Skip to main content
Top
Published in: Journal of Clinical Immunology 8/2023

Open Access 28-09-2023 | Immunodeficiency | Original Article

Missed Opportunities to Diagnose Common Variable Immunodeficiency: a Population-Based Case–Control Study Identifying Indicator Diseases for Common Variable Immunodeficiency

Authors: Christina Dahl, Inge Petersen, Frederik V. Ilkjær, Lena Westh, Terese L. Katzenstein, Ann-Brit E. Hansen, Thyge L. Nielsen, Carsten S. Larsen, Isik S. Johansen, Line D. Rasmussen

Published in: Journal of Clinical Immunology | Issue 8/2023

Login to get access

Abstract

Purpose

Delayed diagnosis of common variable immunodeficiency (CVID) remains a serious problem. We investigated whether some diseases diagnosed during out-patient visits or admission to hospitals could act as indicator conditions for CVID diagnosis.

Methods

In this nested case–control study, we identified 128 cases diagnosed with CVID in Denmark (1999–2013) and 640 age-, gender-, and region-matched controls. We obtained data on diseases diagnosed at hospitals in the five years before CVID diagnosis from The National Hospital Registry. We grouped hospital diagnoses in 33 major disease categories and 210 subcategories. We used conditional logistic regression to calculate the odds ratios (OR) and 95% confidence intervals (CI) to estimate associations between disease exposure and subsequent CVID.

Results

During the five years preceding a CVID diagnosis, cases had four times as many hospital contacts as the controls (p < 0.001). A diagnosis in 18 major disease categories showed a significant OR for subsequent diagnosis of CVID. The most substantial association with a subsequent CVID diagnosis was a diagnosis of lower respiratory tract infections (OR: 29.9; 95% CI: 14.2–63.2) and lung diseases (35.1; 15.0–82.5). We observed a similar association when we removed the last year before diagnosis from analysis and overall, in the years < 1, ≥ 1–3, and ≥ 3–5 before diagnosis, although the absolute number of exposures was small. Twenty-eight specific diseases displayed an at least 3-fold risk of subsequent CVID diagnosis.

