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Coexisting cytomegalovirus infection in immunocompetent patients with Clostridium difficile colitis
Accepted Manuscript Coexisting Cytomegalovirus infection in immunocompetent patients with Clostridium difficile colitis Khee-Siang Chan, Wen-Ying Lee, Wen-Liang Yu, M.D. PII:
S1684-1182(16)00008-6
DOI:
10.1016/j.jmii.2015.12.007
Reference:
JMII 732
To appear in:
Journal of Microbiology, Immunology and Infection
Received Date: 30 June 2015 Revised Date:
31 October 2015
Accepted Date: 14 December 2015
Please cite this article as: Chan K-S, Lee W-Y, Yu W-L, Coexisting Cytomegalovirus infection in immunocompetent patients with Clostridium difficile colitis, Journal of Microbiology, Immunology and Infection (2016), doi: 10.1016/j.jmii.2015.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review Article Coexisting Cytomegalovirus infection in immunocompetent patients
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with Clostridium difficile colitis
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Khee-Siang Chan a, Wen-Ying Lee b, c, Wen-Liang Yu a, d,*
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a
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b
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c
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d
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Running Title: Coexisting Cytomegalovirus and Clostridium difficile Colitis
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Keywords: Clostridium difficile, C. difficile infection, colitis, cytomegalovirus,
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immunocompetent
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*Corresponding author: Wen-Liang Yu, M.D., Department of Medical Research, Chi
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Mei Medical Center, No. 901 Zhonghua Road, Yongkang District, 710 Tainan City,
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Taiwan. Tel: +886-6- 281-2811 ext 52606, Fax: +886-6- 283-3351, E-mail address:
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Department of Pathology, Chi Mei Medical Center, Tainan City, Taiwan
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Department of Pathology, Taipei Medical University, Taipei City, Taiwan
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Department of Medicine, Taipei Medical University, Taipei, Taiwan
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Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, Taiwan
[email protected] (W.-L Yu)
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Abstract
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Cytomegalovirus (CMV) colitis usually occurs in the immunocompromised patients
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with human immunodeficiency virus infection, organ transplantation, and malignancy
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receiving chemotherapy or ulcerative colitis receiving immunosuppressive agents.
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However, CMV colitis is increasingly recognized in the immunocompetent hosts.
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Notably, CMV colitis coexisting with Clostridium difficile infection (CDI) in
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apparently healthy individuals has been published in recent years, which could result
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in high morbidity and mortality. CMV colitis is a rare but possible differential
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diagnosis in the immunocompetent patients with abdominal pain, watery or especially
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bloody diarrhea, which could be refractory to standard treatment for CDI. As a
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characteristic of CDI, however, pseudomembranous colitis may be only caused by
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CMV infection. Real-time CMV-PCR for blood and stool samples may be a useful
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and noninvasive diagnostic strategy to identify CMV infection when treatment of CDI
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eventually fails to show significant benefits. Quantitative CMV-PCR in mucosal
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biopsies may increase the diagnostic yield of traditional histopathology. CMV colitis is potentially life-threatening if severe complications occur, such as sepsis secondary to colitis, massive colorectal bleeding, toxic megacolon and colonic perforation, so
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that may necessity preemptive antiviral treatment for those who are positive for
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CMV-PCR in blood and/or stool samples while pending histological diagnosis. 2
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Background
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Cytomegalovirus (CMV) is a highly prevalent and globally distributed virus. CMV
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infection in healthy adults is usually asymptomatic or causes a mildly infectious
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mononucleosis-like syndrome. CMV then usually becomes dormant until reactivation
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in the patients with severely immunocompromised status, who may potentially
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develop invasive CMV disease with a wide range of manifestations, most commonly
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colorectal infection with hemorrhagic ulceration. Coexistent two entities- CMV colitis
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and Clostridium difficile colitis have usually been reported among the
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immunocompromised patients, who have human immunodeficiency virus (HIV)
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infection, organ transplantation, hematologic malignancy, solitary organ cancer, or
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inflammatory bowel disease receiving immunosuppressive agents.1-9 For example,
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Florescu et al. reviewed 9 patients who developed C. difficile and CMV colitis, among
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them, 8 patients were immunocompromised: 4 transplant recipients, 2 oncology
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patients, 1 patient with advanced acquired immunodeficiency syndrome, and 1 on an
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immunosuppressive regimen for severe ulcerative colitis.8 Besides, CMV colitis can
mimic or present as pseudomembranous colitis in the immunocompromised patients.10-14
CMV gastrointestinal disease rarely occurs in the immunocompetent patients and could resolve completely without the use of antiviral drugs, if the immunity is 3
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obtained.15 In addition, CMV colitis is increasingly recognized in the apparently
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immunocompetent patients in some immunomodulating conditions, such as elderly,
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pregnancy, chronic renal failure, coronary artery disease, ischemic heart disease,
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congestive heart failure, diabetes mellitus, steroid use, blood transfusion and
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prolonged stay in the intensive care units (ICU).15-28 However, CMV colitis in these
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patients has often been neglected by clinical physicians.28 Therefore, this review
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article will mainly focus on the English literature of CMV colitis coexisting、
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following or followed by Clostridium difficile colitis among previously healthy or
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apparently immunocompetent adult patients. We will also review those of CMV
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colitis presenting as a sole cause of pseudomembranous colitis without CDI.
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Epidemiology of CMV Colitis in the immunocompetent patients
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One systemic review identified only 91 immunocompetent patients with
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gastrointestinal CMV infections for the period of 1950-2007.25 Another literature
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review from 1980 to 2003 identified 44 immunocompetent patients with CMV colitis.
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Among them, spontaneous remission occurred in 31.8%, mostly individuals <55 years old.21 In Korea, 51 immunocompetent patients with CMV colitis, including 11 ICU patients and 17.6% with spontaneous remission, were diagnosed at a tertiary care
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university hospital between January 1995 and February 2014.23 In specific hospital
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ICU units, CMV colitis was diagnosed in 14 previously immunocompetent ICU 4
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patients at a teaching hospital in Brazil from January 2000 to March 2013.27 While in
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Taiwan, with intention to diagnosis, CMV colitis was detected in 18 ICU patients at a
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teaching hospital from January 2011 through June 2013.28 Among them, 3 patients
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had malignancy. The biopsy-proven diagnosis was made for 8 patients. Other
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probable cases were diagnosed based on clinical symptoms with detection of blood
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CMV DNA plus either colonoscopic findings or detection of CMV DNA in the stool
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samples.28 Traditionally, CMV colitis was easily neglected and under-diagnosed in the
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ICU patients with chronic critical illness, particularly with chronic renal failure.23, 27, 28
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Epidemiology of Clostridium difficile Colitis
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Diseases caused by Clostridium difficile range from mild diarrhea to potentially
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life-threatening pseudomembranous colitis. Clostridium difficile infections (CDI)
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occur primarily in hospitalized patients with risk factors such as concomitant or recent
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use of antibiotics .29 The colonization rate of C. difficile in adult hospitalized patients
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shows geographic variation, ranging from 4.4% to 23.2%.30 The hypervirulent
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C. difficile strains such as the epidemic clone (027/NAP1/BI) has partly contributed to change the CDI epidemiology to worldwide dissemination.31 Particularly, elderly patients in surgical wards and ICUs are at significant risk of developing CDI.32 After
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2006, a 47% increase in the rate of CDI was noted in the United States.33 In a cohort
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of hospitalized older adults in Michigan, impaired functional status was an 5
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independent risk factor for severe CDI.34 One study in Korea between January 2007
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and July 2012, fifty-five percent of colitis in elderly people in long-term care facilities
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was caused by CDI, whereas non-specific colitis was the most common (63%) in
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elderly people in local communities.35 Diagnosis of CDI is based on the identification
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of C. difficile toxins A and B in diarrheal stool. First-line antibiotics for CDI treatment
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are metronidazole and vancomycin.36 Fidaxomicin, a macrolide antibiotic has shown
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to be significantly effective in treating C. diff infection compared to vancomycin.37
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For recurrence and relapse of CDI, rifaximin and tigecycline have yielded some
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positive outcomes against C. difficile.38 Fecal microbiota transplant is an alternative
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therapy for CDI that is effective and promising in multiple CDI recurrences.39
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Coexisting CMV and C. difficile colitis
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A history of cytomegalovirus infection has been recognized as one of the significant
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risk factors for C. difficile colonization.30, 40 Adult patients colonized with toxigenic C.
