Marroon Thabane

Systematic review and meta-analysis: The incidence and prognosis of post-infectious irritable bowel syndrome.

Background  Individual studies suggest that post‐infectious irritable bowel syndrome is common, but symptoms gradually improve.

Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario

Background : Post‐infectious irritable bowel syndrome is a common clinical phenomenon of uncertain aetiology.

Genetic Risk Factors for Post-Infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis

BACKGROUND & AIMS Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS. METHODS We screened 79 functional variants of genes with products involved in serotoninergic pathways, intestinal epithelial barrier function, and innate immunity and performed fine mapping in regions of interest. We compared data from Walkerton residents who developed gastroenteritis and reported PI-IBS 2 to 3 years after the outbreak (n = 228, cases) with data from residents who developed gastroenteritis but did not develop PI-IBS (n = 581, controls). RESULTS Four variants were associated with PI-IBS, although the association was not significant after correction for the total number of single nucleotide polymorphisms. Two were located in TLR9, which encodes a pattern recognition receptor (rs352139, P545P; P = .0059 and rs5743836, -T1237C; P = .0250; r(2) < 0.14); 1 was in CDH1, which encodes a tight junction protein (rs16260, -C160A; P = .0352); and 1 was in IL6, which encodes a cytokine (rs1800795, -G174C; P = .0420). Denser mapping of these 3 regions revealed 1 novel association in IL6 (rs2069861; P = .0069) and 14 associations that could be accounted for by linkage disequilibrium with the 4 original variants. The TLR9, IL6, and CDH1 variants all persisted as independent risk factors for PI-IBS when controlling for previously identified clinical risk factors. CONCLUSION This is the first descriptive study to assess potential genetic determinants of PI-IBS. Genes that encode proteins involved in epithelial cell barrier function and the innate immune response to enteric bacteria are associated with development of IBS following acute gastroenteritis.

Eight year prognosis of postinfectious irritable bowel syndrome following waterborne bacterial dysentery

Background Although postinfectious irritable bowel syndrome (PI-IBS) is a well-recognised complication of acute gastroenteritis, its prognosis remains poorly defined. The natural history of PI-IBS was assessed among participants in the Walkerton Health Study (WHS), which has followed the long-term effects of a large outbreak of acute gastroenteritis related to municipal water contamination in May 2000. Methods WHS participants were invited to return for annual assessment at a research clinic. Adult residents of Walkerton at the time of the outbreak who enrolled in 2002/2003 and returned for assessment in 2008 were eligible for a PI-IBS study cohort if they had no prior history of IBS or inflammatory bowel disease. A modified Bowel Disease Questionnaire was used to diagnose IBS by Rome I criteria and to identify IBS subtypes. Results Of 4561 WHS participants, 2451 returned for their 8 year assessment and 1166 were eligible for the PI-IBS study cohort (688 females, mean age 46.2 years). The prevalence of IBS among 742 eligible subjects who suffered acute gastroenteritis during the outbreak declined from 28.3% after 2–3 years to 15.4% after 8 years, but remained significantly increased compared with controls who did not have acute gastroenteritis (OR 3.12; 95% CI 1.99 to 5.04). Independent risk factors for PI-IBS at 8 years included female gender, younger age, prior anxiety/depression, and fever or weight loss during the acute enteric illness. IBS subtypes were not stable over time. Conclusions Acute gastroenteritis can trigger IBS symptoms that persist for at least 8 years. Characteristics of the host and the acute enteric illness can predict the long-term risk of PI-IBS.

The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis.

