Top

Published in:

Open Access 01-08-2024 | Humoral Immunodeficiency | Research

Evaluation of Frequency of CMV Replication and Disease Complications Reveals New Cellular Defects and a Time Dependent Pattern in CVID Patients

Authors: Luca Marri, Paola Contini, Federico Ivaldi, Chiara Schiavi, Ottavia Magnani, Chiara Vassallo, Andrea Guastalla, Noemi Traversone, Claudia Angelini, Genny Del Zotto, Andrea De Maria, Raffaele De Palma

Published in: Journal of Clinical Immunology | Issue 6/2024

Abstract

Purpose

Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and failure of specific antibody production due to B-cell defects. However, studies have documented various T-cell abnormalities, potentially linked to viral complications. The frequency of Cytomegalovirus (CMV) replication in CVID cohorts is poorly studied. To address this gap in knowledge, we set up an observational study with the objectives of identifying CVID patients with active viraemia (CMV, Epstein-Barr virus (EBV)), evaluating potential correlations with immunophenotypic characteristics, clinical outcome, and the dynamic progression of clinical phenotypes over time.

Methods

31 CVID patients were retrospectively analysed according to viraemia, clinical and immunologic characteristics. 21 patients with non CVID humoral immunodeficiency were also evaluated as control.

Results

Active viral replication of CMV and/or EBV was observed in 25% of all patients. CMV replication was detected only in CVID patients (16%). CVID patients with active viral replication showed reduced HLA-DR⁺ NK counts when compared with CMV-DNA negative CVID patients. Viraemic patients had lower counts of LIN⁻DNAM^bright and LIN⁻CD16⁺ inflammatory lymphoid precursors which correlated with NK-cell subsets. Analysis of the dynamic progression of CVID clinical phenotypes over time, showed that the initial infectious phenotype progressed to complicated phenotypes with time. All CMV viraemic patients had complicated disease.

Conclusion

Taken together, an impaired production of inflammatory precursors and NK activation is present in CVID patients with active viraemia. Since “Complicated” CVID occurs as a function of disease duration, there is need for an accurate evaluation of this aspect to improve classification and clinical management of CVID patients.

Available only for authorised users

Hammarström L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000;120:225–31. https://doi.org/10.1046/j.1365-2249.2000.01131.x.CrossRefPubMedPubMedCentral

Gathmann B, Mahlaoui N, CEREDIH, Gérard L, Oksenhendler E, Warnatz K, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 2014;134:116–26. https://doi.org/10.1016/j.jaci.2013.12.1077.

Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119:1650–7. https://doi.org/10.1182/blood-2011-09-377945.CrossRefPubMedPubMedCentral

Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med. 1993;86:31–42.PubMed

Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92:34–48. https://doi.org/10.1006/clim.1999.4725.CrossRefPubMed

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;112:277–86. https://doi.org/10.1182/blood-2007-11-124545.CrossRefPubMed

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;27:308–16. https://doi.org/10.1007/s10875-007-9075-1.CrossRefPubMed

Wong GK, Huissoon AP. T-cell abnormalities in common variable immunodeficiency: the hidden defect. J Clin Pathol. 2016;69:672–6. https://doi.org/10.1136/jclinpath-2015-203351.CrossRefPubMed

Oraei M, Aghamohammadi A, Rezaei N, Bidad K, Gheflati Z, Amirkhani A, et al. Naive CD4+ T cells and recent thymic emigrants in common variable immunodeficiency. J Investig Allergol Clin Immunol. 2012;22:160–7.PubMed

10.

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;49:1329–38. https://doi.org/10.1086/606059.CrossRefPubMed

11.

Kutukculer N, Azarsiz E, Aksu G, Karaca NE. CD4+CD25+Foxp3+ T regulatory cells, Th1 (CCR5, IL-2, IFN-γ) and Th2 (CCR4, IL-4, Il-13) type chemokine receptors and intracellular cytokines in children with common variable immunodeficiency. Int J Immunopathol Pharmacol. 2016;29:241–51. https://doi.org/10.1177/0394632015617064.CrossRefPubMed

12.

Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, et al. Unravelling the Complexity of T Cell Abnormalities in Common Variable Immunodeficiency. J Immunol. 2007;178:3932–43. https://doi.org/10.4049/jimmunol.178.6.3932.CrossRefPubMed

13.

