CMV management in IBD

1. Management of
Cytomegalovirus
Infection in IBD
By: Rajesh Kumar
Moderator : Dr. Abdullah Khathlan
March 2012

2. CASE:
• An 18 year old man was
admitted to the hospital,
• Presents with progressive
severe bloody diarrhea for
the for 2 months.
• Stool and rectal swab were
negative for parasites, ova
and pathogenic bacteria.
• Proctoscopy revealed
“beefy-red” friable rectal
mucosa.

3. CASE:
• Treatment with dextrose, electrolytes, penicillin,
streptomycin and hydrocortisone did not result in
improvement.
• However the patient deteriorated and
necessitated surgery on the 65th
hospital day.

4. • Bx: cellular inclusions,
typical of cytomegalic
inclusion disease together
with superficial
inflammation of the colonic
mucosa.
• Diagnosis: CMV +
Ulcerative colitis

5. “We are unable to say whether the primary
disease was UC or salivary gland virus (CMV)
infection resulting in a clinical picture simulating
UC.”
( When a human is first infected, CMV infects the epithelial cells in the salivary
glands, which causes continuous infection and further reproduction and
transmission of the virus to other cells in the body.)

6. Introduction:
• Human cytomegalovirus
(CMV), a member of the
Herpesviridae family, is
an enveloped DNA virus
transmitted through close
personal contact with
body fluids, including
saliva, urine, blood,
breast milk and genital
secretions, or
transplanted organ tissue.
• CMV is responsible for a
common viral infection in
humans.

7. Introduction:
• The initial acquisition of CMV is bimodal,
with a first peak during pregnancy and
early childhood and a second one, mainly
through sexual contact, during adult life.

8. Introduction:
• CMV reactivation, that is common in situations
favouring acquired defect of cellular immunity,
(including pregnancy, immunosuppressive
therapy, malignancy, bone marrow or solid
organ transplantation and HIV/AIDS infection),
can induce high disease activity and mortality.

9. Introduction:
• Reinfection with a new strain of CMV may occur,
notably in blood- or graft-receiving patients from
a CMV-positive donor, which can also induce
CMV infection or disease.

10. Infection:
•CMV antigens or antibodies in blood.
Disease:
•Symptomatic end-organ detection (clinical
symptoms and tissue damage).
CMV colitis:
•Presence of the virus in the colon in sites of
inflamed tissue.
Definations:

11. CMV infection & disease in IBD
Patients
• In IBD patients, CMV infection can have at least
three types of disorders:
(i)CMV disease without involvement of intestinal
lesions :
Characterised by a CMV infection (primary
infection & reactivation) occurring outside the
gut, which combines symptoms of systemic
infection (fever, leukopenia,
haemophagocytosis, extra-intestinal
complications, etc.) and virological stigmata of
blood CMV infection without intestinal lesions.

12. (ii) CMV disease involving the Gut :
Also called CMV colitis, which usually presents
combines clinical (fever, malaise, anorexia,
weight loss, abdominal pain, diarrhoea,
hematochezia, tenesmus, etc.) and endoscopic
signs of CMV infection in the gut together with
systemic and localised stigmata of CMV
infection by virological testing.

13. (iii) Intestinal CMV infection :
Limited to stigmata of local CMV reactivation
without any systemic or local signs of disease.

14. Diagnostic Guidelines for Diagnosis of
CMV Colitis
2010 - American College of Gastroenterology
(ACG)1
:
•Sigmoidoscopic biopsy and viral culture in
refractory colitis.
2009 - European Crohn’s and Colitis Organization
(ECCO)2
:
•Tissue findings or Immunohistochemistry for CMV
in immunomodulator-refractory IBD.

