The Pediatric Infectious Disease Journal Publish Ahead of Print

DOI: 10.1097/INF.0000000000001724

CMV Infection in Pediatric Severe Ulcerative Colitis - A Multicenter Study from the

Pediatric IBD Porto Group of ESPGHAN

Shlomi Cohen1, Christine Martinez-Vinson2, Marina Aloi 3, Dan Turner4, Amit Assa5, Lissy de

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Ridder6, Victorien M. Wolters7, Tim de Meij8, Patrizia Alvisi9, Jiri Bronsky10, and Uri

Kopylov11, on behalf of the Pediatric IBD Porto Group of ESPGHAN

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Correspondence: Shlomi Cohen, MD, Pediatric Gastroenterology Unit, "Dana-Dwek"

Children's Hospital, Tel Aviv Medical Center, 6 Weizmann Street, Tel Aviv, Israel 6423906

Phone:+972-3-6974515; Fax:+ 972-3-6974181, Email: shlomico@tlvmc.gov.il

Abbreviated title - CMV Infection in Pediatric Severe Ulcerative Colitis

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Running head – CMV in Ulcerative Colitis
1
Pediatric Gastroenterology Unit of "Dana-Dwek" Children's Hospital, Tel Aviv Sourasky Medical

Center, affiliated to Sackler Faculty of Medicine4, Tel Aviv University, Tel Aviv, Israel.
2
Service de Gastroentérologie Pédiatrique, Assistance publique-Hôpitaux de Paris, Hôpital Robert
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Debré, Paris, France.

3
Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of
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Rome, Rome, Italy.

4
Institute of Paediatric Gastroenterology, Shaare Zedek Medical Center, Hebrew University of
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Jerusalem, Israel.
5
Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center,

Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

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 6
Pediatric Gastroenterology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The

Netherlands
7
Department of Pediatric Gastroenterology, University Medical Center Utrecht, Wilhelmina

Children's Hospital, Utrecht, The Netherlands

8
Department of Pediatric Gastroenterology, Vrije Universiteit Medical Center, Amsterdam, the

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Netherlands.
9
GI Unit, 'Maggiore Hospital', Bologna, Italy.

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10
Department of Pediatrics, University Hospital Motol, Prague, Czech Republic.
11
Department of Gastroenterology, Chaim Sheba Medical Center, Sackler School of Medicine,

Tel-Aviv University, Tel-Aviv, Israel.

Disclosures:
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UK- research support- Takeda, Jannsen, Medtronic ; Advisor fees- Jannsen, CTS ; Lecture fees-

Abbvie, Jannsen, Takeda

SC, UK- initiated the study and wrote the manuscript

All other coauthors collected the data and critically revised the manuscript
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Conflicts of Interest and Source of Funding – None declared

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 Abstract

Background: Data on the clinical course and outcomes of pediatric patients with

cytomegalovirus (CMV) infection complicating acute severe ulcerative colitis (ASC) are very

limited. The aim of our study was to compare outcomes of children with ASC who were CMV-

positive or CMV-negative.

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Methods: This was a multicenter retrospective case-controlled study, from centers affiliated with

the Pediatric IBD Porto Group of ESPGHAN. We included CMV –positive children hospitalized

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for ASC and compared their colectomy rate during hospitalization and up to 1 year thereafter,

matched with CMV-negative controls.

Results: A total of 56 children were included; 15 CMV-positive and 41 CMV-negative. More

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CMV-positive patients were resistant to intravenous corticosteroids as compare to CMV negative

(93% and 56% respectively, p=0.009). Fourteen of the CMV-positive children (93%) were

treated with ganciclovir (5/14 (36%) with 5mg/kg and 9/14 (64%) with 10mg/kg). During

hospitalization, 3 (20%) CMV-positive and 3 (7.8%) CMV-negative patients required colectomy

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(p=0.17). By 12 months, 5 (33%) and 5 (13%) CMV-positive and negative patients required

colectomy, respectively (p=0.049); the significance was not retained on multivariate analysis.
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Conclusions: A higher prevalence of CMV-positivity was found in pediatric UC patients who

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required colectomy within 12 months of hospitalization for ASC. Further studies are needed to

clarify the impact of CMV infection on the outcome of acute severe colitis in pediatric patients.

