Mark S. Riddle

Postinfectious Irritable Bowel Syndrome—A Meta-Analysis

OBJECTIVES:Irritable bowel syndrome (IBS) is a heterogeneous disorder affecting 12% of the population worldwide. Several studies identify IBS as a sequela of infectious gastroenteritis (IGE) with reported prevalence ranging from 4% to 31% and relative risk from 2.5 to 11.9. This meta-analysis was conducted to explore the differences between reported rates and provide a pooled estimate of risk for postinfectious irritable bowel syndrome (PI-IBS).DATA SOURCES:Electronic databases (MEDLINE, OLDMEDLINE, EMBASE, Cochrane database of clinical trials) and pertinent reference lists (including other review articles).REVIEW METHODS:Data were abstracted from included studies by two independent investigators; study quality, heterogeneity, and publication bias were assessed; sensitivity analysis was performed; and a summative effect estimate was calculated for risk of PI-IBS.RESULTS:Eight studies were included for analysis and all reported elevated risk of IBS following IGE. Median prevalence of IBS in the IGE groups was 9.8% (IQR 4.0–13.3) and 1.2% in control groups (IQR 0.4–1.8) (sign-rank test, p = 0.01). The pooled odds ratio was 7.3 (95% CI, 4.7–11.1) without significant heterogeneity (χ2 heterogeneity statistic, p = 0.41). Subgroup analysis revealed an association between PI-IBS risk and IGE definition used.CONCLUSIONS:This study provides supporting evidence for PI-IBS as a sequela of IGE and a pooled risk estimate revealing a sevenfold increase in the odds of developing IBS following IGE. The results suggest that the long-term benefit of reduced PI-IBS may be gained from primary prevention of IGE.

Trauma-related Infections in Battlefield Casualties From Iraq

Objective:To describe risks for, and microbiology and antimicrobial resistance patterns of, war trauma associated infections from Operation Iraqi Freedom. Background:The invasion of Iraq resulted in casualties from high-velocity gunshot, shrapnel, and blunt trauma injuries as well as burns. Infectious complications of these unique war trauma injuries have not been described since the 1970s. Methods:Retrospective record review of all trauma casualties 5 to 65 years of age evacuated from the Iraqi theatre to U.S. Navy hospital ship, USNS Comfort March to May 2003.War trauma-associated infection was defined by positive culture from a wound or sterile body fluid (ie, blood, cerebrospinal fluid) and at least two of the following infection-associated signs/symptoms: fever, dehiscence, foul smell, peri-wound erythema, hypotension, and leukocytosis. A comparison of mechanisms of injury, demographics, and clinical variables was done using multivariate analysis. Results:Of 211 patients, 56 met criteria for infection. Infections were more common in blast injuries, soft tissue injuries, >3 wound sites, loss of limb, abdominal trauma, and higher Injury Severity Score (ISS). Wound infections accounted for 84% of cases, followed by bloodstream infections (38%). Infected were more likely to have had fever prior to arrival, and had higher probability of ICU admission and more surgical procedures. Acinetobacter species (36%) were the predominant organisms followed by Escherichia coli and Pseudomonas species (14% each). Conclusions:Similar to the Vietnam War experience, gram-negative rods, particularly Acinetobacter species, accounted for the majority of wound infections cared for on USNS Comfort during Operation Iraqi Freedom. Multidrug resistance was common, with the exception of the carbapenem class, limiting antibiotic therapy options.

Exchange Transfusion as an Adjunct Therapy in Severe Plasmodium falciparum Malaria: A Meta-analysis

The efficacy of exchange transfusion as an adjunct treatment for severe falciparum malaria is controversial. No sufficiently powered, randomized, controlled study has been reported. We analyzed 8 studies that compared survival rates associated with adjunct exchange transfusion with those associated with antimalarial chemotherapy alone. Exchange transfusion was not associated with a higher survival rate than was antimalarial chemotherapy alone (odds ratio [OR], 1.2; 95% confidence interval [CI], 0.7-2.1). However, patients who received transfusions had higher levels of parasitemia and more-severe malaria. Sensitivity analysis found that survival rates were higher among patients with partial immunity to malaria (OR, 0.5; 95% CI, 0.2-1.2) than they were among patients with no immunity (OR, 2.1; 95% CI, 0.9-4.8; P=.007). Exchange transfusion does not appear to increase the survival rate; however, there were significant problems with the comparability of treatment groups in the studies reviewed, and a randomized controlled trial is necessary to determine whether exchange transfusion is beneficial.