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difficile were prone to the subsequent development of C. difficile-associated
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diarrhea.30 The critically ill patients and elderly patients are at an increased risk of developing diarrheal illness like CDI and CMV colitis. The literatures of coexisting CMV and C. difficile colitis have been reported in the immunocompetent patients,
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mostly in the years after 2010 (Table 1), implying that effective alerts are increasing
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to current physicians. Presenting symptoms of both diseases included fever, diarrhea, 6
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gastrointestinal bleeding, and abdominal pain, with predominance of severe watery
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diarrhea for CD, whereas bloody stool, occasional massive bleeding for CMV colitis.
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Both may cause toxic megacolon and bowel perforation, leading to a poor
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prognosis.41 However, we proposed that the clinical features of colitis caused by both
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etiologies could vary as following scenarios (Table 1).
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CDI with refractory pseudomembranous colitis
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CDI with pseudomembranous colitis unresponsive to metronidazole and vancomycin
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therapy may need fecal transplantation to overcome the severe colitis. However,
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concomitant CMV colitis may partly contribute the refractory course and necessity
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simultaneous ganciclovir therapy to completely resolve the colitis.42 We previously
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reported a 82 year-old man who had coexistent CMV and CDI-associated
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pseudomembranous colitis (Figure 1).28 Moreover, Kurtz et al. reported an
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immunocompetent elderly woman with CDI, which was unresponsive to
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metronidazole, vancomycin, fidaxomicin and stool transplant due to concomitant
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CMV colitis.43 We also reported a case of toxic megacolon leading to respiratory failure, which developed after therapy with metronidazole, vancomycin and fecal microbiota transplants for CDI-associated pseudomembranous colitis.
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Immunostaining study was performed on initial colon mucosal biopsy and confirmed
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concomitant CMV colitis with CDI.44 7
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CDI with refractory colorectal ulcers or diffuse colitis without pseudomembranes
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Non-immunosuppressed patients with prolonged ICU stay due to chronic critical
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illness are at a high risk for both CDI and CMV colitis. Of the two diagnoses, CMV is
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likely missed more often because a biopsy or with immunostains is required to
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confirm the diagnosis, while CDI can be diagnosed based on non-invasive fecal C.
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difficile toxin assay.8 Many clinicians would only treat CDI infection for a patient with
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severe diarrhea and positive C. difficile toxin in the stool.
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Concomitant CDI and CMV colitis may sometimes manifest with diffuse colitis without pseudomembranes, which was refractory to first-line antibiotics for CDI
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treatment.15, 45-48 For examples, Harano et al. reported a 60-year-old
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immunocompetent woman who presented with abdominal pain and bloody diarrhea
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due to colorectal erosion and ulceration with positive stool isolate of C. difficile.
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Administration of metronidazole did not improve her symptoms. Endoscopic biopsy
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with immunostains revealed CMV colitis.15 Hung et al. reported CMV colitis with the
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presentation of watery diarrhea and stool culture positive for C. difficile, but diarrhea persisted despite oral metronidazole and vancomycin therapy.47 Chen et al. presented
a 90-year-old, critically ill, immunocompetent patient, who had a refractory C.
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difficile-infected multiple ulcers in the sigmoid colon and biopsy confirmed CMV
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colitis.48 This scenario was similar to a patient of lower lip squamous cell carcinoma 8
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who had diffuse pancolitis unresponsive to metronidazole, vancomycin enemas and
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later fidaxomicin, even though his stool C. difficile toxin became negative conversion.
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At this point, his CMV PCR in stool and blood were positive, and preemptive therapy
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with valganciclovir resulted in rapid clinical response and uneventful recovery.9
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CMV colitis following successful therapy for CDI
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Persistent diarrhea or relapse of intestinal symptoms after appropriate antimicrobial
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therapy for CDI may not necessarily indicate ineffective therapy for refractory course
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of CDI. Jawad reported a patient with diarrhea and stool culture was positive for C.
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difficile. Oral vancomycin rendered her stool negative but some bloody diarrhea
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occurred due to sequential CMV colitis.49 We previously reported a patient who had
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therapeutic response to initial C. difficile–associated pseudomembranous colitis but
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the symptoms relapsed 3 weeks later due to emergence of CMV-associated colon
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ulceration.28 This scenario might be related to reactivation of latent CMV infection in
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conditions of immunomodulation caused by pseudomembranous colitis.
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CDI following successful therapy for CMV colitis This rare scenario was ever reported in an elderly patient with adult T cell leukemia lymphoma, who developed CMV colitis on day 5 of chemotherapy. After 2 weeks of
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successful ganciclovir therapy, the patient developed diarrhea again with
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CDI-associated pseudomembranous colitis instead of CMV colitis. At that time, CMV 9
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antigenemia and a histologic study for CMV were negative.2
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CMV colitis as a cause of pseudomembranous colitis without CDI
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In addition to manifesting with solitary ulcer, multiple ulcers, diffuse colitis and
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polypoid lesions, occasionally CMV colitis may present with pseudomembranes,
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leading to misdiagnosis as CDI-associated pseudomembranous colitis.26, 50 This
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scenario should be considered particularly when C. difficile toxin assays or cultures
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are negative.51, 52 We previously described a patient who had CMV-associated
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pseudomembranous colitis (Figure 2), as the result of Clostridium toxin assay was
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negative and the patient experienced poor response to oral metronidazole therapy.28
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Current diagnosis and treatment of CMV colitis
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Historically, the diagnostic gold standard for CMV colitis is the direct
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histopathological identification of the Cowdry owl eye inclusion bodies in colonic
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biopsies or with the aid of immunohistochemistry (IHC) staining. Although CMV
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antigenemia and blood CMV-polymerase chain reaction (PCR) showed low sensitivity
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(<50%) for diagnosing CMV colitis, the specificity values were high (>80%).53 In the
presence of significant colon ulcers, however, the sensitivity of CMV antigenemia or PCR for diagnosing CMV colitis rose to 67.3%.53 Real time PCR for CMV DNA
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quantification in the blood and stool as well as in the colonic biopsy is currently
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considered as a useful diagnostic tool.54 The accuracy of theses diagnostic modalities 10
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as compared with the diagnostic gold standard are summarized in the table 2.
