Disease-specific alterations in the enteric virome in inflammatory bowel disease.

Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point. DESIGN: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab. CONCLUSION: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.

Gut mucosal virome alterations in ulcerative colitis.

OBJECTIVE: The pathogenesis of UC relates to gut microbiota dysbiosis. We postulate that alterations in the viral community populating the intestinal mucosa play an important role in UC pathogenesis. This study aims to characterise the mucosal virome and their functions in health and UC. DESIGN: Deep metagenomics sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on the rectal mucosa of 167 subjects from three different geographical regions in China (UC=91; healthy controls=76). Virome and bacteriome alterations in UC mucosa were assessed and correlated with patient metadata. We applied partition around medoids clustering algorithm and classified mucosa viral communities into two clusters, referred to as mucosal virome metacommunities 1 and 2. RESULTS: In UC, there was an expansion of mucosa viruses, particularly Caudovirales bacteriophages, and a decrease in mucosa Caudovirales diversity, richness and evenness compared with healthy controls. Altered mucosal virome correlated with intestinal inflammation. Interindividual dissimilarity between mucosal viromes was higher in UC than controls. Escherichia phage and Enterobacteria phage were more abundant in the mucosa of UC than controls. Compared with metacommunity 1, metacommunity 2 was predominated by UC subjects and displayed a significant loss of various viral species. Patients with UC showed substantial abrogation of diverse viral functions, whereas multiple viral functions, particularly functions of bacteriophages associated with host bacteria fitness and pathogenicity, were markedly enriched in UC mucosa. Intensive transkingdom correlations between mucosa viruses and bacteria were significantly depleted in UC. CONCLUSION: We demonstrated for the first time that UC is characterised by substantial alterations of the mucosa virobiota with functional distortion. Enrichment of Caudovirales bacteriophages, increased phage/bacteria virulence functions and loss of viral-bacterial correlations in the UC mucosa highlight that mucosal virome may play an important role in UC pathogenesis.

Efficacy of antiviral treatment in cytomegalovirus detected ulcerative colitis: meta-analysis of available data.

Aim: This meta-analysis aimed to pool available data regarding the efficacy of ganciclovir treatment among cytomegalovirus-detected ulcerative colitis patients.Methods: We screened PubMed, Ovid, Web of Science and Cochrane databases for relevant studies, and four investigators independently evaluated the studies for eligibility. The primary outcome was surgical resection or death from ulcerative colitis. The data were then pooled via DerSimonian-Laird estimator and Mantel-Haenszel (MH) method, two points added for continuity correction and random-effects model fitted in the Bayesian framework. We first constructed a Bugs model with Student t-distribution as prior for between-study heterogeneity. The model was fitted by Gibbs sampler (JAGS) to produce a marginal posterior distribution.Results: Our screening identified 15 eligible studies for final data synthesis and combined data from 191 ganciclovir-treated and 166 non-treated patients. Effect estimates from the fixed-effects meta-analysis model did not encourage ganciclovir treatment (OR, 1.43; 95% CIs [0-95, 2.16]), with a negligible unaccounted heterogeneity (I2 = 0%). The Bayesian random-effects model generated high-density credible intervals, suggesting a high probability, that future studies will also not encourage ganciclovir treatment (mu, 1.028; 95% credible intervals [0.054, 2.238]; 80% credible intervals [0.401, 1.703]) which indicates that future studies will favor non-treatment of ulcerative colitis with ganciclovir.Conclusions: Data produced in this study do not encourage ganciclovir treatment for UC patients. However, studies included in this analysis were observational, and thus, inherited severe selection bias. We suggest randomized controlled studies be conducted to make firm recommendations in this context.

True cytomegalovirus colitis is a poor prognostic indicator in patients with ulcerative colitis flares: the 10-year experience of an academic referral inflammatory bowel disease center.

