David R. Tribble

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.

Invasive mold infections following combat-related injuries.

BACKGROUND Major advances in combat casualty care have led to increased survival of patients with complex extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, complication following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity. METHODS The patient population includes US military personnel injured during combat from June 2009 through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and pathologist review of histopathology specimens. RESULTS A total of 37 cases were identified: proven (angioinvasion, n=20), probable (nonvascular tissue invasion, n=4), and possible (positive fungal culture without histopathological evidence, n=13). In the last quarter surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n=16; Aspergillus spp, n=16; Fusarium spp, n=9), commonly with multiple mold species among infected wounds (28%). Clinical outcomes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions (58%). CONCLUSIONS IFIs are an emerging trauma-related infection leading to significant morbidity. Early identification, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending mycology results) among patients with suspicious wounds.

Azithromycin versus Ciprofloxacin for Treatment of Uncomplicated Typhoid Fever in a Randomized Trial in Egypt That Included Patients with Multidrug Resistance

ABSTRACT To compare clinical and bacteriological efficacies of azithromycin and ciprofloxacin for typhoid fever, 123 adults with fever and signs of uncomplicated typhoid fever were entered into a randomized trial. Cultures of blood were positive for Salmonella typhi in 59 patients and for S. paratyphi A in 3 cases; stool cultures were positive for S. typhi in 11 cases and for S. paratyphi A in 1 case. Multiple-drug resistance (MDR; resistance to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole) was present in isolates of 21 of 64 patients with positive cultures. Of these 64 patients, 36 received 1 g of azithromycin orally once on the first day, followed by 500 mg given orally once daily on the next 6 days; 28 patients received 500 mg of ciprofloxacin orally twice daily for 7 days. Blood cultures were repeated on days 4 and 10 after the start of therapy, and stool cultures were done on days 4, 10, and 28 after the start of therapy. All patients in both groups improved during therapy and were cured. Defervescence (maximum daily temperatures of ≤38°C) occurred at the following times [mean ± standard deviation (range)] after the start of therapy: 3.8 ± 1.1 (2 to 7) days with azithromycin and 3.3 ± 1.0 (1 to 5) days with ciprofloxacin. No relapses were detected. Cultures of blood and stool during and after therapy were negative in all cases, except for one patient treated with azithromycin who had a positive blood culture on day 4. These results indicated that azithromycin and ciprofloxacin were similarly effective, both clinically and bacteriologically, against typhoid fever caused by both sensitive organisms and MDRS. typhi.

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.

Infection-associated clinical outcomes in hospitalized medical evacuees after traumatic injury: trauma infectious disease outcome study.

Infections have long been known to complicate care in patients following traumatic injury frequently leading to excess morbidity and mortality.1, 2 In no setting is this more well-recognized than the challenging environment of combat casualty care. During the current military conflicts in Iraq and Afghanistan, Operations Iraqi and Enduring Freedom (OIF/OEF), major advances resulting in increased survival among wounded personnel have been observed. These include enhanced training of medics, forward deployment of surgical assets, rapid medical evacuation, and improvements in body armor.3–5 The significant advances leading to survival are coupled with major challenges in care due to the extensive nature of the injuries, profound bone and soft tissue disruption, and extensive wound contamination.6, 7 In addition, the rapid transit of these patients through multiple echelons of medical care places significant obstacles on infection control in an era of increasing risk due to hospital-associated multidrug resistant (MDRO) organisms.8, 9 The U.S. Department of Defense (DoD) has implemented a range of measures to improve combat casualty care and mitigate risk of infectious complications. A Joint Theater Trauma System and Joint Theater Trauma Registry (JTTR) have been developed to benchmark metrics and to provide a timely assessment of performance improvement interventions.5, 10, 11 Efforts to prevent infection include the development of guidelines for the prevention of infection related to combat injuries through comprehensive review of current evidence and consensus review by military and civilian experts in trauma, infectious disease, infection control, preventive medicine, and surgical specialties.12 In addition, standardized infection control measures across echelons of care accompanied by enhanced MDRO surveillance and serial evaluation have also been implemented.13, 14 Despite the growing literature describing infectious complications of combat-related trauma, there is still a lack of prospectively collected standardized infection data that includes specific therapy, microbiological findings and clinical outcomes across treatment facilities. This report describes the initial data and current status of an ongoing 5-year prospective observational cohort study of infectious complications associated with traumatic injury sustained during deployment, the DoD-Department of Veterans Affairs (VA) Trauma Infectious Disease Outcomes Study (TIDOS).

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.