PREMISE:It has been suggested that proton pump inhibitor (PPI)-related differences in Helicobacter pylori eradication rates are partly because of CYP2C19 polymorphisms and there have been conflicting data in this area. We conducted a meta-analysis to investigate the evidence relating CYP2C19 to first-line H. pylori eradication rates.METHODS:A search of the literature was conducted up to June 2005 using Medline, EMBase, and Cochrane Register of Controlled Trials (CENTRAL). Twenty-eight arms from 17 papers were extracted for omeprazole, lansoprazole, and rabeprazole, collectively. Review Manager 4.2.8 was used for analysis.RESULTS:When all eradication rates, regardless of PPI used, were combined there was no significant difference between poor metabolizers (PM) and heterozygous extensive metabolizers (HetEMs) (odds ratio [OR] = 1.35, 95% confidence interval [CI] 0.89–2.07, p = 0.15); however, there was a significant difference between HetEM and homozygous extensive metabolizers (HomEMs) (OR = 1.90, 95% CI 1.38–2.60, p < 0.0001). Significant heterogeneity was observed in a HomEM and PM comparison, hence additional subanalysis of individual PPIs revealed that dual and triple omeprazole therapies significantly favored higher H. pylori eradication rates in PM over HomEM (OR = 4.03, 95% CI 1.97–8.28, p = 0.0001), and also over HetEM (OR = 2.24, 95% CI 1.09–4.61, p = 0.03). Dual and triple rabeprazole and triple lansoprazole therapies did not show significantly different H. pylori eradication rates between PM and HomEM (OR = 1.04, 95% CI 0.44–2.46, p = 0.25) and (OR = 1.80, 95% CI 0.67–4.85, p = 0.93), respectively.CONCLUSIONS:The impact of CYP2C19 polymorphisms on H. pylori eradication rates in studied populations appears clinically relevant in patients prescribed omeprazole as a component of their dual- or triple-drug therapy, whereas regimens that include lansoprazole or rabeprazole are unaffected. The choice of PPI and/or dose rather than CYP2C19 genotyping could be a more practical approach to assure the highest H. pylori eradication rates in clinical settings.

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how

BackgroundSensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.DiscussionIn this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.SummaryWhen reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

An Outbreak of Acute Bacterial Gastroenteritis Is Associated With an Increased Incidence of Irritable Bowel Syndrome in Children

OBJECTIVES:Acute bacterial gastroenteritis is associated with subsequent post-infectious irritable bowel syndrome (PI-IBS) in adults. Less is known about this relationship in children. In May 2000, contamination of municipal water by Escherichia coli 0157:H7 and Campylobacter species caused a large outbreak of acute gastroenteritis in Walkerton, Ontario. We assessed this association among a cohort of children enrolled in the Walkerton Health Study (WHS).METHODS:WHS participants who were under age 16 at the time of the outbreak but who reached age 16 during the 8-year study follow-up were eligible for the pediatric PI-IBS study cohort. Eligibility also required no diagnosis of IBS or inflammatory bowel disease before the outbreak and permanent residency in the Walkerton postal code at the time of the outbreak. Validated criteria were used to classify subjects as having had no gastroenteritis (unexposed controls), self-reported gastroenteritis, or clinically suspected gastroenteritis during the outbreak. From 2002 to 2008, standardized biennial interviews used a modified Bowel Disease Questionnaire to diagnose IBS by Rome I criteria. Risk factors for IBS were identified by logistic regression.RESULTS:In all, 467 subjects were eligible for the pediatric PI-IBS study cohort (47.1% female; mean age 11.6±2.44 years at the time of the outbreak). Of these, 305 were exposed to GE (130 clinically suspected and 175 self-reported) and 162 were unexposed controls. The cumulative incidence of IBS was significantly increased among exposed subjects vs. controls (10.5% vs. 2.5%; odds ratio 4.6, 95% confidence interval (1.6, 13.3)). In an unadjusted risk factor analysis, IBS was associated with a shorter time interval from exposure to assessment of IBS symptoms, female gender, diarrheal illness lasting more than 7 days, weight loss >10 lb, and antibiotic use during the outbreak. In adjusted analyses, both female gender and time interval to assessment of IBS symptoms remained independent predictors of PI-IBS.CONCLUSIONS:Acute bacterial gastroenteritis is associated with subsequent IBS in children as in adults. Risk factors for PI-IBS in children are similar to those identified among adults. Confirmation of these findings in similar cohorts is needed.