Background and aims: The impact of cytomegalovirus (CMV) colitis on long-term outcomes of ulcerative colitis (UC) flares remains controversial. Methods: A total of 257 UC patients with moderate-to-severe flares were observed for a mean follow-up of 41.2 months. CMV colitis was defined as histopathologic confirmation of CMV inclusions obtained from macroscopic endoscopic lesions in patients with UC flares. An independent gastrointestinal pathologist prospectively reviewed all specimens. A poor outcome was defined as any of hospitalization, colectomy or death during the follow-up period. Results: The prevalence of CMV colitis was 14% (36/257) over the 10-year study period (2007-2016). When compared to the controls, patients with CMV colitis were characterized by older age, higher disease activity, endoscopic deep ulcerations and more frequent use of immunosuppressive drugs (all p < .05). In total, 57 outcome events (50 hospitalizations, seven colectomies) were observed among the study population (44.7% in patients with CMV colitis vs. 18.9% in controls). The cumulative probability of a poor outcome was significantly greater in the patients with CMV colitis than in the controls (log-rank test p < .001). In a multivariable analysis, CMV colitis remained as an independent predictor of a poor outcome (hazard ratio; 2.27; 95% confidence interval: 1.12-4.60). Despite a generally favorable response to antiviral therapy (79%), the risk of recurrent CMV colitis remained quite high (57%). Most of the recurrences developed within 8 months (75%). Conclusions: True CMV colitis is a poor prognostic indicator among patients with UC flares. An effective strategy for managing recurrent CMV colitis is urgently needed (KCT0003296).

Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study.

BACKGROUND: Hepatobiliary and pancreatic manifestations have been reported in patients with Crohn's disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used. METHODS: Data were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center. RESULTS: Our study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated. CONCLUSION: In our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.

Infectious proctitis: a necessary differential diagnosis in ulcerative colitis.

INTRODUCTION: In the last years, there was a rising in the incidence of sexually transmitted infections, including proctitis. Infectious proctitis (IP), mainly caused by agents like Neisseria gonorrhea and Chlamydia trachomatis, is an entity that should be considered when patients with suspected inflammatory bowel disease (IBD) are approached, mainly if they have risk factors such as anal intercourse. CLINICAL CASES/DISCUSSION: The symptoms of IP, like rectal blood, mucous discharge, and anorectal pain, may appear in other causes of proctitis, like IBD. Therefore, to establish the diagnosis, it is crucial to take a detailed history and perform a physical examination, with the diagnosis being supported by complementary tests such as rectosigmoidoscopy, histology, serology, and culture. Depending on the etiology, treatment of IP is based in antibiotics or antivirals, which may be empirically initiated. Co-infections, mainly those that are sexually transmitted, and HIV should be tested and sexual partners should be treated, accordingly. In this article, the authors report three cases of IP, referent to three different patients, and review the initial approach required in cases where there is a clinical and/or endoscopic suspicion of this pathology.

The detection of the cytomegalovirus DNA in the colonic mucosa of patients with ulcerative colitis is associated with increased long-term risk of proctocolectomy: results from an outpatient IBD clinic.

PURPOSE: Cytomegalovirus (CMV) infection has been found to be associated with a reactivation of ulcerative colitis (UC) and with an impaired response to medical therapy. In the past, only limited data were available on the long-term outcome for UC patients with positive tissue CMV-PCR in the colonic mucosa. METHODS: Between January 2010 and April 2015, we performed a qualitative PCR screening for CMV DNA in one biopsy from most actively inflamed rectal mucosa (tCMV-PCR). All tCMV-PCR-positive patients received 900 mg of valganciclovir b.i.d. for at least 15 days. We analyzed the association of the tCMV-PCR status with the time to steroid-free remission (SFR) and with the risk of proctocolectomy during the further course. RESULTS: One hundred eight consecutive patients (50 women, 58 men, median age 41 years, median UC duration 6 years) with active UC not responding to anti-inflammatory medication were analyzed. Eight of the 24 tCMV-PCR-positive patients (33.3%) compared to ten of the 84 tCMV-PCR-negative patients (11.9%) underwent proctocolectomy during a median follow-up of 52 months (p < 0.005). The median time from CMV diagnosis to colectomy was 501 days (median, interquartile range (IQR): 170, 902 days) in tCMV-PCR-positive and 958 days (IQR: 287, 1328 days) in tCMV-PCR-negative patients (p < 0.01). The median time to SFR was 126 days in tCMV-PCR-positive patients vs. 63 days in tCMV-PCR-negative patients (p < 0.01). CONCLUSIONS: The detection of the CMV DNA in the colonic mucosa of patients with active UC is associated with a longer time to steroid-free UC remission and with an increased rate and earlier need of proctocolectomy.

