doi:10.1111/imj.

15085

REVIEW

Cytomegalovirus in inflammatory bowel disease: a clinical

approach
Robert B. Gilmore,1,2 Kirstin M. Taylor,1,3 C. Orla Morrissey3,4 and Bradley J. Gardiner 3,4

Departments of 1Gastroenterology, and 4Infectious Disease, Alfred Health, 2Department of Gastroenterology, Austin Health, and 3Central Clinical
School, Monash University, Melbourne, Victoria, Australia

Key words Abstract

inflammatory bowel disease, ulcerative colitis,
cytomegalovirus.
Correspondence
Bradley J. Gardiner, Department of Infectious
Diseases, Alfred Health, 55 Commercial Road,
Melbourne, Vic. 3004, Australia.
Email: bradgardiner@gmail.com
Cytomegalovirus (CMV) infection can be a challenging clinical problem in patients with
inflammatory bowel disease (IBD), particularly ulcerative colitis. Clinical presentation is
difficult to distinguish from an underlying disease flare. Several diagnostic modalities
are now available and when combined can aid clinicians in the identification of patients
who are most likely to benefit from antiviral therapy. The aim of this article is to review
the available literature and outline a practical approach to the diagnosis and manage-
ment of CMV in patients with IBD.

Received 21 July 2020; accepted

27 September 2020.

Introduction
Reactivation of latent cytomegalovirus (CMV) infection
is increasingly recognised as an important clinical prob-
lem in patients with inflammatory bowel disease (IBD),
particularly among those with acute severe colitis receiv-
ing high doses of immunosuppression.1 Diagnosis can be
complicated given the multiple testing modalities avail-
able, and identifying which patients are most likely to
benefit from antiviral therapy can be challenging. The
aim of this article is to review the relevant literature and
propose an updated practical clinical approach to these
difficult cases.
Epidemiology
CMV is a ubiquitous herpesvirus with a seroprevalence
in Australia around 75%, increasing with age.2 Infection
is frequently acquired in childhood or adolescence via
exposure to blood or body fluids and is typically mini-
mally symptomatic.3 Viral DNA integrates into the host
and persists, resulting in life-long latency. Ongoing
Funding: B. J. Gardiner is supported by the National Health and
Medical Research Council of Australia (grant number
GNT1150351).
Conflict of interest: None.
immune activity is required to inhibit viral replication
and prevent reactivation. With immunosuppression,
CMV reactivation can occur and lead to a spectrum of
clinical disease. It is estimated to affect 10–30% of
patients with active IBD.4 The highest risk subgroup is
patients with steroid-refractory ulcerative colitis (UC),
although it can also affect those with Crohn disease.5
Acute (primary) CMV infection in previously seronega-
tive individuals can also occur, resulting in significant
clinical illness.
Several studies have explored risk factors for CMV
reactivation in patients with IBD. In one large meta-anal-
ysis, glucocorticoids (odds ratio (OR) 2.05; 95% confi-
dence interval (CI) 1.40–2.99) and thiopurines (OR 1.56;
95% CI 1.01–2.39) were associated with CMV reac-
tivation, but not tumour necrosis factor (TNF)-α antago-
nists such as infliximab (OR 1.44; 95% CI 0.93–2.24).6
There is emerging evidence to suggest that patients
receiving the gut-selective integrin inhibitor vedolizumab
are also at higher risk of developing CMV disease com-
pared with those receiving infliximab (hazard ratio 2.3;
95% CI 0.5–9.3).7 While the role of CMV as a pathogen
versus bystander has been long debated, it is increasingly
apparent that CMV colitis can result in significant mor-
bidity and mortality in patients with IBD, and contributes

