Skip to main content

Advertisement

SpringerLink
Log in

Granulomatous Disease in CVID: Retrospective Analysis of Clinical Characteristics and Treatment Efficacy in a Cohort of 59 Patients

  • Original Research
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Background

Granulomatous disease (GD) will develop in a subset of patients with common variable immunodeficiency (CVID). Little is known about the efficacy of therapeutic agents used for treating this disorder.

Objective

To evaluate the efficacy of immunosuppressive drugs with the help of a set of clinical, biological and radiological criteria.

Method

Clinical and laboratory features of CVID patients were collected from the French DEFI cohort, a prospective study on adults with hypogammaglobulinemia. The medical charts of 55 patients (93 %) of the GD cohort were reviewed.

Results

Among 436 subjects with CVID, 59 patients (13.5 %) were diagnosed with GD. Of the 55 patients in whom medical charts were available, 32 patients received treatment for the granulomatous disease. Corticosteroids were the most frequently used drug. Complete response to treatment was infrequent. It was achieved with corticosteroids, cyclophosphamide, hydroxychloroquine, rituximab and methotrexate. Azathioprine, cyclosporine, mycophenolate mofetil, sirolimus, infliximab and thalidomide led to partial or absence of response. Complete and partial responses were observed in lymph nodes, lungs, liver, skin, bone marrow and central nervous system. Absent of response for gastrointestinal tract granulomas was noted in all cases of treatment attempt.

Conclusion

CVID patients with GD exhibit a particular biological phenotype. Treatment should be considered in any symptomatic patient or if there is evidence of organ dysfunction. Corticosteroids are the drug of choice in most instances but response to treatment is often unsatisfactory.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

CVID:

Common variable immunodeficiency

GD:

Granulomatous disease

TR:

Therapeutic regimen

References

  1. Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009;145:709–27.

    Article  PubMed  CAS  Google Scholar 

  2. Chapel H, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112:277–86.

    Article  PubMed  CAS  Google Scholar 

  3. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  5. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin Immunol. 2009;133:198–207.

    Article  PubMed  CAS  Google Scholar 

  6. Fasano MB, et al. Sarcoidosis and common variable immunodeficiency. Report of 8 cases and review of the literature. Medicine (Baltimore). 1996;75:251–61.

    Article  CAS  Google Scholar 

  7. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. 1997;127:613–7.

    PubMed  CAS  Google Scholar 

  8. Morimoto Y, Routes JM. Granulomatous disease in common variable immunodeficiency. Curr Allergy Asthma Rep. 2005;5:370–5.

    Article  PubMed  CAS  Google Scholar 

  9. Oksenhendler E, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008;46:1547–54.

    Article  PubMed  Google Scholar 

  10. Park JES, Beal I, Dilworth JP, Tormey V, Haddock J. The HRCT appearances of granulomatous pulmonary disease in common variable immune deficiency. Eur J Radiol. 2005;54:359–64.

    Article  PubMed  CAS  Google Scholar 

  11. Torigian DA, LaRosa DF, Levinson AI, Litzky LA, Miller WT. Granulomatous-lymphocytic interstitial lung disease associated with common variable immunodeficiency: CT findings. J Thorac Imaging. 2008;23:162–9.

    Article  PubMed  Google Scholar 

  12. Mouillot G, 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.

    Article  PubMed  Google Scholar 

  13. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. J Immunol. 1997;159:6236–41.

    PubMed  CAS  Google Scholar 

  14. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol. 2011;11:119–30.

    Article  PubMed  CAS  Google Scholar 

  15. Melo KM, et al. A decreased frequency of regulatory T cells in patients with common variable immunodeficiency. PLoS One. 2009;4:e6269.

    Article  PubMed  Google Scholar 

  16. Malphettes M, 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.

    Article  PubMed  CAS  Google Scholar 

  17. Kanathur N, Byrd RP, Fields CL, Roy TM. Noncaseating granulomatous disease in common variable immunodeficiency. South Med J. 2000;93:631–3.