Immunosuppression for inflammatory bowel disease does not influence Epstein-Barr viral load in the short-term.

INTRODUCTION: Immunomodulators and biologics are two of the main drugs used for the treatment of inflammatory bowel disease (IBD). Some of these agents have been associated with certain infections and lymphoproliferative disorders, including Epstein-Barr virus (EBV) infection. Our aim was to determine the influence of immunosuppression in the EBV viral load in patients with IBD. MATERIALS AND METHODS: We prospectively included naïve patients with IBD who were starting immunosuppressive therapy in four IBD Units. All patients were assessed at baseline and four months after starting immunosuppression for clinical disease activity, biomarkers, EBV serology (IgM VCA, IgG VCA and IgG EBNA) and viral load. RESULTS: Thirty-two patients were included. At baseline, all patients showed positive results for IgG VCA or IgG EBNA with undetectable EBV viral load. No patient showed detectable EBV viral load after starting the immunosuppressive therapy. CONCLUSION: Immunosuppression did not influence on EBV viral load in the short-term in naïve IBD patients.

A National Survey of the Prevalence and Impact of Cytomegalovirus Infection Among Hospitalized Patients With Ulcerative Colitis.

GOALS: To estimate the effect of cytomegalovirus (CMV) in patients with ulcerative colitis (UC), and compare these outcomes to patients with CMV without UC. BACKGROUND: The impact of CMV infection in UC is not well understood. STUDY: We analyzed records from the Nationwide Inpatient Sample (NIS) of patients with UC and CMV between 2006 and 2012. Differences in outcomes were determined between patients with UC and CMV and those with UC without CMV. Secondary analysis compared outcomes of patients with UC and CMV to patients with CMV alone. RESULTS: Patients with UC and CMV (n=145) had longer length of stay (16.31 vs. 5.52 d, P<0.0001), higher total charges ($111,835.50 vs. $39.895, P=0.001), and were less likely to be discharged home without services (50.0% vs. 81.83%, P<0.0001) compared with patients with UC without CMV (n=32,290). On regression analysis, CMV was significantly associated with higher total charges (P<0.01) and longer length of stay (P<0.01), but not for increased need for colorectal surgery. When comparing patients with UC and CMV to patients with CMV alone (n=14,960), patients with CMV alone had a higher Charlson Comorbidity Index and a trend toward higher in-hospital mortality. CONCLUSIONS: CMV infection in hospitalized patients with UC is associated with a longer length of stay, increased total charges, and fewer routine discharges, but not increased surgery or mortality. Patients with CMV alone had the worst outcomes of all groups suggesting that CMV in UC patients may not have the same negative impact as in other diseases.

Detection of cytomegalovirus by immunohistochemistry of colonic biopsies and quantitative blood polymerase chain reaction: evaluation of agreement in ulcerative colitis.

OBJECTIVES: Cytomegalovirus (CMV) often reactivates in ulcerative colitis (UC). In diagnostics, along with immunohistochemistry (IHC) of colonic biopsies, blood CMV polymerase chain reaction (PCR) is gaining increasing application. We aimed to assess agreement between the density of infected colonic cells by IHC and the viral load in the blood by PCR. MATERIAL AND METHODS: We retrospectively identified patients with active UC or indeterminate colitis in whom blood CMV PCR had been performed while biopsies had been taken simultaneously. The latter were re-evaluated and the numbers of IHC-positive cells per square millimetre counted. RESULTS: The analyses extended to 234 sample pairs, among which there were 184 cases (78.6% of the total) in which IHC was equal to 0. The median among the remaining 50 non-zero values for IHC was 1.7 cells/mm2. PCR was equal to 0 in 192 cases (82.1%), while the median among the remaining 42 non-zero values was 4995.3 IU/ml. The Spearman correlation coefficient was 0.43 (p < .001). The area under the curve (AUC) values did not differ significantly between different IHC cut-offs. The highest AUC of 0.753 was obtained while predicting if IHC would be above the 3rd quartile (>5.6 cells/mm2), where PCR > 0 had a sensitivity of 0.615 and a specificity of 0.846. CONCLUSIONS: In active CMV colitis, the specificity and negative predictive value of blood PCR are high, while the sensitivity grows with the intensity of colon infection. A highly positive result could justify the administration of antiviral treatment being brought forward in selected patients.

