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[Preprint]. 2025 Apr 16:2025.02.20.25322586.

doi: 10.1101/2025.02.20.25322586.

Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients

Gerhard Kindle^{1

2

3}, Mickaël Alligon^{4

3}, Michael H Albert⁵, Matthew Buckland^{6

7}, J David Edgar⁸, Benjamin Gathmann¹, Sujal Ghosh⁹, Antonios Gkantaras¹⁰, Alexandra Nieters^{1

2}, Claudio Pignata¹¹, Peter Robinson^{12

13}, Stephan Rusch^{1

2}, Catharina Schuetz^{14

15}, Svetlana Sharapova¹⁶, Benjamin Shillitoe¹⁷, Fabio Candotti¹⁸, Andrew J Cant^{19

20}, Jean-Laurent Casanova^{21

22

23

24

25}, Amos Etzioni²⁶, Alain Fischer^{27

22}, Isabelle Meyts²⁸, Luigi D Notarangelo²⁹, Martine Pergent³⁰, C I Edvard Smith^{31

32

33}; ESID Registry Working Party; Lennart Hammarström^{34

35}, Bodo Grimbacher^{1

36

37

38

39

35}, Mikko Seppänen^{40

41

35}, Nizar Mahlaoui^{4

42

35}, Stephan Ehl^{1

35}, Markus G Seidel^{43

35}

Affiliations

¹ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
² Centre for Biobanking FREEZE, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ These authors contributed equally and should be considered aequo loco.
⁴ French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁵ Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München, Munich Germany.
⁶ Barts Health National Health Service Trust, London, United Kingdom.
⁷ Molecular and Cellular Immunology Section, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, London, United Kingdom.
⁸ Department of Immunology, St James's Hospital, & School of Medicine, Trinity College Dublin, Ireland.
⁹ Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany.
¹⁰ Pediatric Immunology and Rheumatology Referral Center, 1st Department of Pediatrics, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece.
¹¹ Department of Translational Medical Sciences, Federico II University, Naples, Italy.
¹² Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹³ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
¹⁴ Department of Pediatrics and University Center for Rare Diseases, Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany.
¹⁵ German Center for Child and Adolescent Health (DZKJ), partner site Leipzig/Dresden, Dresden, Germany.
¹⁶ Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus.
¹⁷ Paediatric Immunology and Infectious Diseases, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.
¹⁸ Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁹ Translational and Clinical Research Institute, Newcastle University.
²⁰ Department of Paediatric Immunology and Infectious Diseases, Great North Children's Hospital, Newcastle upon Tyne, England, UK.
²¹ Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
²² Imagine Institute, University Paris Cité, Paris, France.
²³ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
²⁴ Howard Hughes Medical Institute, New York, NY, USA.
²⁵ Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.
²⁶ Faculty of Medicine, Technion, Haifa, Israel.
²⁷ Unité d'immunologie pédiatrique, Hôpital Necker Enfants Malades, Paris.
²⁸ Department of Pediatrics, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, KU Leuven, Leuven, Belgium, ERN-RITA Core Center.
²⁹ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³⁰ International Patient Organisation for Primary Immunodeficiencies (IPOPI), Brussels, Belgium.
³¹ Department of Laboratory Medicine, Clinical Immunology, Karolinska Institutet, Stockholm.
³² Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
³³ Karolinska ATMP Center, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³⁴ Division of Immunology, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
³⁵ These authors jointly designed, coordinated, and supervised the study.
³⁶ Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany.
³⁷ DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany.
³⁸ CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany.
³⁹ RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Germany.
⁴⁰ Rare Disease Center and Pediatric Research Center, Children and Adolescents, University of Helsinki, HUS Helsinki University Hospital, ERN-RITA Core Center, RITAFIN, Helsinki.
⁴¹ Translational Immunology Research Program, University of Helsinki, Finland.
⁴² Pediatric Immuno-Hematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁴³ Styrian Children's Cancer Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.

PMID: 40568655
PMCID: PMC12191083
DOI: 10.1101/2025.02.20.25322586

Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients

Gerhard Kindle et al. medRxiv. 2025.

[Preprint]. 2025 Apr 16:2025.02.20.25322586.

doi: 10.1101/2025.02.20.25322586.

