Pro: In patients with both CMV and
steroid refractory ulcerative colitis, you
must treat the ulcerative colitis with
biologics, but you do not need to also
treat the CMV, because the CMV is an
innocent bystander
David T. Rubin, MD, FACG, AGAF, FACP
@IBDMD
Professor of Medicine
Co-Director, Inflammatory Bowel Disease Center
Interim Chief, Section of Gastroenterology, Hepatology and Nutrition
Innocent Bystander
Innocent bystander: a viewer, watcher, onlooker,
a guiltless witness of a crime.
http://en.wikipedia.org/wiki/Innocent_bystander accessed December 12, 2013
CASE: 18-year old with CMV and UC
• An 18 year old man was admitted
to the Billings Hospital of the
University of Chicago.
• 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.
CASE: 18-year old with CMV and UC
• Treatment with dextrose, electrolytes, penicillin, streptomycin
and hydrocortisone did not result in improvement. ACTH
treatment resulted in gradual improvement.
• However the patient deteriorated and necessitated surgery on
the 65th hospital day.
An 18-year old with CMV and UC
• Bx: cellular inclusions, typical of
cytomegalic inclusion disease
together with superficial
inflammation of the colonic
mucosa.
• Diagnosis: CMV + Ulcerative colitis
Powel RD, Warner NE, Levine RS, Kirsner J B. Am J Med. 1961;30:334-40.
“We are unable to say whether the primary
disease was UC or salivary gland virus (CMV)
infection resulting in a clinical picture simulating
UC.”
Powel RD, Warner NE, Levine RS, Kirsner J B. Am J Med. 1961;30:334-40.
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)
1. “Having CMV” is not the same as CMV disease
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.
Lawlor G, Moss AC. Inflamm Bowel Dis. 2010;16:1620-1627.
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.
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 steroidresistant colitis:
–
–
–
–
Histology 0.5%
Histology + antigenemia 20-40%
Blood PCR  60%
Colon PCR 38%
Garrido E et al. World J Gastroenterol. 2013; 19(1):17-25.
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.
1. Kornbluth A et al. Am J Gastroenterol. 2010;99:1371-1385.
2. Rahier JF et al. J Crohn’s Colitis. 2009;3:47-91.
Transplantation guidelines on Diagnosis of
CMV
• 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)
Camille KN et al. Transplantation Journal. 2013;96(4):333-60.
Prevalence of CMV in Biopsies of SteroidRefractory 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.
2. CMV is Frequently Reactivated and Disappears
Without Antiviral Agents in UC Patients
Methods:
• Prospectively followed 69 moderate-severe (steroidrefractory) 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.
Matsuoka K et al. Am J Gastroenterol. 2007;102:331-337.
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
9.8 ± 1.2
9.2 ± 1.6
0.206
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-Score
Extent of disease
- Proctitis
Not Significant
DAI= Disease Activity Index
Yoshino T et al. Inflamm Bowel Dis 2007;13(12)1516-21.
3. No evidence that biologics (anti-TNF) make CMV
colitis worse
(In fact, it’s the opposite)
Infliximab Does Not Reactivate CMV
• Active CMV infection DOES NOT progress to disease
following infliximab therapy in UC or CD. 1,2
• Active Crohn’s disease and CMV + serology (IgG)
(n=42) developed a CMV + PCR when treated with
infliximab in 14 weeks.2
1. D’Ovidio V et al. J Clin Virol. 2008;43(2):180-3.
2. Lavagna et al. Inflamm Bowel Dis. 2007;13:896-902.
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)
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 followup
• Japan2: UC proctocolectomy cohort of 126 patients
• Only 11% (14) were CMV (+) on immunohistochemistry
staining
1.
2.
Maconi G, et al. Dig Liver Dis 2005;37(6):418-23.
Kojima T, et al. Scand J Gastroenterol 2006;41(6):706-11.
Treatment Algorithm CMV in UC
Steroid refractory colitis
CMV antigens or
antibodies in serum
CMV detected
in biopsies
Clinical symptoms
+ Tissue damage
CMV Infection
CMV Colitis
CMV Disease
Treat CMV with
Anti-viral
Treat the ulcerative colitis
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.
Russell Cohen, MD
David Rubin, MD
Sushila Dalal, MD
Joel Pekow, MD
Stacy Kahn, MD
Barbara Kirschner, MD
Rajana Gokhale, MD
Eugene Chang, MD
John Kwon, MD, PhD
Bana Jabri, MD, PhD
Sonia Kupfer, MD
Jerrold Turner, MD, PhD
John Hart, MD
Shu- Yuan Xiao, MD, PhD
Michele Rubin, APN
Jennifer Labas, APN
Alana Wichmann, APN
Ashley Bochenek, APN
Roger Hurst, MD
Konstantin Umanskiy, MD
Mukta Krane, MD
Mustafa Hussain, MD
Vivek Prachand, MD
Arunas Gasparaitis, MD
Abraham Dachman, MD
Sarah Goeppinger
Ruben Colman, MD
Dylan Rodriquez
Administrator: Anna Gomberg
Britt Christensen, MD
Veena Nannegari, MD
Mary Ayers, RN
Linda Kulig, RN
Debbie James, RN
Vallary Armstrong-Jones, RN
Sharon Bogan-Bell, RN
Rose Arrieta, RN
Kristi Milam, RN
Tracy Shumard, RN
Lori Rowell, RD
Elizabeth Wall, RD