Anti-Integrin αvß6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis.

BACKGROUND & AIMS: Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvß6 (anti-αvß6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvß6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. METHODS: Anti-αvß6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvß6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n = 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n = 104) and associations between anti-αvß6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. RESULTS: Anti-αvß6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvß6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvß6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvß6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvß6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Shigella-Controlled Human Infection Models: Current and Future Perspectives.

Shigella-controlled human infection models (CHIMs) are an invaluable tool utilized by the vaccine community to combat one of the leading global causes of infectious diarrhea, which affects infants, children and adults regardless of socioeconomic status. The impact of shigellosis disproportionately affects children in low- and middle-income countries (LMICs) resulting in cognitive and physical stunting, perpetuating a cycle that must be halted. Shigella-CHIMs not only facilitate the early evaluation of enteric countermeasures and up-selection of the most promising products but also provide insight into mechanisms of infection and immunity that are not possible utilizing animal models or in vitro systems. The greater understanding of shigellosis obtained in CHIMs builds and empowers the development of new generation solutions to global health issues which are unattainable in the conventional laboratory and clinical settings. Therefore, refining, mining and expansion of safe and reproducible infection models hold the potential to create effective means to end diarrheal disease and associated co-morbidities associated with Shigella infection.

SARS-CoV-2 Outbreak Dynamics in an Isolated US Military Recruit Training Center With Rigorous Prevention Measures.

BACKGROUND: Marine recruits training at Parris Island experienced an unexpectedly high rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, despite preventive measures including a supervised, 2-week, pre-entry quarantine. We characterize SARS-CoV-2 transmission in this cohort. METHODS: Between May and November 2020, we monitored 2,469 unvaccinated, mostly male, Marine recruits prospectively during basic training. If participants tested negative for SARS-CoV-2 by quantitative polymerase chain reaction (qPCR) at the end of quarantine, they were transferred to the training site in segregated companies and underwent biweekly testing for 6 weeks. We assessed the effects of coronavirus disease 2019 (COVID-19) prevention measures on other respiratory infections with passive surveillance data, performed phylogenetic analysis, and modeled transmission dynamics and testing regimens. RESULTS: Preventive measures were associated with drastically lower rates of other respiratory illnesses. However, among the trainees, 1,107 (44.8%) tested SARS-CoV-2-positive, with either mild or no symptoms. Phylogenetic analysis of viral genomes from 580 participants revealed that all cases but one were linked to five independent introductions, each characterized by accumulation of mutations across and within companies, and similar viral isolates in individuals from the same company. Variation in company transmission rates (mean reproduction number R 0 ; 5.5 [95% confidence interval [CI], 5.0, 6.1]) could be accounted for by multiple initial cases within a company and superspreader events. Simulations indicate that frequent rapid-report testing with case isolation may minimize outbreaks. CONCLUSIONS: Transmission of wild-type SARS-CoV-2 among Marine recruits was approximately twice that seen in the community. Insights from SARS-CoV-2 outbreak dynamics and mutations spread in a remote, congregate setting may inform effective mitigation strategies.

The Controlled Human Infection Model for Enterotoxigenic Escherichia coli.

The controlled human infection model (CHIM) for enterotoxigenic Escherichia coli (ETEC) has been instrumental in defining ETEC as a causative agent of acute watery diarrhea, providing insights into disease pathogenesis and resistance to illness, and enabling preliminary efficacy evaluations for numerous products including vaccines, immunoprophylactics, and drugs. Over a dozen strains have been evaluated to date, with a spectrum of clinical signs and symptoms that appear to replicate the clinical illness seen with naturally occurring ETEC. Recent advancements in the ETEC CHIM have enhanced the characterization of clinical, immunological, and microbiological outcomes. It is anticipated that omics-based technologies applied to ETEC CHIMs will continue to broaden our understanding of host-pathogen interactions and facilitate the development of primary and secondary prevention strategies.

A site assessment tool for inpatient controlled human infection models for enteric disease pathogens.

The use of the controlled human infection model to facilitate product development and to advance understanding of host-pathogen interactions is of increasing interest. While administering a virulent (or infective) organism to a susceptible host necessitates an ongoing evaluation of safety and ethical considerations, a central theme in conducting these studies in a safe and ethical manner that yields actionable data is their conduct in facilities well-suited to address their unique attributes. To that end, we have developed a framework for evaluating potential sites in which to conduct inpatient enteric controlled human infection model to ensure consistency and increase the likelihood of success.

