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Clinical and Phenotypic Characterization of Common Variable Immunodeficiency Diagnosed in Younger and Older Adults

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Abstract

Purpose

Common variable immunodeficiency (CVID) is the most prevalent symptomatic immunodeficiency in adults. Little is known about the manifestations of CVID presenting in older adults. Herein, we performed a phenotypic characterization of patients diagnosed older than age 40.

Methods

A retrospective chart review of 79 patients seen at UF Health between 2006 and 2020 with a verified diagnosis of CVID per the ICON 2016 criteria was conducted. Patients were classified according to four phenotypes: no-disease-related complications, autoimmune cytopenias, polyclonal lymphoproliferation, and unexplained enteropathy. Patients diagnosed with CVID from age 2 to 40 (n = 41, “younger cohort”) were compared to patients diagnosed with CVID age 41 and older (n = 38, “older cohort”).

Results

Among the younger cohort, pathologic genetic variants, positive family history for immunodeficiency, autoimmunity (49% vs 24%, p = 0.03), and splenomegaly (46% vs 16%, p = 0.004) were more common, as was the “autoimmune cytopenias” phenotype (24% vs 3%, p = 0.007). Among the older cohort, lymphoma (11% vs 0%, p = 0.049) and the “no disease-related complications” phenotype (79% vs 57%, p = 0.03) were more commonly seen. Comorbidities such as bronchiectasis (27% vs 21%, p = 0.61), GI involvement (34% vs 24%, p = 0.33), and GLILD (5% vs 8%, p = 0.67) were equally present among both the younger and older cohorts, respectively.

Conclusion

The lower incidence of autoimmunity and splenomegaly, as well as overlapping clinical features with immunosenescence, may make diagnosing CVID in older patients more challenging; however, the disease is not more indolent as the risks for lymphoma, bronchiectasis, and GLILD are similar to those of younger patients.

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Data Availability

The datasets and analysis are available from the corresponding author on request.

Abbreviations

AID:

Activation-induced cytidine deaminase

BALT:

Bronchus-associated lymphoid tissue

CVID:

Common variable immunodeficiency

GLILD:

Granulomatous lymphocytic interstitial lung disease

ICON:

International consensus document

LOCID:

Late-onset combined immune deficiency

USIDNET:

United States Immunodeficiency Network

UTI:

Urinary tract infection

References

  1. 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):116–126.

  2. Baloh C, Reddy A, Henson M, Prince K, Buckley R, Lugar P. 30-Year Review of Pediatric- and Adult-Onset CVID: Clinical Correlates and Prognostic Indicators. J Clin Immunol. 2019;39(7):678–687.

  3. Aggarwal V, Banday AZ, Jindal AK, Das J, Rawat A. Recent advances in elucidating the genetics of common variable immunodeficiency. Genes Dis. 2020 Mar;7(1):26–37.

  4. van Schouwenburg PA, Davenport EE, Kienzler AK, Marwah I, Wright B, Lucas M, et al. Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders. Clin Immunol. 2015;160(2):301–314.

  5. Abolhassani H, Hammarström L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135(9):656–67.

    Article  Google Scholar 

  6. Li J, Wei Z, Li YR, Maggadottir SM, Chang X, Desai A, et al. Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches. Biochimica et Biophysica Acta (BBA) - General Subjects. 2016; 1860(11):2656–2663.

  7. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650–1657.

  8. Sanchez LA, Maggadottir SM, Pantell MS, Lugar P, Rundles CC, Sullivan KE. Two Sides of the Same Coin: Pediatric-Onset and Adult-Onset Common Variable Immune Deficiency. J Clin Immunol. 2017;37(6):678–687.

  9. Ogershok PR, Hogan MB, Welch JE, Corder WT, Wilson NW. Spectrum of illness in pediatric common variable immunodeficiency. Ann Allergy Asthma Immunol. 2006;97(5):653–656.

  10. Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3):308–316.

  11. Chapel H, Lucas M, Patel S, Lee M, Cunningham-Rundles C, Resnick E, et al. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts. J Allergy Clin Immunol. 2012 Nov;130(5):1197–1198.

