Cytomegalovirus Colitis

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Background

Cytomegalovirus (CMV) is a member of the Herpesviridae family, along with herpes simplex viruses 1 and 2, Epstein-Barr virus, and varicella-zoster virus. It is a double-stranded DNA virus with a protein coat and lipoprotein envelope. Similar to other herpesviruses, CMV is icosahedral and replicates in the host's nucleus. Replication in the host cell typically manifests pathologically with large intranuclear inclusion bodies and smaller cytoplasmic inclusions, and is accompanied by presence of CMV viral particles in the plasma. See the images below.


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Gross specimen of bowel showing ulceration secondary to cytomegalovirus colitis.


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Giant cell with inclusion body characteristic of cytomegalovirus colitis.

Between 50% and 80% of the world's population is seropositive for CMV. Initial CMV infection in the immunocompetent host typically is mild and goes undetected clinically. This is followed by a chronic latent state, during which the virus remains present within host cells, but viral proliferation is prevented by host cell-mediated immunity. Failure of immune containment may lead to reactivation with viral proliferation and severe systemic illness. Systemic CMV disease is characterized by fever, pancytopenia, and inflammatory changes in multiple organs including the liver and lungs, and in the retina. Colitis is a frequent manifestation of this acute systemic illness.

Patients are rendered susceptible to systemic CMV disease by treatment with immunosuppressive medications, or by illnesses that reduce cellular immunity, such as human immunodeficiency virus (HIV) infection. Acute systemic illness caused by CMV is particularly common following initial exposure in an immune compromised individual (in particular, in a CMV-negative transplant recipient who receives an organ from a CMV-positive donor).

Pathophysiology

CMV has 3 major patterns of infection.

The first is primary infection, in which a patient who has never been exposed to the pathogen becomes infected, either by contact with another patient who is actively infected or by transfer of blood or tissue from a seropositive individual with latent virus. The second pattern, reactivation, occurs in a patient who is seropositive with a latent virus when the host's immune system becomes compromised. The third, superinfection, occurs when a patient who is CMV-seropositive receives latently infected cells from another patient who is seropositive. The resulting CMV infection is from the latent donor cells, not from the recipient cells.

Regardless of the pattern of infection, resolution of active infection results in a latent state in which CMV persists indefinitely in the host tissues. Viral proliferation is absent, and viral antigen and DNA are undetectable in plasma. If the host's T-cell response becomes compromised by disease or immunosuppressive therapy, latent virus reactivation can occur.

CMV infection can cause a variety of syndromes. Most primary infections in immunocompetent individuals go undetected. Nonspecific fever, sometimes accompanied by pancytopenia, characterizes uncomplicated CMV infection. Severe cases of tissue-invasive CMV disease may produce a bewildering array of clinical syndromes, depending on the particular organs involved.

When the colon becomes affected by tissue-invasive CMV, ulcerative changes can be seen. As the body mounts an inflammatory response, watery diarrhea may begin to develop. As ulcers increase in depth, erosion into blood vessels can cause profuse bloody diarrhea. Over time, inflammatory polyps may develop, which, rarely, may obstruct the colon. Severe inflammation and vasculitis may lead to ischemia and transmural necrosis of the bowel, resulting in perforation and peritonitis.

Epidemiology

Frequency

United States

CMV colitis is rare in immunocompetent patients. It occurs in 2-16% of patients who have received solid organ transplants and in 3-5% of patients with HIV infection or acquired immunodeficiency syndrome (AIDS). A study documented CMV infection in 27.3% of patients with steroid-refractory ulcerative colitis and 9.1% of patients with nonrefractory colitis.[1, 2]

Mortality/Morbidity

Race

Sex

Age

History

Patients may present with the following symptoms:

Physical

Patients with CMV colitis may exhibit a wide range of abdominal findings depending on the stage of their disease.

Causes

Any factor that causes a decrease in a patient's immunity increases the risk for CMV colitis.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Affected specimens may show acute and chronic inflammatory changes, vasculitis, and/or mucosal ulceration. Deep biopsy specimens are preferred. Staining with Papanicolaou or hematoxylin and eosin stains may reveal classic findings, which include giant cells (usually 25-35 µm) (see the image below) with cytomegaly and large ovoid or pleomorphic nuclei containing basophilic inclusions (owl's eyes, halo rim). Data suggest that immunohistochemical staining may be more sensitive for detecting CMV.


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Giant cell with inclusion body characteristic of cytomegalovirus colitis.

Medical Care

A study of by Maconi et al indicated that antiviral therapy may aid in maintaining remission in patients with CMV colitis; specifically, those with ulcerative colitis or steroid-dependent/refractory disease. The study involved 38 patients with active CMV colitis, including 30 with ulcerative colitis and eight with Crohn disease. Antiviral therapy was administered to 13 patients; over a 1-year follow-up period, 23% of patients in the antiviral group suffered a clinical relapse requiring new treatment or colectomy, compared with 50% of patients who did not receive antiviral treatment. More specifically, among patients with ulcerative colitis, 77.8% of those who underwent antiviral therapy maintained remission over the 12 months, compared with 45% of patients who were not treated, while among patients with steroid-dependent/refractory disease, 77.8% of those who received antiviral therapy maintained remission, compared with 19.4% of the untreated patients.[7]

Surgical Care

Consultations

Because CMV colitis is usually observed as part of a multisystemic disease, the following consultations should be obtained.