Serum Biomarkers Identify Patients Who Will Develop Inflammatory Bowel Diseases Up to 5 Years Before Diagnosis.

BACKGROUND & AIMS: Biomarkers are needed to identify patients at risk for development of inflammatory bowel diseases. We aimed to identify serum biomarkers of Crohn's disease and ulcerative colitis that can be detected and quantified before diagnosis. METHODS: We obtained serum samples from patients archived before a diagnosis of Crohn's disease (n = 200) or ulcerative colitis (n = 199), as well as from 200 healthy individuals (controls), collected from 1998 through 2013 as part of the US Defense Medical Surveillance System. We measured levels of antibodies against microbes (anti-Saccharomyces cerevisiae IgA or IgG, anti-Escherichiacoli outer membrane porin C, anti-CBir1, anti-flagellin 2, anti-flagellin X, and perinuclear anti-neutrophil cytoplasmic antibodies) and 1129 proteins in each sample. We then used functional principal component analysis to derive the time-varying trajectory for each marker, which then was used in a multivariate model to predict disease status. Predictive performances at different prediagnosis timepoints were evaluated using area under the receiver operating characteristic curves (AUROCs). Biological pathways that were up-regulated in serum from patients with Crohn's disease were identified based on changes in protein abundance at different time periods preceding diagnosis. RESULTS: We identified a panel of 51 protein biomarkers that were predictive of Crohn's disease within 5 years with an AUROC of 0.76 and a diagnosis within 1 year with an AUROC of 0.87. Based on the proteins included in the panel, imminent development of CD was associated with changes in the complement cascade, lysosomes, innate immune response, and glycosaminoglycan metabolism. Serum antibodies and proteins identified patients who received a diagnosis of ulcerative colitis within 5 years with an AUROC of only 0.56 and within 1 year with an AUROC of 0.72. CONCLUSIONS: We identified a panel of serum antibodies and proteins that were predictive of patients who will receive a diagnosis of Crohn's disease within 5 years with high accuracy. By contrast we did not identify biomarkers associated with future diagnosis of ulcerative colitis.

Enterotoxigenic E. coli virulence gene regulation in human infections.

Enterotoxigenic Escherichia coli (ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other hallmarks of the intestinal tract, such as low oxygen availability, have not been examined. Further, determining how ETEC integrates these signals in the complex host environment is challenging. To address this, we characterized ETEC's response to the human host using samples from a controlled human infection model. We found ETEC senses environmental oxygen to globally influence virulence factor expression via the oxygen-sensitive transcriptional regulator fumarate and nitrate reduction (FNR) regulator. In vitro anaerobic growth replicates the in vivo virulence factor expression profile, and deletion of fnr in ETEC strain H10407 results in a significant increase in expression of all classical virulence factors, including the colonization factor antigen I (CFA/I) adhesin operon and both heat-stable and heat-labile enterotoxins. These data depict a model of ETEC infection where FNR activity can globally influence virulence gene expression, and therefore proximity to the oxygenated zone bordering intestinal epithelial cells likely influences ETEC virulence gene expression in vivo. Outside of the host, ETEC biofilms are associated with seasonal ETEC epidemics, and we find FNR is a regulator of biofilm production. Together these data suggest FNR-dependent oxygen sensing in ETEC has implications for human infection inside and outside of the host.

Chronic Gastrointestinal and Joint-Related Sequelae Associated with Common Foodborne Illnesses: A Scoping Review.

