Dig Dis Sci (2010) 55:10591065

DOI 10.1007/s10620-010-1126-4

ORIGINAL ARTICLE

Cytomegalovirus Infection in Patients with Active Inflammatory

Bowel Disease
John J. Kim Nicole Simpson Nancy Klipfel
Renee DeBose Nancy Barr Loren Laine

Received: 26 August 2009 / Accepted: 11 January 2010 / Published online: 29 January 2010
Springer Science+Business Media, LLC 2010

Abstract
Background The reported prevalence of cytomegalovirus
(CMV) infection with active inflammatory bowel disease
(IBD) is highly variable, and whether CMV negatively
impacts the clinical course is controversial.
Aims The aim of this study was to determine the prevalence of CMV in patients with active ulcerative colitis
(UC) or Crohns disease (CD) and compare the course of
disease in patients with and without CMV.
Methods Consecutive patients with acute exacerbations
of active IBD colitis had immunohistochemistry staining
for CMV antigen performed on archived specimens. Clinical features were retrospectively reviewed.
Results Twelve (10%) of 122 UC patients had CMV, and
0/20 patients with CD had CMV. Of 12 UC patients with
CMV infection, seven were not taking steroids or immunosuppressives at their index flare. UC patients with CMV
were more likely to have leukocytosis (OR = 5.3, 95% CI
1.518.2), require hospitalization (OR = 4.9, 95% CI 1.2
19.0), and be hospitalized C7 days (OR = 5.0, 95% CI
1.621.3) compared to patients without CMV. Of 12 UC
patients with CMV, ten (83%) were treated for their index
flare with steroids or 6-mercaptopurine. Only one patient

J. J. Kim
N. Simpson
R. DeBose
L. Laine

Department of Medicine, Keck School of Medicine University
of Southern California, Los Angeles, CA, USA
N. Klipfel
N. Barr
Department of Pathology, Keck School of Medicine University
of Southern California, Los Angeles, CA, USA
L. Laine (&)
GI Division, Keck School of Medicine, 2025 Zonal Ave,
Los Angeles, CA 90033, USA
e-mail: Ilaine@usc.edu

(8%) was treated for CMV infection which occurred

14 months after index endoscopy. Over the 6 months after
the index flare, UC patients with CMV had a higher
frequency of IBD-related hospitalizations compared to
patients without CMV (50 vs. 24%, P = 0.021), but none
required surgery or died.
Conclusions The prevalence of CMV with active UC was
10%. Although CMV infection may be a marker of disease
severity, our results suggest it does not cause severe morbidity or mortality in a general population of patients with
a UC flare.
Keywords Cytomegalovirus

Inflammatory bowel disease
Ulcerative colitis

Crohns disease
Abbreviations
CMV Cytomegalovirus
IBD
Inflammatory bowel disease
UC
Ulcerative colitis
CD
Crohns disease
H&E Hematoxylin and eosin
IHC
Immunohistochemistry

Introduction
Although cytomegalovirus (CMV) infection is well recognized in immunocompromised hosts (e.g., HIV infection,
bone marrow transplant recipients) [1, 2], the reported
prevalence and pathogenicity of CMV infection in patients
with inflammatory bowel disease (IBD) are variable. CMV
infection is frequently identified in the colonic mucosa of

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patients with active IBD and often presents a diagnostic