Fevang B, Yndestad A, Sandberg WJ, Holm AM, Müller F, Aukrust P, et al. Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo. Clin Exp Immunol. 2007;147:521–5. https://doi.org/10.1111/j.1365-2249.2006.03314.x.CrossRefPubMedPubMedCentral

14.

Bertinchamp R, Gérard L, Boutboul D, Malphettes M, Fieschi C, Oksenhendler E, et al. Exclusion of Patients with a Severe T-Cell Defect Improves the Definition of Common Variable Immunodeficiency. J Allergy Clin Immunol Pract. 2016;4:1147–57. https://doi.org/10.1016/j.jaip.2016.07.002.CrossRefPubMed

15.

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;170:202–11. https://doi.org/10.1111/j.1365-2249.2012.04643.x.CrossRefPubMedPubMedCentral

16.

Horn J, Manguiat A, Berglund LJ, Knerr V, Tahami F, Grimbacher B, et al. Decrease in phenotypic regulatory T cells in subsets of patients with common variable immunodeficiency. Clin Exp Immunol. 2009;156:446–54. https://doi.org/10.1111/j.1365-2249.2009.03913.x.CrossRefPubMedPubMedCentral

17.

Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77–85. https://doi.org/10.1182/blood-2007-06-091744.CrossRefPubMed

18.

Warnatz K, Wehr C, Dräger R, Schmidt S, Eibel H, Schlesier M, et al. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology. 2002;206:502–13. https://doi.org/10.1078/0171-2985-00198.CrossRefPubMed

19.

Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-Van Der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003;23:385–400. https://doi.org/10.1023/A:1025373601374.

20.

Chan S, Godsell J, Horton M, Farchione A, Howson LJ, Margetts M, et al. Case Report: Cytomegalovirus disease is an under-recognized contributor to morbidity and mortality in common variable immunodeficiency. Front Immunol. 2022;13:1–11. https://doi.org/10.3389/fimmu.2022.815193.CrossRef

21.

Godsell J, Chan S, Slade C, Bryant V, Douglass JA, Sasadeusz J, et al. Cytomegalovirus in primary immunodeficiency. Curr Opin Infect Dis. 2021;34:663–71. https://doi.org/10.1097/QCO.0000000000000797.CrossRefPubMed

22.

Marashi SM, Raeiszadeh M, Workman S, Rahbar A, Soderberg-Naucler C, Klenerman P, et al. Inflammation in common variable immunodeficiency is associated with a distinct CD8+ response to cytomegalovirus. J Allergy Clin Immunol. 2011;127:1–17. https://doi.org/10.1016/j.jaci.2011.04.001.CrossRef

23.

Marashi SM, Raeiszadeh M, Enright V, Tahami F, Workman S, Chee R, et al. Influence of cytomegalovirus infection on immune cell phenotypes in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2012;129:1349-1356.e3. https://doi.org/10.1016/j.jaci.2012.02.011.CrossRefPubMed

24.

Raeiszadeh M, Kopycinski J, Paston SJ, Diss T, Lowdell M, Hardy GAD, et al. The T cell response to persistent herpes virus infections in common variable immunodeficiency. Clin Exp Immunol. 2006;146:234–42. https://doi.org/10.1111/j.1365-2249.2006.03209.x.CrossRefPubMedPubMedCentral

25.

López-Botet M, De Maria A, Muntasell A, Della Chiesa M, Vilches C. Adaptive NK cell response to human cytomegalovirus: Facts and open issues. Semin Immunol. 2023;65:101706. https://doi.org/10.1016/j.smim.2022.101706.CrossRefPubMed

26.

Gumá M, Angulo A, Vilches C, Gómez-Lozano N, Malats N, López-Botet M. Imprint of human cytomegalovirus infection on the NK cell receptor repertoire. Blood. 2004;104:3664–71. https://doi.org/10.1182/blood-2004-05-2058.CrossRefPubMed

27.

Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RAW, Roosnek E. Human NK cells can control CMV infection in the absence of T cells. Blood. 2008;112:914–5. https://doi.org/10.1182/blood-2008-05-157354.CrossRefPubMed

28.