A systematic review of ETEC epidemiology focusing on colonization factor and toxin expression.

INTRODUCTION Vaccine development for enterotoxigenic Escherichia coli (ETEC) is dependent on in-depth understanding of toxin and colonization factor (CF) distribution. We sought to describe ETEC epidemiology across regions and populations, focusing on CF and toxin prevalence. METHODS We conducted a systematic review of the published literature, including studies reporting data on ETEC CF and toxin distributions among those with ETEC infection. Point estimates and confidence intervals were calculated using random effects models. RESULTS Data on 17,205 ETEC isolates were abstracted from 136 included studies. Approximately half of the studies (49%) involved endemic populations, and an additional 17% involved only travel populations. Globally, 60% of isolates expressed LT either alone (27%) or in combination with ST (33%). CFA/I-expressing strains were common in all regions (17%), as were ETEC expressing CFA/II (9%) and IV (18%). Marked variation in toxins and CFs across regions and populations was observed. DISCUSSION/CONCLUSIONS These results demonstrate the relative importance of specific CFs in achieving target product profiles for a future ETEC vaccine. However, heterogeneity across time, population, and region, confounded by variability in CF and toxin detection methodologies, obfuscates rational estimates for valency requirements.

Infectious Gastroenteritis and Risk of Developing Inflammatory Bowel Disease

BACKGROUND & AIMS Infectious gastroenteritis (IGE) is known to exacerbate previously diagnosed inflammatory bowel disease (IBD). However, limited data are available describing a causal link between IGE and incident IBD. METHODS By using a medical encounter data repository of active duty military personnel, a study was conducted to assess IBD risk in subjects with an antecedent case of IGE. RESULTS Between 1999 and 2006, there were 3019 incident IBD cases and 11,646 matched controls who were evaluated in a conditional logistic regression model. To control for potential misclassification, IGE episodes within 6 months of IBD diagnosis were excluded as exposures. After adjusting for potential confounders, an episode of IGE increased the risk of IBD (odds ratio, 1.40; 95% confidence interval, 1.19-1.66). The risk was slightly higher for Crohns disease compared with ulcerative colitis. In addition, there was an approximate 5-fold increase in IBD risk for persons with a previous irritable bowel syndrome diagnosis. CONCLUSIONS These data support theories that the initiation of IBD is a multifactorial process that might include the disruption of normal gut homeostatic mechanisms. Further studies are warranted to evaluate the pathogen-specific risks, identify susceptible populations, and better understand the pathophysiologic relationship between IGE and IBD.

Endoscopic Ultrasound Does Not Accurately Stage Early Adenocarcinoma or High-Grade Dysplasia of the Esophagus

BACKGROUND & AIMS Patients with esophageal high-grade dysplasia or mucosal esophageal cancer can be successfully treated by endoscopy. We performed a systematic review of the literature to determine whether endoscopic ultrasound (EUS) correctly predicts the T-stage of early esophageal cancers, compared with pathology specimens obtained by using endoscopic mucosal resection (EMR) or surgery. METHODS Standard systematic review methods were used to perform reference searches, determine eligibility, abstract data, and analyze data. When possible, individual patient-level data were abstracted, in addition to publication-level aggregate data. RESULTS Twelve studies had sufficient information to abstract and review for quality; 8 had individual patient-level data (n = 132). Compared with surgical or EMR pathology staging, EUS had T-stage concordance of 65%, including all studies (n = 12), but only 56% concordance when limited to individual patient-level data. Factors such as initial biopsy pathology (high-grade dysplasia vs early-stage cancer) did not appear to affect the concordance of staging between EUS and EMR/surgical staging. CONCLUSIONS EUS is not sufficiently accurate in determining the T-stage of high-grade dysplasias or superficial adenocarcinomas; other means of staging, such as EMR, should be used.

