|Year : 2016 | Volume
| Issue : 1 | Page : 4-9
Cytomegalovirus infection of gastrointestinal tract
Mukesh Nasa1, Zubin Sharma1, Randhir Sud1, Lipika Lipi2
1 Institute of Digestive and Hepatobiliary Sciences, Medanta - The Medicity, Gurgaon, Haryana, India
2 Department of Pathology, Medanta The Medicity, Gurgaon, Haryana, India
|Date of Web Publication||23-Mar-2016|
Institute of Digestive and Hepatobiliary Sciences, Medanta - The Medicity, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Gastrointestinal tract infection with CMV can occur from mouth to anal canal. In the immunocompetent subjects, the upper GI tract is most commonly involved while immunocompromised individuals have colon as the most common site of involvement. In a study of CMV infection among AIDS patients, the most common site of CMV infection in the GI tract was the colon (55%), while gastric involvement was reported in 40% of cases. CMV mononucleosis, hepatitis and pneumonitis are among the most common manifestations.' GI tract involvement is common and it is easy to access for taking the diagnostic biopsies. Severity and extent of involvement within the GI tract is variable.
Keywords: Cytomegalovirus, opportunistic infection, ulcerative colitis
|How to cite this article:|
Nasa M, Sharma Z, Sud R, Lipi L. Cytomegalovirus infection of gastrointestinal tract
. Community Acquir Infect 2016;3:4-9
| Introduction|| |
Gastrointestinal (GI) tract infection with cytomegalovirus (CMV) can occur from mouth to anal canal. In the immunocompetent subjects, the upper GI tract is most commonly involved while immunocompromised individuals have a colon as the most common site of involvement. In a study of CMV infection among AIDS patients, the most common site of CMV infection in the GI tract was the colon (55%), while gastric involvement was reported in 40% of cases. The antrum (25%) was the most common site of upper GI tract CMV infection whereas the sigmoid colon and rectum (35%) were the most common sites in lower GI tract involvement. Colonoscopy is recommended for patients suspected of having CMV infection with colon involvement.
CMV mononucleosis, hepatitis, and pneumonitis are among the most common manifestations. GI tract involvement is common, and it is easy to access for taking the diagnostic biopsies. , Severity and extent of involvement within the GI tract are variable. ,
GI CMV infection occurs in two distinct clinical settings: (i) Immunocompetent host; and (ii) immunocompromised patients.
| Cytomegalovirus infection in the immunocompetent|| |
CMV infection can occur as reactivation of latent virus, or it may be acquired from the exogenous source. CMV induces Fc receptors and the infected cells, and CMV-infected cells bind to beta 2 microglobulin thus evading the humoral immune response. By its interaction with the immune system of the body, CMV has an immune-suppressive effect.
This immune-suppressive effect of CMV is transient and thus, may not have overt clinical expression.
GI tract infection with CMV may result in diarrhea, acute colitis, and malaise. CMV infection may be superimposed on chronic, preexisting disease in the GI tract. As majority of GI tract infections are self-limiting, and there is a lack of serological evidence of infection in majority of the cases, the real incidence is difficult to establish.
Within GI tract, CMV infects endothelial cells. It may occur as super-infection in a preexisting inflammatory bowel disease, and CMV superinfection is associated with risk of developing toxic megacolon and may even require surgery and has high associated mortality.  Several cases of CMV vasculitis have been described in association with chronic ulcerative colitis. ,,,,
| Cytomegalovirus as an opportunistic pathogen in the immunocompromised|| |
CMV infection as an opportunistic pathogen in post organ transplant patients on immunosuppressive treatment and in AIDS. Posttransplant infection can occur in renal transplant, liver transplant, and bone-marrow transplant recipients. ,, Congenital immune deficiencies can also result in CMV infections in the bowel. Steroid therapy also predisposes to opportunistic CMV infection. Steroids at low doses used in the management of arthritis and chronic obstructive airway disease also pose the risk of infection. 