Noyola DE, Fortuny C, Muntasell A, Noguera-Julian A, Muñoz-Almagro C, Alarcón A, et al. Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK-cell subset distribution in children. Eur J Immunol. 2012;42:3256–66. https://doi.org/10.1002/eji.201242752.CrossRefPubMed

29.

Bozzano F, Della Chiesa M, Pelosi A, Antonini F, Ascierto ML, Del Zotto G, et al. HCMV-controlling NKG2C+ NK cells originate from novel circulating inflammatory precursors. J Allergy Clin Immunol. 2021;147:2343–57. https://doi.org/10.1016/j.jaci.2020.12.648.CrossRefPubMed

30.

Bozzano F, Marras F, Ascierto ML, Cantoni C, Cenderello G, Dentone C, et al. “Emergency exit” of bone-marrow-resident CD34(+)DNAM-1(bright)CXCR4(+)-committed lymphoid precursors during chronic infection and inflammation. Nat Commun. 2015;6:8109. https://doi.org/10.1038/ncomms9109.CrossRefPubMed

31.

Więsik-Szewczyk E, Rutkowska E, Kwiecień I, Korzeniowska M, Sołdacki D, Jahnz-Różyk K. Patients with common variable immunodeficiency complicated by autoimmune phenomena have lymphopenia and reduced treg, Th17, and NK cells. J Clin Med. 2021;10(15):3356. https://doi.org/10.3390/jcm10153356.

32.

Ho H, Cunningham-Rundles C. Non-infectious complications of common variable immunodeficiency: Updated clinical spectrum, sequelae, and insights to pathogenesis. Front Immunol. 2020;11:149. https://doi.org/10.3389/fimmu.2020.00149.

33.

Mouillot G, Carmagnat M, Gérard L, Garnier J-L, Fieschi C, Vince N, et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol. 2010;30:746–55. https://doi.org/10.1007/s10875-010-9424-3.CrossRefPubMed

34.

Ebbo M, Gérard L, Carpentier S, Vély F, Cypowyj S, Farnarier C, et al. Low circulating natural killer cell counts are associated with severe disease in patients with common variable immunodeficiency. EBioMedicine. 2016;6:222–30. https://doi.org/10.1016/j.ebiom.2016.02.025.CrossRefPubMedPubMedCentral

35.

Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract. 2019;7:1763–70. https://doi.org/10.1016/j.jaip.2019.02.004.CrossRefPubMed

36.

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 Pract. 2016;4:38–59. https://doi.org/10.1016/j.jaip.2015.07.025.CrossRefPubMed

37.

The Jamovi project. Jamovi 2022.

38.

Kralickova P, Mala E, Vokurkova D, Krcmova I, Pliskova L, Stepanova V, et al. Cytomegalovirus disease in patients with common variable immunodeficiency: three case reports. Int Arch Allergy Immunol. 2014;163:69–74. https://doi.org/10.1159/000355957.CrossRefPubMed

39.

Ünal B, Başsorgun Cİ, Çil Gönülcü S, Uçar A, Çelik F, Elpek GÖ. Cytomegalovirus colitis with common variable immunodeficiency and Crohn’s disease. Case Rep Med. 2015;2015:348204. https://doi.org/10.1155/2015/348204.CrossRefPubMedPubMedCentral

40.

Kathi P, Tama M, Reddy V, Kundumadam S, Al-Subee O, Ehrinpreis MN. Acute gastrointestinal bleeding due to cytomegalovirus colitis in a patient with common variable immunodeficiency. ACG Case Reports J 2018;5:e40. https://doi.org/10.14309/crj.2018.40.

41.

Mullighan CG, Read SJ, Bird AG, Kurtz JB, Chapel HM, Welsh KI. Human cytomegalovirus infection is not increased in common variable immunodeficiency. J Clin Immunol. 1996;16:272–7. https://doi.org/10.1007/BF01541392.CrossRefPubMed

42.

Seale H, MacIntyre CR, Gidding HF, Backhouse JL, Dwyer DE, Gilbert L. National serosurvey of cytomegalovirus in Australia. Clin Vaccine Immunol. 2006;13:1181–4. https://doi.org/10.1128/CVI.00203-06.CrossRefPubMedPubMedCentral

43.