15. Diagnostic Guidelines for Diagnosis of
CMV Colitis
• Histology/immunohistochemistry preferred
method for diagnosis of tissue-invasive disease.
• Viral culture of blood or urine has limited role for
the diagnosis of disease.
• Culture and QNAT* of tissue specimens have a
limited role in the diagnosis of invasive disease
but may be helpful in gastrointestinal disease,
where blood QNAT may not be positive.
*Quantitative nucleic acid amplification test (QNAT)

16. Techniques Specimens Diagnosis Quantification Sensitivity Specificity
Usefulness
in clinical
practice
Conventional
culture
Blood, urine,
saliva, tissue
Direct No + +++ in tissue +
Rapid culture
Blood, urine,
saliva, tissue
Direct Yes ++ +++ in tissue +
pp65
antigenemia
Blood Direct Yes ++ + +
Detection of
CMV DNA
Blood, urine,
saliva, tissue
Direct Yes +++ ++ in tissue +++ in tissue
Detection of
pp67 mRNA
Blood Direct Yes ++ + +
Histology Tissue Direct No + +++ +++
Immunohisto
chemistry
Tissue Direct Yes ++ +++ +++
In situ
hybridisation
Tissue Direct Yes ++ +++ +++
IgG
antibodies to
CMV
Blood serum Indirect No NR NR NR
IgM
antibodies to
CMV
Blood serum Indirect No NR NR NR
Methods for diagnosing CMV infection in Body fluids & Intestinal Biopsies

17. Kojima T, et al. Scand J Gastroenterol 2006;41(6):706-11.
Lawlor G, Moss AC. Inflamm Bowel Dis. 2010;16:1620-1627.
Kandiel A, Lashner B. Am J Gastroenterol. 2006;101(12)2857-65.
Typical positive immunohistochemistry (IHC) staining for CMV
(arrow) in a cytomegalic cell; The cells that stain positive for the
presence of CMV (arrows) are a distinctive brown, whereas the
cells that are negative for CMV by IHC are blue, secondary to
counterstaining with H&E. Magnification ×1,000.

18. CMV-infected colonic cell stained with
Immunohistochemistry (IHC).

19. CMV-infected cell
(‘‘Owl-Eyes’’) The presence
of viral inclusion bodies.

20. CMV diagnosis in IBD patients
• The detection of IgG antibodies against CMV should
be detected at the first visit, when the diagnosis of
IBD is confirmed, in order to clarify whether the
patient is at risk of displaying primary infection (IgG
negative) or reactivation/reinfection (IgG positive).
At this stage, the detection of IgM antibodies is not
useful.
• The histological examination of intestinal biopsies
together with the detection of CMV in intestinal
tissue by IHC or PCR assay are now recommended
[4]

21. Clinical & Endoscopic findings in CMV
Colitis
• The diagnosis of active CMV infection in IBD
patients remains difficult, CMV colitis sharing a
lot of clinical features with an active flare of IBD
and notably of UC.
• Some reports have suggested that clinical signs
of fever, lymphadenopathy, splenomegaly, toxic
megacolon and rapid clinical deterioration can
help distinguish a superimposed CMV infection
from an UC flare [26,27]. However, these findings
have not been independently validated [28].

22. Endoscopic Findings
• Although there are no definite endoscopic
findings that are able to reliably distinguish CMV
colitis from an active flare of UC.
• Cases reported a correlation between CMV
infection and the presence of longitudinal
ulcerations [29].

23. Endoscopic findings
• Among UC patients who were Hospitalised for an
exacerbation of symptoms, Colonoscopic findings
were compared between 15 CMV positive and 58
CMV negative patients: irregular ulcerations were
systematically associated with CMV infection.
• Suzuki et al.
• The absence of large ulcer was predictive of latent
CMV infection in UC patients exhibiting CMV DNA in
the intestinal mucosa [30]
• Omiya et al.

24. Typical endoscopic findings of ulcerative changes.
A: Wide mucosal defect; B: Punched-out ulceration;
C: Longitudinal ulceration; D: Irregular ulceration;
E: Cobblestone-like appearance.

25. Pathophysiology of CMV infection in
IBD patients
• The cytokine responses characterizing IBD are
the key pathophysiologic elements that govern
the initiation, the evolution, resolution of these
forms of inflammation.
• In CD, the Th1 and Th17 CD4+ T-cell
differentiation (mainly IFN- gama,secretion by
CD4+ T cells) response is exacerbated and
could participate in increasing the local
activation of specific T-cell response against
CMV, thus leading to highly efficient CMV
elimination.