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 Introduction:

Cytomegalovirus virus (CMV) is a member of the herpes viridae family. The seroprevalence of

CMV varies between 40-100% and is greatly influenced by age and geographic distribution1, 2. In

young and healthy adults, CMV usually manifests as a mild and self-limited disease. However,

in immunocompromised patients such as those receiving immunosuppressive medications after

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bone marrow or solid organ transplantation or for other indications such as chronic inflammatory

conditions, CMV may result in a severe systemic disease or end-organ damage (such as

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pneumonitis, hepatitis, and colitis)3. In adults, the role of colonic CMV infection in the

exacerbations of ulcerative colitis (UC) has been discussed for over 20 years; nevertheless, the

significance and impact on the course of acute ulcerative colitis is still unclear. Although CMV

may be frequently detected in patients with an exacerbation of UC, especially in patients with
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severe disease4, it is unclear whether CMV reactivation is the cause of the exacerbation or rather

an another surrogate marker of severe disease, as the virus is inherently trophic to inflamed

tissue4. In 2011, the consensus statement for managing acute severe ulcerative colitis in children

from ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory
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Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric

Gastroenterology, Hepatology, and Nutrition) and ESPGHAN concluded that children with
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steroid-resistant disease should undergo a sigmoidoscopic examination for biopsy to exclude

CMV infection5. Studies aiming to evaluate the impact of CMV infection on the outcome of
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acute severe ulcerative colitis (ASC) arrived at conflicting results6, 7 8 9, 10. In addition,

disappearance of CMV from colonic biopsies following the resolution of the exacerbation

without any specific antiviral therapy was reported11. In contrast to the abundance of literature in

adults, only a handful of pediatric cases of CMV infection in ASC were published to date 12-15.

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 Importantly, no comparative studies are available in pediatrics. We therefore aimed to compare

the course and outcome of pediatric UC patients with or without concomitant colonic CMV.

Methods

This is a multicenter retrospective case-controlled study, from centers in Europe and Israel

affiliated with the Pediatric IBD Porto Group of ESPGHAN. We included children 0-18 years

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who were admitted for ASC during the years 2010-2016. All included children underwent

sigmoidoscopy/colonoscopy with histological assessment for CMV presence in the colonic tissue

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by hematoxylin eosin (HE) and/or by immunohistochemistry (IHC). We compared the clinical

and demographic characteristics of CMV-positive and CMV-negative patients. Each center

selected 2 CMV negative for any CMV positive patient, sex and age matched. CMV positivity

was defined histologically as positive HE/IHC staining on colonic biopsy. The index date for
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matching the patients was the date of colonoscopy/sigmoidoscopy. Clinical severity was

established using the pediatric ulcerative colitis activity index (PUCAI)16. Clinical remission was

defined as PUCAI < 10, mild disease as PUCAI 10 -34, moderate as PUCAI 35- 64, and severe

disease as PUCA ≥ 65 points17. Corticosteroid resistant was defined by PUCAI >45 on day 3-5
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of hospitalization. Previous anti-TNF exposure was defined by any exposure to any anti-TNF

medication in the any time period prior to index hospitalization. The main outcome was the risk
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of colectomy during the index hospitalization. Secondary outcomes included colectomy by 12

months of the initial admission and risk of recurrence following initial admission.
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Recurrence was defined as clinical exacerbation coupled with evidence of CMV presence in the

colonic tissue, while response to antiviral treatment was evaluated by change in pediatric

ulcerative colitis activity index (PUCAI) in all centers. The study was performed according to

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 the instructions of the institutional ethic review boards of the participating centers (in case

required).

