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Use of Combination Chemotherapy for Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) in Patients with Common Variable Immunodeficiency (CVID)

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Abstract

Purpose

A subset of patients with common variable immunodeficiency (CVID) develops granulomatous and lymphocytic interstitial lung disease (GLILD), a restrictive lung disease associated with early mortality. The optimal therapy for GLILD is unknown. This study was undertaken to see if rituximab and azathioprine (combination chemotherapy) would improve pulmonary function and/or radiographic abnormalities in patients with CVID and GLILD.

Methods

A retrospective chart review of patients with CVID and GLILD who were treated with combination chemotherapy was performed. Complete pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) scans of the chest were done prior to therapy and >6 months later. HRCT scans of the chest were blinded, randomized, and scored independently (in pairs) by two radiologists. The differences between pre- and post-treatment HRCT scores and PFT parameters were analyzed.

Results

Seven patients with CVID and GLILD met inclusion criteria. Post-treatment increases were noted in both FEV1 (p = 0.034) and FVC (p = 0.043). HRCT scans of the chest demonstrated improvement in total score (p = 0.018), pulmonary consolidations (p = 0.041), ground-glass opacities (p = 0.020) nodular opacities (p = 0.024), and both the presence and extent of bronchial wall thickening (p = 0.014, 0.026 respectively). No significant chemotherapy-related complications occurred.

Conclusions

Combination chemotherapy improved pulmonary function and decreased radiographic abnormalities in patients with CVID and GLILD.

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References

  1. Gathmann B, Grimbacher B, Beaute J, Dudoit Y, Mahlaoui N, Fischer A, et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006–2008. Clin Exp Immunol. 2009;157 Suppl 1:3–11.

    Article  PubMed  Google Scholar 

  2. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(5 Suppl 1):S1–S63.

    Article  PubMed  Google Scholar 

  3. Cunningham-Rundles C. Common variable immunodeficiency. Curr Allergy Asthma Rep. 2001;1(5):421–9.

    Article  PubMed  CAS  Google Scholar 

  4. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002;109(6):1001–4.

    Article  PubMed  CAS  Google Scholar 

  5. Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010;125(6):1354–60 e4.

    Article  PubMed  CAS  Google Scholar 

  6. Cunningham-Rundles C, Lieberman P, Hellman G, Chaganti RS. Non-Hodgkin lymphoma in common variable immunodeficiency. Am J Hematol. 1991;37(2):69–74.

    Article  PubMed  CAS  Google Scholar 

  7. Cunningham-Rundles C, Siegal FP, Cunningham-Rundles S, Lieberman P. Incidence of cancer in 98 patients with common varied immunodeficiency. J Clin Immunol. 1987;7(4):294–9.

    Article  PubMed  CAS  Google Scholar 

  8. Kinlen LJ, Webster AD, Bird AG, Haile R, Peto J, Soothill JF, et al. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet. 1985;1(8423):263–6.

    Article  PubMed  CAS  Google Scholar 

  9. Sander CA, Medeiros LJ, Weiss LM, Yano T, Sneller MC, Jaffe ES. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. 1992;16(12):1170–82.

    Article  PubMed  CAS  Google Scholar 

  10. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. 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(1):77–85.

    Article  PubMed  CAS  Google Scholar 

  13. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114(2):415–21.

    Article  PubMed  Google Scholar 

  14. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. 1997;127(8 Pt 1):613–7.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Immunol. 2010;134(2):97–103.

    Article  PubMed  CAS  Google Scholar 

  17. Cunningham-Rundles C. Autoimmune manifestations in common variable immunodeficiency. J Clin Immunol. 2008;28 Suppl 1:S42–5.

    Article  PubMed  Google Scholar 

  18. Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007;31(12):1800–12.

    Article  PubMed  Google Scholar 

  19. Khodadad A, Aghamohammadi A, Parvaneh N, Rezaei N, Mahjoob F, Bashashati M, et al. Gastrointestinal manifestations in patients with common variable immunodeficiency. Dig Dis Sci. 2007;52(11):2977–83.

    Article  PubMed  Google Scholar 

  20. Malamut G, Ziol M, Suarez F, Beaugrand M, Viallard JF, Lascaux AS, et al. Nodular regenerative hyperplasia: the main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities. J Hepatol. 2008;48(1):74–82.