26. Pathophysiology of CMV infection in
IBD patients
• In UC, the increased Th2 response does not
result in the production of cytokines able to
control CMV reactivation. These findings could
explain for the most part the huge difference of
CMV infection in terms of clinical consequences
between CD and UC patients.

27. CMV colitis and Crohn’s disease
• CMV primary infection has been described in CD
patients exhibiting stigmata of acute infection
(IgM antibodies, viraemia, as well as CMV
positive biopsies)
• The prevalence of CMV colitis is low in CD
patients, as reported in several studies that have
recorded CMV infection in intestinal tissue.

28. CMV colitis and Crohn’s disease
• The administration of Ganciclovir
contributed to their clinical remission.
• Immunosuppressive therapy seems to
have no impact on CMV reactivation in CD
patients.
• A prospective study including 60 patients
reported no systemic CMV infection
before, during and after Infliximab therapy.

29. CMV infection, CMV colitis and
Ulcerative Colitis
1. Influence of UC medical treatment on CMV
reactivation:
• The administration of steroids :
for at least 3 months at a dose of at least 10 mg was
associated with CMV reactivation among UC patients.
However, the cumulative steroid dose was not shown
to be a predisposing factor [41].
• Cottone et al.
• CMV infection was detected in 7 (9.7%) and 24 (50%)
cases of severe UC, before and after a high-dose
steroid therapy for 7–14 days, respectively [42].
• Kim et al.

30. Influence of UC medical treatment on CMV
reactivation:
• Infliximab :
has not been associated with an increased risk
of CMV reactivation in patients with IBD.
In 11 consecutive patients with IBD checked
before and after a standard 3-infusion course
with this drug, did not find any intestinal CMV
infection using histology and IHC [24].
d’Ovidio et al.

31. Influence of UC medical treatment on CMV
reactivation:
• Thiopurine ( AZA ):
There are conflicting results about the
association of CMV reactivation with Thiopurine
drugs.
• Cottone et al.
• Previously showed that exposure to Azathioprine
(AZA) did not predispose to CMV infection [41].
• Domènech et al.

32. Influence of UC medical treatment on CMV
reactivation:
• Evaluated the prevalence of CMV infection in
blood and tissue of 114 UC patients through a
prospective, observational study [10]; Patients
were divided into 4 groups according to disease
activity and drug exposure; none of those with
inactive UC under AZA exhibited CMV infection
and previous treatment with AZA in steroid-
resistant patients was not associated with CMV
infection.

33. Influence of CMV infection on UC
progression
• Several studies have suggested that CMV
infection may interfere with the natural
history of UC.

34. Influence of CMV infection on UC
progression
• The majority of these studies described patients
with severe attacks of UC and suggested that
CMV infection was responsible for an increased
morbidity and mortality rate in these patients.
• In a case study and review of the existing
literature reporting 26 UC patients with CMV
infection, colectomy and death of the 20
untreated patients were reported in 67% and
33% of cases, respectively [38]

35. Influence of CMV infection on UC
progression
• Corticodependance [55], increased hospitalisation
rate [42], higher endoscopic activity [56] with large
ulcers [29,30] and severity of UC [17,23,26] were also
associated to CMV infection in these patients.

36. CMV reactivation: In UC Patients
( A risk factor Steroid-refractory disease )
• Only one prospective observational study
analysed predictive factors of resistance to
immunosuppressive therapy in 42 consecutive
patients hospitalised for moderate to severe UC
and treated with steroids. After determination of
CMV DNA load in inflamed tissue by Q-PCR at
inclusion, 16 patients were found positive.

37. CMV reactivation: In UC Patients
( A risk factor Steroid-refractory disease )
• By multivariate analysis, the only factor
associated with the presence of a high viral load
in intestinal tissue (>250 copies/mg) was the
resistance to IV steroids or to three lines of
treatment [25].
• Similarly, Patients with colonic CMV infection
and not previously treated with steroids were
predicted to be refractory to steroid treatment [42].
• Kim et al.

