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Cytomegalovirus Colitis
Article Last Updated: Oct 10, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Deron J Tessier, MD, Staff Surgeon, Kaiser Permanente Medical Center, Fontana, CA
Deron J Tessier is a member of the following medical societies: American College of Surgeons and American Medical Association
Coauthor(s):
Russell A Williams, MBBS, Program Director, Professor, Department of Surgery, University of California Medical Center at Irvine
Editors: Jeffrey D Band, MD, Clinical Professor of Medicine, Wayne State University School of Medicine; Director, Division of Infectious Diseases and International Medicine, William Beaumont Hospital Corporation; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; James L Achord, MD, Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Author and Editor Disclosure
Synonyms and related keywords:
CMV, CMV infection, Herpesviridae, herpesvirus, herpes simplex virus, HSV, Epstein-Barr virus, varicella-zoster virus, HIV, AIDS, CMV colitis, CMV gastrointestinal disease, CMV GI disease, HIV disease complications, bloody diarrhea, watery diarrhea, AIDS complications, CMV ulcerative colitis, cytomegalovirus ulcerative colitis, cytomegalovirus UC, steroid-dependent ulcerative colitis, cytomegalovirus infection, cytomegalovirus
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. Like the other members of this family, CMV has the ability to produce a latent infection. Replication in the host cell is typically represented by large intranuclear inclusion bodies and smaller cytoplasmic inclusions. The virus preferentially grows in fibroblast cells in tissue culture and has been replicated in numerous other cell types.
Studies have shown that 50-80% of the world's population is seropositive for CMV. With the advent of immunosuppressive medications and the rise of HIV infection and AIDS in the early 1980s, a new class of CMV infection has been described. CMV retinitis, adrenalitis, pneumonitis, colitis, and esophagitis are some of the infections observed in immunocompromised hosts. CMV is the third most common pathogen in patients with AIDS, superseded by Pneumocystis carinii and Candida.
CMV GI disease in adults was described in the 1960s. CMV colitis is the second most common CMV infection in patients with AIDS (after retinitis) and was first described in 1983. Of patients with AIDS who have GI infection caused by CMV, 67% had involvement of the colon. CMV colitis is uncommon in patients who are not severely immunocompromised with only 44 cases described in the literature. GI tract involvement may occur either alone or in the setting of disseminated disease.
CMV may complicate steroid-dependent ulcerative colitis (UC), further complicating both disease processes. Patients with steroid-dependent UC who present with refractory disease should be evaluated for CMV infection. Up to 59% of patients with steroid-refractory UC have been shown to also have CMV colitis. The prognosis for patients with UC complicated by CMV infection is worse than that for patients with UC alone.
Pathophysiology
CMV has 3 major patterns of infection.
The first is primary infection, in which the patient has never been exposed to the pathogen but becomes infected by a patient who is seropositive for the virus (60%). Primary infection in immunocompetent hosts causes few or no symptoms. After the initial infection, the genome of the virus persists in the host.
The second, reactivation, occurs in a patient who is seropositive with a latent virus that becomes reactivated if the host's immune system becomes compromised (10-20%).
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 (20-40%).
Once a patient becomes infected, CMV can persist indefinitely in the host tissues. If the host's T-cell response becomes compromised by disease or iatrogenic processes, latent virus can reactivate and cause a variety of syndromes. When the colon becomes affected, 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.
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 AIDS. A recent study documented CMV infection in 27.3% of patients with steroid-refractory UC and 9.1% of patients with nonrefractory colitis.
Mortality/Morbidity
- Since the introduction of effective antiviral agents, morbidity and mortality have been reduced.
Race
- No racial predilection has been documented.
Sex
- No sexual predilection is recognized.
Age
- Reports of patients who are not immunocompromised contracting CMV colitis indicate that the illness tends to occur in patients older than 70 years. Otherwise, no age predilection is documented for CMV colitis in immunocompromised patients.
- Newborns infected with HIV have contracted CMV colitis.
History
Patients 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
Physical
Patients with CMV colitis may exhibit a wide range of abdominal findings depending on the stage of their disease.
- 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, stigmata of an acute abdomen may develop.
Causes
Any factor that causes a decrease in a patient's immunity increases the risk for CMV colitis.
- Adults older than 70 years, especially if nutritionally depleted
- HIV infection and 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
Campylobacter Infections
Clostridium Difficile Colitis
Colon Cancer, Adenocarcinoma
Crohn Disease
Cryptosporidiosis
Gastroenteritis, Bacterial
Gastroenteritis, Viral
Megacolon, Toxic
Mycobacterium Avium-Intracellulare
Ulcerative Colitis
Other Problems to be Considered
Acquired immunodeficiency syndrome
Entamoeba histolytica infection
Ischemic colitis
Lab Studies
- Antigen detection: Direct specific immunofluorescent antibody detects viral antigens or viral DNA.