Statistical analysis

Univariate analysis was used to determine correlation between CMV status and other

demographic and clinical parameters with the risk of colectomy, and to compare the clinical and

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demographic characteristic of CMV-positive and negative patients.

Continuous variables that follow a normal distribution are reported as means and standard

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deviations and compared using the two sample Student’s t-test. Continuous variables that do not

follow a normal distribution are reported by medians and interquartile range and compared using

the two sample Wilcoxon rank sum test. Categorical variables were reported by their relative

frequencies and compared by the Chi-Square test or Fisher exact test. A multivariate binary
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logistic regression model was constructed to identify the independent predictors of colectomy at

both time-points. Variables with significance level <0.1 in the univariate analysis were included

in the model. A p value of 0.05 was considered significant. The analysis was performed with

SPSS version 20.0 (SPSS Inc, Armonk, NY, USA).

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Results:

A total of 56 patients from 10 centers (Israel, Italy, France, The Netherlands and Czech
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Republic) were included. The study cohort included 23 (41%) males/ 33 (59%) females, with a

median age of 11.5 (interquartile range (IQR)- 7-14) years. Fifteen patients were CMV-positive
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and 41 CMV-negative (Table 1).

CMV diagnosis and treatment

Colonic CMV results were available in each center - 8 (IQR- 5-10) days after endoscopy. On

index date (date of colonoscopy/sigmoidoscopy), the treatment included intravenous

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 corticosteroids in 46 (82%), oral corticosteroids in 9 (16%), infliximab in 18 (32%) and

adalimumab in 3 (5%) patients, respectively (Table 1).

Colonic CMV diagnosis was determined by HE stain or IHC in 7 (47%) and 8 (53%) patients,

respectively; no patient was diagnosed as having CMV solely based on PCR (which is

considered too sensitive in the absence of histological confirmation) or serology. CMV serology

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results were available in 9/15 patients; 5/9 were IgG positive and none IgM positive. CMV

viremia was demonstrated in 10/15 (66%); quantitative results were available in 5/10 patients

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(median viral load- 2800 (106-12717) copies/ml).

After the diagnosis of CMV infection, 14/15 patients were started on ganciclovir (5 mg/kg- 5/14

(36%) or 10 mg/kg – 9/14 (64%). One patient did not receive antiviral treatment due to severe

disease that necessitated urgent colectomy. The median duration of intravenous treatment was 13
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(IQR -7-21) days. Five patients were switched to oral valganciclovir. Corticosteroids were

gradually tapered in all patients. Four of seven CMV-positive patients received an additional

dose of infliximab after CMV diagnosis (2 patients – 5mg/kg; 2 patients -10 mg/kg).

Patient outcomes
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During hospitalization, 6 patients required colectomy (3/15 (20%)- CMV-positive, and 3/41

(7.3%)- CMV-negative, p=0.17). By 3 months of follow-up, 1 additional CMV-positive patient

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and one CMV-negative (4/14 (29%) vs 4/41 (9.8%), p=0.085) required colectomy (1 patient was

lost to follow-up). By 12 months, 5 (33%) and 5 (13%) CMV-positive and negative patients
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required colectomy, respectively (p=0.049). There was a higher proportion of intravenous

corticosteroid resistant patients in the CMV-positive group (14/15 (93%) vs 23/41 (56%),

p=0.009). The median duration of hospitalization was significantly longer in CMV-positive (21

days (IQR 14-21)) than negative (13 days (4-14)) patients (p=0.001).