and therapeutic challenge. Some investigators have estimated the prevalence of CMV infection in patients hospitalized for IBD at 0.53.4% when routine investigation for
CMV infection was not done [3, 4]. Since the clinical
history and endoscopic findings of CMV colitis can
resemble those of lBD, examination of pathology specimens is crucial for making the correct diagnosis. CMV
infection may be diagnosed if typical intranuclear inclusion
bodies are seen on standard hematoxylin and eosin (H&E)
stain. However, the sensitivity of H&E exam for CMV
infection is low [5]. Immunohistochemistry (IHC) exam
performed on colon biopsy specimens is more sensitive
than routine histologic exam and has excellent specificity
[6]. Currently IHC is considered the gold standard for
detecting CMV [7]. In fact, the prevalence of colonic CMV
has been reported to be as high as 1457% in patients with
IBD who had IHC examination [810]. However, this is
not routinely done in general practice.
The clinical significance of finding CMV infection on
colonic biopsy is controversial. CMV infection may be an
innocent bystander, resulting from secondary infection in
an inflamed mucosa [11]. However, some patients with
steroid refractory disease have concurrent CMV infection
associated with high morbidity and mortality [12]. Furthermore, clinical improvement may be achieved in some
patients only with antiviral therapy and steroid reduction
[3]. Thus, in these patients, CMV likely caused clinically
significant disease.
The reported prevalence of cytomegalovirus (CMV)
infection with active IBD is highly variable and not well
described in patients with mild to moderate disease, and
whether CMV negatively impacts the clinical course is
controversial. For the most part, previous studies have only
evaluated patients with steroid-refractory or steroiddependent IBD. We hypothesize that a subset of patients
previously thought to have IBD flares also had concurrent
CMV infection. By utilizing IHC staining for CMV antigen, we evaluated the pathology specimens from all IBD
patients who underwent diagnostic endoscopy for IBD
flare. The aim of this study was to determine the prevalence
of colonic CMV infection in patients with active IBD and
also to compare characteristics and clinical outcomes of
active IBD patients with and without CMV infection.

Methods

Dig Dis Sci (2010) 55:10591065

underwent colonoscopy or sigmoidoscopy for suspected

IBD flare at Los Angeles County ? University of Southern
California Medical Center who were confirmed to have
clinical, histologic, and endoscopic evidence of idiopathic
IBD and active colitis were included. Potentially eligible
patients were initially identified by searching the endoscopy
records for patients who underwent colonoscopy or sigmoidoscopy for suspected IBD colitis based on symptoms
of new onset or worsening hematochezia and/or diarrhea.
All colonic specimens for each case were reviewed for
every patient. The most severely inflamed specimens for
each case were selected for IHC examination [10]. When
multiple procedures were performed on the same patient,
the first documented procedure at our institution or the
procedure that yielded the most histologically-active specimen on hematoxylin & eosin (H&E) stain was selected.
Patients who underwent endoscopy for screening or surveillance of dysplasia were excluded. Medical records
including inpatient and outpatient charts, laboratory test
results, endoscopic findings, and pathology reports were
reviewed to confirm patients who met enrollment criteria
and to characterize the patients clinical course before,
during, and after their IBD flare.
Definition and Study Endpoints
The paraffin blocks from archived specimens of subjects in
this study were reprocessed and stained with immunoperoxidase to determine the prevalence of CMV infection in
IBD patients. In addition to IHC, the patients had histological reexamination with H&E. No other evaluation for
CMV, such as viral culture, was performed. CMV infection
was defined by the presence of CMV immediate early
antigen by immunoperoxidase staining on colonic specimens. Anemia was defined as hemoglobin \10.5 g/dL and
elevated ESR was defined as [30 mm/h according to
Truelove and Witts classification for severe ulcerative
colitis [13]. Leukocytosis was defined as white blood cell
count [10,300/mm [3]. Hypoalbuminemia was defined as
albumin \3.0 g/dL, a level reported to be associated with
medical treatment failure in ulcerative colitis [14]. The
primary endpoints of the study were IBD-related hospitalizations and requirement of surgery within 6 months of
the index IBD flare. IBD-related hospitalization was
defined by an IBD-related discharge diagnosis per ICD-9CM code and verified by the medical chart. Surgery was
defined by an operation of the intestine per ICD-9-CM
code and verified by the operative record.

Patient Population
Statistics
An Institutional Review Board waiver of consent was
obtained prior to initiating this retrospective study.
Between January 2002 and January 2006, patients who

123

Descriptive statistics are reported as mean standard

deviation. Univariate analysis to determine patient and

Dig Dis Sci (2010) 55:10591065

1061

disease characteristics associated with CMV infection in

patients with active ulcerative colitis (UC) was conducted
by utilizing a Pearson chi-square test. All tests were
two-sided. Multivariate analysis was not possible due
to insufficient number of patients with CMV infection.
KaplanMeier estimates of the days without hospitalization
and days to surgery were produced, and comparisons were
made using the generalized log-rank test. Statistical analysis was performed using SPSS 16.0 (SPSS Inc., Chicago,
IL). P value \0.05 was considered significant.