Conclusion

Targeted screening for antibody deficiency in patients diagnosed with specific diseases associated with CVID may lead to earlier CVID diagnosis and treatment and thereby potentially reduced morbidity and mortality.
Appendix
Available only for authorised users
Literature
1.
go back to reference Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, Morena TDL, et al. International consensus document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(1):38–59.CrossRef Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, Morena TDL, et al. International consensus document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(1):38–59.CrossRef
2.
go back to reference Westh L, Mogensen TH, Dalgaard LS, Bernth Jensen JM, Katzenstein T, Hansen AE, et al. Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort. Scand J Immunol. 2017;85(6):450–61.CrossRefPubMed Westh L, Mogensen TH, Dalgaard LS, Bernth Jensen JM, Katzenstein T, Hansen AE, et al. Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort. Scand J Immunol. 2017;85(6):450–61.CrossRefPubMed
3.
go back to reference Peng Y, Chen Y, Wang Y, Wang W, Qiao S, Lan J, Wang M. Dysbiosis and primary B-cell immunodeficiencies: current knowledge and future perspective. Immunol Res. 2023;71(4):528–36. Peng Y, Chen Y, Wang Y, Wang W, Qiao S, Lan J, Wang M. Dysbiosis and primary B-cell immunodeficiencies: current knowledge and future perspective. Immunol Res. 2023;71(4):528–36.
4.
go back to reference Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, Aghamohammadi A. Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management. J Investig Allergol Clin Immunol. 2020;30(1):14–34.CrossRefPubMed Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, Aghamohammadi A. Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, diagnosis, classification, and management. J Investig Allergol Clin Immunol. 2020;30(1):14–34.CrossRefPubMed
5.
go back to reference Mormile I, Punziano A, Riolo CA, Granata F, Williams M, de Paulis A, Spadaro G, Rossi FW. Common variable immunodeficiency and autoimmune diseases: a retrospective study of 95 adult patients in a single tertiary care center. Front Immunol. 2021;12:652487.CrossRefPubMedPubMedCentral Mormile I, Punziano A, Riolo CA, Granata F, Williams M, de Paulis A, Spadaro G, Rossi FW. Common variable immunodeficiency and autoimmune diseases: a retrospective study of 95 adult patients in a single tertiary care center. Front Immunol. 2021;12:652487.CrossRefPubMedPubMedCentral
6.
go back to reference Ho HE, Cunningham-Rundles C. Non-infectious complications of common variable immunodeficiency: updated clinical spectrum, sequelae, and insights to pathogenesis. Front Immunol. 2020;11:149.CrossRefPubMedPubMedCentral Ho HE, Cunningham-Rundles C. Non-infectious complications of common variable immunodeficiency: updated clinical spectrum, sequelae, and insights to pathogenesis. Front Immunol. 2020;11:149.CrossRefPubMedPubMedCentral
7.
go back to reference Bruns L, Panagiota V, von Hardenberg S, Schmidt G, Adriawan IR, Sogka E, et al. Common variable immunodeficiency-associated cancers: the role of clinical phenotypes, immunological and genetic factors. Front Immunol. 2022;13:742530.CrossRefPubMedPubMedCentral Bruns L, Panagiota V, von Hardenberg S, Schmidt G, Adriawan IR, Sogka E, et al. Common variable immunodeficiency-associated cancers: the role of clinical phenotypes, immunological and genetic factors. Front Immunol. 2022;13:742530.CrossRefPubMedPubMedCentral
8.
go back to reference Gathmann B, Mahlaoui N, Gérard L, Oksenhendler E, Warnatz K, Schulze I, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116–26.CrossRefPubMed Gathmann B, Mahlaoui N, Gérard L, Oksenhendler E, Warnatz K, Schulze I, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116–26.CrossRefPubMed
9.
go back to reference Graziano V, Pecoraro A, Mormile I, Quaremba G, Genovese A, et al. Delay in diagnosis affects the clinical outcome in a cohort of CVID patients with marked reduction of iga serum levels. Clin Immunol. 2017;180:1–4.CrossRefPubMed Graziano V, Pecoraro A, Mormile I, Quaremba G, Genovese A, et al. Delay in diagnosis affects the clinical outcome in a cohort of CVID patients with marked reduction of iga serum levels. Clin Immunol. 2017;180:1–4.CrossRefPubMed
10.