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 Predictors of colectomy

On univariate analysis, previous anti-TNF exposure ( 5/6 (83%) vs 19/50 (38%) p=0.037) and

median PUCAI (85 (IQR78.5-85) vs 72.5 (IQR62.5-82) p=0.021) score on index date were

significantly associated with the risk of colectomy during hospitalization. CMV positive status (

5/10 (50%) vs 9/45 (20%) p=0.049), male gender (7/10 (70%) vs 16/45 (36%) p=0.046),

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previous anti-TNF exposure ( 9/10 (90%) vs 17/45 (38%) p=0.01) and median index PUCAI (85

(IQR 75.5-85) vs 70 (IQR 65-80) p=0.019) were associated with colectomy at 12 months (Table

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2). The multivariate model included CMV positivity status, anti- TNF exposure and PUCAI on

index date as predictors of colectomy during hospitalization and after 1 year. On multivariate

analysis, none retained statistical significance for colectomy at any time point. Due to a small

sample size and in order to avoid overfitting, we also performed the analysis with 2 out of 3
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predictors in all possible variations: however still none retained statistical significance. In the

CMV-positive group, neither ganciclovir dose nor switch to valgancyclovir were significantly

associated with the risk of colectomy (both p>0.2).

In order to determine the role of CMV infection in steroid resistant patient we also performed a
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sensitivity analysis limited to these 37 (14 CMV-positive and 23 CMV-negative patients)

children who were corticosteroid resistant. None of the variables were significantly associated
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with the risk of colectomy during hospitalization. For colectomy at 12 months, both male gender

( 5/8 (62.5%) vs 7/28 (25%) p=0.047) and past anti-TNF exposure ( 6/8 (75%) vs 9/8 (32.1%)
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,p=0.03) were significantly associated with the risk of colectomy. CMV positive status was not

associated with the risk of colectomy at any time point in this subgroup. The results did not

change when patients with moderate disease or left-sided colitis (4 patients) were excluded (data

not shown).

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 CMV colitis recurrence

CMV recurrence was documented in 3/56 patients (5.3%) at 3, 10 and 12 months since index

hospitalization. All patients were retreated with ganciclovir, one patient (1.7%) required

colectomy during the subsequent hospitalization.

Discussion

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This multicenter, retrospective, case control study on CMV infection in pediatric acute severe

ulcerative colitis patients with a 12 months follow-up demonstrated that CMV infection was

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significantly more prevalent in patients who required colectomy at 1 year; a trend for a higher

risk of colectomy during hospitalization was observed as well. The results did not sustain

statistical significance multivariate analysis, possibly due to a limited sample size.

In our study 5/15(33%) CMV positive ASC children had colectomy within 12 months of follow-
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up from index date. As compared to adult series, colectomy rates among CMV positive ASC

patients are similar to our findings in the pediatric age group (23-30% )2 . Previous reports have

shown that CMV is frequently detected in the colonic tissue of UC patients for example in

surgical specimens of patients referred for colectomy due to severe colitis18. Corticosteroid
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treatment is associated with a significantly higher risk of CMV reactivation; however there is no

evidence to indicate that other anti-inflammatory medications such as immunomodulators and

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anti-TNFs pose a similar risk1, 19, 20. Nevertheless, a causal relationship between CMV

reactivation and UC exacerbation is not established, and the impact of CMV infection on
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exacerbation of UC remains controversial4. While some studies in adult patients suggest that the

risk of colectomy is higher in CMV-positive patients, others arrived at different conclusions 1-3, 8,
21-23
. All available studies are retrospective and plagued by significant heterogeneity and

inclusion bias. A recent meta-analysis demonstrated a higher risk of colectomy for patients

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 treated with gancyclovir as compared to CMV-negative patients that did not receive antiviral

treatment2.

A different meta-analysis demonstrated a significantly increased risk in CMV-positive patients

that was confined to corticosteroid resistant patients only21. In our study CMV positive status

was not associated with the risk of colectomy in steroid resistant patient at any time point due to

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probably relatively small CMV-positive cohort.

