Original Article | Published:

Identification of clinically relevant cytomegalovirus infections in patients with inflammatory bowel disease

Modern Pathology volume 31, pages 527538 (2018) | Download Citation

Abstract

Several lines of evidence indicate that cytomegalovirus infection can be substantially associated with onset of inflammatory bowel disease, especially in patients refractory to immunosuppressive treatment. As cytomegalovirus is widely spread in the population, here we present a quantitative detection system suitable to differentiate clinically relevant cytomegalovirus infection from common latent cytomegalovirus. Using a quantitative real-time PCR approach, cytomegalovirus viral load was evaluated in 917 formalin-fixed and paraffin-embedded colon biopsy samples of 136 patients diagnosed with inflammatory bowel disease. Besides initial cytomegalovirus testing, the PCR system was also used to monitor therapy response after antiviral treatment. Cytomegalovirus DNA was detected in 37 patients (27%) with varying viral loads ranging from 5 to 8.7 × 105 copies/105 cells. Thereof, 13 patients (35%) received an antiviral treatment with 12 of them going into remission (92%). Later, five patients displayed a relapse and three patients who agreed to restart antiviral treatment again showed positive therapy response. A retrospective comparison of viral loads with antiviral therapy response revealed a threshold of 600 cytomegalovirus copies/105 cells as indicative for clinically relevant infection. Of note, sensitivity of cytomegalovirus detection by immunohistochemistry was found to be insufficient to reliably identify antiviral therapy responders. In conclusion, quantitative real-time PCR using formalin-fixed biopsy samples is suitable for detection of cytomegalovirus infection in tissue samples of patients with inflammatory bowel disease. Moreover, it allows the definition of a viral load threshold, predictive for clinical relevance concerning antiviral therapy response.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , et al. Latent cytomegalovirus infection exacerbates experimental colitis. Am J Pathol 2009;175:2034–2042.

  2. 2.

    , , et al. Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease. World J Gastroenterol 2013;19:17–25.

  3. 3.

    , , et al. Cytomegalovirus infection in steroid-refractory ulcerative colitis: a case-control study. Am J Surg Pathol 2004;28:365–373.

  4. 4.

    , , et al. Severe acute colitis associated with CMV: a prevalence study. Dig Liver Dis 2004;36:818–820.

  5. 5.

    , . Prevalence of cytomegalovirus infection in inflammatory bowel disease patients. Dis Colon Rectum 2004;47:722–726.

  6. 6.

    , , et al. A prospective assessment of cytomegalovirus infection in active inflammatory bowel disease. Aliment Pharmacol Ther 2004;20:1323–1327.

  7. 7.

    , . Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander? Inflamm Bowel Dis 2010;16:1620–1627.

  8. 8.

    , , et al. A comparison of routine light microscopy, immunohistochemistry, and in situ hybridization for the detection of cytomegalovirus in gastrointestinal biopsies. Am J Gastroenterol 1989;84:1517–1520.

  9. 9.

    , , et al. Frequent detection of cytomegalovirus in the intestine of patients with inflammatory bowel disease. Inflamm Bowel Dis 2006;12:879–884.

  10. 10.

    , , et al. Real-time automated PCR for early diagnosis and monitoring of cytomegalovirus infection after bone marrow transplantation. J Clin Microbiol 2000;38:2536–2542.

  11. 11.

    , , et al. A comparison of CMV detection in gastrointestinal mucosal biopsies using immunohistochemistry and PCR performed on formalin-fixed, paraffin-embedded tissue. Am J Surg Pathol 2013;37:995–1000.

  12. 12.

    , , 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.

  13. 13.

    , , 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.

  14. 14.

    , , . Detection and monitoring of virus infections by real-time PCR. Mol Aspects Med 2006;27:254–298.

  15. 15.

    , , et al. Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis. Gastroenterol 2007;133:1099–1105.

  16. 16.

    , , et al. Quantification of human cytomegalovirus DNA in bone marrow transplant recipients by real-time PCR. J Clin Microbiol 2001;39:4362–4369.

  17. 17.

    , , et al. Use of the non-invasive components of the Mayo score to assess clinical response in ulcerative colitis. Inflamm Bowel Dis 2008;14:1660–1666.

  18. 18.

    , , et al. Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS ONE 2012;14:e51862.

  19. 19.

    , , et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009;55:611–622.

  20. 20.

    , , et al. Cytomegalic inclusion disease and ulcerative colitis: report of a case in a young adult. Am J Med 1961;30:334–340.

  21. 21.

    , , et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2014;8:443–468.

  22. 22.

    , , et al. Cytomegalovirus infection in patients with active inflammatory bowel disease. Dig Dis Sci 2010;55:1059–1065.

  23. 23.

