.
4.
Azizi G, Ziaee V, Tavakol M, et al. (2017): Approach to the management of autoimmunity in primary immunodeficiency. Scand J Immunol 85: 13-29.
5.
Abolhassani H, Rezaei N, Mohammadinejad P, et al. (2015): Important differences in the diagnostic spectrum of primary immunodeficiency in adults versus children. Expert Rev Clin Immunol 11: 289-302.
6.
McCusker C, Upton J, Warrington R (2018): Primary immunodeficiency. Allergy Asthma Clin Immunol 14: 61.
7.
Janssen LMA, Reijnen ICGM, Milito C, et al. (2022): Protocol for the unclassified primary antibody deficiency (unPAD) study: Characterization and classification of patients using the ESID online Registry. PLoS One 17: e0266083.
8.
Poli MC, Aksentijevich I, Bousfiha AA, et al. (2025): Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee. J Hum Immun 1: e20250003.
9.
Ho H, Cunningham-Rundles C (2020): Non-infectious complications of common variable immunodeficiency: updated clinical spectrum, sequelae, and insights to pathogenesis. Front Immunol 11: 149.
10.
Lehman HK (2015): Autoimmunity and immune dysregulation in primary immune deficiency disorders. Curr Allergy Asthma Rep 15: 53.
11.
Hauck F, Voss R, Urban C, et al. (2018): Intrinsic and extrinsic causes of malignancies in patients with primary immunodeficiency disorders. J Allergy Clin Immunol 141: 59-68.e4.
12.
Agarwal S, Mayer L (2013): Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol 11: 1050-1063.
13.
Baloh C, Reddy A, Henson M, et al. (2019): 30-year review of pediatric- and adult-onset CVID: Clinical correlates and prognostic indicators. J Clin Immunol 39: 678-687.
14.
Abolhassani H, Avcin T, Bahceciler N, et al. (2022): Care of patients with inborn errors of immunity in thirty J Project countries between 2004 and 2021. Front Immunol 13: 1032358.
15.
Abunin M, Albert M, Cohen SB, et al. (2019): ESID Registry – Working definitions for clinical diagnosis of PID. https://esid.org/working-parti....
16.
Ziętkiewicz M, Więsik-Szewczyk E, Matyja-Bednarczyk A, et al. (2020): Shorter diagnostic delay in Polish adult patients with common variable immunodeficiency and symptom onset after 1999. Front Immunol 11: 982.
17.
Amaya-Uribe L, Rojas M, Azizi G, et al. (2019): Primary immunodeficiency and autoimmunity: A comprehensive review. J Autoimmun 99: 52-72.
18.
Gathmann B, Mahlaoui N, Gérard L, et al. (2014): Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 134: 116-126.e11.
19.
Fischer A, Provot J, Jais JP, et al. (2017): Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol 140: 1388-1393.e8.
20.
Costagliola G, Peroni DG, Consolini R (2022): Beyond infections: new warning signs for inborn errors of immunity in children. Front Pediatr 10: 855445.
21.
Jolles S (2013): The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract 1: 545-556.
22.
Milota T (2022): Lung manifestation of Common variable immunodeficiency – the results from the nationwide multicenter study. In 01.01 – Clinical problems – no related to asthma or COPD European Respiratory Society. 3513.
23.
Maglione PJ, Overbey JR, Radigan L, et al. (2014): Pulmonary radiologic findings in common variable immunodeficiency: clinical and immunological correlations. Ann Allergy Asthma Immunol 113: 452-459.
24.
Israni M, Alderson E, Mahlaoui N, et al. (2025): Recommendations for transitioning young people with primary immunodeficiency disorders and autoinflammatory diseases to adult care. J Clin Immunol 45: 57.
25.
Bonilla FA (2020): Vaccines in patients with primary immune deficiency. Immunol Allergy Clin North Am 40: 421-435.
26.
Walter JE, Ayala IA, Milojevic D (2019): Autoimmunity as a continuum in primary immunodeficiency. Curr Opin Pediatr 31: 851-862.
27.
Staels F, Collignon T, Betrains A, et al. (2021): Monogenic adult-onset inborn errors of immunity. Front Immunol 12: 753978.
28.
Segura-Tudela A, Nieto-López C, Bermejo-Olivera FJ, et al. (2025): Malignancy and autoimmune susceptibility in adult patients with human inborn errors of immunity. J Clin Immunol 45: 136.
29.
Csóka DL, Kovács KT, Kumánovics G (2024): A clinical picture of unselected patients with systemic lupus erythematosus in a tertiary Hungarian center – a spectrum ranging from pure lupus to overlap syndromes. J Clin Med 13: 3251.
30.
Nagy G, Dobrota R, Becker MO, et al. (2023): Characteristics of ScleroID highlighting musculoskeletal and internal organ implications in patients afflicted with systemic sclerosis. Arthritis Res Ther 25: 84.
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