The Incidence and gastrointestinal infectious risk of functional gastrointestinal disorders in a healthy US adult population.

OBJECTIVES:Functional gastrointestinal disorders (FGDs) are recognized sequelae of infectious gastroenteritis (IGE). Within the active duty military population, a group with known high IGE rates, the population-based incidence, risk factors, and attributable burden of care referable to FGD after IGE are poorly defined.METHODS:Using electronic medical encounter data (1999–2007) on active duty US military, a matched, case-control study describing the epidemiology and risk determinants of FGD (irritable bowel syndrome (IBS), functional constipation (FC), functional diarrhea (FD), dyspepsia (D)) was conducted. Incidence rates and duration of FGD-related medical care were estimated, and conditional logistic regression was utilized to evaluate FGD risk after IGE.RESULTS:A total of 31,866 cases of FGD identified were distributed as follows: FC 55% (n=17,538), D 21.2% (n=6,750), FD 2.1% (n=674), IBS 28.5% (n=9,091). Previous IGE episodes were distributed as follows: specific bacterial pathogen (n=65, 1.2%), bacterial, with no pathogen specified (n=2155, 38.9%), protozoal (n=38, 0.7%), viral (n=3431, 61.9%). A significant association between IGE and all FGD (odds ratio (OR) 2.64; P<0.001) was seen, with highest risk for FD (OR 6.28, P<0.001) and IBS (OR 3.72, P<0.001), and moderate risk for FC (2.15, P<0.001) and D (OR 2.39, P<0.001). Risk generally increased with temporal proximity to, and bacterial etiology of, exposure. Duration of FGD-related care was prolonged with 22.7% having FGD-associated medical encounters 5 years after diagnosis.CONCLUSIONS:FGD are common in this population at high risk for IGE. When considering effective countermeasures and mitigation strategies, attention directed toward prevention as well as the acute and chronic sequelae of these infections is needed.

The incidence and risk of celiac disease in a healthy US adult population.

OBJECTIVES:Celiac disease (CD) is an increasingly common disease that may affect as many as 1% of the North American population. Recent population-based data suggest a substantial increase in the prevalence of CD over the last several decades. Several factors are hypothesized as possible disease triggers including intercurrent illnesses, such as gastroenteritis, surgeries, and trauma. We used the active duty US military, a unique healthy worker population with essentially complete medical diagnostic coding, as an opportunity to describe trends in CD and deployment-related risk factors.METHODS:Using electronic medical encounter data (1999–2008) on active duty US military (over 13.7 million person-years), a matched, nested case–control study describing the epidemiology and risk determinants of CD (based on ≥2 ICD-9 medical encounters) was conducted. Incidence and duration of CD-related medical care were estimated, and conditional logistic regression was utilized to evaluate CD risk following infectious gastroenteritis (IGE) occurring within 3 years before CD diagnosis while controlling for other risk factors.RESULTS:A total of 455 incident cases of CD were identified and age, gender, and time matched to 1,820 controls. The incidence of CD increased five-fold from 1.3 per 100,000 in 1999 to 6.5 per 100,000 in 2008, with the highest rates of increase among those over 34 years of age (average annual increase of 0.8 cases per 100,000). A total of 172 IGE episodes, predominately of “viral etiology” (60.5%), were documented. In multivariate models, a significant association between IGE and CD was found (Odds ratio (OR): 2.06, 95% confidence interval (CI) 1.43, 2.97). Risk generally increased with temporal proximity to, and non-viral etiology of, exposure. Other notable risk factors for CD in multivariate models were Caucasian race (OR: 3.1, P<0.001), non-Army service (OR: 1.5, P=0.001), and greater than a high-school education (OR: 1.3, P=0.05).CONCLUSIONS:Incidence of CD diagnosis in the US military is increasing, particularly among those in the fourth and fifth decades of life and appears higher than other population-based estimates. An association between antecedent IGE and risk of CD was noted, but the potential for exposure misclassification cannot be ruled out and further study is needed to link pathogen-specific exposure to incident CD anti-gluten antibody development or symptom onset.

