Cytomegalovirus Colitis

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 the 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. The 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 the host cells, but viral proliferation is prevented by the 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).

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Pathophysiology

Cytomegalovirus (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 an 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 by 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.

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Etiology

Any factor that causes a decrease in a patient's immunity increases the risk for cytomegalovirus (CMV) colitis, including the following:

• Adults older than 70 years, especially if nutritionally depleted
• Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS)
• High- and low-dose steroid therapy and therapy with other immunosuppressive medications
• Transplantation patients (especially patients receiving CMV-positive organs)
• Hemodialysis
• Neoplasia
• Inflammatory bowel disease
• Alcoholism
• Collagen-vascular disease (seems to be related to immunosuppressive therapy)
• Blood transfusions
• Malnutrition

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Epidemiology

United States data

Cytomegalovirus (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 human immunodeficiency virus (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]}

International data

In a systematic review of published studies on HIV and CMV coinfection in Africa, investigators found a high CMV seroprevalence throughout the continent, (>90% in the majority of the population).^[3] Of those with gastrointestinal manifestations, CMV was found in 0% to 14%.^[3]

Race-, sex-, and age-related demographics

No racial or sexual predilection has been& recognized.

Reports of patients who are not immunocompromised contracting CMV colitis indicate that the illness tends to occur in patients older than 70 years. In immunocompromised patients, CMV can occur at any age, including the newborn period.

CMV reactivation has a reported 4.5-16.6% prevalence in patients with severe colitis; it can reach 25% in those who require colectomy for severe colitis.^[4]

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Prognosis

Morbidity/mortality

With rapid diagnosis and proper antiviral therapy, the prognosis of patients with cytomegalovirus (CMV) colitis is good if the underlying disease itself is controllable.

In patients without immunocompromised status, the prognosis appears to be age dependent, with patients older than 55 years having a higher mortality. Males and patients who need surgery also have a poorer prognosis.

Since the introduction of effective antiviral agents, morbidity and mortality have been reduced.

CMV reactivation has been known to occur in patients with inflammatory bowel disease-related colitis, particularly in those who have steroid-refractory colitis.^[5] In cases of CMV reactivation that give rise to true CMV colitis (on the basis of histology and immunohistochemistry findings), antiviral agents may provide benefit.^[5]

Complications

Complications include the following:

• Toxic megacolon and necrotizing colitis: Once diagnosed, patients with these complications usually have diffuse disease and a poor prognosis. In these patients, generous resection of all the affected colon is indicated to avert perforation and sepsis.
• Perforation
• Sepsis
• Peritonitis
• Death

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History

Patients with cytomegalovirus (CMV) colitis may present with the following symptoms:

• Fever
• Anorexia
• Malaise
• Weight loss
• Dehydration
• Abdominal pain
• Abdominal distention
• Nausea
• Vomiting
• Chronic watery diarrhea
• Bloody diarrhea
• Constipation
• Worsening symptoms of inflammatory bowel disease^{[6, 7, 8]}

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Physical Examination

Patients with cytomegalovirus (CMV) colitis may exhibit a wide range of abdominal findings depending on the stage of their disease, including the following:

• Abdominal signs are not present early in the disease.
• Tenderness may develop in the descending and sigmoid colon as the bowel becomes more involved.
• Peritoneal signs and fever may be present. If the bowel becomes ischemic or perforates, clinical signs of an acute abdomen may develop.

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Laboratory Studies

There is some supportive evidence for testing for cytomegalovirus (CMV) colonic disease to improve sensitivity in suspected CMV colitis cases or in cases of moderate to severe colitis (eg, hematoxylin and eosin staining with immunohistochemistry of biopsy specimens and/or CMV DNA real-time polymerase chain reaction).^{[10, 11]}

Antigen detection

Direct specific immunofluorescent antibody detects viral antigens or viral DNA.

In a retrospective study that evaluated the clinical utility of CMV antigenemia assay and blood CMV polymerase chain reaction (PCR) in 229 patients with moderate to severe ulcerative colitis (UC) to predict CMV colitis and outcomes, Kim et al found both tests had low sensitivity (47.0% and 44.3%, respectively) but high specificity (81.7% and 87.9%, respectively) for diagnosing CMV colitis among the 83 patients (36.2%) with confirmed CMV colitis.^[12] There was a significant association between positive CMV antigenemia and subsequent colectomy among patients with CMV colitis (P= 0.015).

Culture techniques

The shell viral assay using monoclonal antibodies can detect immediate early antigens. Shell viral assay cultures reduce the time to positivity to 24-72 hours, whereas other cultures take days to weeks.

Other diagnostic studies

Tests such as antibody tests, qualitative or quantitative PCR, or studies of serum or other body fluids yield less diagnostic information.

Other co-infecting pathogens must be excluded by appropriate smears, cultures, and serologic studies.

A rising alkaline phosphatase level was the initial laboratory abnormality seen in one patient with CMV colitis.