    PubMed  CAS  Google Scholar 

  18. Lin JH, Liebhaber M, Roberts RL, Dyer Z, Stiehm ER. Etanercept treatment of cutaneous granulomas in common variable immunodeficiency. J Allergy Clin Immunol. 2006;117:878–82.

    Article  PubMed  CAS  Google Scholar 

  19. Rohart C, Badelon I, Fajnkuchen F, Nghiem-Buffet S, Chaine G. Ophthalmologic disease in sarcoid-like granulomatosis and true sarcoidosis in immunodeficiency. Four case reports. J Fr Ophtalmol. 2008;31:683–91.

    Article  PubMed  CAS  Google Scholar 

  20. Benoit G, et al. Renal granuloma and immunoglobulin M-complex glomerulonephritis: a case of common variable immunodeficiency? Pediatr Nephrol. 2009;24:601–4.

    Article  PubMed  Google Scholar 

  21. Krupnick AI, Shim H, Phelps RG, Cunningham-Rundles C, Sapadin AN. Cutaneous granulomas masquerading as tuberculoid leprosy in a patient with congenital combined immunodeficiency. Mt Sinai J Med. 2001;68:326–30.

    PubMed  CAS  Google Scholar 

  22. Meyer A, Lachmann HJ, Webster AD, Burns A, Thway K. Hypercalcemia in a patient with common variable immunodeficiency and renal granulomas. Am J Kidney Dis. 2005;45:e90–93.

    Article  PubMed  Google Scholar 

  23. Misbah SA, et al. Recurrent intra-cranial granulomata presenting as space-occupying lesions in a patient with common variable immunodeficiency. Postgrad Med J. 1992;68:359–62.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  25. James DG. Mimics of sarcoidosis. Granulomatous hypogammaglobulinaemia. Sarcoidosis. 1992;9:1–2.

    PubMed  CAS  Google Scholar 

  26. Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Immunol. 2010;134:97–103.

    Article  PubMed  CAS  Google Scholar 

  27. Bates CA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114:415–21.

    Article  PubMed  Google Scholar 

  28. North ME, Webster AD, Farrant J. Primary defect in CD8+ lymphocytes in the antibody deficiency disease (common variable immunodeficiency): abnormalities in intracellular production of interferon-gamma (IFN-gamma) in CD28+ (’cytotoxic’) and CD28- (’suppressor’) CD8+ subsets. Clin Exp Immunol. 1998;111:70–5.

    Article  PubMed  CAS  Google Scholar 

  29. Mike N, Hansel TT, Newman J, Asquith P. Granulomatous enteropathy in common variable immunodeficiency: a cause of chronic diarrhoea. Postgrad Med J. 1991;67:446–9.

    Article  PubMed  CAS  Google Scholar 

  30. Kashani S, Gazzard G, Jolles S, Larkin G. Asymptomatic choroidal granulomas in common variable immunodeficiency. Clin Experiment Ophthalmol. 2005;33:663–4.

    Article  PubMed  Google Scholar 

  31. Malphettes M, Oksenhendler E, Galicier L, Fieschi C. Granulomatous disease in common variable immunodeficiency. Rev Med Interne. 2008;29:28–32.

    Article  PubMed  CAS  Google Scholar 

  32. Abdel-Naser MB, Wollina U, El Hefnawi MA, Habib MA, El Okby M. Non-sarcoidal, non-tuberculoid granuloma in common variable immunodeficiency. J Drugs Dermatol. 2006;5:370–2.

    PubMed  CAS  Google Scholar 

  33. Pujol RM, et al. Cutaneous granulomatous lesions in common variable immunodeficiency: complete resolution after intravenous immunoglobulins. Dermatology (Basel). 1999;198:156–8.

    Article  CAS  Google Scholar 

  34. Aghamohammad A, et al. Cutaneous granulomas in common variable immunodeficiency: case report and review of literature. Acta Dermatovenerol Croat. 2010;18:107–13.