Prevalence of Uninvestigated Dyspepsia 8 Years After a Large Waterborne Outbreak of Bacterial Dysentery: A Cohort Study

BACKGROUND & AIMS Symptoms of dyspepsia may occur following an episode of acute gastroenteritis, but data are conflicting. We assessed prevalence of uninvestigated dyspepsia in a cohort of individuals, some of whom were exposed to bacterial dysentery in May 2000, as well as risk factors for dyspepsia in exposed individuals. METHODS This was a cohort study conducted in the town of Walkerton, Ontario, Canada. Involved individuals were recruited into the Walkerton Health Study between 2002 and 2003 and were attending for annual assessment in 2008. Exposed individuals were subdivided into those with self-reported gastroenteritis, with acute illness unconfirmed by health records, and those with clinically confirmed gastroenteritis, with substantiation of acute illness by health record review. Presence of dyspepsia at 8 years, according to a broad definition (any symptom referable to the upper gastrointestinal tract), and the Rome II criteria, was compared between exposed and nonexposed individuals. RESULTS Of 2597 subjects eligible, 1088 (41.9%) provided data for analysis, and 706 (64.9%) had reported acute gastroenteritis. Multivariate odd ratios for dyspepsia at 8 years in exposed individuals using a broad definition and the Rome II definition were 2.09 (95% confidence interval: 1.58-2.78) and 2.30 (95% confidence interval: 1.63-3.26), respectively. Prevalence of dyspepsia was higher in females; smokers; those with premorbid irritable bowel syndrome, anxiety, or depression; and those reporting >7 days of diarrhea or abdominal cramps during the acute illness. CONCLUSIONS Symptoms of dyspepsia 8 years after an outbreak of acute gastroenteritis were significantly more prevalent in exposed compared with nonexposed individuals.

Development and validation of a risk score for post-infectious irritable bowel syndrome.

OBJECTIVES:Acute gastroenteritis (GE) is an important risk factor for the development of irritable bowel syndrome (IBS). We used observational data from the Walkerton Health Study (WHS) to develop and validate a risk score for post-infectious (PI) IBS.METHODS:Model derivation and validation were based on a split-sample method from a cohort of patients with exposure to GE (n=1,368). Study participants were randomly assigned to the derivation and validation cohorts in a 1:1 ratio. Within the derivation cohort, univariate and multivariable logistic regression were used to identify risk factors associated with IBS. The risk model was then applied to the validation cohort. Overall model performance was assessed using the area under the receiver operating curve (ROC). The risk score was developed using multivariable regression coefficients obtained from the derivation set and validated in the validation set. Classification and regression tree (CART) modeling was used to determine cutoff values for high, intermediate, and low risk based on the total score.RESULTS:Nine variables were identified as important predictors of IBS (gender, age<60, longer duration of diarrhea, increased stool frequency, abdominal cramping, bloody stools, weight loss, fever, and psychological disorders (anxiety and depression)). The discriminatory power of the risk model based on the area under ROC was 0.70 and was similar in the validation set. The risk score model showed good accuracy in both the derivation and validation sets and was able to distinguish among cohorts at low, intermediate, and high risk for developing PI-IBS. Percentages of patients with PI-IBS in the low, intermediate and high risk were 10, 35, and 60% in the derivation cohort and 17, 36, and 62% in the validation cohort.CONCLUSIONS:A simple risk tool that uses demographics and symptoms of acute GE can predict which patients with acute GE are at risk of developing PI-IBS. This tool may be used clinically to assess risk and to guide treatment.

Clustering and stability of functional lower gastrointestinal symptom after enteric infection

Background  Current diagnostic criteria for functional gut disorder are based on symptom clusters observed after sporadic onset. It remains unclear whether symptoms group similarly in functional disorders of postinfectious etiology. We utilized observational data from the Walkerton Health Study (WHS) to: (i) determine groupings of functional gastrointestinal symptoms among patients exposed to acute gastroenteritis (GE), and (ii) assess the stability of these symptoms grouping over time.