Diet

Activity

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Ganciclovir (Cytovene)

Clinical Context:  Acyclic nucleoside analogue of 2'deoxyguanasine. Phosphorylates first to monophosphate form by CMV-encoded protein kinase homologue, then to diphosphate and triphosphate forms by cellular kinases, allowing for a 100-fold greater concentration in CMV-infected cells. Thought to inhibit CMV replication by competitive inhibition of viral DNA polymerases and by incorporating itself into viral DNA, causing termination of viral DNA elongation. Like acyclovir, ganciclovir is virostatic and only exerts its effect on replicating virus.

Foscarnet (Foscavir)

Clinical Context:  Organic analogue of inorganic pyrophosphate that inhibits replication of herpes simplex viruses, including CMV. Selectively inhibits at pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular polymerases. Unlike ganciclovir, does not require activation by a kinase and is active in vitro.

Class Summary

Inhibit replication of target virus.

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications

Transfer

Deterrence/Prevention

In CMV-naive patients receiving solid organ transplants from CMV-positive donors, risk of CMV disease exceeds 40%. Prophylactic administration of ganciclovir or valganciclovir for 100 days post transplant markedly reduces the incidence of tissue invasive CMV infection. However, after prophylaxis is discontinued, some patients develop delayed CMV disease.

An alternative approach is weekly monitoring of CMV DNA with preemptive antiviral treatment when viremia is detected. The preemptive approach has theoretical appeal, as it may encourage activation of endogenous immune responses to CMV while arresting infection before tissue invasive disease can develop. Preemption also avoids the cost and toxicity of antiviral medications in those patients who achieve spontaneous immunity to CMV. Prophylaxis versus preemption is currently an area of controversy in the transplant literature.

Prophylaxis is also commonly administered in CMV-seropositive transplant patients during periods when intensified immunosuppression is required for treatment of acute or chronic rejection.

Complications

Prognosis

Author

Douglas M Heuman, MD, FACP, FACG, AGAF, Chief of GI, Hepatology, and Nutrition at North Shore University Hospital/Long Island Jewish Medical Center; Professor, Department of Medicine, Hofstra North Shore-LIJ School of Medicine

Disclosure: Novartis Grant/research funds Other; Bayer Grant/research funds Other; Otsuka Grant/research funds None; Bristol Myers Squibb Grant/research funds Other; Scynexis None None; Salix Grant/research funds Other; MannKind Other

Coauthor(s)

Jasmohan S Bajaj, MD, MSc, Assistant Professor of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center

Disclosure: Nothing to disclose.

Vivek V Gumaste, MD, Associate Professor of Medicine, Mount Sinai School of Medicine of New York University; Adjunct Clinical Assistant, Mount Sinai Hospital; Director, Division of Gastroenterology, City Hospital Center at Elmhurst; Program Director of GI Fellowship (Independent Program); Regional Director of Gastroenterology, Queens Health Network

Disclosure: Nothing to disclose.

Specialty Editors

Jeffrey D Band, MD, Professor of Medicine, Oakland University William Beaumont School of Medicine; Director, Division of Infectious Diseases and International Medicine, Corporate Epidemiologist, William Beaumont Hospital; Clinical Professor of Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

James L Achord, MD, Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP, Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous authors Deron J. Tessier, MD, and Russell A. Williams, MBBS, to the development and writing of this article.

References

  1. Maconi G, Colombo E, Zerbi P, et al. Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection. Dig Liver Dis. Jun 2005;37(6):418-23. [View Abstract]
  2. Kim YS, Kim YH, Kim JS, Cheon JH, Ye BD, Jung SA, et al. Cytomegalovirus infection in patients with new onset ulcerative colitis: a prospective study. Hepatogastroenterology. Jun 2012;59(116):1098-101. [View Abstract]
  3. Onyeagocha C, Hossain MS, Kumar A, et al. Latent cytomegalovirus infection exacerbates experimental colitis. Am J Pathol. Nov 2009;175(5):2034-42. [View Abstract]
  4. Al-Zafiri R, Gologan A, Galiatsatos P, Szilagyi A. Cytomegalovirus complicating inflammatory bowel disease: a 10-year experience in a community-based, university-affiliated hospital. Gastroenterol Hepatol (N Y). Apr 2012;8(4):230-9. [View Abstract]
  5. Pillet S, Pozzetto B, Jarlot C, Paul S, Roblin X. Management of cytomegalovirus infection in inflammatory bowel diseases. Dig Liver Dis. Jul 2012;44(7):541-8. [View Abstract]
  6. Jones A, McCurdy JD, Loftus EV Jr, Bruining DH, Enders FT, Killian JM, et al. Effects of Antiviral Therapy for Patients with Inflammatory Bowel Disease and a Positive Intestinal biopsy for Cytomegalovirus. Clin Gastroenterol Hepatol. Oct 2 2014;[View Abstract]
  7. Maconi G, Lombardini M, Furfaro F, et al. Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment. Eur J Gastroenterol Hepatol. Oct 2014;26(10):1146-51. [View Abstract]

Gross specimen of bowel showing ulceration secondary to cytomegalovirus colitis.

Giant cell with inclusion body characteristic of cytomegalovirus colitis.

Gross specimen of bowel showing ulceration secondary to cytomegalovirus colitis.

Giant cell with inclusion body characteristic of cytomegalovirus colitis.

Gross specimen of bowel showing ulceration secondary to cytomegalovirus colitis.

Giant cell with inclusion body characteristic of cytomegalovirus colitis.