    Article  PubMed  Google Scholar 

  21. Yong PF, Thaventhiran JE, Grimbacher B. “A rose is a rose is a rose,” but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011? Adv Immunol. 2011;111:47–107.

    Article  PubMed  CAS  Google Scholar 

  22. Abolhassani H, Aghamohammadi A, Abolhassani F, Eftekhar H, Heidarnia M, Rezaei N. Health policy for common variable immunodeficiency: burden of the disease. J Investig Allergol Clin Immunol. 2011;21(6):454–8.

    PubMed  CAS  Google Scholar 

  23. Torigian DA, LaRosa DF, Levinson AI, Litzky LA, Miller Jr WT. Granulomatous-lymphocytic interstitial lung disease associated with common variable immunodeficiency: CT findings. J Thorac Imaging. 2008;23(3):162–9.

    Article  PubMed  Google Scholar 

  24. MacDermott RP. Immunomodulator therapy in Crohn’s disease. In: UpToDate. Basow DS, editor. Waltham, MA: UpToDate; 2012.

  25. MacDermott RP. 6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the treatment of inflammatory bowel disease with 6-MP or azathioprine. In: UpToDate. Basow DS, editor. Waltham, MA: UpToDate; 2012.

  26. Gregersen S, Aalokken TM, Mynarek G, Kongerud J, Aukrust P, Froland SS, et al. High resolution computed tomography and pulmonary function in common variable immunodeficiency. Respir Med. 2009;103(6):873–80.

    Article  PubMed  Google Scholar 

  27. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.

    Article  PubMed  CAS  Google Scholar 

  28. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, et al. Standardisation of the measurement of lung volumes. Eur Respir J. 2005;26(3):511–22.

    Article  PubMed  CAS  Google Scholar 

  29. Piatosa B, Wolska-Kusnierz B, Pac M, Siewiera K, Galkowska E, Bernatowska E. B cell subsets in healthy children: reference values for evaluation of B cell maturation process in peripheral blood. Cytometry B Clin Cyto. 2010;78(6):372–81.

    Article  Google Scholar 

  30. Comans-Bitter WM, de Groot R, van den Beemd R, Neijens HJ, Hop WC, Groeneveld K, et al. Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations. J Pediatr. 1997;130(3):388–93.

    Article  PubMed  CAS  Google Scholar 

  31. Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37(8):820–8.

    Article  PubMed  CAS  Google Scholar 

  32. Mouillot G, Carmagnat M, Gerard L, Garnier JL, 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(5):746–55.

    Article  PubMed  Google Scholar 

  33. Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom Q, Jennings S, Lougaris V, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2008;113(9):1967–76.

    Article  PubMed  Google Scholar 

  34. Chua I, Quinti I, Grimbacher B. Lymphoma in common variable immunodeficiency: interplay between immune dysregulation, infection and genetics. Curr Opin Hematol. 2008;15(4):368–74.

    Article  PubMed  Google Scholar 

  35. Hatab AZ, Ballas ZK. Caseating granulomatous disease in common variable immunodeficiency treated with infliximab. J Allergy Clin Immunol. 2005;116(5):1161–2.

    Article  PubMed  CAS  Google Scholar 

  36. 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(4):878–82.

    Article  PubMed  CAS  Google Scholar 

  37. 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(3):293–300.

    Article  PubMed  Google Scholar 

  38. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948–68.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We would like to acknowledge and thank Dr. Mitchell Grayson for his thoughtful review of the manuscript.

This research was supported by National Institutes of Health grant R01CA122539 (www.nih.gov), and the Children’s Research Institute of the Children’s Hospital of Wisconsin (www.chw.org/display/PPF/DocID/30477/router.asp).

Conflict of interest

The authors of this manuscript declare that they have no financial conflicts of interest.

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Correspondence to John M. Routes.

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Chase, N.M., Verbsky, J.W., Hintermeyer, M.K. et al. Use of Combination Chemotherapy for Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) in Patients with Common Variable Immunodeficiency (CVID). J Clin Immunol 33, 30–39 (2013). https://doi.org/10.1007/s10875-012-9755-3

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  • DOI: https://doi.org/10.1007/s10875-012-9755-3

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