Results
Patient Population
During the study period, 142 patients underwent endoscopy
for indication of suspected IBD flare and had endoscopic
and histological evidence of IBD with active colitis. The
mean age was 40 13 years (Table 1); 90 (63%) were
male, and 98 (69%) were Latino. Sixty-one patients (43%)
were hospitalized at the time of endoscopy, and 68 (48%)
were newly diagnosed with IBD. One hundred twenty-two
patients (86%) had UC and 20 patients (14%) had CD. Of
the 122 patients with UC, 22 (26%) were being treated with
steroids, nine (7%) were being treated with immunemodulators, and one (1%) was being treated with biologics
at the time of endoscopy. Of the 20 patients with CD, eight
(40%) were being treated with steroids, four (20%) were
Table 1 Characteristics of patients at time of endoscopy for index
flare
Characteristic

Overall
n = 142

Ulcerative
colitis
n = 122

Crohns
disease
n = 20

Mean age (years)

40 13

40 13

39 14

Male (%)

90 (63%)

78 (64%)

12 (60%)

Latino

98 (69%)

84 (69%)

14 (70%)

African American (%)

19 (13%)

14 (11%)

5 (25%)

Race

Caucasian

18 (13%)

17 (14%)

1 (5%)

Asian (%)

6 (4%)

6 (5%)

0 (0%)

Native American Indian (%)

New diagnosis (%)

1 (1%)
68 (48%)

1 (1%)
61 (50%)

0 (0%)
7 (35%)

Hospitalization (%)

61 (43%)

51 (42%)

10 (50%)

5-ASA (%)

52 (37%)

46 (38%)

6 (30%)

Steroids (%)

30 (21%)

22 (18%)

8 (40%)

6-MP/AZA/MTX (%)

12 (8%)

9 (7%)

3 (15%)

Anti-TNF (%)

3 (2%)

1 (1%)

2 (10%)

being treated with immune-modulators, and two (10%)

were being treated with biologics at the time of endoscopy.
UC Patients with CMV Infection
Twelve of the 122 patients (10%) with UC had CMV
infection (Fig. 1). For each index case, a median of 16
specimens (range 165) was obtained for histologic evaluation during endoscopy. On retrospective review of H&E
examination, none of the patients with CMV infection had
viral cytopathic changes. None of the 20 patients with CD
had CMV infection. Due to the absence of CMV infection
and the small number of patients with CD, the remaining
analysis was conducted only on UC patients. The CMV
prevalence in UC patients not on steroids was eight of 100
patients (8%), whereas in patients not hospitalized for their
index flare it was three of 71 (4%), and in patients not on
steroids and not hospitalized for their flare it was one out of
59 (2%).
On univariate analysis (Table 2), leukocytosis (odds
ratio [OR] 4.6; 95% confidence interval [CI] 1.315.8),
hospitalization at time of index endoscopy (OR 4.9; 95%
CI 1.219.0), and hospital length of stay [7 days (OR 5.0;
95% CI 1.319.6) were associated with CMV infection in
patients with active UC. Treatment with immunosuppressive medications prior to endoscopy, including steroids,
immune-modulators, and biologics, was not associated
with CMV infection. At the time of the index flare, IHC
exam was not performed on any of the biopsy specimens
and none of the patients were diagnosed with CMV colitis
based on H&E examination. Consequently, ten of 12
patients (83%) with CMV infection were treated with steroids and/or immune-modulators (Table 3) for presumptive
UC flare. Nine patients (75%) with CMV infection who
were admitted for UC flare were discharged after clinical
improvement with a mean length of stay of 9.9 7.2 days.
Only one out of 12 patients (patient 5) was later diagnosed with CMV infection. Fourteen months after the
index endoscopy, he was admitted for severe UC and an
endoscopy revealed active colitis with positive IHC staining for CMV. He had clinical improvement with intravenous ganciclovir followed by oral valganciclovir for
Active IBD
N=142
1/02-1/06