The concern of CMV infection in patients with ASC is the impact on clinical outcomes4. In our

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study, although there were no differences during hospitalization (p=0.17 in the univariate

analysis) more CMV positive children required colectomy after 12 months from index date

(p=0.049 in the univariate analysis). The fact that CMV positivity only showed impact during

follow-up (after CMV therapy), favors the possibility that CMV is possibly a surrogate marker of
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severe colitis. In both CMV-positive and negative children, index day PUCAI and history of

anti-TNF treatment were associated with a higher risk of colectomy on univariate analysis at any

time point. On the other hand, CMV -positive patients had a significantly higher risk of being

resistant to intravenous corticosteroid treatment. Importantly, even though the duration of

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hospitalization was significantly higher is CMV-positive patients, this is most likely the result of

the required duration of intravenous ganciclovir treatment.

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Several diagnostic techniques for CMV infection in ulcerative colitis patients have been

described in the literature including viral culture, serology, blood CMV DNA and tissue CMV
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status by hematoxylin eosin staining, immunohistochemistry as well as PCR in colonic biopsy2.

Significant variability in the definition of CMV infection limits our understanding of its

influence on the outcome of UC exacerbation. In a recent systematic review devoted to

definitions of CMV infection in IBD, 21 different definitions were found in the current

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 literature3. The prevalence of CMV colitis depends heavily on the definition applied4. In

compliance with the current recommendations by the consensus for managing ASC in children

from ECCO, ESPGHAN and the Porto IBD working 5, only patients diagnosed by IHC or HE

(and not colonic PCR as a sole finding) were considered CMV-positive in our study.

As prospective studies to evaluate the effect of antiviral treatment in CMV-positive UC are

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lacking, current IBD guidelines rely on the data derived from other clinical scenarios such as

post solid organ or bone marrow transplantation. Current ECCO guidelines recommend

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intravenous gancyclovir 5mg/kg bid for 2-3 weeks with a switch to valgancyclovir for up to 3

months; an earlier switch is possible in patients with a rapid and durable response to the initial

intravenous therapy24. No written guidelines or protocol exist regarding treatment of CMV

colitis in pediatric ASC patients. In our cohort, all CMV-positive patients (with the exclusion of
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one patient who underwent colectomy before treatment for CMV) received ganciclovir; two

different dosing schemes were employed and only a small subgroup of the patients was switched

to oral treatment. No significant differences in the outcomes were detected between different

treatment strategies, however the study was not powered to detect such differences.
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This study has several limitations. Primarily, this study design is retrospective and multicenter,

and thus CMV detection methods and treatment strategies were not standardized. Moreover,
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despite the multicenter nature of our study, the CMV-positive cohort was relatively small. This

may at least partially account for the lack of clear statistical significance for the effect of CMV
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infection in the multivariate modeling. Thus, future large prospective studies are needed to fully

clarify the clinical impact of CMV colitis on the outcome of pediatric CMV patients.

Despite the aforementioned limitations, this is the largest study to address the effect of CMV on

UC exacerbation in children and the only comparative one. In contrast to the abundant, albeit

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 contradictory, literature addressing CMV reactivation in adult UC, the pediatric literature is very

limited and comprised mostly of case reports, the largest describing 6 patients 12-15 .

In conclusion, this case-controlled pediatric study suggests that CMV colitis is more frequent in

children with acute severe colitis who require colectomy at 12 months from the initial

hospitalization, but we could not determine whether the infection is the cause for the poor

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outcome or merely a reflection of a more severe disease. Nonetheless, children with steroid-

resistant ASC disease should undergo a sigmoidoscopic examination for biopsy to exclude CMV

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infection as recommended by the ECCO, ESPGHAN and the Porto IBD working group and

treated accordingly until more data are available to better understand the role of CMV in

pediatric ASC.
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 legends:

Figure 1 – Colectomy rate at different time points

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 Table 1- Clinical and demographic characteristics of the included patients