Symptoms of GI tract CMV infection vary depending on the site, severity and the extent of involvement within the GI tract. Diarrhea is the most common presenting symptom in the immunocompetent subjects.  Weight loss and fever are the common manifestations. Other common symptoms are hematochezia, dysphagia, abdominal distension, pain abdomen, and hematemesis. Perforation has been described especially in the organ transplant recipients. ,,
CMV infection of GI tract can cause erythema, erosions, ulcerations, pseudotumor formation and perforation. ,,,,
Among the various macroscopic lesions due to CMV infection of GI tract, the ulcerative colonic lesions are the most common manifestation. Esophageal involvement can occur with deep ulcerations.  Colonic skip ulcers with normal intervening mucosa can endoscopically appear like Crohn's disease.
CMV can cause toxic megacolon in patient with preexisting inflammatory bowel disease, but CMV itself can cause vasculitis with toxic megacolon.
Bowel perforation has been described, most commonly involving terminal ileum and splenic flexure of the colon. ,,
Bowel obstruction due to inflammatory pseudotumor involving the ileocaecal region has been described.  Features of gastric outlet obstruction may occur because of inflammatory mass involving gastric antrum.
Ulcero-stenotic lesion in colon may have a radiological resemblance of neoplasm. 
Hemorrhagic colitis from active proctocolitis is well described. 
Pseudomembrane formation as a manifestation of CMV colitis has been described.
Pneumatosis intestinalis has been reported in renal transplant recipient with CMV colitis. ,
Biliary tract involvement has been reported in form of cholangitis, acalculous cholecystitis, and papillary stenosis. 
| Patient profile and endoscopic features of patients with gastrointestinal tract cytomegalovirus infection|| |
In our patients of GI tract CMV disease [Table 1], three patients were immunocompromised, and one had preexisting underlying ulcerative colitis.
First patient was a diagnosed case of common variable immunodeficiency (CVID) on replacement dose of intravenous (IV) immunoglobulin (Ig). He presented with 3 weeks history of diarrhea associated with epigastric pain. Endoscopy was done and duodenal biopsies were taken to rule out gluten-enteropathy. [Figure 1] shows the microscopic image of duodenal biopsy with CMV inclusion bodies. A similar case has been reported where duodenal CMV infection was reported complicating the CVID associated sprue. 
|Figure 1: Microscopic image of duodenal biopsy, showing large cells with cytomegalovirus intranuclear inclusion bodies|
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|Table 1: Patient profile, site involved, and treatment outcomes in gastrointestinal cytomegalovirus disease |
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Our second patient was HIV-positive female with CD-4+ cell count 7/mm 3 . She had fever and odynophagia for 3 weeks. She was empirically treated with anti-fungal drugs elsewhere. Endoscopy was done for the evaluation of esophagus, showed diffuse erythema and large ulcers involving the entire esophagus [Figure 2]. There was a large, oblong, deep ulcer in the distal third of the esophagus, from which multiple biopsies were taken. The biopsy showed stratified squamous epithelium with plenty of inflammatory cells with large cells showing typical intranuclear inclusion bodies suggestive of CMV esophagitis [Figure 3]. Ophthalmology review was done to rule out concomitant retinal involvement. There was no retinal involvement in the present case. She was started on IV gancyclovir along with antiretroviral therapy (ART). ,
|Figure 2: Endoscopy image showing large, deep punched-out ulcer in the lower esophagus|
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|Figure 3: Esophageal biopsy showing positive immunohistochemical for cytomegalovirus|
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The third patient was postrenal transplant on immunosuppressive therapy for last 6 months. He presented with upper abdominal pain with a history of occasional vomiting for 2 weeks. Endoscopic evaluation showed erythema with multiple small clean-based ulcers in the gastric antrum. Biopsy from the ulcer base showed large cells with intranuclear inclusion bodies typical of CMV infection [Figure 4] and [Figure 5] GI symptoms-pain abdomen, nausea, and diarrhea are common postrenal transplant patients. There have been few case reports of CMV gastric ulcer in renal-transplant recipient in the literature. ,
|Figure 4: Microscopy image of antral biopsy showing large intranuclear inclusion bodies typical of cytomegalovirus infection|
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|Figure 5: Photomicrograph showing cytomegalovirus - immunohistochemical positive stain on antral biopsy|
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The fourth patient was a known case of ulcerative colitis on maintenance mesalamine treatment. She had increased stool frequency with urgency and tenesmus. Sigmoidoscopy showed erythema with confluent ulcers in recto-sigmoid. Biopsy from the ulcers confirmed super-imposed CMV infection. She responded well to oral ganciclovir treatment. Increased re-activation of CMV in patients of ulcerative colitis has been reported in the literature. 
