Cytomegalovirus Colitis

Article Author:
Samy Azer
Article Editor:
Faten Limaiem
Updated:
6/4/2019 2:52:22 PM
PubMed Link:
Cytomegalovirus Colitis

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 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.[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 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 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 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.[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 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 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.[26] The success in the management of patients is the outcome of effective teamwork planning and coordination.


References

[1] Karigane D,Takaya S,Seki Y,Mastumoto Y,Onose A,Kosakai A,Sugaya N,Mori T, Cytomegalovirus enteritis in immunocompetent subjects: a case report and review of the literature. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2014 May;     [PubMed PMID: 24751234]
[2] Ko JH,Peck KR,Lee WJ,Lee JY,Cho SY,Ha YE,Kang CI,Chung DR,Kim YH,Lee NY,Kim KM,Song JH, Clinical presentation and risk factors for cytomegalovirus colitis in immunocompetent adult patients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015 Mar 15;     [PubMed PMID: 25452594]
[3] Lee HS,Park SH,Kim SH,Kim J,Choi J,Lee HJ,Kim WS,Lee JM,Kwak MS,Hwang SW,Yang DH,Kim KJ,Ye BD,Byeon JS,Myung SJ,Yoon YS,Yu CS,Kim JH,Yang SK, Risk Factors and Clinical Outcomes Associated with Cytomegalovirus Colitis in Patients with Acute Severe Ulcerative Colitis. Inflammatory bowel diseases. 2016 Apr;     [PubMed PMID: 26829410]
[4] Banerjee D,Deb R,Dar L,Mirdha BR,Pati SK,Thareja S,Falodia S,Ahuja V, High frequency of parasitic and viral stool pathogens in patients with active ulcerative colitis: report from a tropical country. Scandinavian journal of gastroenterology. 2009;     [PubMed PMID: 19040190]
[5] Wada Y,Matsui T,Matake H,Sakurai T,Yamamoto J,Kikuchi Y,Yorioka M,Tsuda S,Yao T,Yao S,Haraoka S,Iwashita A, Intractable ulcerative colitis caused by cytomegalovirus infection: a prospective study on prevalence, diagnosis, and treatment. Diseases of the colon and rectum. 2003 Oct;     [PubMed PMID: 14530660]
[6] Criscuoli V,Casà A,Orlando A,Pecoraro G,Oliva L,Traina M,Rizzo A,Cottone M, Severe acute colitis associated with CMV: a prevalence study. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2004 Dec;     [PubMed PMID: 15646428]
[7] Domènech E,Vega R,Ojanguren I,Hernández A,Garcia-Planella E,Bernal I,Rosinach M,Boix J,Cabré E,Gassull MA, Cytomegalovirus infection in ulcerative colitis: a prospective, comparative study on prevalence and diagnostic strategy. Inflammatory bowel diseases. 2008 Oct;     [PubMed PMID: 18452205]
[8] Maconi G,Lombardini M,Furfaro F,Bezzio C,Zerbi P,Ardizzone S, Long-term outcome of inflammatory bowel diseases with cytomegalovirus colitis: effect of antiviral treatment. European journal of gastroenterology     [PubMed PMID: 25089547]
[9] Park SC,Jeen YM,Jeen YT, Approach to cytomegalovirus infections in patients with ulcerative colitis. The Korean journal of internal medicine. 2017 May;     [PubMed PMID: 28490715]
[10] Papadakis KA,Tung JK,Binder SW,Kam LY,Abreu MT,Targan SR,Vasiliauskas EA, Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. The American journal of gastroenterology. 2001 Jul;     [PubMed PMID: 11467645]
[11] Shukla T,Singh S,Tandon P,McCurdy JD, Corticosteroids and Thiopurines, But Not Tumor Necrosis Factor Antagonists, are Associated With Cytomegalovirus Reactivation in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Journal of clinical gastroenterology. 2017 May/Jun;     [PubMed PMID: 27875356]