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CMV-PCR in colonic mucosal biopsies
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Yoshino et al. reported that quantitative real-time PCR (qPCR) for detecting CMV
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infection in inflamed colonic mucosa is useful for accurate diagnosis of CMV
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infection.55 Mills et al. reported that CMV DNA was detected by PCR in 90.9%
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(30/33) of IHC-positive and 14.5% (8/55) of IHC-negative mucosal biopsies,
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respectively. Their study indicated that CMV-PCR in gastrointestinal mucosal
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biopsies complements IHC and has the potential to identify additional patients who
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may benefit from anti-CMV therapy.56 McCoy et al. further reported that qPCR is
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highly sensitive and specific to aid in early diagnosis of CMV infection on equivocal
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gastrointestinal biopsies.57 The mean value of CMV DNA load in gastrointestinal
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biopsies was 3,845 copies/µg total DNA (range, 15-15,500). However, the cutoff
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values for diagnosis of CMV colitis were not determined.58
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It should be highlighted that negative histopathological findings of small colonic
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mucosal biopsies could not definitively exclude the diagnosis of CMV colitis. Theoretically, multiple biopsy specimens from longitudinal ulcers or diffuse colitis combined with qPCR in mucosal biopsies could increase the diagnostic yield of CMV
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colitis, especially in those patients known for positive CMV-PCR for blood and/or
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stool samples. 11
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CMV real-time PCR for blood samples
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Quantification of plasma CMV DNA by real-time PCR is a non-invasive method of
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aiding the diagnosis and can be used to monitor the treatment of CMV infection in the
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immunocompetent patients.20, 59 Concordance between the plasma real-time PCR and
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the pp65 antigenemia assay was 82.2%.60 However, the plasma real-time PCR is more
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sensitive than the antigenemia assay for monitoring active CMV infection.60, 61
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However, blood CMV-PCR stands for CMV reactivation, and further direct evidences
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of CMV colitis by other diagnostic tools are required.
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CMV real-time PCR for fecal samples
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Michel et al. first adopted CMV- PCR from stool specimens as a diagnostic tool for
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patients with suspected CMV colitis. They concluded that absence of CMV DNA in
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stool samples may prove useful in ruling out CMV-related colitis.62 Thereafter, Boom
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et al. quantified CMV DNA loads in clinical fecal specimens to monitor the efficacy
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of antiviral treatment.63 In a small pilot study, the sensitivity, specificity, and accuracy
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of the PCR-based stool test for detection of CMV DNA compared to PCR-based detection of CMV in mucosal biopsies were 83, 93, and 90%, respectively.64 We also
found qualitative CMV-PCR for stool samples helpful in aiding the diagnosis of CMV
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colitis.28 In a recent study from Germany, quantitative CMV real-time PCR in fecal
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samples was positive in 8/12 patients of the CMV intestinal disease (sensitivity, 67%), 12
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and was negative in the non-CMV group (45/47), indicating a good specificity of
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96%.65 Therefore, negative CMV PCR results from fecal samples cannot exclude
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CMV intestinal disease, whereas positive fecal PCR results could facilitate an earlier
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detection of ongoing CMV infections and might help to circumvent invasive biopsy
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via endoscopy. Otherwise, fecal PCR may guide a preemptive therapy for
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life-threatening conditions, such as massive colonic bleeding, when a conclusive
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histopathological proof of CMV infection is not available yet.28
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Strategy for diagnosis and controversy in treatment of CMV colitis
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The development of abdominal pain, fever, watery diarrhea, and bleeding stool in a
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critically ill patient should prompt the clinician to consider the diagnosis of CMV and
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CDI-associated colitis. Diagnostic strategy could be designed as follows.
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If standard stool pathogens and C. difficile toxin studies are nondiagnostic, endoscopic evaluation and CMV-PCR for blood and stool samples should be obtained.
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Quantitative CMV-PCR in mucosal biopsies seems to be a useful tool for diagnosis
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when combined with blood/stool PCR and endoscopic findings. In another way, if the results of stool C. difficile toxin assay are positive, the possibility of coexistent or sequential CMV colitis should not be neglected. For those patients with diagnosis of
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Clostridium colitis but unresponsive or partially responsive to therapy with
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metronidazole and/or vancomycin, and especially if CMV-PCR for blood and/or stool 13
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samples were positive, then re-evaluation of the initial colon mucosal biopsies by
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qPCR for CMV would be helpful. It is possible that complete resolution of colonic ulceration could be
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spontaneously achieved without use of antiviral drugs in some immunocompromised
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or immunocompetent patients with CMV colitis.15, 21, 23 However, if CMV infection is
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confirmed, ganciclovir therapy should be initiated without delay in critically ill
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patients to avoid severe complications of colorectal massive bleeding and perforation.
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Most of the reported cases of CMV colitis coexisting or following CDI as well as
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presenting as pseudomembranous colitis had good clinical outcome under appropriate
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medical therapy (Table 1). If bowel perforation occurs, prompt surgical resection is
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indicated.66
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Conclusion
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Currently, CMV colitis is increasingly recognized in the immunocompetent patients,
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manifesting with symptoms similar to or consisting with CDI-associated
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pseudomembranous colitis. CMV colitis most commonly presents with bloody stool in chronic status of critically ill patients with immunomodulating comorbidities, whereas C. difficile may produce severe watery diarrhea in those exposed to broad
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spectrum antibiotics. Coexisting CMV in the apparently CDI-associated colitis could
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correspond to intractable colorectal symptoms. If CMV-PCR for blood and stool 14
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samples were positive, endoscopic biopsy with immunostains on mucosal specimens
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is a definitive procedure for diagnosing CMV colitis, even in a case of
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pseudomembranous colitis or positive for fecal C. difficile toxin assay. In case of
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coexisting CMV and C. difficile colitis, ganciclovir therapy for CMV colitis in time
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may circumvent the unnecessary second-line therapeutic method or fecal
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transplantation for CDI, supposed that persistent diarrhea were not due to treatment
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failure for C. difficile.
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Conflicts of interest
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All contributing authors declare no financial interests related to the material in the
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manuscript.
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Ethical consent
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The figures cited in the current review were approved by the institutional review
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board of Chi Mei Medical Center, Tainan, Taiwan (no. 10207-005).
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Acknowledgments
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This work had no financial and material support.