Cytomegalovirus colitis in hospitalized inflammatory bowel disease patients in Taiwan: a referral center study.

BACKGROUND: Colitis is exacerbated in patients with concurrent cytomegalovirus (CMV) infection and inflammatory bowel disease (IBD). We assessed the prevalence and clinical features of CMV colitis in hospitalized IBD patients. METHODS: A retrospective study reviewed the data from January 1, 1998 through December 31, 2013 compiled at the National Taiwan University Hospital. The CMV colitis patients' demographic data, clinical information, treatment regimens, pathologic findings, and outcome were analyzed. RESULTS: A total of 673 IBD patients were hospitalized during the study period. There were 312 patients diagnosed with Crohn's disease (CD) and 361 with ulcerative colitis (UC). CMV colitis was diagnosed as having positive inclusion bodies in colonic tissue. Six of the 312 CD patients (1.9%) and five of the 361 UC patients (1.4%) were diagnosed with CMV colitis. Compared to CD patients without CMV colitis, patients with CMV colitis were more often older (p < 0.005). Higher steroid usage was noted in the CMV positive group compared to age and gender matched CMV negative IBD patients (81.8% vs. 51.5%). Eight patients received ganciclovir treatment. Three patients who did not receive antiviral treatment had colitis flare-ups after the index admission. CONCLUSIONS: The prevalence of CMV colitis in hospitalized IBD inpatients was 1.6% in Taiwan. Two associated factors for CMV colitis in hospitalized IBD patients were that they were elderly in CD and were on higher doses of steroids. Routine histopathology studies and/or PCR for refractory colitis patients are suggested to diagnose CMV colitis. Once the diagnosis is made, antiviral treatment is recommended to decrease the colitis relapse rate.

Cytomegalovirus, inflammatory bowel disease, and anti-TNFα.

BACKGROUND AND PURPOSE: Anti-TNFα agents emerged in inflammatory bowel disease (IBD) as an effective option in situations that, otherwise, would be refractory to medical therapy. Cytomegalovirus infection may present with a high spectrum of manifestations and lead to high morbidity and mortality. However, its clinical significance in IBD course remains unknown and data on its association with anti-TNFα are limited. AIMS: This study aims to evaluate cytomegalovirus (CMV) infection/disease in patients with IBD treated with anti-TNFα; if possible, possible risk factors associated with CMV infection/disease in IBD patients under anti-TNFα as well as the influence of CMV infection/disease in IBD course would be determined. METHODS: During three consecutive years, all IBD patients starting infliximab in our department were included. Cytomegalovirus status before anti-TNFα was evaluated. Data regarding IBD, therapeutic and IBD course after infliximab, were recorded. CMV analysis was performed with polymerase chain reaction (PCR)-cytomegalovirus in peripheral blood and colonoscopy with biopsies (histopathology/immunohistochemistry). RESULTS: We included 29 patients: female-83%; Crohn's disease-51.8%, ulcerative colitis-44.8%, non-classified colitis-3.4%; 23 cytomegalovirus seropositive. Median follow-up: 19 months (3-36). During follow-up, 14 patients were under combination therapy with azathioprine and 5 did at least 1 cycle of corticosteroids. Twenty-one patients responded to infliximab. We registered 8 exacerbations of IBD. Four patients discontinued infliximab: none had CMV infection. We documented 1 case of intestinal cytomegalovirus infection-detected in biopsies performed per protocol in an asymptomatic UC patient, who responded to valganciclovir without infliximab discontinuation. CONCLUSIONS: Infliximab, with/without immunosuppression, does not confer an increased risk of (re)activation of cytomegalovirus. Cytomegalovirus was not responsible neither for significant morbidity nor mortality in IBD.

Diagnosis of Cytomegalovirus Infection during Exacerbation of Ulcerative Colitis.

