Continuing Education Activity

The management of cytomegalovirus (CMV) colitis is complex, and new approaches have been introduced. To achieve satisfactory outcomes, the basic and clinical aspects of cytomegalovirus colitis must be clearly defined. This activity reviews cytomegalovirus colitis and focuses on the etiology, epidemiology, pathophysiology, evaluation, management, and complications of cytomegalovirus colitis and highlights the role of an interprofessional team in improving healthcare outcomes.

Objectives:

• Identify the etiology and risk factors for cytomegalovirus colitis.
• Outline the clinical presentation of this disease and the investigations used to diagnose cytomegalovirus colitis.
• Review current treatment guidelines and potential complications of therapy for patients with cytomegalovirus colitis.
• Describe the role of an interprofessional team in care coordination and management of patients with cytomegalovirus colitis.

Introduction

Cytomegalovirus (CMV) is a double-stranded DNA virus and a member of the human herpesvirus family. It is a common viral infection in 50% to 100% of humans worldwide, depending on the age and race of the population tested. This activity discusses current approaches to diagnose and manage CMV colitis. 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 corticosteroid-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 index of suspicion is necessary, and laboratory investigations are essential in diagnosing 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 diagnosing CMV colitis. Rapid diagnosis and management are usually recommended, especially in critically ill patients.

Etiology

Cytomegalovirus colitis occurs most commonly in immunocompromised hosts, including patients with acquired immunodeficiency syndrome (AIDS), organ transplantation, hematological malignancy, cancer therapy, and corticosteroid therapy. However, colitis can also occur in healthy patients without immunodeficiency. These patients usually have a median age of 68 years 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.[1]

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 the intensive care unit, or exposed to antibiotics, antacids, corticosteroids, or red blood cell transfusion within one month of diagnosis of colitis.[2] Further analysis by the authors revealed that the use of corticosteroids and red blood transfusion within one month were independent risk factors for CMV colitis in immunocompromised subjects.  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, are admitted to the intensive care unit, or are treated with corticosteroids or red blood transfusion.     

Cytomegalovirus colitis is also associated with acute, severe ulcerative colitis, particularly in patients treated with high-dose corticosteroids.[3] Cytomegalovirus infection, including CMV colitis, is also a significant problem in patients after solid organ transplantation or allogeneic stem cell transplantation.

Epidemiology

The prevalence of CMV assessed by serology in the general population is 70% in adults and reaching 100% in poor communities and developing countries.[4] The prevalence of CMV infection in severe acute colitis is in the range of 21% to 34%.[5][6] Cytomegalovirus reactivation in patients with severe ulcerative colitis is reported to have a prevalence of 4.5% to 16.6% and as high as 25% in patients requiring colectomy for severe colitis. The cytomegalovirus infection rate in patients with severe corticosteroid-refractory ulcerative colitis ranges from 20% to 40% when infection was diagnosed using both antigenemia and histological examination of tissue biopsies.[7][8]

Pathophysiology

Primary CMV infection in immunocompetent patients is usually asymptomatic. The virus reactivation in these patients is typically asymptomatic. However, immunocompromised patients develop symptoms in different body organs, including CMV colitis. Antibody response to CMV infection results in raised specific immunoglobulin (IgM) antibodies reflecting an acute or relapsing-infection pattern. Raised IgM antibody levels eventually decrease over the next 3 to 6 months and may take up to 12 to 24 months. The persistence of IgM antibodies could be related to concomitant immunosuppression. Immunoglobulin IgG antibodies are produced within a week of IgM antibodies. Patients who develop CMV IgG antibodies are considered “seropositive.”

The gastrointestinal tract, particularly the colon, then the esophagus, are common sites of CMV infection. The role of CMV in patients with inflammatory bowel disease is a topic of debate; whether the CMV reactivation is responsible for the exacerbation of the disease in patients with established inflammatory bowel disease, or the reactivation is a consequence of the disease or treatment, and the possibility that CMV acts as an innocent bystander.[9][10] In addition to inflammation caused by inflammatory bowel disease, studies have shown that immunosuppression, due to high dose systemic corticosteroids, is associated with CMV colitis in patients with active ulcerative colitis. Other immunomodulators used in the treatment of ulcerative colitis, such as thiopurines and methotrexate but not anti-TNF agents, are associated with CMV in patients with ulcerative colitis.[11][12] Patients after allogeneic stem cell transplantation are at risk of CMV infection or reactivation. However, it is important to differentiate between gastrointestinal graft-versus-host disease (GVHD) and CMV colitis in these patients. CMV viremia in these patients is misleading, and colonic mucosal biopsies and histological examination are essential to reach an accurate diagnosis.[13]

Histopathology

The diagnosis of CMV colitis requires histological examination of biopsy tissues taken from the ulcer edge or base. Patients with punched-out ulcers have a higher number of inclusion bodies on histology.[14] The histological examination will enable the treating clinician to diagnose CMV colitis and differentiate it from other colitis causes (infectious colitis, ulcerative colitis, or drug-induced colitis) or rectal carcinoma.[15] Colonic mucosal biopsies stained with hematoxylin and eosin (H & E) may reveal the typical inclusions 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 diagnosing CMV colitis.

History and Physical

CMV infection is frequently asymptomatic in immunocompetent patients. Immunocompromised patients may present with symptoms, but clinical presentation alone is not specific. Symptoms, if present, 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 in confirmed cases of CMV colitis. 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 alone.[16]

Evaluation

Diagnosis of CMV colitis requires serologic testing and endoscopic biopsies to confirm the diagnosis.

Serologic Testing

The CMV IgG test can verify prior exposure to CMV. However, for the diagnosis of CMV colitis, this test has no diagnostic value. CMV IgM testing can verify an acute systemic infection with CMV or an acute systemic reactivation of CMV but does not help diagnose CMV colitis. CMV antigenemia assay may aid in early diagnosis and the prediction of clinical outcomes for CMV colitis but has less sensitivity for such diagnosis.

Endoscopic Evaluation

One of the significant endoscopic findings in CMV colitis is the presence of ulcerations with a well-defined, punched-out appearance, which is usually a finding in 70% to 80% of patients.[16][17] However, ulcerations could be irregular and have a cobblestone-like-appearance as well. An ulcer of the cecum or involving the ileocecal valve is proposed to be a specific finding in CMV colitis in patients with graft-versus-host disease.[18] The identification of CMV disease by H&E-stained tissue sections relies on the presence of CMV viral inclusions. These are “owl eye” appearance inclusions and are highly specific for CMV. CMV-specific immunohistochemistry (IHC) is considered the gold standard for the identification of CMV in tissue biopsies.[19] Therefore, tissue sections should be considered for IHC staining and examination if the H&E-stained tissues are negative, particularly if there is a higher suspicion of CMV colitis.

Real-time PCR CMV DNA Quantification

This test may be combined with endoscopy findings to make the diagnosis. However, it was found positive in only 50% of patients with biopsy-proven CMV colitis/enteritis.[13]

CMV Culture

This test has high sensitivity and specificity for the diagnosis of CMV colitis. It is non-invasive and readily available in clinical practice. However, it takes a long time to obtain the results, which delays the diagnosis and prevents timely treatment in vulnerable patients.[20]

Treatment / Management

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, 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. However, antiviral treatment in immunocompetent patients with CMV colitis could be limited to males over the age of 55 who suffer from severe disease and have co-morbidities affecting the immune system such as diabetes mellitus or chronic renal failure. The drug of choice is oral or intravenous ganciclovir.[21]

Patients with CMV reactivation, which frequently occur in severe or corticosteroid-resistant inflammatory bowel disease, do not necessarily need antiviral treatment. This is because, in most cases, the virus is not pathogenic, and antiviral treatment may not be helpful. The indications for antiviral therapy in these patients include:

• When CMV reactivation results in the development of CMV colitis and histological examination of mucosal tissue reveals high-grade CMV density[22]
• Patients with low-grade CMV density who have corticosteroid-refractory disease or are corticosteroid dependent
• An endoscopically large ulcer may indicate that antiviral therapy is required

It is important to note that there are insufficient publications with poor quality data regarding the treatment of CMV colitis with antiviral agents and whether it improves colectomy and mortality outcomes. Further research is necessary with large randomized trials to define subgroups that can benefit from treatment. Concomitant use of anti-TNF therapy with antiviral therapy may be considered to treat CMV reactivation in ulcerative colitis patients. Ganciclovir is effective in treating and preventing CMV disease in bone marrow transplantation patients.[23] The question of identifying high-risk groups and the use of prophylactic therapy is currently a topic of research.[13]

Differential Diagnosis

• Viral/bacterial gastroenteritis
• Inflammatory bowel disease
• Colorectal cancer
• Toxic megacolon
• Diverticulitis
• Irritable bowel disease
• Celiac disease
• Graft-versus-host disease

Prognosis

The overall prognosis of CMV colitis is excellent; however, some risk factors for poor prognosis and higher mortality have been reported. In immunocompetent patients, the prognosis is age-dependent, with patients older than 55 years having slightly higher mortality. Patients requiring surgery tend to have a poorer prognosis as well. Some studies correlate the male gender with higher mortality in patients with CMV colitis. Timely diagnosis and treatment of CMV colitis have been shown to greatly improve prognosis in immunocompromised patients. Patients with CMV colitis reactivation in association with ulcerative colitis tend to have a poor prognosis; however, this can be greatly improved with timely treatment as well.[22]

Complications

Complications of CMV include:[24][25]

• Chronic inflammation
• Large bowel perforation
• Toxic megacolon
• Pseudo-membrane formation
• Development of ischemic colitis
• Patients with CMV colitis complicating inflammatory bowel disease may develop severe hemorrhage, colon perforation

Deterrence and Patient Education

Primary prevention of CMV colitis in immunocompromised patients receiving a solid organ transplant is crucial to improve clinical outcomes. Multiple strategies for the prevention of CMV infection in this population have been developed, and newer therapies are under investigation. However, despite ongoing work, no clear universal thresholds have been defined. Most authors recommend strategies based on local and individual factors.[26] A summary of recommendations by the Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation are listed below:[27]

• Strong recommendation for either universal prophylaxis or preemptive therapy for prevention of CMV disease in all solid organ transplant recipients
• Recommended duration of prophylaxis for kidney, liver, heart, and pancreas recipients is 3 to 6 months (strong recommendation).
• Strong recommendation for use of leukoreduced or CMV-seronegative blood products in highest risk group with seronegative status
• Recommend against routine use of secondary prophylaxis after treatment of CMV infection (weak recommendation)
• Recommend use of mTOR inhibitors in CMV seropositive kidney, liver, heart, and lung transplant recipients (moderate-strong recommendation)

Enhancing Healthcare Team Outcomes

The diagnosis and management of CMV colitis are complex. They require an interprofessional team that includes gastroenterologists, internists, infectious disease specialists, pathologists, clinical pharmacists, specialized nurses, and in some cases, transplant physicians. A collaborative approach to patients at high risk of disease can help diagnose this infection early and allow for timely treatment. Specialty-trained nurses can assist the clinical care team by educating the patient on symptom monitoring as well as compliance with clinical/serologic monitoring after solid-organ transplantation to help identify potential infections early. The clinical pharmacist can assist in drug monitoring and identifying potential drug-drug interactions to minimize adverse outcomes. A well-coordinated and collaborative interprofessional team can ensure that patients at the highest risk of this disease receive optimal prophylaxis, monitoring, and treatment. This, in turn, will improve clinical outcomes for these patients.[Level 5]