[12] McCurdy JD,Jones A,Enders FT,Killian JM,Loftus EV Jr,Smyrk TC,Bruining DH, A model for identifying cytomegalovirus in patients with inflammatory bowel disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2015 Jan;     [PubMed PMID: 24993369]
[13] Bhutani D,Dyson G,Manasa R,Deol A,Ratanatharathorn V,Ayash L,Abidi M,Lum LG,Al-Kadhimi Z,Uberti JP, Incidence, risk factors, and outcome of cytomegalovirus viremia and gastroenteritis in patients with gastrointestinal graft-versus-host disease. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2015 Jan;     [PubMed PMID: 25445637]
[14] Yang H,Zhou W,Lv H,Wu D,Feng Y,Shu H,Jin M,Hu L,Wang Q,Wu D,Chen J,Qian J, The Association Between CMV Viremia or Endoscopic Features and Histopathological Characteristics of CMV Colitis in Patients with Underlying Ulcerative Colitis. Inflammatory bowel diseases. 2017 May;     [PubMed PMID: 28426459]
[15] Chidlovskii E,Deroux A,Bernard S,Couturier P, Cytomegalovirus colitis mimicking rectal carcinoma in an immunocompetent elderly woman. BMJ case reports. 2016 May 10;     [PubMed PMID: 27166009]
[16] Levin A,Yaari S,Stoff R,Caplan O,Wolf DG,Israeli E, Diagnosis of Cytomegalovirus Infection during Exacerbation of Ulcerative Colitis. Digestion. 2017;     [PubMed PMID: 28848127]
[17] Suzuki H,Kato J,Kuriyama M,Hiraoka S,Kuwaki K,Yamamoto K, Specific endoscopic features of ulcerative colitis complicated by cytomegalovirus infection. World journal of gastroenterology. 2010 Mar 14;     [PubMed PMID: 20222169]
[18] Matsuda K,Ono S,Ishikawa M,Miyamoto S,Abiko S,Tsuda M,Yamamoto K,Kudo T,Shimizu Y,Hayase E,Hashimoto D,Teshima T,Matsuno Y,Sakamoto N, Cecum ulcer is a reliable endoscopic finding in cytomegalovirus colitis concomitant with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Annals of hematology. 2018 May;     [PubMed PMID: 29340759]
[19] Juric-Sekhar G,Upton MP,Swanson PE,Westerhoff M, Cytomegalovirus (CMV) in gastrointestinal mucosal biopsies: should a pathologist perform CMV immunohistochemistry if the clinician requests it? Human pathology. 2017 Feb;     [PubMed PMID: 27666768]
[20] Landry ML,Ferguson D, Comparison of quantitative cytomegalovirus antigenemia assay with culture methods and correlation with clinical disease. Journal of clinical microbiology. 1993 Nov;     [PubMed PMID: 8263166]
[21] Yerushalmy-Feler A,Padlipsky J,Cohen S, Diagnosis and Management of CMV Colitis. Current infectious disease reports. 2019 Feb 15;     [PubMed PMID: 30771028]
[22] Beswick L,Ye B,van Langenberg DR, Toward an Algorithm for the Diagnosis and Management of CMV in Patients with Colitis. Inflammatory bowel diseases. 2016 Dec;     [PubMed PMID: 27763950]
[23] Goodrich JM,Mori M,Gleaves CA,Du Mond C,Cays M,Ebeling DF,Buhles WC,DeArmond B,Meyers JD, Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. The New England journal of medicine. 1991 Dec 5;     [PubMed PMID: 1658652]
[24] Barling DR,Tucker S,Varia H,Isaacs P, Large bowel perforation secondary to CMV colitis: an unusual primary presentation of HIV infection. BMJ case reports. 2016 Dec 21;     [PubMed PMID: 28003231]
[25] Hasegawa T,Aomatsu K,Nakamura M,Aomatsu N,Aomatsu K, Cytomegalovirus colitis followed by ischemic colitis in a non-immunocompromised adult: a case report. World journal of gastroenterology. 2015 Mar 28;     [PubMed PMID: 25834346]
[26] Kotton CN, CMV: Prevention, Diagnosis and Therapy. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Feb;     [PubMed PMID: 23347212]