Medications

6-MP 6-mercaptopurine, AZA azathioprine, MTX methotrexate,

TNF tumor necrosis factor, 5-ASA 5-aminosalicylic acid

UC

CD

N=122

N=20

CMV+

CMV-

CMV+

CMV-

N=12

N=110

N=0

N=20

Fig. 1 Flow chart of 142 consecutive patients undergoing colonoscopy or sigmoidoscopy for acute inflammatory bowel disease (IBD)
colitis flare

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Dig Dis Sci (2010) 55:10591065

Table 2 Baseline clinical, biochemical and endoscopic characteristics of patients with ulcerative colitis flare related to cytomegalovirus
(CMV) status

UC Patients Undergoing IBD-Related Hospitalization

and Surgery

Characteristic

CMV?
n = 12

CMVn = 110

OR
(95% CI)

Age [40 years

5 (42%)

54 (49%)

0.7 (0.22.5)

Male
New diagnosis

9 (75%)
5 (42%)

69 (63%)
56 (51%)

1.8 (0.57.0)
0.7 (0.22.3)

Steroids

4 (33%)

18 (16%)

2.6 (0.79.4)

6MP/AZA

1 (8%)

8 (7%)

1.4 (0.211.9)

Anti-TNF

0 (0%)

1 (1%)

1.0 (1.01.0)

In patients with at least 6 months follow-up from the time

of index endoscopy (Fig. 2), UC patients with CMV
infection required more frequent hospitalizations compared
to patients without CMV infection (5 of 10 patients [50%]
vs. 20 of 82 patients [24%]; P = 0.021). In addition, at
6 months from the time of index endoscopy, none of the
UC patients with CMV infection required surgery while
three of 80 patients (4%) without CMV infection underwent surgery.

Oral/topical 5-ASA

7 (58%)

40 (36%)

2.5 (0.88.6)

WBC [10,300/mm3

7 (58%)

23 (21%)

5.3 (1.518.2)
1.4 (0.45.0)

Hgb \10.5 g/dL

4 (33%)

29 (26%)

Albumin \3.0 g/dL

6 (50%)

30 (27%)

2.7 (0.88.9)

ESR [30 mm/h

6 (50%)

32 (27%)

2.7 (0.88.9)

Distal colitis

1 (8%)

42 (38%)

0.2 (0.01.2)

Left-sided colitis

7 (58%)

35 (32%)

3.0 (0.93.2)

Pancolitits

4 (33%)

33 (30%)

1.2 (0.34.1)

Hospitalization required

9 (75%)

42 (38%)

4.9 (1.219.0)

Hospitalization [7 days

5 (42%)

12 (11%)

5.0 (1.621.3)

OR odds ration, CI confidence interval, WBC white blood cell count,

6-MP 6-Mercaptopurine, AZA azathioprine, TNF tumor necrosis
factor, Hgb hemoglobin, ESR erythrocyte sedimentation rate, 5-ASA
5-aminosalicylic acid

10 months. However, at 42 months from the index flare, he

underwent total proctocolectomy due to steroid-refractory
UC despite induction with infliximab. The colectomy
specimen did not demonstrate evidence of reactivation of
CMV on H&E stain or IHC exam. During a mean followup of 23 19 months in patients with CMV infection and
29 23 months in patients without CMV infection, none
of the patients died.

Discussion
The role of CMV in active IBD has been controversial.
Early studies have highlighted the association of CMV
infection with severe active IBD and high doses of
immunosuppressive medications. Initial studies reported
CMV inclusion bodies in colectomy specimens with fulminant or steroid-refractory UC [8, 15, 16]. In addition,
treatment with steroids [17], cyclosporine [18], anti-TNF
agents [19], and leukapharesis [20] has been associated
with an increased risk of CMV infection. However, other
studies have challenged the pathogenicity of CMV in
active IBD by demonstrating a lack of correlation of
CMV and clinical severity of IBD [21]. Based on the
association of CMV with severe steroid-refractory IBD,
one can hypothesize that CMV plays a role in flares of IBD,
either by causing CMV colitis directly or by exacerbating
underlying IBD. However, it is also possible that
CMV may be an innocent bystander detected in the