    , , et al. Effects of antiviral therapy for patients with inflammatory bowel disease and a positive intestinal biopsy for cytomegalovirus. Clin Gastroenterol Hepatol 2015;13:949–955.

  24. 24.

    , , et al. Low prevalence of CMV infection in patients with Crohn's disease in comparison with ulcerative colitis: effect of different immune response on prevalence of CMV infection. Dig Dis Sci 2010;55:1498–1499.

  25. 25.

    , , et al. Human cytomegalovirus and Epstein-Barr virus infection in inflammatory bowel disease: need for mucosal viral load measurement. World J Gastroenterol 2015;21:1915–1926.

  26. 26.

    , , et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis. Am J Gastroenterol 2001;96:773–775.

  27. 27.

    , , et al. Review article: cytomegalovirus and inflammatory bowel disease. Aliment Pharmacol Ther 2015;41:725–733.

  28. 28.

    , , et al. Cytomegalovirus infection in patients with inflammatory bowel disease. Am J Gastroenterol 1999;94:1053–1056.

  29. 29.

    , , et al. Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment. Eur J Gastroenterol Hepatol 2014;26:1146–1151.

  30. 30.

    , , et al. The impact of cytomegalovirus reactivation and its treatment on the course of inflammatory bowel disease. Aliment Pharmacol Ther 2014;39:712–720.

  31. 31.

    , , et al. Long-term outcomes of cytomegalovirus reactivation in patients with moderate to severe ulcerative colitis: a multicenter study. Gut Liver 2014;8:643–647.

  32. 32.

    , , et al. Antiviral therapy in cytomegalovirus-positive ulcerative colitis: a systematic review and meta-analysis. World J Gastroenterol 2014;20:2695–2703.

  33. 33.

    , , et al. Unfavorable outcome of antiviral therapy in cytomegalovirus-positive ulcerative colitis may be due to inappropriate study inclusion in meta-analysis. World J Gastroenterol 2015;21:1689–1690.

  34. 34.

    , , et al. Quantification of cytomegalovirus DNA levels in intestinal biopsies as a diagnostic tool for CMV intestinal disease. J Clin Virol 2009;46:254–258.

  35. 35.

    , , et al. Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients. Am J Gastroenterol 2007;102:331–337.

  36. 36.

    , , et al. qPCR increases sensitivity to detect cytomegalovirus in formalin-fixed, paraffin-embedded tissue of gastrointestinal biopsies. Human Pathol 2014;45:48–53.

  37. 37.

    , , et al. Diagnosing cytomegalovirus in patients with inflammatory bowel disease-by immunohistochemistry or polymerase chain reaction? Virchows Arch 2015;466:533–539.

  38. 38.

    , , et al. Clinical utility of cytomegalovirus antigenemia assay and blood cytomegalovirus DNA PCR for cytomegaloviral colitis patients with moderate to severe ulcerative colitis. J Crohns Colitis 2014;8:693–701.

  39. 39.

    , , et al. Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis. Dig Dis Sci 2006;51:1052–1055.

  40. 40.

    , , et al. Human cytomegalovirus end-organ disease is associated with high or low systemic viral load in preemptively treated solid-organ transplant recipients. New Microbiol 2012;35:279–287.

  41. 41.

    , , et al. Cytomegalovirus infection of the colon: a possible role in exacerbations of inflammatory bowel disease. Am J Gastronterol 1985;80:355–360.

  42. 42.

    , , et al. Cytomegalivirus infection associated with ulcerative colitis in immunocompetent individuals. Postgrad Med J 1998;74:486–489.

  43. 43.

    , . Case report: recurrence of chronic ulcerative colitis induced by intercurrent cytomegalic virus infection. Md Med J 1995;44:1047–1048.

  44. 44.

    , . CMV-colitis complicates IBD. Am J Gastroenterol 2006;101:1857–1865.

Download references

Acknowledgements

We thank Marion Menke for performing immunohistochemistry experiments and for technical assistance.

Author information

Author notes

    • Ulf Helwig
    •  & Michael Respondek

    U Helwig and M Respondek shared senior authorship.

Affiliations

  1. Molecular Diagnostics, Practice of Pathology, Vechta, Germany

    • Nils Wethkamp
    •  & Michael Respondek
  2. Gastroenterology, Medical Department, St Marien-Hospital, Vechta, Germany

    • Eva-Maria Nordlohne
    •  & Volker Meister
  3. Shared Practice for Internal Medicine, Oldenburg, Germany

    • Ulf Helwig

Authors

  1. Search for Nils Wethkamp in:

  2. Search for Eva-Maria Nordlohne in:

  3. Search for Volker Meister in:

  4. Search for Ulf Helwig in:

  5. Search for Michael Respondek in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Nils Wethkamp.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/modpathol.2017.149

Supplementary Information accompanies the paper on Modern Pathology website (http://www.nature.com/modpathol)