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47. Hung YP, Lin HJ, Wu CJ, Chen PL, Lee JC, Liu HC, et al. Vancomycin-resistant Clostridium innocuum bacteremia following oral vancomycin for Clostridium
difficile infection. Anaerobe 2014; 30:24-6. 48. Chen PH, Lu IT, Lee BJ, Wang CY, Lee CK. Age can be a problem: Clostridium 22
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49. Jawad SH. Cytomegalovirus colitis in an elderly patient. Postgrad Med J. 1992;
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53. Kim JW, Boo SJ, Ye BD, Kim CL, Yang SK, Kim J, et al. Clinical utility of cytomegalovirus antigenemia assay and blood cytomegalovirus DNA PCR for
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54. Banerjee D, Deb R, Dar L, Mirdha BR, Pati SK, Thareja S, et al. High frequency of parasitic and viral stool pathogens in patients with active ulcerative colitis: report from a tropical country. Scand J Gastroenterol 2009; 44:325-31. 55. Yoshino T, Nakase H, Ueno S, Uza N, Inoue S, Mikami S, et al. Usefulness of 23
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quantitative real-time PCR assay for early detection of cytomegalovirus infection
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56. Mills AM, Guo FP, Copland AP, Pai RK, Pinsky BA. A comparison of CMV
detection in gastrointestinal mucosal biopsies using immunohistochemistry and
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57. McCoy MH, Post K, Sen JD, Chang HY, Zhao Z, Fan R, et al. qPCR increases
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sensitivity to detect cytomegalovirus in formalin-fixed, paraffin-embedded tissue
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of gastrointestinal biopsies. Hum Pathgol 2014; 45: 48-53.
58. Bernard S, Germi R, Lupo J, Laverrière MH, Masse V, Morand P, et al.
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Symptomatic cytomegalovirus gastrointestinal infection with positive quantitative
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real time PCR in apparently immunocompetent patients: a case series. Clin
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10.1016/j.cmi.2015.05.016.
59. Helgason KO, Raby SJ, Kamel HM, Laurenson IE, Templeton K, Walsh TS. Cytomegalovirus colitis in a critically ill patient following elective repair of an abdominal aortic aneurysm. Anaesth Intensive Care 2008; 36:107-9. 60. Gimeno C, Solano C, Latorre JC, Hernández-Boluda JC, Clari MA, Remigia MJ, 24
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et al. Quantification of DNA in plasma by an automated real-time PCR assay
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(cytomegalovirus PCR kit) for surveillance of active cytomegalovirus infection
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and guidance of preemptive therapy for allogeneic hematopoietic stem cell
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transplant recipients. J Clin Microbiol 2008; 46:3311-8.
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61. Yakushiji K, Gondo H, Kamezaki K, Shigematsu K, Hayashi S, Kuroiwa M, et al. Monitoring of cytomegalovirus reactivation after allogeneic stem cell
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transplantation: comparison of an antigenemia assay and quantitative real-time
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polymerase chain reaction. Bone Marrow Transplant 2002; 29:599-606.
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62. Michel D, Marre E, Hampl W, Roczkos J, Müller S, Hertenstein B, et al. Intestinal
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cytomegalovirus disease in immunocompromised patients may be ruled out by
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search for cytomegalovirus DNA in stool samples. J Clin Microbiol 1995;
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33:3064-7.
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63. Boom R, Sol C, Weel J, Lettinga K, Gerrits Y, van Breda A, et al. Detection and quantitation of human cytomegalovirus DNA in faeces. J Virol Methods 2000;
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84:1-14.
64. Herfarth HH, Long MD, Rubinas TC, Sandridge M, Miller MB. Evaluation of a non-invasive method to detect cytomegalovirus (CMV)-DNA in stool samples of
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patients with inflammatory bowel disease (IBD): a pilot study. Dig Dis Sci 2010;
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55:1053-8. 25
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65. Ganzenmueller T, Kluba J, Becker JU, Bachmann O, Heim A. Detection of cytomegalovirus (CMV) by real-time PCR in fecal samples for the non-invasive
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diagnosis of CMV intestinal disease. J Clin Virol 2014; 61:517-522.
475
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66. Chamberlain RS, Atkins S, Saini N, White JC. Ileal perforation caused by
cytomegalovirus infection in a critically ill adult. J Clin Gastroenterol 2000;
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30:432-5.
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Table 1. The clinical features of cytomegalovirus colitis coexisting, following or mimicking Clostridium difficile colitis in the immunocompetent patients
478 479
1 2
Age/ sex
Diarrhea
Diagnosis modality positive for CDI
CMV colitis
Time lag of 2nd diagnosis
CMV colitis coexisting CDI with refractory pseudomembranous colitis >3weeks 78/F bloody stool toxin1 colon biopsy2 3 immunostain 1 colon biopsy2 3 days 82/M bloody stool toxin immunostain3 CMV-PCR(1)4 watery
stool toxin1
4
63/F
watery
stool toxin1
8 9
10 11
12
recovery
2012[43]
recovery
2014[28]
NA
recovery
2014[42]
recovery
2015[44]
recovery
2009[45]
recovery
2013[46]
recovery
2014[47]
recovery
2015[15]
recovery
2015[48]
V, G
dieda
1992[49]
M, G
diedb
2014[28]
V, no
diedc
2000[51]
antiviral M, G
recovery
2011[52]
M, V, G
diedd
2014[28]
M, V, R, S, G M, V, S, G
>7 days
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CMV colitis following successful therapy for CDI 83/F some stool culture1 colon biopsy2 blood CMV-IgM3
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M,V, F, S, G, TC M, G,
CMV colitis coexisting CDI with refractory non-pseudomembranous colitis 81/M bloody stool toxin1 colon biopsy2 NA M, V, 3 CMV-PCR(1) G 1 2 37/F watery stool toxin colon biopsy >2 weeks M, V, G, 3 antigenemia FC 1 2 NA M, V, G 85/M watery stool culture colon biopsy 3 immunostain 1 immunostain 2 >10 days M, no 60/F bloody stool culture 3 CMV-IgM antiviral 1 2 90/M bloody stool toxin colon biopsy 14 days M, G 3 immunostain
stool toxin1
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CMV-IgM2 colon biopsy3 CMV-PCR(1)2 immunostain3
Year of ref.
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Outcome
VG
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3
Therapy
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Case
74/F
bloody
NA
CMV-PCR(1)2 3 weeks 2nd colonoscopyimmunostain3
CMV colitis as a cause of pseudomembranous colitis without CDI 63/M NA Colonoscopy1 CMV-PCR(1-3)3 No time lag
13
29/M
watery
14
69/M
watery
and biopsy2 colonoscopic finding1 colonoscopic finding1
immunostain4 2nd colonoscopy NA with biopsy2 CMV-PCR(1-2)2 9 days immunostain3
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Note. CDI: Clostridium difficile infection; CMV: Cytomegalovirus; stool toxin:
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Clostridium difficile toxin assay for stool sample; colon biopsy: histopathological
482
findings of colonic mucosa with hematoxylin and eosin stain; immunostain: CMV
483
immunohistochemical staining; F: female, M: male; Superscript (1, 2, 3, 4): sequential
484
order of positive diagnosis modalities; PCR: polymerase chain reaction for samples of
485
(1): blood, (2): stool, and (3): mucosal biopsies; M: metronidazole; V: vancomycin; G:
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ganciclovir; F: fidaxomicin; R: rifaximin; S: stool microbiota transplant; TC: total
487
colectomy; VG: valganciclovir; FC: foscarnet; NA: not available; Superscript:
488
a
489
CMV inclusion bodies; bganciclovir was delayed to commence after 3 weeks of CMV
490
diagnosis but was discontinued due to worsening leukopenia, and thus failed to give
491
improvement; cpostmortem examination revealed CMV myocarditis, pneumonitis and
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colitis; dpatient had symptomatic improvement of CMV colitis but died in other
493
comorbidities.