| Diagnosis of cytomegalovirus infection of the gastrointestinal tract|| |
During the active CMV infection, there is the stage of early antigen production which is associated with IgM antibody response. This is followed by late antigen production and stage of latency during which CMV genome is incorporated in the host cell nucleus.
High titer of IgM antibodies or increasing titers of IgG antibody indicates present infection. In the immunocompromised persons, the interpretation of serology may be difficult.
CMV can be cultured in the medium with human embryo fibroblasts. Positive culture does not necessarily mean an active infection as virus can be excreted for months after the primary infection. 
Detection of CMV antigen is a marker of an active infection. Antigen can be detected in circulation in the early stage of infection thus CMV antigenemia helps to detect active infection at an early stage. 
Histology and immunohistology
"Owl's eye" intranuclear inclusions are the hallmark of CMV in routine hematoxylin, and eosin staining of the tissue. These inclusions may be seen in the endothelial cells, stromal cells, and epithelial cells.
Presence of inclusion bodies in the stained tissue indicates present CMV infection. Atypical inclusions may cause diagnostic difficulty due to confusion with HSV inclusion body. In cases with diagnostic difficulty immunohistochemical staining helps to confirm the CMV infection. Both, early and late antigens can be detected by immunocytochemistry. Therefore, immunocytochemical staining is more sensitive for diagnosing active infection. 
Detection of viral nucleic acid
Detection of CMV nucleic acid by polymerase chain reaction (PCR) is a sensitive method but it does not always indicate the active infection. The PCR technique requires the homogenized tissue sample, so the histological details are not available. Contrary to this, in-situ hybridization allows the viral detection within the cells, thus histological details are available. PCR and in-situ hybridization positivity does not necessarily mean active infection as these may be positive in latent infection. ,
Light microscopy for a demonstration of CMV inclusion bodies is an easy technique, but viral inclusion bodies are not always demonstrable. 
| Location and morphology of cytomegalovirus infected cells|| |
In the esophageal biopsy, CMV was detected in the endothelial cells, pericytes, and the inflammatory cells but it was not demonstrable in the epithelial cells.
In the gastric biopsy, virus was found to infect the glandular epithelial cells. While in the colonic biopsy, endothelial cells, lamina propria cells, and pericytes were infected.
| Management of cytomegalovirus infections in the gut|| |
For the treatment of documented CMV infection of GI tract, gancyclovir is considered the drug of choice regardless of the cause of the underlying immunosuppression.  The recommended dose is 250 mg IV, twice in a day for at least 3 weeks. ,,,
Oral ganciclovir prophylaxis is given to HIV-infected persons with CD-4+ count <50/mm 3 . 
Cessation of prophylaxis may be considered when the CD-4 count becomes >100-150/mm 3 in response to highly active ART and the prophylaxis restarted if the CD-4 count becomes <100/mm 3 . ,,
Foscarnet can be used as an alternative to ganciclovir.  It is a pyrophosphate derivative and has virostatic action. Esophageal ulcers heal well with the foscarnet treatment. Relapses may occur after the treatment is stopped.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]