To strengthen the burden estimates for chronic sequelae of foodborne illness, we conducted a scoping review of the current literature for common foodborne pathogens and their associated sequelae. We aim to describe the current literature and gaps in knowledge of chronic sequelae associated with common foodborne illnesses. A comprehensive search was conducted in PubMed, EMBASE, and Web of Science for peer-reviewed articles published January 1, 2000 to April 1, 2018. Articles available in English, of any epidemiological study design, for 10 common foodborne pathogens (Campylobacter, Salmonella, Escherichia coli, Listeria, Shigella, Cryptosporidium, Cyclospora, Giardia, Yersinia, and norovirus) and their associated gastrointestinal (GI)- and joint-related sequelae were included. Of the 6348 titles screened for inclusion, 380 articles underwent full-text review; of those 380, 129 were included for data extraction. Of the bacterial pathogens included in the search terms, the most commonly reported were Salmonella (n = 104) and Campylobacter (n = 99); E. coli (n = 55), Shigella (n = 49), Yersinia (n = 49), and Listeria (n = 15) all had fewer results. Norovirus was the only virus included in our search, with 28 article that reported mostly GI-related sequelae and reactive arthritis (ReA) reported once. For parasitic diseases, Giardia (n = 26) and Cryptosporidium (n = 18) had the most articles, and no results were found for Cyclospora. The most commonly reported GI outcomes were irritable bowel syndrome (IBS; n = 119) and inflammatory bowel disease (n = 29), and ReA (n = 122) or "joint pain" (n = 19) for joint-related sequelae. Salmonella and Campylobacter were most often associated with a variety of outcomes, with ReA (n = 34 and n = 27) and IBS (n = 17 and n = 20) reported most often. This scoping review shows there are still a relatively small number of studies being conducted to understand specific pathogen/outcome relationships. It also shows where important gaps in the impact of chronic sequelae from common foodborne illnesses still exist and where more focused research would best be implemented.

Hyperimmune Bovine Colostral Anti-CS17 Antibodies Protect Against Enterotoxigenic Escherichia coli Diarrhea in a Randomized, Doubled-Blind, Placebo-Controlled Human Infection Model.

BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) commonly cause diarrhea in children living in developing countries and in travelers to those regions. ETEC are characterized by colonization factors (CFs) that mediate intestinal adherence. We assessed if bovine colostral IgG (bIgG) antibodies against a CF, CS17, or antibodies against CsbD, the minor tip subunit of CS17, would protect subjects against diarrhea following challenge with a CS17-expressing ETEC strain. METHODS: Adult subjects were randomized (1:1:1) to receive oral bIgG against CS17, CsbD, or placebo. Two days prior to challenge, subjects began dosing 3 times daily with the bIgG products (or placebo). On day 3, subjects ingested 5 × 109 cfu ETEC strain LSN03-016011/A in buffer. Subjects were assessed for diarrhea for 120 hours postchallenge. RESULTS: A total of 36 subjects began oral prophylaxis and 35 were challenged with ETEC. While 50.0% of the placebo recipients had watery diarrhea, none of the subjects receiving anti-CS17 had diarrhea (P = .01). In contrast, diarrhea rates between placebo and anti-CsbD recipients (41.7%) were comparable (P = 1.0). CONCLUSIONS: This is the first study to demonstrate anti-CS17 antibodies provide significant protection against ETEC expressing CS17. More research is needed to better understand why anti-CsbD was not comparably efficacious. Clinical Trials Registration. NCT00524004.

Consensus Report on Shigella Controlled Human Infection Model: Clinical Endpoints.

The Shigella controlled human infection model (CHIM) is valuable for assessing candidate Shigella vaccine efficacy and potentially accelerating regulatory approval. The Shigella CHIM is currently being conducted at 3 sites in the United States using Shigella flexneri 2a strain 2457T and Shigella sonnei strain 53G. Shigellosis can present variably as watery diarrhea alone or with dysentery, and can be accompanied by manifestations including fever, abdominal cramps, tenesmus, and malaise. For comparability, it is important to harmonize the primary clinical endpoint. An expert working group was convened on 2 February 2018 to review clinical data from Shigella CHIM studies performed to date and to develop a consensus primary endpoint. The consensus endpoint enabled "shigellosis" to present as severe diarrhea or moderate diarrhea or dysentery. The latter 2 criteria are met when concurrent with fever of 38.0°C and/or vomiting, and/or a constitutional/enteric symptom graded at least as "moderate" severity. The use of a blinded independent committee to adjudicate the primary endpoint by subject was also regarded as important. As safety of volunteers in challenge studies is of paramount importance and treatment timing can affect primary outcomes, a standard for early antibiotic administration was established as follows: (1) when the primary endpoint is met; (2) if a fever of ≥39.0°C develops; or (3) if the study physician deems it appropriate. Otherwise, antibiotics are given at 120 hours postinfectious challenge. The working group agreed on objective and subjective symptoms to be solicited, and standardized methods for assessing subject-reported severity of symptoms.

Consensus Report on Shigella Controlled Human Infection Model: Conduct of Studies.