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Imaging Studies

Imaging studies may demonstrate bowel wall thickening, mucosal ulcerations (see the following image), and luminal narrowing.

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Gross specimen of bowel showing ulceration secondary to cytomegalovirus colitis.

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Procedures

The study of choice is sigmoidoscopy or colonoscopy, which allows direct visualization and the opportunity to obtain biopsy specimens that may aid in the diagnosis.

Endoscopy may demonstrate mucosal erythema, erosions, ulcerations, hemorrhage, or nodular-plaque or polypoid lesions.

Specimens should be submitted for histologic examination, antigen detection, and viral cultures.

Lesions may mimic neoplastic processes.

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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 the 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.

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Medical Care

Patients with HIV infection

Studies have documented the profound effect of potent antiretroviral therapy on the natural history of infection with human immunodeficiency virus (HIV). Because most patients affected by cytomegalovirus (CMV) colitis have HIV infection, the increasing use of these newer therapies has fortuitously helped the treatment and prevention of CMV colitis.

Patients receiving antiretroviral therapy have shown a decrease in HIV viral load, increased CD4⁺ lymphocyte counts, decreased hospitalization, and decreased opportunistic infections (eg, CMV colitis). For these patients, aggressive treatment of HIV infection is the key in treating and preventing CMV infection.

Patients who have CMV colitis benefit from antiviral therapy.^[13]

Long-term prophylaxis with peroral ganciclovir is considered in patients infected with HIV who have CD4⁺ lymphocyte counts of less than 50 cells/µL.

Patients with other types of immunosuppressive factors (eg, transplantation, long-term steroid use, renal dialysis)

Because these patients are immunosuppressed by other illnesses or iatrogenic causes, the only treatment is ganciclovir.^{[4, 10]} Discontinuation of steroid or immunosuppressive agents in these patients is discouraged, unless the infection is not responding to antiviral therapy.

Patients who are not immunosuppressed

Treat with antiviral agents.

Limited evidence suggests that targeted therapy with ganciclovir or valganciclovir may be used to manage severe CMV disease in immunocompetent adults.^[10] In some patients with steroid-refractory ulcerative colitis with CMV, steroid therapy may be of benefit.^[14]

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.^[15] 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.^[15]

Hospitalization

Patients with symptomatic disease should undergo induction therapy with intravenous ganciclovir or intravenous foscarnet. Combination therapy with ganciclovir and foscarnet may be effective if monotherapy fails; however, this is associated with significant toxicity.

Maintenance therapy may be considered, especially in patients who require reinduction for relapse.

Diet and activity

Unless a patient has severe diarrhea, no special diet is needed. Patients with severe diarrhea may require bowel rest until the diarrhea subsides. Parenteral nutritional support may be needed.

No activity restriction is usually required.

Transfer

Patients may be transferred to a skilled nursing facility or equal care provider during treatment, as long as their clinical situation is controlled. Patients with severe CMV colitis should be monitored closely in either an acute-care setting or a regular hospital floor.

Patient monitoring and patient education

Patients should receive routine ophthalmologic screening for CMV retinitis (self-screen for visual acuity and floaters).

Therapy may need to be discontinued in patients infected with HIV who have clinical resolution and CD4⁺ lymphocyte counts greater than 100-150 cells/μL.

Patients should be educated about the nature of their disease and the possibility of recurrence; in particular, patients with HIV infection or AIDS should be aware of the possibility of recurrence.

For patient education resources, see HIV/AIDS and HIV Testing.

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Surgical Care

Bowel resection should be considered only in patients with life-threatening ischemia or uncontrolled bleeding.

Patients presenting with signs of peritonitis should undergo immediate laparotomy. Laparotomy may reveal discoloration of the serosa and small perforations.

Patients who undergo resection for perforation should have a diverting stoma, and the incision should be allowed to heal by secondary intention.

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Consultations

Because cytomegalovirus (CMV) colitis is usually observed as part of a multisystemic disease, the following consultations should be obtained:

• Consult an ophthalmologist to evaluate the patient for the presence of CMV retinitis. Patients should be instructed to monitor their vision and report any change in visual acuity or the presence of floaters.
• Consult a gastroenterologist to aid in diagnosis and treatment.
• Consult a surgeon for patients who may require bowel resection or for those who develop complications.
• Infectious disease experts should be consulted to help treat CMV infection and to help exclude underlying human immunodeficiency virus (HIV) infection.

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Prevention

In cytomegalovirus (CMV)-naive patients receiving solid organ transplants from CMV-positive donors, the 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 the 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 the treatment of acute or chronic rejection.

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Medication Summary

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

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Ganciclovir (Cytovene)

• Dosing, Interactions, etc.

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 the replicating virus.

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Foscarnet (Foscavir)

• Dosing, Interactions, etc.

Clinical Context:  Organic analogue of inorganic pyrophosphate that inhibits the 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, foscarnet does not require activation by a kinase and is active in vitro.

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Class Summary

Inhibit replication of target virus.

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