CMV-positive CMV- Total P

N=15(%) negative N=56(%)
N=41(%)
Age on admission, 11 (5-14) 12(10-14) 11.5 (7- 0.44
years (median +IQR) 14)
Gender female 10 (66.6) 23 (56.1) 33 (58.9) 0.51
male 5 (33.3) 18 (43.9) 23 (41.1)
Disease extent left sided 0 (0) 4 (9.8) 4 (7.1) 0.21

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pancolitis 15 (100) 37 (90.2) 52 (92.9)
Disease severity upon moderate 0 (0) 4 (9.8) 4 (7.1) 0.21
admission* severe 15 (100) 37 (90.2) 52 (92.9)

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Previous anti-TNF 8 (53.3) 16 (39) 24 (42.9) 0.39
therapy
Past thiopurine therapy 10 (66.7) 22 (53.7) 32 (57.1) 0.38
Corticosteroid therapy IV 12 (80) 34 (82.9) 46 (82.1) 0.596
on index date oral 3 (20) 6 (14.6) 9 (16.1) 0.8
Treatment at index Infliximab 7 (46.7) 11 (26.8) 18 (32.1) 0.19
date** Adalimumab 0 (0) 3 (7.3) 3 (5.2) 0.545
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IV corticosteroid 14 (93.3%) 23 (56.1%) 37 (66.1) 0.009
resistance on index
date**
CMV- cytomegalovirus; IV- intravenous; TNF- tumor necrosis factor ; HE- hematoxylin eosin;
IHC- immunohistochemistry; PCR- polymerase chain reaction;
* Disease severity - PUCAI 35- 64 moderate, and severe disease as PUCA ≥ 65 points (PUCAI-
Pediatric Ulcerative Colitis Activity Index)
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** Index date - The day of colonoscopy/sigmoidoscopy

** Corticosteroid resistant was defined by PUCAI >45 on day 3-5 of hospitalization
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Table 2- Predictors of colectomy during hospitalization and at 12 months

Colectomy during hospitalization Colectomy at 12 months

p p

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No n=50 Yes n=6 p multivariate) No n=45 Yes n=10 p multivariate)
CMV status Positive 16 (32%) 3 (50%) 0.17 9 (20%) 5 (50%) 0.049 0.24
Negative 34 (68%) 3 (50%) 36 (80%) 5 (50%)
Gender Male 19 (38%) 4 (67%) 0.17 16 (36%) 7 (70%) 0.046
Female 31 (62%) 2 (33%) 29 (65%) 3 (30%)
Disease Left sided 4 (8%) 0 (0.0%) 0.47 4 (8.9%) 0 (0.0%) 0.32
extent Extensive 46 (92%) 6 (12%) 41 (91%) 10 (100%)
Past anti-

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TNF 19 (38%) 5 (83%) 0.037 0.22 17 (38%) 9 (90%) 0.01 0.53
treatment
PUCAI score 72.5 (62.5- 85 (78.5- 85 (75.5-
0.021 0.19 70 (65-80) 0.019 0.18
at admission (median (IQR)) 82) 85) 85)
Disease Moderate 4 (8%) 0 (0.0%) 0.47 4 (8.9.0%) 0 (0.0%) 0.32
activity Severe 46 (92%) 6 (100%) 41 (41%) 10 (100%)
Treatment at Corticosteroids
41 (82%) 5 (83%) 0.35 37 (82%) 8 (80%) 0.28
index date IV
15 (30%) 3(50%) 0.51 12 (27%) 5 (50%) 0.32
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Infliximab
IV
corticosteroid 32 (64%) 5(83%) 0.37 28(62%) 8 (80%) 0.46
resistant

CMV- cytomegalovirus; IV- intravenous; TNF- tumor necrosis factor ; HE- hematoxylin eosin; IHC- immunohistochemistry; PCR-
C
polymerase chain reaction; PUCAI- Pediatric Ulcerative Colitis Activity Index,; IQR- interquartile range

18

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 Figure 1

D
TE
EP
C
C
A

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Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.