Abstract
Common variable immunodeficiency disorders (CVID) are the most frequent symptomatic primary immune deficiencies in adults and children. In addition to recurrent and severe infections, patients with CVID are susceptible to autoimmune and inflammatory complications. The aetiologies of these uncommon conditions are, by definition, unknown. When the causes of complex disorders are uncertain, diagnostic criteria may offer valuable guidance to the management of patients. Over the last two decades, there have been four sets of diagnostic criteria for CVID in use. The original 1999 European Society for Immunodeficiencies and Pan-American Society for Immunodeficiency (ESID/PAGID) criteria are less commonly used than the three newer criteria: Ameratunga et al (Clin Exp Immunol 174:203–211, 2013), ESID (J Allergy Clin Immunol Pract, 2019) and ICON (J Allergy Clin Immunol Pract 4:38–59, 2016) criteria. The primary aim of the present study was to compare the utility of diagnostic criteria in a well-characterised cohort of CVID patients. The New Zealand CVID cohort study (NZCS) commenced in 2006 and currently comprises one hundred and thirteen patients, which represents approximately 70% of all known CVID patients in NZ. Many patients have been on subcutaneous or intravenous (SCIG/IVIG) immunoglobulin treatment for decades. Patients were given a clinical diagnosis of CVID as most were diagnosed before the advent of newer diagnostic criteria. Application of the three commonly used CVID diagnostic criteria to the NZCS showed relative sensitivities as follows: Ameratunga et al (Clin Exp Immunol 174:203–211, 2013), possible and probable CVID, 88.7%; ESID (J Allergy Clin Immunol Pract, 2019), 48.3%; and ICON (J Allergy Clin Immunol Pract 4:38–59, 2016), 47.1%. These differences were mostly due to the low rates of diagnostic vaccination challenges in patients prior to commencing SCIG/IVIG treatment and mirror similar findings in CVID cohorts from Denmark and Finland. Application of the Ameratunga et al (Clin Exp Immunol 174:203–211, 2013) CVID diagnostic criteria to patients on SCIG/IVIG may obviate the need to stop treatment for vaccine studies, to confirm the diagnosis.
Similar content being viewed by others
References
Abbott JK, Gelfand EW (2015) Common variable immunodeficiency : diagnosis, management, and treatment. Immunol Allergy Clin North Am 35:637–658
Ameratunga R. (2018) Assessing disease severity in common variable immunodeficiency disorders (CVID) and CVID-like disorders. Frontiers in immunology 9
Ameratunga R, Brewerton M, Slade C et al (2014) Comparison of diagnostic criteria for Common Variable Immunodeficiency Disorder. Front Immunol 5:415
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R (2013) New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clin Exp Immunol 174:203–211
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
Bonilla FA, Barlan I, Chapel H et al (2016) International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract 4:38–59
Maffucci P, Filion CA, Boisson B et al (2016) Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol 7:220
Abolhassani H, Chou J, Bainter W et al (2018) Clinical, immunologic, and genetic spectrum of 696 patients with combined immunodeficiency. J Allergy Clin Immunol 141:1450–1458
Conley ME, Notarangelo LD, Etzioni A (1999) Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clinical immunology (Orlando, Fla) 93:190–7
Seppanen M, Aghamohammadi A, Rezaei N (2013) Is there a need to redefine the diagnostic criteria for common variable immunodeficiency? Expert review of clinical immunology
Sorensen RU, Leiva LE, Javier FC 3rd et al (1998) Influence of age on the response to Streptococcus pneumoniae vaccine in patients with recurrent infections and normal immunoglobulin concentrations. J Allergy Clin Immunol 102:215–221
Paris K, Sorensen RU (2007) Assessment and clinical interpretation of polysaccharide antibody responses. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 99:462–464