    Google Scholar 

  35. Mitra A, et al. Cutaneous granulomas associated with primary immunodeficiency disorders. Br J Dermatol. 2005;153:194–9.

    Article  PubMed  CAS  Google Scholar 

  36. Paul C, et al. Cutaneous granulomatous lesions in congenital immune deficiencies. 5 cases. Ann Dermatol Venereol. 1995;122:501–6.

    PubMed  CAS  Google Scholar 

  37. Viallard JF, Pellegrin JL, Moreau JF. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. 1998;128:781–2. author reply 782–783.

    PubMed  CAS  Google Scholar 

  38. Lun KR, Wood DJ, Muir JB, Noakes R. Granulomas in common variable immunodeficiency: a diagnostic dilemma. Australas J Dermatol. 2004;45:51–4.

    Article  PubMed  Google Scholar 

  39. Siegfried EC, Prose NS, Friedman NJ, Paller AS. Cutaneous granulomas in children with combined immunodeficiency. J Am Acad Dermatol. 1991;25:761–6.

    Article  PubMed  CAS  Google Scholar 

  40. Torrelo A, Mediero IG, Zambrano A. Caseating cutaneous granulomas in a child with common variable immunodeficiency. Pediatr Dermatol. 1995;12:170–3.

    Article  PubMed  CAS  Google Scholar 

  41. Artac H, Bozkurt B, Talim B, Reisli I. Sarcoid-like granulomas in common variable immunodeficiency. Rheumatol Int. 2009. doi:10.1007/s00296-009-0897-4.

  42. Cornejo P, et al. Cutaneous and hepatic granulomas in a young woman with common variable immunodeficiency. Br J Dermatol. 1999;140:546–7.

    Article  PubMed  CAS  Google Scholar 

  43. Fakhouri F, et al. Granulomatous renal disease in a patient with common variable immunodeficiency. Am J Kidney Dis. 2001;38:E7.

    Article  PubMed  CAS  Google Scholar 

  44. Stigant C, Sapir D, Sweet J, Downey G, Bargman JM. A unique renal lesion in common variable immunodeficiency. Clin Nephrol. 2002;57:74–9.

    PubMed  CAS  Google Scholar 

  45. Sutor G, Fabel H. Sarcoidosis and common variable immunodeficiency. A case of a malignant course of sarcoidosis in conjunction with severe impairment of the cellular and humoral immune system. Respiration. 2000;67:204–8.

    Article  PubMed  CAS  Google Scholar 

  46. Spickett GP, Zhang JG, Green T, Shrimankar J. Granulomatous disease in common variable immunodeficiency: effect on immunoglobulin replacement therapy and response to steroids and splenectomy. J Clin Pathol. 1996;49:431–4.

    Article  PubMed  CAS  Google Scholar 

  47. Sacco O, et al. Common variable immunodeficiency presenting in a girl as lung infiltrates and mediastinal adenopathies leading to severe ‘superior vena caval’ syndrome. Eur Respir J. 1996;9:1958–61.

    Article  PubMed  CAS  Google Scholar 

  48. Mrusek S, et al. Development of granulomatous common variable immunodeficiency subsequent to infection with Toxoplasma gondii. Clin Exp Immunol. 2004;137:578–83.

    Article  PubMed  CAS  Google Scholar 

  49. Fernández-Ruiz M, et al. Fever of unknown origin in a patient with common variable immunodeficiency associated with multisystemic granulomatous disease. Intern Med. 2007;46:1197–202.

    Article  PubMed  Google Scholar 

  50. Reshamwala PA, Kleiner DE, Heller T. Nodular regenerative hyperplasia: not all nodules are created equal. Hepatology. 2006;44:7–14.

    Article  PubMed  Google Scholar 

  51. Al-Mukhaizeem KA, Rosenberg A, Sherker AH. Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders. Am J Hematol. 2004;75:225–30.