Shigella causes morbidity and mortality worldwide, primarily affecting young children living in low-resource settings. It is also of great concern due to increasing antibiotic resistance, and is a priority organism for the World Health Organization. A Shigella vaccine would decrease the morbidity and mortality associated with shigellosis, improve child health, and decrease the need for antibiotics. Controlled human infection models (CHIMs) are useful tools in vaccine evaluation for early up- or down-selection of vaccine candidates and potentially useful in support of licensure. Over time, the methods employed in these models have become more uniform across sites performing CHIM trials, although some differences in conduct persist. In November 2017, a Shigella CHIM workshop was convened in Washington, District of Columbia. Investigators met to discuss multiple aspects of these studies, including study procedures, clinical and immunological endpoints, and shared experiences. This article serves as a uniform procedure by which to conduct Shigella CHIM studies.

Campylobacter jejuni capsule types in a Peruvian birth cohort and associations with diarrhoeal disease severity.

Campylobacter jejuni is a leading cause of bacterial diarrhoea worldwide. The objective of this study was to examine the association between C. jejuni capsule types and clinical signs and symptoms of diarrhoeal disease in a well-defined birth cohort in Peru. Children were enrolled in the study at birth and followed until 2 years of age as part of the Malnutrition and Enteric Infections birth cohort. Associations between capsule type and clinical outcomes were assessed using the Pearson's χ2 and the Kruskal-Wallis test statistics. A total of 318 C. jejuni samples (30% from symptomatic cases) were included in this analysis. There were 22 different C. jejuni capsule types identified with five accounting for 49.1% of all isolates. The most common capsule types among the total number of isolates were HS4 complex (n = 52, 14.8%), HS5/31 complex (n = 42, 11.9%), HS15 (n = 29, 8.2%), HS2 (n = 26, 7.4%) and HS10 (n = 24, 6.8%). These five capsule types accounted for the majority of C. jejuni infections; however, there was no significant difference in prevalence between symptomatic and asymptomatic infection (all p > 0.05). The majority of isolates (n = 291, 82.7%) were predicted to express a heptose-containing capsule. The predicted presence of methyl phosphoramidate, heptose or deoxyheptose on the capsule was common.

Rifaximin Fails to Prevent Campylobacteriosis in the Human Challenge Model: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Campylobacter species are a leading cause of diarrheal disease globally with significant morbidity. Primary prevention efforts have yielded limited results. Rifaximin chemoprophylaxis decreases rates of travelers' diarrhea and may be suitable for high-risk persons. We assessed the efficacy of rifaximin in the controlled human infection model for Campylobacter jejuni. Methods: Twenty-eight subjects were admitted to an inpatient facility and randomized to a twice-daily dose of 550 mg rifaximin or placebo. The following day, subjects ingested 1.7 × 105 colony-forming units of C. jejuni strain CG8421. Subjects continued prophylaxis for 3 additional days, were followed for campylobacteriosis for 144 hours, and were subsequently treated with azithromycin and ciprofloxacin. Samples were collected to assess immunologic responses to CG8421. Results: There was no difference (P = 1.0) in the frequency of campylobacteriosis in those receiving rifaximin (86.7%) or placebo (84.6%). Additionally, there were no differences in the clinical signs and symptoms of C. jejuni infection to include abdominal pain/cramps (P = 1.0), nausea (P = 1.0), vomiting (P = .2), or fever (P = 1.0) across study groups. Immune responses to the CG8421 strain were comparable across treatment groups. Conclusions: Rifaximin did not prevent campylobacteriosis in this controlled human infection model. Given the morbidity associated with Campylobacter infection, primary prevention efforts remain a significant need. Clinical Trials Registration: NCT02280044.

Post-Infectious Functional Gastrointestinal Disorders Among Populations Living in Areas of High Enteric Infection Risk: Adding Some Clarity or Further Muddying the Waters.

Post-infectious functional gastrointestinal disorders (FGID) are a relatively well-studied phenomenon among individuals who are resident in temperate and higher-income regions around the world. Less is known about the risk of FGID among residents in tropical and hyperendemic settings where acute gastroenteritis risk and exposure is high. This editorial summarizes the primary results from a recently published study focusing on this unique clinical scenario and considers the interpretation of the data as well as highlights additional research needs.