Beck SC (2013) Making sense of serotype-specific pneumococcal antibody measurements. Ann Clin Biochem 50:517–519
Ferry BL, Misbah SA, Stephens P et al (2004) Development of an anti-Salmonella typhi Vi ELISA: assessment of immunocompetence in healthy donors. Clin Exp Immunol 136:297–303
Ameratunga R, Storey P, Barker R, Jordan A, Koopmans W, Woon ST (2015) Application of diagnostic and treatment criteria for common variable immunodeficiency disorder. Expert Rev Clin Immunol 12:257–266
Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R (2014) New diagnostic criteria for CVID. Expert Rev Clin Immunol 10:183–186
Ameratunga R, Gillis D, Steele R (2016) Diagnostic criteria for common variable immunodeficiency disorders. J Allergy Clin Immunol Pract 4:1017–1018
Oksenhendler E, Gerard L, Fieschi C et al (2008) Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis 46:1547–1554
Ameratunga R, Ahn Y, Tse D et al (2019) The critical role of histology in distinguishing sarcoidosis from common variable immunodeficiency disorder (CVID) in a patient with hypogammaglobulinemia. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 15:78
Ameratunga R, Becroft DM, Hunter W (2000) The simultaneous presentation of sarcoidosis and common variable immune deficiency. Pathology 32:280–282
Ameratunga R, Ahn Y, Jordan A, Lehnert K, Brothers S, Woon ST (2018) Keeping it in the family: the case for considering late onset combined immunodeficiency a subset of common variable immunodeficiency disorders. Expert Rev Clin Immunol 14:549–556
Ameratunga R, Jordan A, Cavadino A et al (2021) Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study. Clinical and experimental immunology
Ameratunga R, Ahn Y, Steele R, Woon S-T (2019) The natural history of untreated primary hypogammaglobulinemia in adults: Implications for the diagnosis and treatment of Common Variable Immunodeficiency Disorders (CVID). Frontiers Immunology 17(10):1541
Ameratunga R, Steele R, Jordan A et al (2016) The case for a national service for primary immune deficiency disorders in New Zealand. N Z Med J 129:75–90
Empson M, Sinclair J, O’Donnell J, Ameratunga R, Fitzharris P, Steele R (2004) The assessment and management of primary antibody deficiency. N Z Med J 117:U914
Orange JS, Ballow M, Stiehm ER et al (2012) Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol 130:S1-24
Rose MA, Buess J, Ventur Y et al (2013) Reference ranges and cutoff levels of pneumococcal antibody global serum assays (IgG and IgG2) and specific antibodies in healthy children and adults. Med Microbiol Immunol 202:285–294
Lopez B, Bahuaud M, Fieschi C et al (2017) Value of the overall pneumococcal polysaccharide response in the diagnosis of primary humoral immunodeficiencies. Frontiers in immunology 8
Ameratunga R, Allan C, Lehnert K, Woon ST (2021) Perspective: Application of the American College of Medical Genetics Variant Interpretation Criteria to Common Variable Immunodeficiency Disorders. LID - https://doi.org/10.1007/s12016-020-08828-z. Clin Rev Allergy Immunol 2021;in press
Ameratunga R, Barker R, Steele R et al (2015) Profound reversible hypogammaglobulinemia caused by celiac disease in the absence of protein losing enteropathy. J Clin Immunol 35:589–594
Ameratunga R, Lindsay K, Woon S-T, Jordan A, Anderson NE, Koopmans W (2015) New diagnostic criteria could distinguish common variable immunodeficiency disorder from anticonvulsant-induced hypogammaglobulinemia. Clinical and experimental Neuroimmunology 6:83–88
Smith J, Fernando T, McGrath N, Ameratunga R (2004) Lamotrigine-induced common variable immune deficiency. Neurology 62:833–834
Ameratunga R. V CP, Parry S, Kendi C (2013) Hypogammaglobulinemia factitia. Munchausen syndrome presenting as Common Variable Immune Deficiency. Allergy Asthma and Clinical Immunology 2013;9
Fliegauf M, L. Bryant V, Frede N et al (2015) Haploinsufficiency of the NF-κB1 Subunit p50 in common variable immunodeficiency. The American Journal of Human Genetics 97:389–403