Andrews DM, Scalzo AA, Yokoyama WM, Smyth MJ, Degli-Esposti MA. Functional interactions between dendritic cells and NK cells during viral infection. Nat Immunol. 2003;4:175–81. https://doi.org/10.1038/ni880.CrossRefPubMed

44.

Benedict CA, Loewendorf A, Garcia Z, Blazar BR, Janssen EM. Dendritic cell programming by cytomegalovirus stunts naive T cell responses via the PD-L1/PD-1 pathway. J Immunol. 2008;180:4836–47. https://doi.org/10.4049/jimmunol.180.7.4836.CrossRefPubMed

45.

Klenerman P, Oxenius A. T cell responses to cytomegalovirus. Nat Rev Immunol. 2016;16:367–77. https://doi.org/10.1038/nri.2016.38.CrossRefPubMed

46.

Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202:673–85. https://doi.org/10.1084/jem.20050882.CrossRefPubMedPubMedCentral

47.

Gordon CL, Miron M, Thome JJC, Matsuoka N, Weiner J, Rak MA, et al. Tissue reservoirs of antiviral T cell immunity in persistent human CMV infection. J Exp Med. 2017;214:651–67. https://doi.org/10.1084/jem.20160758.CrossRefPubMedPubMedCentral

48.

Boileau J, Mouillot G, Gérard L, Carmagnat M, Rabian C, Oksenhendler E, et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J Autoimmun. 2011;36:25–32. https://doi.org/10.1016/j.jaut.2010.10.002.CrossRefPubMed

Title: Evaluation of Frequency of CMV Replication and Disease Complications Reveals New Cellular Defects and a Time Dependent Pattern in CVID Patients
Authors: Luca Marri
Paola Contini
Federico Ivaldi
Chiara Schiavi
Ottavia Magnani
Chiara Vassallo
Andrea Guastalla
Noemi Traversone
Claudia Angelini
Genny Del Zotto
Andrea De Maria
Raffaele De Palma
Publication date: 01-08-2024
Publisher: Springer US
Keywords: Humoral Immunodeficiency
Epstein-Barr Virus
Human Cytomegalovirus
Published in: Journal of Clinical Immunology / Issue 6/2024
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-024-01744-3

Unconventional T Cells Influence Clinical Outcome After Allogeneic Hematopoietic Cell Transplantation

Graft-Versus-Host Disease
Research

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections

Opportunistic Infection
Research

Disseminated BCG Disease in a Child with a Novel PSMG2 Deletion

Correspondence

An Exploratory Approach of Clinically Useful Biomarkers of Cvid by Logistic Regression

Open Access
Secondary Immunodeficiency
Research

Cancer Prevalence in Children with Inborn Errors of Immunity: Report from a Single Institution

Primary Immunodeficiency
Original Article

Growth Failure in STAT3 Gain-of-Function Syndrome Persists After Hematopoietic Stem Cell Transplantation

Graft-Versus-Host Disease
Correspondence

Keynote series | Spotlight on managing health in obesity

Obesity
Video Series

Obesity is a major contributor to cardiorenal metabolic disease, but its impact extends throughout the body. Understand how obesity can affect other organ systems and impact treatment, and whether weight-loss measures improve outcomes.

Prof. Eva L. Feldman

Prof. Jonette Keri

Developed by: Springer Medicine

Watch now

Women’s health knowledge hub

Menopause
Clinical Collection

Elevate your patient care with our comprehensive, evidence-based medical education on women's health. Designed to help you provide exceptional care for your female patients at every stage of life, we provide expert insights into topics such as reproductive health, menopause, breast cancer and sex-specific health risks and precision medicine.

Live
Webinar | 27-05-2025 | 18:00 (CEST)

Systemic lupus erythematosus is a severe autoimmune disease that can cause damage to almost every system of the body. Join this session to learn more about novel biomarkers for diagnosis and monitoring and familiarise yourself with current and emerging targeted therapies.

Join us live: Tuesday 27th May, 18:00-19:15 (CEST)

Prof. Edward Vital

Prof. Ronald F. van Vollenhoven

Developed by: Springer Medicine

Navigating neuroimaging in Alzheimer disease care

Springer Medicine

Evaluation of Frequency of CMV Replication and Disease Complications Reveals New Cellular Defects and a Time Dependent Pattern in CVID Patients