    Article  PubMed  Google Scholar 

  52. Schwartz M, Cohen R. Optimizing conventional therapy for inflammatory bowel disease. Curr Gastroenterol Rep. 2008;10:585–90.

    Article  PubMed  Google Scholar 

  53. Hatab AZ, Ballas ZK. Caseating granulomatous disease in common variable immunodeficiency treated with infliximab. J Allergy Clin Immunol. 2005;116:1161–2.

    Article  PubMed  CAS  Google Scholar 

  54. Malbrán A, Juri MC, Fernández Romero DS. Common variable immunodeficiency and granulomatosis treated with infliximab. Clin Immunol. 2010;134:359–60.

    Article  PubMed  Google Scholar 

  55. Thatayatikom A, Thatayatikom S, White AJ. Infliximab treatment for severe granulomatous disease in common variable immunodeficiency: a case report and review of the literature. Ann Allergy Asthma Immunol. 2005;95:293–300.

    Article  PubMed  Google Scholar 

  56. Smith KJ, Skelton H. Common variable immunodeficiency treated with a recombinant human IgG, tumour necrosis factor-alpha receptor fusion protein. Br J Dermatol. 2001;144:597–600.

    Article  PubMed  CAS  Google Scholar 

  57. Antoniu SA. Targeting the TNF-alpha pathway in sarcoidosis. Expert Opin Ther Targets. 2010;14:21–9.

    Article  PubMed  CAS  Google Scholar 

  58. Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients with sarcoidosis with neurological involvement. Arch Neurol. 1998;55:1248–54.

    Article  PubMed  CAS  Google Scholar 

  59. Stone, J. A Clinician’s Pearls & Myths in Rheumatology. (Springer: 2009).

  60. Levine TS, Price AB, Boyle S, Webster AD. Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders. Br J Dermatol. 1994;130:118–20.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Immunology and Allergy, Centre Hospitalier Universitaire de Québec, Laval University, Quebec City, Quebec, Canada

    Jean-Nicolas Boursiquot

  2. Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique- Hôpitaux de Paris, 1, rue Claude-Vellefaux, 75010, Paris, France

    Laurence Gérard, Marion Malphettes, Claire Fieschi, Lionel Galicier, David Boutboul & Eric Oksenhendler

  3. Department of Respirology, Hôpital Tenon, Paris, France

    Raphael Borie

  4. Department of Internal Medicine, Hôpital Haut Lévêque, Pessac, France

    Jean-François Viallard

  5. Department of Internal Medicine and INSERM UMR S737, Strasbourg, France

    Pauline Soulas-Sprauel

  6. Department of Internal Medicine, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France

    Alice Berezne

  7. Department of Hematology, Hôpital Dupuytren, Limoges, France

    Arnaud Jaccard

  8. Department of Internal Medicine, Hôpital Claude Huriez, Lille, France

    Eric Hachulla

  9. Department of Internal Medicine, Hôpital de la Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France

    Julien Haroche

  10. Department of Internal Medicine, Hôpital de la Conception, Marseille, France

    Nicolas Schleinitz

  11. Service de Pneumologie, Hôpital Rangueil-Larrey, Toulouse, France

    Laurent Têtu

Authors
  1. Jean-Nicolas Boursiquot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laurence Gérard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marion Malphettes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire Fieschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lionel Galicier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Boutboul
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raphael Borie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jean-François Viallard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pauline Soulas-Sprauel
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alice Berezne
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Arnaud Jaccard
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eric Hachulla
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Julien Haroche
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nicolas Schleinitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Laurent Têtu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Eric Oksenhendler
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the DEFI study group

Corresponding author

Correspondence to Jean-Nicolas Boursiquot.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boursiquot, JN., Gérard, L., Malphettes, M. et al. Granulomatous Disease in CVID: Retrospective Analysis of Clinical Characteristics and Treatment Efficacy in a Cohort of 59 Patients. J Clin Immunol 33, 84–95 (2013). https://doi.org/10.1007/s10875-012-9778-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-012-9778-9

Keywords

Search

Navigation