38. Prevalence of intestinal tissue Cytomegalovirus (CMV)
infection in steroid-refractory patients and frequency of
Colectomy.
Reference(s
)/publicatio
n year
Type of study Subj
ects
Mode of
CMV
detection
CMV
positi
ve
Colectomy:
no. (%)
CMV+ CMV−
[21]/2004 Retrospective 40 Immunohist
ochemistry
10 6 (60) –
[18]/2007 Prospective 30 Qualitative
PCR
17 – –
[10]/2008 Prospective 19 Immunohist
ochemistry
6 3 (50) 3 (23.1)
[20]/2011 Retrospective 64 Qualitative
PCR
31 4 (12.9) 2 (6.5)
[25]/2011 Prospective 32 Quantitative
PCR
16 – –
[67]/2012 Prospective 21 Immunohist
ochemistry
14 – –

39. Treatment of CMV infection with in UC
Patients
• In IBD patients, Ganciclovir administration is
indicated for primary CMV infection associated with
exacerbation of colitis. [62,63].
• Case reports as well as punctual experimental
studies have reported the clinical improvement and
reduction of colectomy when patients received
Ganciclovir (or Foscavir exceptionally) in cases of
CMV reactivation.
• CMV colitis is usually treated with Ganciclovir. This
drug has a poor bioavailability when given orally and
thus is given intravenously at least at the beginning
of treatment.

40. Treatment of CMV infection with in UC
Patients

41. Treatment of CMV infection with in UC
Patients
Kim et al. reported :
• A prospective, multicenter study including 21
patients presenting an active UC with a Mayo
score between 8 and 12, and treated with
intravenous steroids.

42. Treatment of CMV infection with in UC
Patients
• The authors defined a strict study protocol for
reducing the heterogeneity of treatment; steroid
refractory disease was defined as the absence
of clinical improvement after 7–14 days of
intravenous steroid administration, regardless of
the CMV infection status.

43. Treatment of CMV infection with in UC
Patients
• 14 of the 21 subjects responded to this case
definition and were treated by intravenous
Ganciclovir for 2 or 3 weeks; 11 of them
improved under antiviral therapy and only 3
needed a colectomy [67].

44. Fig.Suggested algorithm for the management of cytomegalovirus infection in inflammatory bowel diseases. The indicative thresholds
of viral load proposed for patients with ulcerative colitis have been validated in Ref. [25].
CMV: cytomegalovirus; DNA: deoxyribonucleic acid; TNF: Tumour Necrosis Factor.
Treatment Algorithm CMV in UC

45. Treatment Algorithm CMV in UC
Steroid refractory colitis
CMV Colitis
Treat the ulcerative colitis
CMV Infection CMV Disease
CMV antigens or
antibodies in serum
CMV detected
in biopsies
Clinical symptoms
+ Tissue damage
Treat CMV with
Anti-viral
Treat CMV with
Anti-viral

46. Conclusions
• Recent immunological investigations cast a new
light on the complex relationships between CMV
and IBD.
• The treatment of CMV infection by potent
antiviral drugs are able to restore the sensitivity
to immunosuppressive drugs and even to avoid
colectomy.

47. Conclusions
• The quantification of CMV DNA in intestinal
tissue appears as an excellent tool for
monitoring CMV infection in UC patients.
• Large randomised clinical trials are now needed
to demonstrate the benefit for UC patients with
steroid-refractory disease to receive a
pre-emptive antiviral treatment in case of CMV
reactivation.

51. Overview
1. “Having CMV” is not the same as CMV disease.
2. The presence of CMV may not require therapy
for CMV in UC.
3. No evidence that biologic therapy make CMV
colitis worse.
4. If biologics made CMV worse and CMV is often
a bystander, we would expect to see much
worse CMV colectomy rates or refractory colitis
(and we don’t)

52. Epidemiology of CMV in
Inflammatory Bowel Disease
• Prevalence of CMV infection is about 70% (similar to the
general population).
• Prevalence of CMV disease per test modality in severe colitis:
– Serological tests+rectal biopsies  around 20%
– Antigenemia  34%
– Histology +immunohistochemistry  3%
• Prevalence of CMV disease per test modality in severe
steroid-resistant colitis:
– Histology 0.5%
– Histology + antigenemia 20-40%
– Blood PCR  60%
– Colon PCR 38%