Prophylactic Efficacy of Hyperimmune Bovine Colostral Antiadhesin Antibodies Against Enterotoxigenic Escherichia coli Diarrhea: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Trial.

Background: Tip-localized adhesive proteins of bacterial fimbriae from diverse pathogens confer protection in animal models, but efficacy in humans has not been reported. Enterotoxigenic Escherichia coli (ETEC) commonly elaborate colonization factors comprising a minor tip adhesin and major stalk-forming subunit. We assessed the efficacy of antiadhesin bovine colostral IgG (bIgG) antibodies against ETEC challenge in volunteers. Methods: Adults were randomly assigned (1:1:1) to take oral hyperimmune bIgG raised against CFA/I minor pilin subunit (CfaE) tip adhesin or colonization factor I (CFA/I) fimbraie (positive control) or placebo. Two days before challenge, volunteers began a thrice-daily, 7-day course of investigational product administered in sodium bicarbonate 15 minutes after each meal. On day 3, subjects drank 1 × 109 colony-forming units of colonization factor I (CFA/I)-ETEC strain H10407 with buffer. The primary efficacy endpoint was diarrhea within 120 hours of challenge. Results: After enrollment and randomization, 31 volunteers received product, underwent ETEC challenge, and were included in the per protocol efficacy analysis. Nine of 11 placebos developed diarrhea, 7 experiencing moderate to severe disease. Protective efficacy of 63% (P = .03) and 88% (P = .002) was observed in the antiadhesin bIgG and positive control groups, respectively. Conclusions: Oral administration of anti-CFA/I minor pilin subunit (CfaE) antibodies conferred significant protection against ETEC, providing the first clinical evidence that fimbrial tip adhesins function as protective antigens.

Trial Evaluating Ambulatory Therapy of Travelers' Diarrhea (TrEAT TD) Study: A Randomized Controlled Trial Comparing 3 Single-Dose Antibiotic Regimens With Loperamide.

BACKGROUND: Recommended treatment for travelers' diarrhea includes the combination of an antibiotic, usually a fluoroquinolone or azithromycin, and loperamide for rapid resolution of symptoms. However, adverse events, postdose nausea with high-dose azithromycin, effectiveness of single-dose rifaximin, and emerging resistance to front-line agents are evidence gaps underlying current recommendations. METHODS: A randomized, double-blind trial was conducted in 4 countries (Afghanistan, Djibouti, Kenya, and Honduras) between September 2012 and July 2015. US and UK service members with acute watery diarrhea were randomized and received single-dose azithromycin (500 mg; 106 persons), levofloxacin (500 mg; 111 persons), or rifaximin (1650 mg; 107 persons), in combination with loperamide (labeled dosing). The efficacy outcomes included clinical cure at 24 hours and time to last unformed stool. RESULTS: Clinical cure at 24 hours occurred in 81.4%, 78.3%, and 74.8% of the levofloxacin, azithromycin, and rifaximin arms, respectively. Compared with levofloxacin, azithromycin was not inferior (P = .01). Noninferiority could not be shown with rifaximin (P = .07). At 48 and 72 hours, efficacy among regimens was equivalent (approximately 91% at 48 and 96% at 72 hours). The median time to last unformed stool did not differ between treatment arms (azithromycin, 3.8 hours; levofloxacin, 6.4 hours; rifaximin, 5.6 hours). Treatment failures were uncommon (3.8%, 4.4%, and 1.9% in azithromycin, levofloxacin, and rifaximin arms, respectively) (P = .55). There were no differences between treatment arms with postdose nausea, vomiting, or other adverse events. CONCLUSIONS: Single-dose azithromycin, levofloxacin, and rifaximin with loperamide were comparable for treatment of acute watery diarrhea. CLINICAL TRIAL REGISTRATION: NCT01618591.

Increased risk of functional gastrointestinal sequelae after Clostridium difficile infection among active duty United States military personnel (1998-2010).