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postmortem examination revealed severe pneumonia and inflamed colitis but without
28
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494
Table 2. The diagnostic test evaluation of new diagnostic modalities for
495
cytomegalovirus colitis or digestive tract infections Gold standard
Sensitivity
Specificity Positive
modalities
predictive value
predictive value
Histopathology 47.0%
81.7%
59.1%
73.0%
PCR for blood in UC Histopathology 44.3%
87.9%
67.3%
73.6%
patients53
patients53 Histopathology 100%
colon mucosal biopsies55 Real-time (qPCR) in
Histopathology 90.9%
94.0%
98.7%
98.9%
96.3%
PCR for stool62
Histopathology 100%
94.1%
80.0%
100%
PCR in colon
83.3%
93.3%
83.3%
93.3%
Histopathology 66.7%
95.7%
80.0%
91.8%
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PCR for stool64
Histopathology 96.7%
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biopsies 57
100%
79.0%
biopsies56
digestive mucosal
23.5%
85.5%
digestive mucosal
Real-time (qPCR) in
50.0%
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Real-time (qPCR) in
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Antigenemia in UC
Negative
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CMV Diagnostic
mucosal biopsies
Real-time (qPCR) for stool65 496
Note. UC: ulcerative colitis
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Legend:
498
Figure 1. Colonoscopic finding is showing pseudomembranous colitis (A). Colon
499
mucosal biopsy showing enlarged atypical lymphocytes with eosinophilic inclusion
500
bodies (B, arrow), which was positive for CMV immunostaining (C, arrow). The
501
results of blood CMV-PCR and stool Clostridium toxin assay were both positive.
SC
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502
Figure 2. Colonoscopic finding is showing colitis with pseudomembranes. The
504
CMV-PCR for blood and stool were positive. The stool Clostridium toxin assay was
505
negative. The histopathological findings were consistent with pseudomembranous
506
colitis but immunostains confirmed CMV colitis (not shown).
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S1684-1182(16)00008-6
DOI:
10.1016/j.jmii.2015.12.007
Reference:
JMII 732
To appear in:
Journal of Microbiology, Immunology and Infection
Received Date: 30 June 2015 Revised Date:
31 October 2015
Accepted Date: 14 December 2015
Please cite this article as: Chan K-S, Lee W-Y, Yu W-L, Coexisting Cytomegalovirus infection in immunocompetent patients with Clostridium difficile colitis, Journal of Microbiology, Immunology and Infection (2016), doi: 10.1016/j.jmii.2015.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Review Article Coexisting Cytomegalovirus infection in immunocompetent patients
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with Clostridium difficile colitis
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Khee-Siang Chan a, Wen-Ying Lee b, c, Wen-Liang Yu a, d,*
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a
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b
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c
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d
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Running Title: Coexisting Cytomegalovirus and Clostridium difficile Colitis
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Keywords: Clostridium difficile, C. difficile infection, colitis, cytomegalovirus,
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immunocompetent
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*Corresponding author: Wen-Liang Yu, M.D., Department of Medical Research, Chi
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Mei Medical Center, No. 901 Zhonghua Road, Yongkang District, 710 Tainan City,
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Taiwan. Tel: +886-6- 281-2811 ext 52606, Fax: +886-6- 283-3351, E-mail address:
SC
Department of Pathology, Chi Mei Medical Center, Tainan City, Taiwan
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Department of Pathology, Taipei Medical University, Taipei City, Taiwan
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Department of Medicine, Taipei Medical University, Taipei, Taiwan
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Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, Taiwan
[email protected] (W.-L Yu)
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Abstract
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Cytomegalovirus (CMV) colitis usually occurs in the immunocompromised patients
18
with human immunodeficiency virus infection, organ transplantation, and malignancy
19
receiving chemotherapy or ulcerative colitis receiving immunosuppressive agents.
20
However, CMV colitis is increasingly recognized in the immunocompetent hosts.
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Notably, CMV colitis coexisting with Clostridium difficile infection (CDI) in
22
apparently healthy individuals has been published in recent years, which could result
23
in high morbidity and mortality. CMV colitis is a rare but possible differential
24
diagnosis in the immunocompetent patients with abdominal pain, watery or especially
25
bloody diarrhea, which could be refractory to standard treatment for CDI. As a
26
characteristic of CDI, however, pseudomembranous colitis may be only caused by
27
CMV infection. Real-time CMV-PCR for blood and stool samples may be a useful
28
and noninvasive diagnostic strategy to identify CMV infection when treatment of CDI
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eventually fails to show significant benefits. Quantitative CMV-PCR in mucosal
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biopsies may increase the diagnostic yield of traditional histopathology. CMV colitis is potentially life-threatening if severe complications occur, such as sepsis secondary to colitis, massive colorectal bleeding, toxic megacolon and colonic perforation, so
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that may necessity preemptive antiviral treatment for those who are positive for
34
CMV-PCR in blood and/or stool samples while pending histological diagnosis. 2
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Background
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Cytomegalovirus (CMV) is a highly prevalent and globally distributed virus. CMV
37
infection in healthy adults is usually asymptomatic or causes a mildly infectious
38
mononucleosis-like syndrome. CMV then usually becomes dormant until reactivation
39
in the patients with severely immunocompromised status, who may potentially
40
develop invasive CMV disease with a wide range of manifestations, most commonly
41
colorectal infection with hemorrhagic ulceration. Coexistent two entities- CMV colitis
42
and Clostridium difficile colitis have usually been reported among the
43
immunocompromised patients, who have human immunodeficiency virus (HIV)
44
infection, organ transplantation, hematologic malignancy, solitary organ cancer, or
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inflammatory bowel disease receiving immunosuppressive agents.1-9 For example,
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Florescu et al. reviewed 9 patients who developed C. difficile and CMV colitis, among
47
them, 8 patients were immunocompromised: 4 transplant recipients, 2 oncology
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patients, 1 patient with advanced acquired immunodeficiency syndrome, and 1 on an
50 51 52 53
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immunosuppressive regimen for severe ulcerative colitis.8 Besides, CMV colitis can
mimic or present as pseudomembranous colitis in the immunocompromised patients.10-14
CMV gastrointestinal disease rarely occurs in the immunocompetent patients and could resolve completely without the use of antiviral drugs, if the immunity is 3
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obtained.15 In addition, CMV colitis is increasingly recognized in the apparently
55
immunocompetent patients in some immunomodulating conditions, such as elderly,
56
pregnancy, chronic renal failure, coronary artery disease, ischemic heart disease,
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congestive heart failure, diabetes mellitus, steroid use, blood transfusion and
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prolonged stay in the intensive care units (ICU).15-28 However, CMV colitis in these
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patients has often been neglected by clinical physicians.28 Therefore, this review
60
article will mainly focus on the English literature of CMV colitis coexisting、
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following or followed by Clostridium difficile colitis among previously healthy or
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apparently immunocompetent adult patients. We will also review those of CMV
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colitis presenting as a sole cause of pseudomembranous colitis without CDI.
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Epidemiology of CMV Colitis in the immunocompetent patients
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One systemic review identified only 91 immunocompetent patients with
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gastrointestinal CMV infections for the period of 1950-2007.25 Another literature
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review from 1980 to 2003 identified 44 immunocompetent patients with CMV colitis.