Internal Medicine Journal 52 (2022) 365–368 365

© 2020 Royal Australasian College of Physicians

Gilmore et al.
to increased risk of hospitalisation and colectomy.5,8,9
Antiviral treatment can lead to clinical improvement in
IBD patients with CMV, facilitating ongoing immuno-
modulatory therapy and sustained remission
afterwards.10
Clinical features
In patients with IBD, CMV typically presents as colitis
with or without systemic features such as fever, malaise
and leukopenia. CMV can also cause a diverse variety of
syndromes best described in transplant recipients includ-
ing pneumonitis, colitis, hepatitis and a non-specific
febrile illness termed ‘CMV syndrome’. While not com-
monly seen in patients with IBD, symptoms apart from
colitis are possible. Although CMV disease occurs most
commonly in those with acute severe or chronically
active UC, and in particular steroid-refractory disease, it
should be considered in all patients with acute colitis,
due to the inability to distinguish clinically or endoscopi-
cally from an idiopathic disease flare. A recent meta-
analysis has concluded that patients with acute severe
colitis and concurrent CMV are more likely to have
steroid-refractory disease, with an increase in steroid
resistance from 30% in the CMV-negative group to 52%
in the CMV positive group (OR 3.63; 95% CI 1.99–6.62;
P < 0.0001).11
Diagnosis
There are several diagnostic modalities available to detect
CMV, each with their own advantages and limitations.
These tests must be used in combination when evaluat-
ing a suspected case for optimal results. Serology is a
simple, highly sensitive, inexpensive and readily avail-
able way to confirm prior exposure to CMV or evaluate
for acute infection. Negative serology can preclude the
need for further investigation for CMV if obtained
promptly. Quantitative serum viral load (polymerase
chain reaction (PCR)) testing is now widespread and able
to detect very low levels of CMV. While high viral loads
are more likely to indicate severe disease in a more
heavily immunosuppressed patient, the absence of vir-
aemia does not rule out CMV colitis.
Histopathologic evaluation of tissue specimens remains
the gold-standard diagnostic investigation. Early flexible
sigmoidoscopy is recommended, targeting inflamed areas
for biopsy, with more biopsies increasing the diagnostic
yield. Sampling error is minimised with 11–16 biopsies
but this number can be difficult to obtain routinely.12,13
The presence of viral inclusions is highly specific for CMV
and sensitivity is increased with immunohistochemical
(IHC) staining.9,12 While it can be difficult to determine
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the relative contribution of CMV to a patient’s presenta-
tion, in general the higher the burden of CMV seen on
microscopic examination of the colon, the more likely
that antiviral treatment will be helpful in achieving reso-
lution of colitis. The presence of >5 IHC positive cells per
2 mm tissue is significantly higher in patients with
steroid-refractory disease.14 Patients with >10 IHC posi-
tive cells per section, have an increased risk of cole-
ctomy.15 Tissue PCR is increasingly used and can detect
very small amounts of CMV present in tissue, which may
at times be of questionable clinical significance.13 Sensitiv-
ity is higher on fresh tissue, although many laboratories
are able to perform it on formalin-fixed paraffin-
embedded samples. Higher tissue viral loads may be more
significant but have not been well validated and quantita-
tive testing of biopsy samples is not routinely available.10
While stool CMV PCR is appealing due to the ease of sam-
ple collection, this test is not currently recommended out-
side of a research setting as the sensitivity and specificity
are not well established.16
A suggested approach to evaluating IBD patients with
suspected CMV colitis is shown in Figure 1.
Management
Identifying which patients are most likely to benefit from
antiviral therapy can be challenging; however, it is clear
that treatment is of most benefit in patients with a high
burden of CMV who have received corticosteroids with-
out clinical improvement. Antiviral therapy has been
associated with reduced need for colectomy in this sub-
group.5 In patients with a low burden of CMV identified
on diagnostic testing (e.g. isolated positive tissue PCR or
low-level viraemia), antiviral treatment can be deferred
while awaiting a response to empiric corticosteroids.17
Two studies looking at patients with active UC and CMV
infection diagnosed on positive serum PCR alone found
no differences in length of hospital stay, rate of relapse,
colectomy rates or mortality compared to CMV negative
patients.18,19 If salvage therapy is used, the case for CMV
treatment becomes stronger as increased immunosup-
pression can lead to further CMV reactivation. Once a
diagnosis of CMV colitis is made, priority should be given
to weaning corticosteroids while using another agent to
reduce inflammation and induce remission. Infliximab is
preferred over ciclosporin where possible due to the
potential TNF-avidity of CMV.20 Thiopurines should be
ceased, at least temporarily. A randomised controlled
trial is underway to determine the optimal strategy for
patients receiving vedolizumab.21
The mainstay of antiviral therapy is intravenous ganci-
clovir and its oral equivalent valganciclovir. Patients
should be initiated on intravenous therapy, then
Internal Medicine Journal 52 (2022) 365–368
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Figure 1 An approach to the clinical evaluation of inflammatory bowel disease patients with suspected cytomegalovirus (CMV) colitis. †Biopsies sent
both fresh for CMV tissue polymerase chain reaction (PCR) and in formalin for histopathologic examination and immunohistochemical staining.
switched to valganciclovir once improving and reliably
absorbing oral medications. Myelosuppression is the
most common serious adverse event. Patients require
weekly monitoring with full blood count and G-CSF sup-
port is occasionally required. Optimising antiviral dosing
is crucial, particularly in patients with renal dysfunction,
as dose reduction is required but underdosing can
increase the risk of treatment failure and subsequent
resistance.22
The overall duration of treatment should be individua-
lised and guided by the clinical and virologic response.
The minimum recommended duration is 2 weeks but can
extend to 6 or more if required. If the viral load is detect-
able at initial diagnosis, serum PCR can be performed
weekly to guide ongoing therapy beyond the resolution
of viraemia. In patients without viraemia, assessing
response can be more challenging and is generally guided
by symptomatic improvement in diarrhoea.22,23 Repeat
endoscopic evaluation may be required if symptoms fail
to improve.
While antiviral prophylaxis is used routinely in trans-
plant recipients, there is little evidence to guide primary
or secondary prophylaxis in patients with IBD. Recur-
rent, refractory and resistant CMV can occur and can be
Internal Medicine Journal 52 (2022) 365–368
© 2020 Royal Australasian College of Physicians
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Cytomegalovirus infection in IBD
extremely challenging to manage in some cases, requir-
ing alternative agents such as foscarnet and cidofovir
which have problematic side effect profiles.24 Guidelines
have not traditionally recommended routine CMV sero-
logical screening in patients with IBD, but this could be
considered at baseline to inform of risk of reactivation
and facilitate rapid diagnostic evaluation during the pre-
sentation of a flare.22,23,25
Conclusion
CMV infection is an increasingly common clinical prob-
lem in patients with IBD and is associated with adverse
outcomes. Despite advances in diagnostic techniques and
effective treatment strategies, selecting which patients
will benefit from antiviral therapy remains challenging.
A growing body of evidence suggests that patients most
likely to benefit are those with steroid-refractory colitis,
particularly where serum viral loads are high or multiple
inclusions are seen on histology. A collaborative
approach to management involving gastroenterologists,
infectious diseases physicians and colorectal surgeons is
recommended to ensure optimal outcomes for these
complex patients.
367

Gilmore et al.
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