Campylobacter Polysaccharide Capsules: Virulence and Vaccines

Campylobacter jejuni remains a major cause of bacterial diarrhea worldwide and is associated with numerous sequelae, including Guillain Barré Syndrome, inflammatory bowel disease, reactive arthritis, and irritable bowel syndrome. C. jejuni is unusual for an intestinal pathogen in its ability to coat its surface with a polysaccharide capsule (CPS). These capsular polysaccharides vary in sugar composition and linkage, especially those involving heptoses of unusual configuration and O-methyl phosphoramidate linkages. This structural diversity is consistent with CPS being the major serodeterminant of the Penner scheme, of which there are 47 C. jejuni serotypes. Both CPS expression and expression of modifications are subject to phase variation by slip strand mismatch repair. Although capsules are virulence factors for other pathogens, the role of CPS in C. jejuni disease has not been well defined beyond descriptive studies demonstrating a role in serum resistance and for diarrhea in a ferret model of disease. However, perhaps the most compelling evidence for a role in pathogenesis are data that CPS conjugate vaccines protect against diarrheal disease in non-human primates. A CPS conjugate vaccine approach against this pathogen is intriguing, but several questions need to be addressed, including the valency of CPS types required for an effective vaccine. There have been numerous studies of prevalence of CPS serotypes in the developed world, but few studies from developing countries where the disease incidence is higher. The complexity and cost of Penner serotyping has limited its usefulness, and a recently developed multiplex PCR method for determination of capsule type offers the potential of a more rapid and affordable method. Comparative studies have shown a strong correlation of the two methods and studies are beginning to ascertain CPS-type distribution worldwide, as well as examination of correlation of severity of illness with specific CPS types.

Effect of Adjunctive Loperamide in Combination with Antibiotics on Treatment Outcomes in Traveler's Diarrhea: A Systematic Review and Meta-Analysis

BACKGROUND A previous Cochrane Collaboration review established an effective advantage of antibiotic therapy, compared with placebo, for treatment of travelers diarrhea. The goal of the present study was to conduct a systematic review of the literature to establish the effect on treatment outcomes of using antimotility agents in conjunction with antibiotic therapy. METHODS The meta-analysis was conducted through searches of electronic databases and pertinent reference lists (including other review articles) and consultation with experts in the field. Clinical trials on therapy of infectious diarrhea in adult populations that met eligibility criteria were studied. Data were extracted and verified by 2 independent investigators and were analyzed for outcomes of clinical cure at 24 h, 48 h, and 72 h and time to last unformed stool. Study quality, heterogeneity, and publication bias were assessed. When appropriate, effect estimates among studies were pooled and sensitivity analyses were performed. RESULTS Nine studies consisting of 12 different adjunctive loperamide antibiotic regimens were included for analysis. Among 6 paired studies comparing antibiotics alone versus antibiotics in combination with loperamide, the odds of clinical cure at 24 h and 48 h favored combination therapy, with summary odds ratios of 2.6 (95% confidence interval, 1.8-3.6; P = .20 by chi(2) heterogeneity statistic) and 2.2 (95% confidence interval, 1.5-3.1; P = .20, by chi(2) heterogeneity statistic), respectively, with no evidence of heterogeneity. Factors that possibly affect advantage of combination therapy over solo therapy included increased frequency of pretreatment diarrhea and higher prevalence of noninvasive pathogens. CONCLUSION Antibiotic therapy with adjunctive loperamide offers an advantage over antibiotics alone by decreasing the illness duration and increasing the probability of early clinical cure.