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Among them, spontaneous remission occurred in 31.8%, mostly individuals <55 years old.21 In Korea, 51 immunocompetent patients with CMV colitis, including 11 ICU patients and 17.6% with spontaneous remission, were diagnosed at a tertiary care
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university hospital between January 1995 and February 2014.23 In specific hospital
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ICU units, CMV colitis was diagnosed in 14 previously immunocompetent ICU 4
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patients at a teaching hospital in Brazil from January 2000 to March 2013.27 While in
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Taiwan, with intention to diagnosis, CMV colitis was detected in 18 ICU patients at a
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teaching hospital from January 2011 through June 2013.28 Among them, 3 patients
76
had malignancy. The biopsy-proven diagnosis was made for 8 patients. Other
77
probable cases were diagnosed based on clinical symptoms with detection of blood
78
CMV DNA plus either colonoscopic findings or detection of CMV DNA in the stool
79
samples.28 Traditionally, CMV colitis was easily neglected and under-diagnosed in the
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ICU patients with chronic critical illness, particularly with chronic renal failure.23, 27, 28
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Epidemiology of Clostridium difficile Colitis
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Diseases caused by Clostridium difficile range from mild diarrhea to potentially
83
life-threatening pseudomembranous colitis. Clostridium difficile infections (CDI)
84
occur primarily in hospitalized patients with risk factors such as concomitant or recent
85
use of antibiotics .29 The colonization rate of C. difficile in adult hospitalized patients
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shows geographic variation, ranging from 4.4% to 23.2%.30 The hypervirulent
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C. difficile strains such as the epidemic clone (027/NAP1/BI) has partly contributed to change the CDI epidemiology to worldwide dissemination.31 Particularly, elderly patients in surgical wards and ICUs are at significant risk of developing CDI.32 After
90
2006, a 47% increase in the rate of CDI was noted in the United States.33 In a cohort
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of hospitalized older adults in Michigan, impaired functional status was an 5
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independent risk factor for severe CDI.34 One study in Korea between January 2007
93
and July 2012, fifty-five percent of colitis in elderly people in long-term care facilities
94
was caused by CDI, whereas non-specific colitis was the most common (63%) in
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elderly people in local communities.35 Diagnosis of CDI is based on the identification
96
of C. difficile toxins A and B in diarrheal stool. First-line antibiotics for CDI treatment
97
are metronidazole and vancomycin.36 Fidaxomicin, a macrolide antibiotic has shown
98
to be significantly effective in treating C. diff infection compared to vancomycin.37
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For recurrence and relapse of CDI, rifaximin and tigecycline have yielded some
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positive outcomes against C. difficile.38 Fecal microbiota transplant is an alternative
101
therapy for CDI that is effective and promising in multiple CDI recurrences.39
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Coexisting CMV and C. difficile colitis
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A history of cytomegalovirus infection has been recognized as one of the significant
104
risk factors for C. difficile colonization.30, 40 Adult patients colonized with toxigenic C.
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difficile were prone to the subsequent development of C. difficile-associated
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diarrhea.30 The critically ill patients and elderly patients are at an increased risk of developing diarrheal illness like CDI and CMV colitis. The literatures of coexisting CMV and C. difficile colitis have been reported in the immunocompetent patients,
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mostly in the years after 2010 (Table 1), implying that effective alerts are increasing
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to current physicians. Presenting symptoms of both diseases included fever, diarrhea, 6
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gastrointestinal bleeding, and abdominal pain, with predominance of severe watery
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diarrhea for CD, whereas bloody stool, occasional massive bleeding for CMV colitis.
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Both may cause toxic megacolon and bowel perforation, leading to a poor
114
prognosis.41 However, we proposed that the clinical features of colitis caused by both
115
etiologies could vary as following scenarios (Table 1).
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CDI with refractory pseudomembranous colitis
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CDI with pseudomembranous colitis unresponsive to metronidazole and vancomycin
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therapy may need fecal transplantation to overcome the severe colitis. However,
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concomitant CMV colitis may partly contribute the refractory course and necessity
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simultaneous ganciclovir therapy to completely resolve the colitis.42 We previously
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reported a 82 year-old man who had coexistent CMV and CDI-associated
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pseudomembranous colitis (Figure 1).28 Moreover, Kurtz et al. reported an
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immunocompetent elderly woman with CDI, which was unresponsive to
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metronidazole, vancomycin, fidaxomicin and stool transplant due to concomitant
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CMV colitis.43 We also reported a case of toxic megacolon leading to respiratory failure, which developed after therapy with metronidazole, vancomycin and fecal microbiota transplants for CDI-associated pseudomembranous colitis.
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Immunostaining study was performed on initial colon mucosal biopsy and confirmed
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concomitant CMV colitis with CDI.44 7
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CDI with refractory colorectal ulcers or diffuse colitis without pseudomembranes
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Non-immunosuppressed patients with prolonged ICU stay due to chronic critical
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illness are at a high risk for both CDI and CMV colitis. Of the two diagnoses, CMV is
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likely missed more often because a biopsy or with immunostains is required to
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confirm the diagnosis, while CDI can be diagnosed based on non-invasive fecal C.
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difficile toxin assay.8 Many clinicians would only treat CDI infection for a patient with
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severe diarrhea and positive C. difficile toxin in the stool.
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Concomitant CDI and CMV colitis may sometimes manifest with diffuse colitis without pseudomembranes, which was refractory to first-line antibiotics for CDI
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treatment.15, 45-48 For examples, Harano et al. reported a 60-year-old
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immunocompetent woman who presented with abdominal pain and bloody diarrhea
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due to colorectal erosion and ulceration with positive stool isolate of C. difficile.
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Administration of metronidazole did not improve her symptoms. Endoscopic biopsy
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with immunostains revealed CMV colitis.15 Hung et al. reported CMV colitis with the
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presentation of watery diarrhea and stool culture positive for C. difficile, but diarrhea persisted despite oral metronidazole and vancomycin therapy.47 Chen et al. presented
a 90-year-old, critically ill, immunocompetent patient, who had a refractory C.
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difficile-infected multiple ulcers in the sigmoid colon and biopsy confirmed CMV
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colitis.48 This scenario was similar to a patient of lower lip squamous cell carcinoma 8
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who had diffuse pancolitis unresponsive to metronidazole, vancomycin enemas and
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later fidaxomicin, even though his stool C. difficile toxin became negative conversion.
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At this point, his CMV PCR in stool and blood were positive, and preemptive therapy
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with valganciclovir resulted in rapid clinical response and uneventful recovery.9
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CMV colitis following successful therapy for CDI
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Persistent diarrhea or relapse of intestinal symptoms after appropriate antimicrobial
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therapy for CDI may not necessarily indicate ineffective therapy for refractory course
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of CDI. Jawad reported a patient with diarrhea and stool culture was positive for C.
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difficile. Oral vancomycin rendered her stool negative but some bloody diarrhea
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occurred due to sequential CMV colitis.49 We previously reported a patient who had
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therapeutic response to initial C. difficile–associated pseudomembranous colitis but
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the symptoms relapsed 3 weeks later due to emergence of CMV-associated colon
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ulceration.28 This scenario might be related to reactivation of latent CMV infection in
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conditions of immunomodulation caused by pseudomembranous colitis.