go back to reference Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed diagnosis and complications of predominantly antibody deficiencies in a cohort of Australian Adults. Front Immunol. 2018;9:694.CrossRefPubMedPubMedCentral Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed diagnosis and complications of predominantly antibody deficiencies in a cohort of Australian Adults. Front Immunol. 2018;9:694.CrossRefPubMedPubMedCentral
11.
go back to reference Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Italian primary immunodeficiency network. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3):308–16.CrossRefPubMed Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Italian primary immunodeficiency network. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3):308–16.CrossRefPubMed
12.
go back to reference Ziętkiewicz M, Więsik-Szewczyk E, Matyja-Bednarczyk A, Napiórkowska-Baran K, Zdrojewski Z, Jahnz-Różyk K. Shorter diagnostic delay in Polish adult patients with common variable immunodeficiency and symptom onset after 1999. Front Immunol. 2020;11:982.CrossRefPubMedPubMedCentral Ziętkiewicz M, Więsik-Szewczyk E, Matyja-Bednarczyk A, Napiórkowska-Baran K, Zdrojewski Z, Jahnz-Różyk K. Shorter diagnostic delay in Polish adult patients with common variable immunodeficiency and symptom onset after 1999. Front Immunol. 2020;11:982.CrossRefPubMedPubMedCentral
13.
go back to reference Odnoletkova I, Kindle G, Quinti I, Grimbacher B, Knerr V, Gathmann B, et al. The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J Rare Dis. 2018;13(1):201.CrossRefPubMedPubMedCentral Odnoletkova I, Kindle G, Quinti I, Grimbacher B, Knerr V, Gathmann B, et al. The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J Rare Dis. 2018;13(1):201.CrossRefPubMedPubMedCentral
14.
go back to reference Rider NL, Kutac C, Hajjar J, Scalchunes C, Seeborg FO, Boyle M, Orange JS. Health-related quality of life in adult patients with common variable immunodeficiency disorders and impact of treatment. J Clin Immunol. 2017;37(5):461–75.CrossRefPubMedPubMedCentral Rider NL, Kutac C, Hajjar J, Scalchunes C, Seeborg FO, Boyle M, Orange JS. Health-related quality of life in adult patients with common variable immunodeficiency disorders and impact of treatment. J Clin Immunol. 2017;37(5):461–75.CrossRefPubMedPubMedCentral
15.
go back to reference Ilkjær FV, Rasmussen LD, Martin-Iguacel R, Westh L, Katzenstein TL, Hansen AE, et al. How to identify common variable immunodeficiency patients earlier: general practice patterns. J Clin Immunol. 2019;39(7):641–52.CrossRefPubMed Ilkjær FV, Rasmussen LD, Martin-Iguacel R, Westh L, Katzenstein TL, Hansen AE, et al. How to identify common variable immunodeficiency patients earlier: general practice patterns. J Clin Immunol. 2019;39(7):641–52.CrossRefPubMed
16.
go back to reference Janssen LMA, van der Flier M, de Vries E. Lessons learned from the clinical presentation of common variable immunodeficiency disorders: a systematic review and meta-analysis. Front Immunol. 2021;12:620709.CrossRefPubMedPubMedCentral Janssen LMA, van der Flier M, de Vries E. Lessons learned from the clinical presentation of common variable immunodeficiency disorders: a systematic review and meta-analysis. Front Immunol. 2021;12:620709.CrossRefPubMedPubMedCentral
18.
go back to reference Schmidt M, Schmidt SAJ, Adelborg K, Sundbøll J, Laugesen K, Ehrenstein V, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11:563–91.CrossRefPubMedPubMedCentral Schmidt M, Schmidt SAJ, Adelborg K, Sundbøll J, Laugesen K, Ehrenstein V, et al. The Danish health care system and epidemiological research: from health care contacts to database records. Clin Epidemiol. 2019;11:563–91.CrossRefPubMedPubMedCentral
19.
20.
go back to reference Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39(7 Suppl):30–3.CrossRefPubMed Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39(7 Suppl):30–3.CrossRefPubMed
21.
go back to reference Søgaard OS, Lohse N, Østergaard L, Kronborg G, Røge B, Gerstoft J, et al. Morbidity and risk of subsequent diagnosis of HIV: a population based case control study identifying indicator diseases for HIV infection. PloS One. 2012;7(3):e32538.CrossRefPubMedPubMedCentral Søgaard OS, Lohse N, Østergaard L, Kronborg G, Røge B, Gerstoft J, et al. Morbidity and risk of subsequent diagnosis of HIV: a population based case control study identifying indicator diseases for HIV infection. PloS One. 2012;7(3):e32538.CrossRefPubMedPubMedCentral
