Cytomegalovirus (CMV), a double-stranded DNA virus and a member of the human herpesvirus family, is a common viral infection in 50 to 100% of humans worldwide depending on age and race of population tested. This chapter discusses current approaches to diagnose and manage CMV colitis and how to make a high index of suspicion based on clinical presentation and use investigation methods to reach a final diagnosis. The CMV genome is the largest among human viruses (approximately 230 kb), containing 200 genes encoding proteins. In healthy subjects, CMV colitis is usually asymptomatic or causes self-limited disease but may result in chronic infection or a life-long carrier state with intermittent reactivation. Cytomegalovirus reactivation is frequent in severe or steroid-resistant ulcerative colitis. However, what science does not yet know is whether CMV causes exacerbation of ulcerative colitis or simply serves as an innocent bystander of severe disease. Patients with CMV colitis present with non-specific symptoms, including diarrhea, abdominal pain, fever, rectal bleeding, and weight loss. Hematochezia and diarrhea are the most frequently observed symptoms in these patients. Therefore, a high suspicion index is necessary, and laboratory investigations are essential in making the diagnosis of CMV colitis. Several methods are possible, including antigenemia, endoscopy, histological examination of biopsy tissues, CMV culture, and tissue polymerase chain reaction (PCR) quantification. Colonic mucosal biopsies stained with hematoxylin and eosin (H & E) may reveal the typical inclusion associated with CMV colitis, “owl eye appearance” inclusion bodies, which are highly specific for CMV. However, H & E staining has low sensitivity compared to immunohistochemistry, which is the “gold standard” for the diagnosis of CMV colitis. Rapid diagnosis and management are usually recommended, especially in critically ill patients.
Cytomegalovirus colitis occurs most commonly in immunocompromised hosts including acquired immunodeficiency syndrome (AIDS), organ transplantation, hematological malignancy, cancer therapy, and steroid therapy. However, colitis can also occur in healthy patients without immunodeficiency. These patients usually have a median age of 68 and have accompanying symptoms of diarrhea, abdominal pain, and hematochezia or melena. The outcomes are typically favorable, including resolution without antiviral treatment in nearly 25% of these patients.
The work of Ko JH et al., in a case-control study, identified several risk factors associated with CMV colitis in immunocompetent individuals including renal diseases, patients on hemodialysis, neurological disorders, rheumatic disease, or those in intensive care unit, or exposed to antibiotics, antacids, steroids, or red blood cell transfusion within one month of diagnosis of colitis. Further analysis by the authors revealed that the use of steroids and red blood transfusion within one month were independent risk factors for CMV colitis in immunocompromised subjects.
Taken together, CMV colitis should be a consideration in the differential diagnosis not only in immunocompromised patients but also in immunocompetent patients particularly elderly presenting with hematochezia, who have comorbidities, in intensive care, or treated with steroids or red blood transfusion.
Cytomegalovirus colitis occurs in patients with acute severe ulcerative colitis, particularly patients treated with high-dose steroids.
Cytomegalovirus infection, including CMV colitis is a significant problem in patients after solid organ transplantation or allogeneic stem cell transplantation.
The prevalence of CMV assessed by serology in general population is 70% in adults and reaching 100% in poor communities and developing countries.
Primary CMV infection in immunocompetent patients is usually asymptomatic. The virus reactivation in these patients is again typically asymptomatic. However, in patients whose immune response is compromised, they develop symptoms in different body organs, including CMV colitis.
The diagnosis of CMV colitis requires histological examination of biopsy tissues, taken from the ulcer edge or base. Patients with punched-out ulcers are associated with a higher number of inclusion bodies on histology. (See evaluation).
The histological examination will enable the treating doctor not to misdiagnose CMV colitis with other causes of colitis (infectious colitis, ulcerative colitis, or drug-induced colitis), or rectal carcinoma.
Colonic mucosal biopsies stained with hematoxylin and eosin (H & E) may reveal the typical inclusion associated with CMV colitis, “owl eye appearance” inclusion bodies, which are highly specific for CMV. However, H & E staining has low sensitivity compared to immunohistochemistry, which is considered the “gold standard” for the diagnosis of CMV colitis.
CMV infection is frequently symptomatic in immune competent patients. Symptoms are usually non-specific, and include, diarrhea, abdominal pain, fever, malaise, rectal bleeding, and weight loss. However, hematochezia and diarrhea are the most frequent symptoms observed. The symptoms tend to mimic inflammatory bowel disease exacerbation, and it is difficult to distinguish between ulcerative colitis from CMV colitis based on clinical presentation.
Diagnosis of CMV colitis has its basis on clinical findings, laboratory tests, and endoscopy. Endoscopy and tissue biopsies are needed to confirm the diagnosis.
1. CMV IgG: This test verifies prior exposure to CMV. However, for the diagnosis of CMV colitis, this test has no diagnostic value.
2. CMV IgM: This test verifies acute infection with CMV or reactivation of CMV. Again, it may help in a systematic disease but not in CMV colitis.
3. CMV antigenemia assay: This test may aid in early diagnosis and the prediction of clinical outcomes, but has less sensitivity for such diagnosis.
5. Histological examination of biopsy tissues:
6. Real-time PCR CMV DNA quantification:
7. CMV culture: This test has high sensitivity and specificity for the diagnosis of CMV colitis. But it takes a long time to obtain the results.
The majority of patients with CMV colitis who are immunocompetent may need no treatment with antiviral medications; because of the severity of side-effects of antiviral drugs such as ganciclovir, and there is no evidence that treatment with antiviral medications in these patients will make significant differences in patient outcomes. The side effects of ganciclovir include myelosuppression, hepatotoxicity, nephrotoxicity, and central nervous system disorders.
Processing colonic biopsies for H&E and immunochemistry and/or if available CMV DNA real-time PCR is essential for confirmation of the diagnosis of CMV colitis. Treatment with antiviral agents should be individualized based on patient age, immunological status, the severity of presentation, presence of comorbidities, medications used, and the grade of CMV density.
The diagnosis and management of CMV colitis are complex and require a multidisciplinary team that includes, depending on the condition: a gastroenterologist, internist, pathologist, virologist, immunologist, clinical pharmacologist, specialized nurse, oncologist, pharmacist, and transplant physician. All these disciplines need to practice interprofessional communication and collaboration to drive patient outcomes effectively. [Level V]
Careful assessment of the patient condition and involvement of the healthcare team in the evaluation and decision making is needed. Transplant programs should choose an appropriate prophylaxis method to prevent CMV reactivation/disease based on local practices, experiences, and current guidelines. Prophylaxis and treatment for CMV should be individualized and tailored. The success in the management of patients is the outcome of effective teamwork planning and coordination.
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