BACKGROUND & AIMS: Some acute enteric infections are associated with the development of functional gastrointestinal disorders, most commonly irritable bowel syndrome but also other functional and organic gastrointestinal sequelae. Clostridium difficile infection has increased in incidence and severity, however, few studies have evaluated functional disorders after this infection. METHODS: We evaluated the epidemiology and sequelae of C difficile in the US military population by using the US Department of Defense's Armed Forces Health Surveillance Center Defense Medical Ecounter Database. We then performed a retrospective cohort study of 891 active-duty US military personnel who developed C difficile from 1998 to 2010 and 3231 matched subjects who had not been exposed to C difficile. Subjects were identified based on International Classification of Diseases, 9th revision, Clinical Modification codes for C difficile disease. RESULTS: C difficile was associated independently with increased rate ratios (RRs) for incident irritable bowel syndrome (RR, 6.1; 95% confidence interval [CI], 2.9-12.9), gastroesophageal reflux disease (GERD) (RR, 1.9; 95% CI, 1.4-2.6), dyspepsia (RR, 3.3; 95%, 1.4-7.7), and constipation (RR, 2.2; 95% CI, 1.3-3.7). Approximately 14.1% of subjects with C difficile later were identified with one of these functional gastrointestinal disorders (FGDs), compared with 6% of controls. Community- and health care-associated C difficile were associated at similar rates with these sequelae. Patients were at increased risk for FGDs within 3 months of a C difficile episode, with one additional case of FGD developing for every 12 diagnoses of C difficile. CONCLUSIONS: The incidence of community- and health care-associated C difficile has increased in the US military population from 1998 through 2010. As for other gastrointestinal infections, C difficile disease is associated with clinically relevant functional sequelae in this military population.

The Epidemiology of Irritable Bowel Syndrome in the US Military: Findings from the Millennium Cohort Study.

OBJECTIVES: Functional gastrointestinal disorders occur more frequently among deployed veterans, although studies evaluating the relative impact of risk factors, including stress and antecedent infectious gastroenteritis (IGE), are limited. We examined risk factors for new-onset irritable bowel syndrome (IBS) among active duty participants in the military's Millennium Cohort Study. METHODS: Medical encounter data from 2001 to 2009, limited to Cohort members on active duty, were used to identify incident IBS cases (any and highly probable). IGE was identified using medical encounter or self-report. Covariate data were obtained from the Millennium Cohort Study surveys and analyzed using Cox proportional hazards methods. RESULTS: Overall, 41,175 Cohort members met the eligibility criteria for inclusion and 314 new-onset cases of IBS were identified among these. Significant risk factors (adjusted hazard ratio, 95% confidence interval) included antecedent IGE (2.05, 1.53-2.75), female gender (1.96, 1.53-2.52), number of life stressors (1: 1.82, 1.37-2.41; 2: 2.86, 2.01-4.06; 3+: 6.69, 4.59-9.77), and anxiety syndrome (1.74, 1.17-2.58). Limited to highly probable IBS, a stronger association with antecedent IGE was observed, particularly when based on medical encounter records (any IGE: 2.20, 1.10-4.43; medical encounter IGE only: 2.84, 1.33-6.09). Precedent anxiety or depression and IGE interacted with increased IBS risk compared with IGE alone. CONCLUSIONS: These results confirm previous studies on the association between sociodemographic or life stressors and IBS. IGE was significantly associated with IBS risk. Whether deployed or not, US service members often encounter repeated exposure to high levels of stress, which, combined with other environmental factors such as IGE, may result in long-term debilitating functional gastrointestinal disorders.

Typhoid fever cases in the U.S. military.

BACKGROUND: Salmonella enterica, serovar Typhi (S. Typhi), a causative agent of enteric fever (typhoid fever), predominately affects populations in developing regions with poor access to clean food and water. In addition, travelers to these regions are at risk of exposure. METHODS: We report the epidemiological characteristics of S. Typhi cases among active duty United States military personnel from 1998 to 2011 using data obtained from the Defense Medical Surveillance System. Cases were identified based on International Classification for Disease Ninth Edition - Clinical Modification codes. RESULTS: We identified a total of 205 cases S. Typhi for an incidence of 1.09 per 100,000 person-years. Cases were on average 31.7 years old, predominately married (n = 129, 62.9 %), Caucasian (n = 142, 69.3 %), male (n = 176, 85.9 %), and had a high school education (n = 101, 49.3 %). Of the identified cases, 122 had received a Typhoid vaccination within 4 years of diagnosis. CONCLUSION: This study provides an overview of enteric fever in the United States military. The incidence was similar to the general U.S. population except for increased incidence from 1998 to 2000, perhaps attributable to operational deployments in that period. Given that vaccination is an effective primary prevention measure against typhoid fever, active monitoring of pre-deployment vaccine history is warranted.