Table 3 Summary of the 12 ulcerative colitis patients with cytomegalovirus (CMV) infection
Patient

Age/
gender

Duration of
UC (years)

Medication

Endoscopic
involvement

Treatment

Length of
stay (days)

Days to subsequent
hospitalization

Follow-up
(months)

65/M

8.0

29/M

0.2

5-ASA, 6MP

Left-sided

5-ASA, 6-MP

Not hospitalized

13.6

5-ASA, S

Distal

S, 5-ASA

24

Not hospitalized

32/M

14.2

5.0

5-ASA, S

Left-sided

S, 5-ASA

14

Not hospitalized

52.4

19/M

None

Left-sided

5-ASA

15

41.0

53/M

0.5

5-ASA, S

Left-sided

S, 5-ASA

104

49.4

30/F

0.8

5-ASA

Pancolitis

S, 5-ASA

18

9.9

33/M

None

Pancolitis

S, 5-ASA

18

Not hospitalized

46.1

34/M

0.4

5-ASA, S

Left-sided

5-ASA, S

Not hospitalized

14.5

43/F

None

Pancolitis

S, 5-ASA

32.0

10

57/M

None

Pancolitis

S, 5-ASA

Not hospitalized

0.3

11
12

33/M
40/F

2.0
0

5-ASA
None

Left-sided
Left-sided

S, 5-ASA
5-ASA

5
5

Not hospitalized
25

0.2
2.9

UC ulcerative colitis, M male, F female, 5-ASA 5-aminosalicylic acid, 6-MP 6-Mercaptopurine, S steroid

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Dig Dis Sci (2010) 55:10591065

Fig. 2 KaplanMeier estimates of ulcerative colitis-related hospitalization rates for patients with CMV infection (n = 12) and without
CMV infection (n = 110)

background of colonic mucosa during active IBD. With

emerging therapies that increase immunosuppression, a
clear understanding of the role of CMV infection in active
IBD is needed. Many previous studies were limited in size,
were done in highly selected populations, and/or do not
provide information on long-term clinical outcomes.
In our study, 12 of the 120 patients (10%) with UC and
none of the 20 patients with CD had CMV infection.
Although our study had a limited number of patients with
CD, a higher incidence of CMV in UC compared to CD is
consistent with prior reports [8, 22]. We found the prevalence of CMV infection in patients with active UC to be
lower than previously reported in patients with acute severe
colitis (2138%) [2024] and steroid-refractory colitis
(3236%) [17, 23, 25]. This finding may be due to the
inclusion of patients with mild to moderate disease activity in
our study, unlike previous studies that selected patients with
more severe disease. Considering the higher sensitivity of
IHC exam for CMV infection compared to the routine H&E
exam utilized by some of the previous studies, the discrepancy in the prevalence of CMV infection may be even
greater. Our results are close to the 16% prevalence of CMV
infection in a study from India that also included both outpatients and inpatients [26]. However, in that study diagnosis
of CMV was made with serum CMV DNA, serum IgM
antibody, or histological inclusion body.
Nearly half of our patients were newly diagnosed with
IBD, thus comprising a large inception cohort. A new
diagnosis of UC was not associated with an increased
incidence of CMV infection (OR 0.7; 95% CI 0.22.3) in
our study. In contrast, some previous studies suggested that