Lorenzini T, Fliegauf M, Klammer N et al (2020) Characterization of the clinical and immunological phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J Allergy Clin Immunol 9:051
Ameratunga R, Koopmans W, Woon ST et al (2017) Epistatic interactions between mutations of TACI (TNFRSF13B) and TCF3 result in a severe primary immunodeficiency disorder and systemic lupus erythematosus. Clin Transl Immunology 6:e159
Ameratunga R, Woon ST, Bryant VL et al (2018) Clinical implications of digenic inheritiance and epistasis in primary immunodeficiency disorders. Front Immunol 8:1965
Pan-Hammarstrom Q, Salzer U, Du L et al (2007) Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 39:429–430
Ameratunga R, Allan C, Woon ST (2020) Defining common variable immunodeficiency disorders in 2020. Immunol Allergy Clin North Am 40:403–420. https://doi.org/10.1016/j.iac.2020.03.001 (Epub Jun 7)
Romberg N, Chamberlain N, Saadoun D et al (2013) CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Investig 123:4283–4293
Ameratunga R, Ahn Y, Steele R, Woon ST (2019) Transient hypogammaglobulinemia of infancy: many patients recover in adolescence and adulthood. Clin Exp Immunol 198:224–232
Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY (1998) Reference distributions for immunoglobulins A, G, and M: a practical, simple, and clinically relevant approach in a large cohort. J Clin Lab Anal 12:363–370
Ameratunga R, Woon ST (2019) Perspective: evolving concepts in the diagnosis and understanding of common variable immunodeficiency disorders (CVID). Clinical reviews in allergy & immunology 2019;(in press)
Ameratunga R, Lehnert K, Woon ST et al (2018) Review: Diagnosing common variable immunodeficiency disorder in the era of genome sequencing. Clin Rev Allergy Immunol 54:261–268
Ameratunga R, Lehnert K, Woon ST (2019) All patients with common variable immunodeficiency disorders (CVID) should be routinely offered diagnostic genetic testing. Front Immunol 10:2678
Westh L, Mogensen TH, Dalgaard LS et al (2017) Identification and characterization of a nationwide danish adult common variable immunodeficiency cohort. Scand J Immunol 85:450–461
Bright P, Grigoriadou S, Kamperidis P, Buckland M, Hickey A, Longhurst HJ (2013) Changes in B cell immunophenotype in common variable immunodeficiency: cause or effect—is bronchiectasis indicative of undiagnosed immunodeficiency? Clin Exp Immunol 171:195–200
Koopmans W, Woon ST, Zeng IS et al (2013) Variability of memory B cell markers in a cohort of common variable immune deficiency patients over six months. Scand J Immunol 77:470–475
Selenius JS, Martelius T, Pikkarainen S et al (2017) Unexpectedly high prevalence of common variable immunodeficiency in Finland. Front Immunol 8:1190
Acknowledgements
This nation-wide study was approved by the multiregional ethics committee of the New Zealand Ministry of Health (MEC 06/10/134) and the Auckland District Health Board (ADHB) ethics committee (3435). Informed consent was required for this study. Consent to publish was part of the ethics approval and patient consent. RA conducted the study, S-TW checked the data, and HL and RS made editorial contributions to the manuscript. We thank our patients for participating in these studies for the benefit of others. We thank colleagues for referring patients to our studies. The original publications relevant to diagnostic criteria and NZ patients described in case reports are cited in this article. No data will be made available as it could identify individual patients.
Funding
The authors received financial support from ASCIA, the A + Trust, and IDFNZ.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Ameratunga, R., Longhurst, H., Steele, R. et al. Comparison of Diagnostic Criteria for Common Variable Immunodeficiency Disorders (CVID) in the New Zealand CVID Cohort Study. Clinic Rev Allerg Immunol 61, 236–244 (2021). https://doi.org/10.1007/s12016-021-08860-7
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12016-021-08860-7