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CDI following successful therapy for CMV colitis This rare scenario was ever reported in an elderly patient with adult T cell leukemia lymphoma, who developed CMV colitis on day 5 of chemotherapy. After 2 weeks of
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successful ganciclovir therapy, the patient developed diarrhea again with
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CDI-associated pseudomembranous colitis instead of CMV colitis. At that time, CMV 9
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antigenemia and a histologic study for CMV were negative.2
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CMV colitis as a cause of pseudomembranous colitis without CDI
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In addition to manifesting with solitary ulcer, multiple ulcers, diffuse colitis and
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polypoid lesions, occasionally CMV colitis may present with pseudomembranes,
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leading to misdiagnosis as CDI-associated pseudomembranous colitis.26, 50 This
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scenario should be considered particularly when C. difficile toxin assays or cultures
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are negative.51, 52 We previously described a patient who had CMV-associated
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pseudomembranous colitis (Figure 2), as the result of Clostridium toxin assay was
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negative and the patient experienced poor response to oral metronidazole therapy.28
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Current diagnosis and treatment of CMV colitis
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Historically, the diagnostic gold standard for CMV colitis is the direct
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histopathological identification of the Cowdry owl eye inclusion bodies in colonic
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biopsies or with the aid of immunohistochemistry (IHC) staining. Although CMV
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antigenemia and blood CMV-polymerase chain reaction (PCR) showed low sensitivity
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(<50%) for diagnosing CMV colitis, the specificity values were high (>80%).53 In the
presence of significant colon ulcers, however, the sensitivity of CMV antigenemia or PCR for diagnosing CMV colitis rose to 67.3%.53 Real time PCR for CMV DNA
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quantification in the blood and stool as well as in the colonic biopsy is currently
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considered as a useful diagnostic tool.54 The accuracy of theses diagnostic modalities 10
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as compared with the diagnostic gold standard are summarized in the table 2.
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CMV-PCR in colonic mucosal biopsies
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Yoshino et al. reported that quantitative real-time PCR (qPCR) for detecting CMV
190
infection in inflamed colonic mucosa is useful for accurate diagnosis of CMV
191
infection.55 Mills et al. reported that CMV DNA was detected by PCR in 90.9%
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(30/33) of IHC-positive and 14.5% (8/55) of IHC-negative mucosal biopsies,
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respectively. Their study indicated that CMV-PCR in gastrointestinal mucosal
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biopsies complements IHC and has the potential to identify additional patients who
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may benefit from anti-CMV therapy.56 McCoy et al. further reported that qPCR is
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highly sensitive and specific to aid in early diagnosis of CMV infection on equivocal
197
gastrointestinal biopsies.57 The mean value of CMV DNA load in gastrointestinal
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biopsies was 3,845 copies/µg total DNA (range, 15-15,500). However, the cutoff
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values for diagnosis of CMV colitis were not determined.58
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mucosal biopsies could not definitively exclude the diagnosis of CMV colitis. Theoretically, multiple biopsy specimens from longitudinal ulcers or diffuse colitis combined with qPCR in mucosal biopsies could increase the diagnostic yield of CMV
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colitis, especially in those patients known for positive CMV-PCR for blood and/or
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stool samples. 11
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CMV real-time PCR for blood samples
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Quantification of plasma CMV DNA by real-time PCR is a non-invasive method of
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aiding the diagnosis and can be used to monitor the treatment of CMV infection in the
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immunocompetent patients.20, 59 Concordance between the plasma real-time PCR and
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the pp65 antigenemia assay was 82.2%.60 However, the plasma real-time PCR is more
211
sensitive than the antigenemia assay for monitoring active CMV infection.60, 61
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However, blood CMV-PCR stands for CMV reactivation, and further direct evidences
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of CMV colitis by other diagnostic tools are required.
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CMV real-time PCR for fecal samples
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Michel et al. first adopted CMV- PCR from stool specimens as a diagnostic tool for
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patients with suspected CMV colitis. They concluded that absence of CMV DNA in
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stool samples may prove useful in ruling out CMV-related colitis.62 Thereafter, Boom
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et al. quantified CMV DNA loads in clinical fecal specimens to monitor the efficacy
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of antiviral treatment.63 In a small pilot study, the sensitivity, specificity, and accuracy
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of the PCR-based stool test for detection of CMV DNA compared to PCR-based detection of CMV in mucosal biopsies were 83, 93, and 90%, respectively.64 We also
found qualitative CMV-PCR for stool samples helpful in aiding the diagnosis of CMV
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colitis.28 In a recent study from Germany, quantitative CMV real-time PCR in fecal
224
samples was positive in 8/12 patients of the CMV intestinal disease (sensitivity, 67%), 12
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and was negative in the non-CMV group (45/47), indicating a good specificity of
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96%.65 Therefore, negative CMV PCR results from fecal samples cannot exclude
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CMV intestinal disease, whereas positive fecal PCR results could facilitate an earlier
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detection of ongoing CMV infections and might help to circumvent invasive biopsy
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via endoscopy. Otherwise, fecal PCR may guide a preemptive therapy for
230
life-threatening conditions, such as massive colonic bleeding, when a conclusive
231
histopathological proof of CMV infection is not available yet.28
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Strategy for diagnosis and controversy in treatment of CMV colitis
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The development of abdominal pain, fever, watery diarrhea, and bleeding stool in a
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critically ill patient should prompt the clinician to consider the diagnosis of CMV and
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CDI-associated colitis. Diagnostic strategy could be designed as follows.
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If standard stool pathogens and C. difficile toxin studies are nondiagnostic, endoscopic evaluation and CMV-PCR for blood and stool samples should be obtained.
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Quantitative CMV-PCR in mucosal biopsies seems to be a useful tool for diagnosis
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when combined with blood/stool PCR and endoscopic findings. In another way, if the results of stool C. difficile toxin assay are positive, the possibility of coexistent or sequential CMV colitis should not be neglected. For those patients with diagnosis of
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Clostridium colitis but unresponsive or partially responsive to therapy with
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metronidazole and/or vancomycin, and especially if CMV-PCR for blood and/or stool 13
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samples were positive, then re-evaluation of the initial colon mucosal biopsies by
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qPCR for CMV would be helpful. It is possible that complete resolution of colonic ulceration could be
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spontaneously achieved without use of antiviral drugs in some immunocompromised
248
or immunocompetent patients with CMV colitis.15, 21, 23 However, if CMV infection is
249
confirmed, ganciclovir therapy should be initiated without delay in critically ill
250
patients to avoid severe complications of colorectal massive bleeding and perforation.
251
Most of the reported cases of CMV colitis coexisting or following CDI as well as
252
presenting as pseudomembranous colitis had good clinical outcome under appropriate
253
medical therapy (Table 1). If bowel perforation occurs, prompt surgical resection is
254
indicated.66
255
Conclusion
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Currently, CMV colitis is increasingly recognized in the immunocompetent patients,
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manifesting with symptoms similar to or consisting with CDI-associated
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pseudomembranous colitis. CMV colitis most commonly presents with bloody stool in chronic status of critically ill patients with immunomodulating comorbidities, whereas C. difficile may produce severe watery diarrhea in those exposed to broad
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spectrum antibiotics. Coexisting CMV in the apparently CDI-associated colitis could
262
correspond to intractable colorectal symptoms. If CMV-PCR for blood and stool 14
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samples were positive, endoscopic biopsy with immunostains on mucosal specimens
264
is a definitive procedure for diagnosing CMV colitis, even in a case of
265
pseudomembranous colitis or positive for fecal C. difficile toxin assay. In case of
266
coexisting CMV and C. difficile colitis, ganciclovir therapy for CMV colitis in time
267
may circumvent the unnecessary second-line therapeutic method or fecal
268
transplantation for CDI, supposed that persistent diarrhea were not due to treatment
269
failure for C. difficile.