53. Prevalence of CMV in Biopsies of
Steroid-Refractory Colitis
Study H&E IHC PCR
Cottone et al, 2001 36% 36% -
Domenech et al,
2008
26% 32% 42%
Kambham et al,
2004
5% 25% -
Minami et al, 2007 17% - -
Yoshino et al, 2007 3% 6% 57%
H&E; Hematoxylin & eosin; IHC, immunohistochemistry; PCR, Polymerase chain reaction.
Adapted from Lawlor G, Moss AC. Inflamm Bowel
Dis. 2010;16:1620-1627.

54. 2. CMV is Frequently Reactivated and
Disappears Without Antiviral Agents in
UC Patients
Methods:
•Prospectively followed 69 moderate-severe (steroid-
refractory) UC patients with positive CMV IgG or IgM for
8 wks. (on steroids and immunosuppressants)
Results:
•~79% of patients had reactivation of CMV (antigenemia
and PCR).
•Reactivation resolved in all patients at 10 wks
WITHOUT THERAPY
•Outcome: (+) CMV and (-) CMV had similar remission
and colectomy rates.

55. 3. No evidence that biologics (anti-TNF)
make CMV colitis worse
(In fact, it’s the opposite)

56. Infliximab Does Not Reactivate CMV
• Active CMV infection DOES NOT progress to
disease following infliximab therapy in UC or CD.
• Active Crohn’s disease and CMV + serology
(IgG) (n=42) developed a CMV + PCR when
treated with infliximab in 14 weeks.2

57. 4. If biologics made CMV worse
and CMV is often a “bystander,” we
would expect to see much worse
CMV in colectomies or in refractory
colitis
(and we don’t)

58. CMV findings in colectomy specimens
Italy1
: UC proctocolectomy cohort of 77 patients
•21% (16) were CMV (+) on surgical specimen
•15/55 CMV(+) in steroid-refractory UC
•NONE of the patients required antiviral therapy
during follow-up
•Japan2
: UC proctocolectomy cohort of 126
patients
•Only 11% (14) were CMV (+) on
immunohistochemistry staining
1. Maconi G, et al. Dig Liver Dis 2005;37(6):418-23.
2. Kojima T, et al. Scand J Gastroenterol 2006;41(6):706-11.

59. CMV in the Colon is Not Associated
with a Higher Disease Activity or
Colectomy Rate
(+) CMV-DNA
(n=17)
(-) CMV-DNA
(n=13)
P-Value
DAI-Score 9.8 ± 1.2 9.2 ± 1.6 0.206
Extent of disease
- Proctitis 0 (0) 1 (7.7) 0.245
- Left-sided 4 (23.5) 3 (23.1) 0.977
- Pancolitis 13 (76.5) 9 (69.2) 0.657
Endscopic DAI
score
2.4 ± 0.7 2.1 ± 0.6 0.194
Matts grade 3.1 ± 0.8 2.9 ± 0.8 0.687
Endoscopic index
of Rachmilewitz
9.5 ±2.4 8.8 ± 2.4 0.444
Colectomy rate 5 (29.4) 1(7.7) 0.196
DAI= Disease Activity Index Not Significant Yoshino T et al. Inflamm Bowel Dis 2007;13(12)1516-
21.

60. Conclusions
1. “Having CMV” is not the same as CMV disease.
2. Whether CMV is present or not doesn’t change the
need for CMV therapy in UC.
3. There is no evidence that biologics (anti-TNF) make
CMV colitis worse.
4. If biologics made CMV worse and CMV is often a
bystander, we would expect to see much worse CMV
colectomy rates or refractory colitis (and we don’t).
Therefore:
We must treat the colitis and distinguish CMV
infection from CMV disease.

62. • Widmann et al. suggest
• a dose-dependent effect of steroids on
suppression of CMV specific
• T cell function [43]. Another study
confirmed an increase in
• the