BACKGROUND/AIMS: The role of cytomegalovirus (CMV) reactivation during exacerbations of ulcerative colitis (UC) is yet a matter of debate, and assessment of CMV infection in UC patients remains an ongoing challenge. We aimed to identify associated parameters and compare detection methods for CMV infection during UC exacerbation. METHODS: Clinical, pathological and virological parameters were retrospectively analyzed in all patients hospitalized in our institution for UC exacerbation between January 2009 and April 2015, who underwent full evaluation for CMV infection in colonic tissue by histopathology, immunohistochemistry (IHC) and CMV-PCR. RESULTS: Of 28 patients who underwent full examination for tissue CMV-infection, 13 (46.4%) were found to be positive for CMV. Tissue CMV-PCR was more sensitive for the detection of CMV infection than histopathology and IHC. CMV-positive patients had a statistically higher frequency of recent steroid treatment and fever, with higher mean partial Mayo scores and lower mean albumin levels. There were no significant differences between CMV-positive and CMV-negative patients in terms of age, severity of colitis and disease duration. In a multivariable model, only recent steroid treatment and fever were independently associated with colonic CMV infection. CONCLUSIONS: This study provides a clinical model to detect the presence of CMV infection in patients hospitalized with UC exacerbation, which could direct proper investigation and facilitate timely empirical therapy.

[Cytomegalovirus reactivation and steroid refractory are the independent risk factors for colonic surgery in ulcerative colitis].

OBJECTIVE: To explore the risk factors of surgery in patients with ulcerative colitis (UC). METHODS: Patients with UC, hospitalized from January 2005 to October 2012 were retrospectively enrolled in this study. Univariate and multivariate analyses were used to reveal the risk factors of colon surgery, including demographic features, clinical manifestations, laboratory examinations and medication. RESULTS: A total of 273 UC patients were enrolled in this study with 39 (14.3%) patients receiving colon surgery. Compared with the flare group, patients in surgery group 71.8% (28/39) had more proportion with severe disease (P=0.008), higher prevalence of active cytomegalovirus (CMV) infection [47.6% (10/21) vs 10.9% (11/101), P<0.001], higher ratio of steroid resistance [60.0% (15/25) vs 10.7% (18/168), P<0.001], more receiving cyclosporine A [28.2% (11/39) vs 7.3% (17/234), P<0.001], and lesser with 5-aminosalicylic acid [82.1% (32/39) vs 95.3% (223/234), P=0.007]. Based on multivariate logistic regression analyses, active CMV infection and steroid resistance were two independent risk factors of colon surgery in UC patients (P=0.006 and 0.030, OR=6.040 and 17.928). CONCLUSION: Active CMV infection and steroid resistance are independent risk factors of colon surgery in UC.

Prevalence of hepatitis-B viral markers in patients with inflammatory bowel disease in a hepatitis-B-endemic area: inadequate protective antibody levels in young patients.

BACKGROUND: There are few data regarding the prevalence of hepatitis-B virus (HBV) markers in inflammatory bowel disease (IBD) patients in Korea, which is a hepatitis-B-endemic area. The aim of this study was to assess the prevalence of HBV markers in IBD patients in comparison with controls. METHODS: We enrolled 513 IBD patients [241 Crohn's disease (CD) and 272 ulcerative colitis (UC)] whose hepatitis-B surface antigen and anti-HBs levels were evaluated. Anti-HBc was assayed in 357 patients. These markers were compared with those of 1020 sex-matched and age-matched controls. RESULTS: Prevalence of hepatitis-B surface antigen in IBD patients was 3.7% and there was no significant difference between groups (CD 4.1%, UC 3.3%, control 4.4%, P=0.713). The frequency of effective vaccination against HBV (positive anti-HBs, without anti-HBc) was lower in IBD patients less than 30 years old compared with the same-aged controls (CD 43.3%, UC 48.5%, control 61.9%, P=0.002), whereas there was no difference between groups in subjects more than 30 years old. One third of IBD patients were at risk of susceptibility to HBV infection (nonimmune), particularly those less than 30 years old, compared with controls of the same age (CD 43.3%, UC 36.4%, control 21%, P<0.001). In IBD patients, multivariate analysis identified that age less than 30 years was an independent risk factor for nonimmune status. CONCLUSIONS: IBD was not a risk factor for HBV infection even in endemic areas. However, many young IBD patients were susceptible to HBV infection. It is crucial to screen for HBV immunity and to implement a meticulous vaccination strategy for young Korean IBD patients.