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Clinical applications of interferon-γ releasing assays for cytomegalovirus to differentiate cytomegalovirus disease from bystander activation: a pilot proof-of-concept study

  • Kim, Sung-Han (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Ho-Su (Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Hyun-Jung (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Sun-Mi (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Shin, Sung (Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Park, Sang-Hyoung (Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Kyung-Jo (Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Young-Hoon (Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Sung, Heungsup (Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Sang-Oh (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Sang-Ho (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yang, Suk-Kyun (Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Yang Soo (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Woo, Jun Hee (Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Han, Duck-Jong (Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2015.10.20
  • Accepted : 2016.02.22
  • Published : 2017.09.01

Abstract

Background/Aims: We evaluated the proposed clinical application of the combined interpretation of host factors and viral factors in two different cytomegalovirus (CMV) co-infection models. Methods: We prospectively enrolled all human immunodeficiency virus non-infected patients with confirmed Pneumocystitis jirovecii pneumonia (PCP) and those with suspected gastrointestinal CMV disease in a tertiary hospital. All patients underwent CMV interferon-${\gamma}$ releasing assay (IGRA) for CMV (T-track CMV, Lophius Biosciences). We created the 2-axis model with the CMV IGRA results as the x-axis and the results for CMV virus replication as the y-axis, and hypothesized that cases falling in the left upper quadrant (high viral load and low CMV-specific immunity) of the model would be true CMV infections. The CMV IGRA results were concealed from the attending physicians. Results: Of 39 patients with PCP, four (10%) were classified as combined CMV pneumonia, 13 (33%) as bystander activation, and the remaining 22 (56%) as no CMV infection. The data for all four patients with PCP and CMV pneumonia fell in the left upper quadrant of the 2-axis model. Of 24 patients with suspected gastrointestinal CMV disease, 12 (50%) were classified as gastrointestinal CMV disease and the remaining 12 (50%) as bystander activation with no gastrointestinal CMV disease. The data for 11 of the 12 patients (92%) with gastrointestinal CMV disease were located in the left upper quadrant of the 2-axis model. Conclusions: Cases yielding low CMV IGRA results and high CMV viral replication appear to be true CMV infections. Further studies with large number of cases in different types of CMV disease should be proposed.

Keywords

Acknowledgement

Supported by : Korean Society of Internal Medicine

References

  1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother 2013;45:260-271. https://doi.org/10.3947/ic.2013.45.3.260
  2. Egli A, Humar A, Kumar D. State-of-the-art monitoring of cytomegalovirus-specific cell-mediated immunity after organ transplant: a primer for the clinician. Clin Infect Dis 2012;55:1678-1689. https://doi.org/10.1093/cid/cis818
  3. Moon SM, Sung H, Kim MN, et al. Diagnostic yield of the cytomegalovirus (CMV) antigenemia assay and clinical features in solid organ transplant recipients and hematopoietic stem cell transplant recipients with CMV pneumonia. Transpl Infect Dis 2012;14:192-197. https://doi.org/10.1111/j.1399-3062.2011.00703.x
  4. Jang EY, Park SY, Lee EJ, et al. Diagnostic performance of the cytomegalovirus (CMV) antigenemia assay in patients with CMV gastrointestinal disease. Clin Infect Dis 2009;48:e121-e124. https://doi.org/10.1086/599116
  5. Park SY, Lee SO, Choi SH, et al. Efficacy and safety of low-dose ganciclovir preemptive therapy in allogeneic haematopoietic stem cell transplant recipients compared with conventional-dose ganciclovir: a prospective observational study. J Antimicrob Chemother 2012;67:1486-1492. https://doi.org/10.1093/jac/dks043
  6. Park SY, Lee SO, Choi SH, et al. Paradoxical rising cytomegalovirus antigenemia during preemptive ganciclovir therapy in hematopoietic stem cell transplant recipients: incidence, risk factors, and clinical outcomes. J Clin Microbiol 2011;49:4179-4184. https://doi.org/10.1128/JCM.05464-11
  7. Millar AB, Patou G, Miller RF, et al. Cytomegalovirus in the lungs of patients with AIDS: respiratory pathogen or passenger? Am Rev Respir Dis 1990;141:1474-1477. https://doi.org/10.1164/ajrccm/141.6.1474
  8. Dolin R. AIDS therapy. In: Huang L, Masur H. Pneumocystitis Pneumonia. 3rd ed. Philadelphia: Churchill Livingstone, 2008:637-658.
  9. Miles PR, Baughman RP, Linnemann CC Jr. Cytomegalovirus in the bronchoalveolar lavage fluid of patients with AIDS. Chest 1990;97:1072-1076. https://doi.org/10.1378/chest.97.5.1072
  10. Kim T, Moon SM, Sung H, et al. Outcomes of non-HIV-infected patients with Pneumocystis pneumonia and concomitant pulmonary cytomegalovirus infection. Scand J Infect Dis 2012;44:670-677. https://doi.org/10.3109/00365548.2011.652665
  11. Galiatsatos P, Shrier I, Lamoureux E, Szilagyi A. Meta-analysis of outcome of cytomegalovirus colitis in immunocompetent hosts. Dig Dis Sci 2005;50:609-616. https://doi.org/10.1007/s10620-005-2544-6
  12. Roblin X, Pillet S, Oussalah A, et al. Cytomegalovirus load in inflamed intestinal tissue is predictive of resistance to immunosuppressive therapy in ulcerative colitis. Am J Gastroenterol 2011;106:2001-2008. https://doi.org/10.1038/ajg.2011.202
  13. Matsuoka K, Iwao Y, Mori T, et al. Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol 2007;102:331-337. https://doi.org/10.1111/j.1572-0241.2006.00989.x
  14. Lawlor G, Moss AC. Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? Inflamm Bowel Dis 2010;16:1620-1627. https://doi.org/10.1002/ibd.21275
  15. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2004;99:1371-1385. https://doi.org/10.1111/j.1572-0241.2004.40036.x
  16. Yoshino T, Nakase H, Ueno S, et al. Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with ulcerative colitis refractory to immunosuppressive therapies. Inflamm Bowel Dis 2007;13:1516-1521. https://doi.org/10.1002/ibd.20253
  17. Bunde T, Kirchner A, Hoffmeister B, et al. Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med 2005;201:1031-1036. https://doi.org/10.1084/jem.20042384
  18. Malouli D, Hansen SG, Nakayasu ES, et al. Cytomegalovirus pp65 limits dissemination but is dispensable for persistence. J Clin Invest 2014;124:1928-1944. https://doi.org/10.1172/JCI67420
  19. Pipeling MR, John ER, Orens JB, Lechtzin N, McDyer JF. Primary cytomegalovirus phosphoprotein 65-specific CD8+ T-cell responses and T-bet levels predict immune control during early chronic infection in lung transplant recipients. J Infect Dis 2011;204:1663-1671. https://doi.org/10.1093/infdis/jir624
  20. Bestard O, Lucia M, Crespo E, et al. Pretransplant immediately early-1-specific T cell responses provide protection for CMV infection after kidney transplantation. Am J Transplant 2013;13:1793-1805. https://doi.org/10.1111/ajt.12256

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