1063

CMV infection may be associated with the development of

IBD in a subset of patients [2729].
Our results suggest that CMV infection is associated
with more severe UC. For example, univariate analysis
showed significant associations of CMV infection with
elevated white blood cell count, hospitalization at the time
of index endoscopy, and hospitalization C7 days. In contrast to some prior reports, our study did not show a significant association of steroid or other immunosuppressive
therapy with CMV infection [17, 30]. However, steroids
were used twice as often in patients with CMV infection in
our study, raising the possibility of a type II error. In
addition to increased disease severity in UC patients with
CMV infection, we found a higher rate of hospitalization in
CMV-positive patients during the 6 months following their
index flare.
CMV was not diagnosed at the time of index flare in any
of our patients. Therefore, 83% of the patients with CMV
infection were treated with immunosuppressive medications and none received antiviral medications for the flare.
The absence of CMV-directed therapy allowed examination of the natural history of CMV infection in UC patients.
However, none of the UC patients with CMV infection
required surgery during the 6-month follow-up and none
developed fulminant colitis or died despite the lack of
immediate antiviral medication and the use of immunosuppressive medication. Interestingly, all the patients
recovered from their IBD exacerbation without associated
morbidity or mortality. This is in stark contrast to some
case series of CMV infection in IBD patients that have
reported a colectomy rate of 64% and mortality rate of 44%
[11, 31].
The increased severity of UC with CMV is consistent
with either CMV being an innocent bystander in UC (with
CMV more common in patients with more severe disease)
or with CMV inducing more severe disease in patients with
UC. However, the lack of surgery, fulminant colitis, or
death in the face of immunosuppressive therapy without
antiviral therapy suggests that CMV, even if pathogenic, is
not generally of great clinical importance in our population.
Other authors have challenged the pathogenic role of
CMV in patients with active IBD and supported the theory
of CMV as an innocent bystander. Matsuoka et al. previously compared 25 moderate to severe UC patients with
reactivation of CMV detected by serum antigenemia or
real-time polymerase chain reaction assay and 45 moderate
to severe UC patients without CMV reactivation or naive to
CMV infection [21]. In this series, the clinical outcomes
including rates of remission and colectomy were not significantly different whether or not there was reactivation of
CMV infection. Furthermore, CMV disappeared without
treatment in most of the CMV reactivation-positive
patients. Pfau et al. demonstrated that rapidly proliferating

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cells in granulation tissue are susceptible to CMV infection

[11]. Furthermore, CMV tropism for site of inflammation
[3] and increased levels of procytokines, TNF-a and IGN-c
[32], may activate viral latency in the setting of IBD
exacerbation. Thus, colonic CMV may be more reflective
of IBD disease severity rather than viral pathogenicity.
Criscuoli et al. [23] also suggested that a possible difference in clinical manifestations of CMV infection may be
explained by the existence of pathogenic and non-pathogenic genotype.
Our results do not provide support for recommending
routine IHC to detect CMV in IBD patients. We cannot rule
out that detection and treatment of CMV might have
decreased disease severity and the rate of repeat hospitalization. Because patients did not receive anti-CMV therapy
at the time of their flare, our data do not allow us to determine whether CMV detection and treatment would improve
outcomes. A randomized placebo-controlled trial of CMV
therapy should provide the best assessment of the clinical
importance of CMV in IBD, i.e., if CMV therapy leads to
significant benefit it would indicate that CMV does play a
meaningful role in the clinical course of IBD. Our study does
suggest that routine IHC and treatment of CMV-positive
patients is unlikely to decrease fulminant colitis, surgery, or
death in a general population of patients with a UC flare.
A limitation of our study is the relatively small number of
patients with CMV infection, which precluded us from
conducting a multivariate analysis to identify independent
risk factors for CMV infection. Another limitation is that not
all patients received full colonoscopy. It is possible that some
patients may have isolated right sided involvement [33] and,
if so, our results would underestimate CMV prevalence.
In summary, the prevalence of CMV infection in
patients with active UC was 10%. UC patients with CMV
infection may have more severe disease, given the more
frequent and longer hospitalizations at their index IBD
flare. However, despite the frequent use of immunosuppressive therapy and the absence of antiviral treatment,
none of the patients developed fulminant colitis, required
surgery, or died with their IBD flare. In conclusion,
although CMV infection in the setting of active UC may be
a marker of disease severity, our results suggest it does not
cause severe morbidity or mortality in a general population
of patients with a UC flare.

Dig Dis Sci (2010) 55:10591065

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.
14.

15.

16.

17.

18.

Conflict of interest statement None of the authors have conflict of

interest or funding source to declare in connection with this study.
19.

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