- 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 polymerase chain reaction, 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.
Imaging Studies
- Imaging studies may demonstrate bowel wall thickening, mucosal ulcerations (see Media file 1), and luminal narrowing.
Procedures
- The study of choice is sigmoidoscopy or colonoscopy, which allows direct visualization and the opportunity to obtain biopsy specimens that may aid in 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.
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 Media file 2) with cytomegaly and large ovoid or pleomorphic nuclei containing basophilic inclusions (owl's eyes, halo rim). Recent data suggest that immunohistochemical staining may be more sensitive for detecting CMV.
Medical Care
- Patients with HIV infection
- Recent studies have documented the profound effect of potent antiretroviral therapy on the natural history of HIV infection. Because most patients affected by 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+ lymphocytes, decreased hospitalization, and decreased opportunistic infections (eg, CMV colitis). For these patients, aggressive treatment of HIV infection is key in treating and preventing CMV infection.
- Patients who have CMV colitis benefit from antiviral therapy.
- 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.
- 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.
Surgical Care
- 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.
Consultations
Because 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 resection or for those who develop complications.
- Infectious disease experts should be consulted to help treat CMV infection and to help exclude underlying HIV infection.
Diet
- 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.
Activity
- No activity restriction is usually required.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antivirals
Inhibit replication of target virus.
| Drug Name | Ganciclovir (Cytovene) |
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| Description | 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. |
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| Adult Dose | Not well absorbed PO
Induction: 5 mg/kg IV q12h for at least 21 d
Maintenance: 6 mg/kg/d IV (5 times/wk); PO ganciclovir maintenance at doses of 1 g tid is of uncertain value |
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| Pediatric Dose | <3 months: Not established
>3 months: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Concomitant administration with cytotoxic drugs (eg, dapsone, vinblastine, doxorubicin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim-sulfamethoxazole combinations, other nucleoside analogs) may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem-cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; in presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously; bioavailability may decrease in presence of zidovudine, while bioavailability of zidovudine is increased |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Phlebitis or pain may occur at injection site; clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; because PO ganciclovir is associated with higher rate of CMV retinitis progression compared with IV formulation, use only when benefits outweigh risks (advanced HIV disease); half-life and plasma/serum concentrations may increase as a result of reduced renal clearance; dosages > 6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at injection site despite further dilution in IV fluids; administration should be accompanied by adequate hydration; photosensitization (photoallergy or phototoxicity) may occur; myelosuppression is main dose-limiting toxicity; must be used with caution in patients with preexisting cytopenias |
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| Drug Name | Foscarnet (Foscavir) |
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| Description | 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. |
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| Adult Dose | Induction: 90 mg/kg IV q12h for 3-6 wk
Maintenance: 90-120 mg/kg/d IV |
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| Pediatric Dose | <12 years: Not established
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Coadministration with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) may increase nephrotoxicity (do not administer unless potential benefits outweigh risks); coadministration with IV pentamidine may cause hypocalcemia |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Has adverse nephrotoxic effects and should be used with caution in patients with renal disease or those taking nephrotoxic medications (volume or saline loading may diminish renal toxicity); renal function must be monitored closely; may cause derangements in electrolytes, including calcium, phosphorous, magnesium, and potassium; seizures have been noted in some patients with electrolyte disturbances secondary to drug; anemia has been reported, and patients should be monitored closely |
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Further Inpatient Care
- 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.
Further Outpatient Care
- 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 of higher than 100-150 cells/µL.
In/Out Patient Meds
- Maintenance therapy may be considered, especially in patients who require reinduction for relapse.
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.
Complications
- 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 affected colon is indicated to avert perforation and sepsis.
- Perforation
- Sepsis
- Peritonitis
- Death
Prognosis
- With rapid diagnosis and proper antiviral therapy, the prognosis of patients with CMV colitis is good if the underlying disease itself is controllable.
- In patients without immunocompromise, the prognosis appears to be age dependent, with patients older than 55 years having higher mortality. Males and patients who need surgery also have a poorer prognosis.
Patient Education
- 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 excellent patient education resources, visit eMedicine's Immune System Center. Also, see eMedicine's patient education articles HIV/AIDS and HIV Testing.
Special Concerns
- In high-risk patients, only use CMV-seronegative blood.
- When matching organs, only use organs from seronegative donors.
- CMV vaccines are being developed.
- Prophylactic colon screening has not been beneficial.
| Media file 1:
Gross specimen of bowel showing ulceration secondary to cytomegalovirus colitis. |
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Media type: Photo
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| Media file 2:
Giant cell with inclusion body characteristic of cytomegalovirus colitis. |
 | View Full Size Image | |
Media type: Photo
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Cytomegalovirus Colitis excerpt Article Last Updated: Oct 10, 2006
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