Authors

Affiliations

¹ Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
² Centre for Biobanking FREEZE, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ These authors contributed equally and should be considered aequo loco.
⁴ French National Reference Center for Primary Immune Deficiencies (CEREDIH), Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁵ Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München, Munich Germany.
⁶ Barts Health National Health Service Trust, London, United Kingdom.
⁷ Molecular and Cellular Immunology Section, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, London, United Kingdom.
⁸ Department of Immunology, St James's Hospital, & School of Medicine, Trinity College Dublin, Ireland.
⁹ Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University and University Hospital, Duesseldorf, Germany.
¹⁰ Pediatric Immunology and Rheumatology Referral Center, 1st Department of Pediatrics, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece.
¹¹ Department of Translational Medical Sciences, Federico II University, Naples, Italy.
¹² Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹³ The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
¹⁴ Department of Pediatrics and University Center for Rare Diseases, Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany.
¹⁵ German Center for Child and Adolescent Health (DZKJ), partner site Leipzig/Dresden, Dresden, Germany.
¹⁶ Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus.
¹⁷ Paediatric Immunology and Infectious Diseases, Sheffield Children's NHS Foundation Trust, Sheffield, United Kingdom.
¹⁸ Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁹ Translational and Clinical Research Institute, Newcastle University.
²⁰ Department of Paediatric Immunology and Infectious Diseases, Great North Children's Hospital, Newcastle upon Tyne, England, UK.
²¹ Laboratory of Human Genetics of Infectious Diseases, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
²² Imagine Institute, University Paris Cité, Paris, France.
²³ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
²⁴ Howard Hughes Medical Institute, New York, NY, USA.
²⁵ Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.
²⁶ Faculty of Medicine, Technion, Haifa, Israel.
²⁷ Unité d'immunologie pédiatrique, Hôpital Necker Enfants Malades, Paris.
²⁸ Department of Pediatrics, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, KU Leuven, Leuven, Belgium, ERN-RITA Core Center.
²⁹ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³⁰ International Patient Organisation for Primary Immunodeficiencies (IPOPI), Brussels, Belgium.
³¹ Department of Laboratory Medicine, Clinical Immunology, Karolinska Institutet, Stockholm.
³² Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
³³ Karolinska ATMP Center, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³⁴ Division of Immunology, Dept of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
³⁵ These authors jointly designed, coordinated, and supervised the study.
³⁶ Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany.
³⁷ DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany.
³⁸ CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany.
³⁹ RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Germany.
⁴⁰ Rare Disease Center and Pediatric Research Center, Children and Adolescents, University of Helsinki, HUS Helsinki University Hospital, ERN-RITA Core Center, RITAFIN, Helsinki.
⁴¹ Translational Immunology Research Program, University of Helsinki, Finland.
⁴² Pediatric Immuno-Hematology and Rheumatology Unit, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁴³ Styrian Children's Cancer Research Unit for Cancer and Inborn Errors of the Blood and Immunity in Children; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.

PMID: 40568655
PMCID: PMC12191083
DOI: 10.1101/2025.02.20.25322586

Abstract

The European Society for Immunodeficiencies patient registry (ESID-R), established in 1994, is one of the world's largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy. Data from 194 centers in 33 countries capture clinical manifestations and treatments from birth onward, with annually expected updates. This report reviews the ESID-R's structure, data content, and impact. The registry includes 30,628 patient datasets (aged 0-97.9 years; median follow-up: 7.2 years; total 825,568.2 patient-years), with 13,550 cases in 15 sub-studies. It has produced 84 peer-reviewed publications (mean citation rate: 95). Findings include real-world observations of IEI diagnoses, genetic causes, clinical manifestations, treatments, and survival trends. The ESID-R fosters global collaboration, advancing IEI research and patient care. This report highlights the key role of the multi-national ESID-R, led by an independent medical society, in evidence-based discovery.

Keywords: Inborn error of immunity (IEI); online database; overall survival; patient registry; primary immune disorder (PID); primary immunodeficiency (PID).

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Conflict of interest statement

MGS received advisory board honoraria from Pharming. MHA received research support, consulting fees, and speaker honoraria from Octapharma. GK, FC declare no conflict of interest. LRD KU Leuven receives research funding and advisory board honoraria for IM from CSL-Behring and Boehringer-Ingelheim. BS has received travel grants from Pharming, and speaker honoraria from Takeda.Conflict of interest statement at the end of the article.

Figures

**Figure 1.. Ages and main manifestations at onset of inborn errors of immunity (IEI) or primary immune disorders (PID).**
A, age groups of age at disease onset, clinical diagnosis of IEI/PID, and of genetic diagnosis are shown. B, Venn diagram of main manifestations of IEI/PID with absolute patient numbers and proportions.

**Figure 2.. Representation of genetic diagnoses of known IEI/PID in the ESID registry.**
A, the number and proportion of patients with a genetic versus those without a genetic diagnosis is shown in descending order. B, the top 5 genetic defects or deletions registered in the ESIDR per all 10 IUIS categories of IEI are presented; the nomenclature in registry diagnosis and gene fields was not regularly updated/changed, showing, *e.g*., GP91-phox instead of *CYBB* and p47-phox instead of *NCF1*.

**Figure 3.. Major treatment modalities of patients with IEI/PID as recorded in the ESID-R.**
Relative proportions of major treatments such as immunoglobulin replacement therapy (data on route, interval and dose were recorded but are not shown), allogeneic hematopoietic stem cell transplantation (AlloSCT), autologous gene therapy (GT) and on splenectomy. Only a proportion of centers recorded data on immune modifying treatment (not shown), and the ESID-R does not capture data on antimicrobial therapy. “Unknown/not listed” and IgRT refer to the latest follow-up time point.

**Figure 4.. Survival probabilities of main categories of IEI/PID and the living status at last news.**
A, Inverse cumulative incidence curves as described and referenced in the supplementary material. Start = age at diagnosis, stop = age at last news, event = living status (0= censored, 1 = deceased first, 2 = curative therapy first). There were 21,206 patients censored, 1,960 patients who deceased first, and 2,901 patients who had a curative therapy first (not showing deaths after curative therapy); roman numbers refer to the IUIS categories for IEI/PID as listed in Figure 2B.

**Figure 5.. Number, categories and citation counts of ESID-R-based publications.**
A total of 7,980 citations of 84 peer-reviewed ESID-R-based publications until early 2024 was recorded. See also the website for regular updates of ESID-R-related publications at https://esid.org/working-parties/registry-working-party/registry-publications/

See this image and copyright information in PMC

References

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1. Vaseghi-Shanjani M, Smith KL, Sara RJ, Modi BP, Branch A, Sharma M, Lu HY, James EL, Hildebrand KJ, Biggs CM, Turvey SE. Inborn errors of immunity manifesting as atopic disorders. The Journal of allergy and clinical immunology 2021;148(5):1130–39 doi: 10.1016/j.jaci.2021.08.008. - DOI - PubMed

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This is a preprint.

Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients

Affiliations

Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

LinkOut - more resources

Full Text Sources