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Conflicts of interest
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All contributing authors declare no financial interests related to the material in the
272
manuscript.
273
Ethical consent
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The figures cited in the current review were approved by the institutional review
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board of Chi Mei Medical Center, Tainan, Taiwan (no. 10207-005).
276
Acknowledgments
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This work had no financial and material support.
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63. Boom R, Sol C, Weel J, Lettinga K, Gerrits Y, van Breda A, et al. Detection and quantitation of human cytomegalovirus DNA in faeces. J Virol Methods 2000;
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84:1-14.
64. Herfarth HH, Long MD, Rubinas TC, Sandridge M, Miller MB. Evaluation of a non-invasive method to detect cytomegalovirus (CMV)-DNA in stool samples of
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patients with inflammatory bowel disease (IBD): a pilot study. Dig Dis Sci 2010;
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65. Ganzenmueller T, Kluba J, Becker JU, Bachmann O, Heim A. Detection of cytomegalovirus (CMV) by real-time PCR in fecal samples for the non-invasive
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diagnosis of CMV intestinal disease. J Clin Virol 2014; 61:517-522.
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66. Chamberlain RS, Atkins S, Saini N, White JC. Ileal perforation caused by
cytomegalovirus infection in a critically ill adult. J Clin Gastroenterol 2000;
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30:432-5.
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Table 1. The clinical features of cytomegalovirus colitis coexisting, following or mimicking Clostridium difficile colitis in the immunocompetent patients
478 479
1 2
Age/ sex
Diarrhea
Diagnosis modality positive for CDI
CMV colitis
Time lag of 2nd diagnosis
CMV colitis coexisting CDI with refractory pseudomembranous colitis >3weeks 78/F bloody stool toxin1 colon biopsy2 3 immunostain 1 colon biopsy2 3 days 82/M bloody stool toxin immunostain3 CMV-PCR(1)4 watery
stool toxin1
4
63/F
watery
stool toxin1
8 9
10 11
12
recovery
2012[43]
recovery
2014[28]
NA
recovery
2014[42]
recovery
2015[44]
recovery
2009[45]
recovery
2013[46]
recovery
2014[47]
recovery
2015[15]
recovery
2015[48]
V, G
dieda
1992[49]
M, G
diedb
2014[28]
V, no
diedc
2000[51]
antiviral M, G
recovery
2011[52]
M, V, G
diedd
2014[28]
M, V, R, S, G M, V, S, G
>7 days
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CMV colitis following successful therapy for CDI 83/F some stool culture1 colon biopsy2 blood CMV-IgM3
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M,V, F, S, G, TC M, G,
CMV colitis coexisting CDI with refractory non-pseudomembranous colitis 81/M bloody stool toxin1 colon biopsy2 NA M, V, 3 CMV-PCR(1) G 1 2 37/F watery stool toxin colon biopsy >2 weeks M, V, G, 3 antigenemia FC 1 2 NA M, V, G 85/M watery stool culture colon biopsy 3 immunostain 1 immunostain 2 >10 days M, no 60/F bloody stool culture 3 CMV-IgM antiviral 1 2 90/M bloody stool toxin colon biopsy 14 days M, G 3 immunostain
stool toxin1
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CMV-IgM2 colon biopsy3 CMV-PCR(1)2 immunostain3
Year of ref.
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Outcome
VG
M AN U
3
Therapy
RI PT
Case
74/F
bloody
NA
CMV-PCR(1)2 3 weeks 2nd colonoscopyimmunostain3
CMV colitis as a cause of pseudomembranous colitis without CDI 63/M NA Colonoscopy1 CMV-PCR(1-3)3 No time lag
13
29/M
watery
14
69/M
watery
and biopsy2 colonoscopic finding1 colonoscopic finding1
immunostain4 2nd colonoscopy NA with biopsy2 CMV-PCR(1-2)2 9 days immunostain3
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Note. CDI: Clostridium difficile infection; CMV: Cytomegalovirus; stool toxin:
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Clostridium difficile toxin assay for stool sample; colon biopsy: histopathological
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findings of colonic mucosa with hematoxylin and eosin stain; immunostain: CMV
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immunohistochemical staining; F: female, M: male; Superscript (1, 2, 3, 4): sequential
484
order of positive diagnosis modalities; PCR: polymerase chain reaction for samples of
485
(1): blood, (2): stool, and (3): mucosal biopsies; M: metronidazole; V: vancomycin; G:
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ganciclovir; F: fidaxomicin; R: rifaximin; S: stool microbiota transplant; TC: total
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colectomy; VG: valganciclovir; FC: foscarnet; NA: not available; Superscript:
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a
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CMV inclusion bodies; bganciclovir was delayed to commence after 3 weeks of CMV
490
diagnosis but was discontinued due to worsening leukopenia, and thus failed to give
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improvement; cpostmortem examination revealed CMV myocarditis, pneumonitis and
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colitis; dpatient had symptomatic improvement of CMV colitis but died in other
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comorbidities.
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Table 2. The diagnostic test evaluation of new diagnostic modalities for
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cytomegalovirus colitis or digestive tract infections Gold standard
Sensitivity
Specificity Positive
modalities
predictive value
predictive value
Histopathology 47.0%
81.7%
59.1%
73.0%
PCR for blood in UC Histopathology 44.3%
87.9%
67.3%
73.6%
patients53
patients53 Histopathology 100%
colon mucosal biopsies55 Real-time (qPCR) in
Histopathology 90.9%
94.0%
98.7%
98.9%
96.3%
PCR for stool62
Histopathology 100%
94.1%
80.0%
100%
PCR in colon
83.3%
93.3%
83.3%
93.3%
Histopathology 66.7%
95.7%
80.0%
91.8%
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Histopathology 96.7%
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100%
79.0%
biopsies56
digestive mucosal
23.5%
85.5%
digestive mucosal
Real-time (qPCR) in
50.0%
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Real-time (qPCR) in
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Antigenemia in UC
Negative
RI PT
CMV Diagnostic
mucosal biopsies
Real-time (qPCR) for stool65 496
Note. UC: ulcerative colitis
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Legend:
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Figure 1. Colonoscopic finding is showing pseudomembranous colitis (A). Colon
499
mucosal biopsy showing enlarged atypical lymphocytes with eosinophilic inclusion
500
bodies (B, arrow), which was positive for CMV immunostaining (C, arrow). The
501
results of blood CMV-PCR and stool Clostridium toxin assay were both positive.
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Figure 2. Colonoscopic finding is showing colitis with pseudomembranes. The
504
CMV-PCR for blood and stool were positive. The stool Clostridium toxin assay was
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negative. The histopathological findings were consistent with pseudomembranous
506
colitis but immunostains confirmed CMV colitis (not shown).
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