  12. Lord JM, Butcher S, Killampali V, Lascelles D, Salmon M. Neutrophil ageing and immunesenescence. Mech Ageing Dev. 2001;122(14):1521–1535.

  13. Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, et al. Shortage of circulating naive CD8+ T cells provides new insights on immunodeficiency in aging. Blood. 2000;95(9):2860–2868.

  14. Paget J, Spreeuwenberg P, Charu V, Taylor RJ, Iuliano AD, Bresee J, et al. Global mortality associated with seasonal influenza epidemics: New burden estimates and predictors from the GLaMOR Project. J Global Health. 2019;9(2):020421.

  15. Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev. 2011;10(3):330–335.

  16. Bulati M, Buffa S, Candore G, Caruso C, Dunn-Walters DK, Pellicanò M, et al. B cells and immunosenescence: A focus on IgG+IgD−CD27− (DN) B cells in aged humans. Ageing Res Rev. 2011;10(2):274–284.

  17. Dorrington MG, Bowdish DME. Immunosenescence and Novel Vaccination Strategies for the Elderly. Front Immunol. 2013;4:171.

  18. Hainz U, Jenewein B, Asch E, Pfeiffer KP, Berger P, Grubeck-Loebenstein B. Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. Vaccine. 2005;23(25):3232–3235.

  19. Stervbo U, Bozzetti C, Baron U, Jürchott K, Meier S, Mälzer JN, et al. Effects of aging on human leukocytes (part II): immunophenotyping of adaptive immune B and T cell subsets. AGE. 2015;37(5):93.

  20. Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology. 2007;120(4):435–446.

  21. Vadasz Z, Haj T, Kessel A, Toubi E. Age-related autoimmunity. BMC Medicine. 2013;11:94.

  22. Malphettes M, Gérard L, Carmagnat M, Mouillot G, Vince N, Boutboul D, et al. Late‐Onset Combined Immune Deficiency: A Subset of Common Variable Immunodeficiency with Severe T Cell Defect. Clin Infect Dis. 2009;49(9):1329–1338.

  23. Papakonstantinou I, Baraboutis IG, Karnesis L. Late Onset Combined Immunodeficiency Presenting with Recurrent Pneumocystis jiroveci Pneumonia. Case Rep Med. 2014;2014:801805.

  24. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol: In Practice. 2016;4(1):38–59.

  25. Hare ND, Smith BJ, Ballas ZK. Antibody response to pneumococcal vaccination as a function of preimmunization titer. J Allergy Clin Immunol. 2009;123(1):195–200.

    Article  CAS  Google Scholar 

  26. Orange JS, Ballow M, Stiehm ER, Ballas ZK, Chinen J, de La Morena M, et al. 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. 2012;130(3):S1–24.

    Article  Google Scholar 

  27. Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186–1205.e78.

    Article  Google Scholar 

  28. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277–86.

    Article  CAS  Google Scholar 

  29. Ameratunga R, Woon ST. Perspective: Evolving Concepts in the Diagnosis and Understanding of Common Variable Immunodeficiency Disorders (CVID). Clin Rev Allergy Immunol. 2020;59(1):109–121.

  30. Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116(1):7–15.

  31. Khan R, Habbal M, Scaffidi MA, Bukhari AA, Rumman A, al Ghamdi S, et al. Gastrointestinal Disease in Patients with Common Variable Immunodeficiency: A Retrospective Observational Study. J Can Assoc Gastroenterol. 2020;3(4):162–168.

  32. 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 Dec 12;13(1):201.

  33. Cunningham-Rundles C, Bodian C. Common Variable Immunodeficiency: Clinical and Immunological Features of 248 Patients. Clin Immunol. 1999 Jul;92(1):34–48.

  34. Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, et al. Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. Journal of Investigational Allergology Clin Immunol. 2020 Feb 20;30(1):14–34.

  35. Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016;13:7.

    Google Scholar 

  36. de Valles-Ibáñez G, Esteve-Solé A, Piquer M, González-Navarro EA, Hernandez-Rodriguez J, Laayouni H, et al. Evaluating the Genetics of Common Variable Immunodeficiency: Monogenetic Model and Beyond. Front Immunol. 2018;14:9.