22.
go back to reference Ilkjær FV, Rasmussen LD, Martin-Iguacel R, Westh L, Katzenstein TL, Nielsen TL, et al. Evaluating of drug prescription patterns in undiagnosed common variable immunodeficiency patients. J Clin Immunol. 2023 (In review). Ilkjær FV, Rasmussen LD, Martin-Iguacel R, Westh L, Katzenstein TL, Nielsen TL, et al. Evaluating of drug prescription patterns in undiagnosed common variable immunodeficiency patients. J Clin Immunol. 2023 (In review).
23.
go back to reference Cabañero-Navalon MD, Garcia-Bustos V, Nuñez-Beltran M, Císcar Fernández P, Mateu L, Solanich X, et al. Current clinical spectrum of common variable immunodeficiency in Spain: the multicentric nationwide GTEM-SEMI-CVID registry. Front Immunol. 2022;13:1033666.CrossRefPubMedPubMedCentral Cabañero-Navalon MD, Garcia-Bustos V, Nuñez-Beltran M, Císcar Fernández P, Mateu L, Solanich X, et al. Current clinical spectrum of common variable immunodeficiency in Spain: the multicentric nationwide GTEM-SEMI-CVID registry. Front Immunol. 2022;13:1033666.CrossRefPubMedPubMedCentral
24.
go back to reference Zainaldain H, Rizvi FS, Rafiemanesh H, Alizadeh M, Jamee M, Mohammadi S, Kiaee F, et al. Infectious complications reporting in common variable immunodeficiency: a systematic review and meta-analysis. Oman Med J. 2020;35(4):e157.CrossRefPubMedPubMedCentral Zainaldain H, Rizvi FS, Rafiemanesh H, Alizadeh M, Jamee M, Mohammadi S, Kiaee F, et al. Infectious complications reporting in common variable immunodeficiency: a systematic review and meta-analysis. Oman Med J. 2020;35(4):e157.CrossRefPubMedPubMedCentral
25.
go back to reference Mohammadi F, Yadegar A, Mardani M, Ayati A, Abolhassani H, Rezaei N. Organ-based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians. Immun Inflamm Dis. 2023;11(4):e833.CrossRefPubMedPubMedCentral Mohammadi F, Yadegar A, Mardani M, Ayati A, Abolhassani H, Rezaei N. Organ-based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians. Immun Inflamm Dis. 2023;11(4):e833.CrossRefPubMedPubMedCentral
27.
go back to reference Fioranelli M, Bottaccioli AG, Bottaccioli F, Bianchi M, Rovesti M, Roccia MG. Stress and inflammation in coronary artery disease: a review psychoneuroendocrineimmunology-based. Front Immunol. 2018;9:2031.CrossRefPubMedPubMedCentral Fioranelli M, Bottaccioli AG, Bottaccioli F, Bianchi M, Rovesti M, Roccia MG. Stress and inflammation in coronary artery disease: a review psychoneuroendocrineimmunology-based. Front Immunol. 2018;9:2031.CrossRefPubMedPubMedCentral
28.
go back to reference Cunningham-Rundles C, Sidi P, Estrella L, Doucette J. Identifying undiagnosed primary immunodeficiency diseases in minority subjects by using computer sorting of diagnosis codes. J Allergy Clin Immunol. 2004;113(4):747–55.CrossRefPubMed Cunningham-Rundles C, Sidi P, Estrella L, Doucette J. Identifying undiagnosed primary immunodeficiency diseases in minority subjects by using computer sorting of diagnosis codes. J Allergy Clin Immunol. 2004;113(4):747–55.CrossRefPubMed
29.
go back to reference Modell V, Quinn J, Ginsberg G, Gladue R, Orange J, Modell F. Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement. Immunol Res. 2017;65(3):713–20.CrossRefPubMed Modell V, Quinn J, Ginsberg G, Gladue R, Orange J, Modell F. Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement. Immunol Res. 2017;65(3):713–20.CrossRefPubMed
30.
go back to reference Nickelsen TN. Data validity and coverage in the Danish National Health Registry. A literature review. Ugeskr Laeger. 2001;164(1):33–7.PubMed Nickelsen TN. Data validity and coverage in the Danish National Health Registry. A literature review. Ugeskr Laeger. 2001;164(1):33–7.PubMed
Metadata
Title
Missed Opportunities to Diagnose Common Variable Immunodeficiency: a Population-Based Case–Control Study Identifying Indicator Diseases for Common Variable Immunodeficiency
Authors
Christina Dahl
Inge Petersen
Frederik V. Ilkjær
Lena Westh
Terese L. Katzenstein
Ann-Brit E. Hansen
Thyge L. Nielsen
Carsten S. Larsen
Isik S. Johansen
Line D. Rasmussen
Publication date
28-09-2023
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 8/2023
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-023-01590-9

Other articles of this Issue 8/2023

Journal of Clinical Immunology 8/2023 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine