Cytomegalovirus Colitis


Article Author:
Samy Azer


Article Editor:
Faten Limaiem


Editors In Chief:
Sisira Reddy
Joseph Nahas
CHOKKALINGAM SIVA


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
11/10/2019 5:52:15 PM

Introduction

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.   

Etiology

Cytomegalovirus colitis occurs most commonly in immunocompromised hosts, including 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 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 intensive care unit, or exposed to antibiotics, antacids, steroids, or red blood cell transfusion within one month of diagnosis of colitis.[2] 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.[3]

Cytomegalovirus infection, including CMV colitis, is 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 steroid-refractory ulcerative colitis ranged 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, again, typically asymptomatic. However, in patients whose immune response is compromised, they 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 antibodies levels fall over the next 3 to 6 months and up to 12 to 24 months.
  • Persistence of IgM antibodies could be related to concomitant immunosuppression.
  • Immunoglobulin IgG antibodies are produced within a week of IgM increases. 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, such as high doses of systemic corticosteroids, is dependent on risk factors for CMV-associated colitis in patients with active ulcerative colitis. Also, 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 the reactivation and develop symptoms suggestive of colitis. However, it is important in these patients to differentiate between gastrointestinal graft-versus-host disease (GVHD) and CMV colitis. CMV viremia in these patients is misleading, and colonic mucosal biopsies and histological examination are essential to reach a final 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 are associated with a higher number of inclusion bodies on histology.[14] (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.[15]

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.

History and Physical

CMV infection is frequently symptomatic in immunocompetent 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.[16]

Evaluation

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.

4. Endoscopy:

  • The findings are usually not specific.
  • One of the significant endoscopic findings in CMV colitis is the presence of ulcerations with well-defined, punched-out appearance, which is usually a finding in 70% to 80% of patients.[16][17]
  • However, ulcerations could be irregular, and a cobblestone-like-appearance may be present in CMV colitis.
  • 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]

5. Histological examination of biopsy tissues:

  • 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 were negative, particularly if there is a higher suspicion of CMV colitis.

6. Real-time PCR CMV DNA quantification:

  • This test may be combined with endoscopy findings.
  • However, it was found only positive in 50% of patients with biopsy-proven CMV colitis/enteritis[13], supporting the need for endoscopy and histological examination to confirm the diagnosis of CMV colitis.

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.[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, 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.

  • 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 steroid-resistant inflammatory bowel disease, do not necessarily all 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 are:
    • First: when CMV reactivation results in the development of CMV colitis histological examination of mucosal tissue biopsies with immunohistochemistry (and high-grade CMV density), the patient should receive treatment with antiviral agents.[22]
    • Second: Antiviral therapy should be considered for patients with low-grade CMV density who are steroid-refractory or dependent.
    • Third: when such assessment is not available, an endoscopically large ulcer may indicate that antiviral therapy is required.
  • It is important to note that there are insufficient publications with good quality to determine if treating CMV colitis with antiviral agents will improve patient outcomes regarding colectomy and mortality. Further research is necessary in 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-associated reactivation in ulcerative colitis patients.
  • Ganciclovir has shown to be effective in both the treatment and prevention of 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

Complications

Complications with 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, megacolon, fulminant colitis, or colon perforation
    • These complications contribute to the high risk of mortality

Pearls and Other Issues

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.

Enhancing Healthcare Team Outcomes

The diagnosis and management of CMV colitis are complex and require an interprofessional team that includes, depending on the condition: gastroenterologist, internist, infectious disease, 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. Pharmacists review medications prescribed, check for interactions, and educate patients. Nurses administer treatment, monitor patients, and provide updates on patient status to the team. [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.[26] The success in the management of patients is the outcome of effective teamwork planning and coordination.


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Cytomegalovirus Colitis - Questions

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A 42-year-old male presents with the complaint of bloody diarrhea for the past one week. He also reports abdominal pain for the same duration. He was diagnosed with HIV 3 years ago and has been noncompliant with medications. Colonoscopy with biopsy is done, and histopathology yields owl's eye inclusions in the colonic mucosa. Which of the following is the drug of choice?



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A 37-year-old woman known to have ulcerative colitis for seven years presents to the emergency department because of recurrence of diarrhea, abdominal pain, fever, blood in stools, and malaise. She is on mesalamine and corticosteroids. Colonoscopy is performed, which shows irregular and a cobblestone-like appearance. Hematoxylin-eosin (H&E) tissue examination is negative for CMV. Which of the following is the next best step in the management of this patient?



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A 66-year-old male presents with severe diarrhea, abdominal pain, hematochezia, fever, and fatigue. He has been on treatment for diabetes for twenty years. Investigations, including coloscopy and immunohistochemistry, identify cytomegalovirus (CMV) in tissue biopsies. Other tests excluded bacterial, parasitic, ischemic, microscopic colitis. No evidence of immunodeficiency is found. Which of the following is the next best step in the management of this patient?



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A 55-year-old woman, who recently had allogeneic stem cell transplantation, presents to the emergency department with severe diarrhea, abdominal pain, bleeding per rectum, and fever. Her investigations show raised cytomegalovirus IgG and IgM. Which of the following is the next best step in the management of this patient?



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A 29-year-old woman who was diagnosed with ulcerative colitis eight years ago presents with severe diarrhea, abdominal pain, fever, tiredness, and blood in stools. She also has s history of cytomegalovirus (CMV) complicating her ulcerative colitis. Bloodwork reveals a hemoglobin of 9.5 g/dL and ESR 55 mm/h. Stool microscopy shows red blood cells and inflammatory cells, but no parasites, cysts, or ova. Tissue biopsies taken during colonoscopy are negative for CMV as per hematoxylin and eosin stain. Immunohistochemistry staining is not available. Which of the following is the next best investigation to confirm CMV infection in this patient?



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A 32-year-old woman with a history of ulcerative colitis for the last six years presents to the hospital with a recurrence of diarrhea, abdominal pain, arthralgia, fever, and hematochezia. Workup, including colonoscopy and tissue biopsies (hematoxylin & eosin and, immunohistochemistry), confirms that she has cytomegalovirus (CMV) complicating ulcerative colitis. Which of the following is the most appropriate medication for this patient, along with ganciclovir?



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Cytomegalovirus Colitis - References

References

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