    Google Scholar 

  37. Urschel S, Kayikci L, Wintergerst U, Notheis G, Jansson A, Belohradsky BH. Common Variable Immunodeficiency Disorders in Children: Delayed Diagnosis Despite Typical Clinical Presentation. J Pediatr. 2009;154(6):888–894.

  38. Yakaboski E, Fuleihan RL, Sullivan KE, Cunningham-Rundles C, Feuille E. Lymphoproliferative disease in cvid: a report of types and frequencies from a US patient registry. J Clin Immunol. 2020;40(3):524–530.

  39. Smith A, Crouch S, Lax S, Li J, Painter D, Howell D, et al. Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Br J Cancer. 2015;112(9):1575–1584.

  40. Pedini V, Verga JU, Terrenato I, Menghini D, Mezzanotte C, Danieli MG. Incidence of malignancy in patients with common variable immunodeficiency according to therapeutic delay: an Italian retrospective, monocentric cohort study. Allergy Asthma Clin Immunol. 2020 Dec 26;16(1):54

  41. Khan SR, Chaker L, Ikram MA, Peeters RP, van Hagen PM, Dalm VASH. Determinants and reference ranges of serum immunoglobulins in middle-aged and elderly individuals: a population-based study. J Clin Immunol. 2021;41(8):1902–14.

    Article  CAS  Google Scholar 

  42. Lock RJ, Unsworth DJ. Immunoglobulins and immunoglobulin subclasses in the elderly. Ann Clin Biochem: Int J Lab Med. 2003;40(2):143–8.

    Article  CAS  Google Scholar 

  43. Rosenberg E, Dent PB, Denburg JA. Primary immune deficiencies in the adult: a previously underrecognized common condition. J Allergy Clin Immunol: In Practice. 2016 Nov;4(6):1101–1107.

  44. Pawelec G. Age and immunity: What is “immunosenescence”? Exp Gerontol. 2018;105:4–9.

  45. Schulz AR, Mälzer JN, Domingo C, Jürchott K, Grützkau A, Babel N, et al. Low thymic activity and dendritic cell numbers are associated with the immune response to primary viral infection in elderly humans. J Immunol. 2015;195(10):4699–4711.

  46. Ventura MT, Casciaro M, Gangemi S, Buquicchio R. Immunosenescence in aging: between immune cells depletion and cytokines up-regulation. Clin Mol Allergy. 2017;15(1):21.

  47. Li M, Yao D, Zeng X, Kasakovski D, Zhang Y, Chen S, et al. Age related human T cell subset evolution and senescence. Immunity Ageing. 2019;16(1):24.

  48. Wong GK, Huissoon AP. T-cell abnormalities in common variable immunodeficiency: the hidden defect. J Clin Pathol. 2016 Aug;69(8):233–243.

  49. Bateman EAL, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, et al. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol. 2012;170(2):202–211.

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Funding

This work was in part completed by a student who received a stipend of $2,000 from her academic institution, which was funded through the Maren Endowment, Lawrence M. Goodman trust, and UF COM Educational Affairs office.

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Authors

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All authors grant final approval of the version to be published and agree to be accountable for the work. In addition, the authors contributed more specifically to the following aspects of the manuscript:

JF: Data acquisition, analysis, and interpretation; completed first draft.

EH: Data acquisition; revised draft for intellectual content.

VCC: Interpretation and analysis of the data; revised draft for intellectual content.

DG: Wrote the IRB for project approval; data acquisition; revised draft for intellectual content.

JDS: Interpretation of the data; revised draft for intellectual content.

WHR: Interpretation of the data; revised draft for intellectual content.

LCP: Interpretation and analysis of the data; revised draft for intellectual content.

Corresponding author

Correspondence to Lyda Cuervo-Pardo.

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This retrospective chart review involving human participants was approved by the University of Florida Institutional Review Board (IRB).

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Fortier, J.C., Haltigan, E., Cavero-Chavez, V. et al. Clinical and Phenotypic Characterization of Common Variable Immunodeficiency Diagnosed in Younger and Older Adults. J Clin Immunol 42, 1270–1279 (2022). https://doi.org/10.1007/s10875-022-01290-w

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