Assessment of the Duration of Protection in Campylobacter jejuni Experimental Infection in Humans

ABSTRACT A human Campylobacter jejuni infection model provided controlled exposure to assess vaccine efficacy and investigate protective immunity for this important diarrheal pathogen. A well-characterized outbreak strain, C. jejuni 81-176, was investigated using a volunteer experimental infection model to evaluate the dose range and duration of protection. Healthy Campylobacter-seronegative adults received C. jejuni strain 81-176 via oral inoculation of 105, 107, or 109 CFU (5 adults/dose), which was followed by clinical and immunological monitoring. Based on dose range clinical outcomes, the 109-CFU dose (n = 31) was used to assess homologous protection at 28 to 49 days (short-term veterans [STV]; n = 8) or 1 year (long-term veterans [LTV]; n = 7) after primary infection. An illness dose effect was observed for naïve subjects (with lower doses, 40 to 60% of the subjects were ill; with the 109-CFU dose, 92% of the subjects were ill) along with complete protection for the STV group and attenuated illness for the LTV group (57%). Partial resistance to colonization was seen in STV (25% of the subjects were not infected; 3-log-lower maximum excretion level). Systemic and mucosal immune responses were robust in naïve subjects irrespective of the dose or the severity of illness. In contrast, in STV there was a lack of circulating antibody-secreting cells (ASC), reflecting the local mucosal effector responses. LTV exhibited comparable ASC responses to primary infection, and anamnestic fecal IgA responses likely contributed to self-resolving illness prior to antibiotic treatment. Campylobacter antigen-dependent production of gamma interferon by peripheral blood mononuclear cells was strongly associated with protection from illness, supporting the hypothesis that TH1 polarization has a primary role in acquired immunity to C. jejuni. This study revealed a C. jejuni dose-related increase in campylobacteriosis rates, evidence of complete short-term protection that waned with time, and immune response patterns associated with protection.

Update on human Campylobacter jejuni infections.

Purpose of review The present review will update the reader to the clinical, epidemiological and immunologic advances in the field of human campylobacteriosis. Recent findings New advances in human campylobacteriosis include an increased appreciation of the role of Campylobacter jejuni in postinfectious sequelae, a broadened understanding of Campylobacter-associated disease burden and the interplay between host immunity and bacterial factors. Antibiotic management has also become more complex: C. jejuni has undergone a rapid increase in resistance to the fluoroquinolone antibiotics and concurrently, postinfectious irritable bowel syndrome has been associated with a longer duration of untreated infection. In anticipation of new candidate C. jejuni vaccines, progress in understanding human immune responses to infection has been made via human experimental infections. These tightly controlled studies have also increased our understanding of the natural history of campylobacteriosis as well as observations of recrudescent infection following treatment with C. jejuni-sensitive antibiotics. Summary As one of the most common agents of bacterial gastroenteritis and a major health burden for both developing world and industrialized nations, Campylobacter infections remain a high priority for research efforts to improve prevention and management. Priorities for the future include vaccine development, pathogen-specific immunity and identification of risk factors for postinfectious sequelae.

In Vivo Phase Variation and Serologic Response to Lipooligosaccharide of Campylobacter jejuni in Experimental Human Infection

ABSTRACT Some Campylobacter jejuni strains which exhibit mimicry of gangliosides in their lipooligosaccharides (LOSs) are associated with development of Guillain-Barré syndrome, which complicates the selection of a suitable C. jejuni strain in a live-attenuated vaccine. C. jejuni 81-176 is the most well characterized strain available, but structurally, LOS of C. jejuni 81-176 exhibits mimicry of predominantly GM2 and GM3 gangliosides. We compared the antiganglioside human serologic responses of 22 volunteers post-oral vaccination (two-dose series, 14 days apart) with a killed whole-cell C. jejuni vaccine, those of volunteers (22 following initial challenge and 5 upon rechallenge) experimentally infected with the homologous C. jejuni vaccine strain 81-176, and those of 12 volunteers used as controls (placebo recipients). All volunteers were evaluated using thin-layer chromatography immuno-overlay and a panel of nine gangliosides at days 0, 21, and 28 either postvaccination or postinoculation. Antiganglioside antibodies were identified at baseline in 6 of the 61 volunteers (9.8%). There were no antiganglioside antibodies observed following vaccination or experimental infection rechallenge. Evidence of seroconversion was observed in 2 of 22 (9.1%) in the initial infection challenge group, comparable to 1 of 12 (8.3%) in the placebo recipients. Additional testing of seven selected volunteers in the initial challenge group at days 0, 3, 7, 10, 21, 28, and 60 showed that when antiganglioside antibodies occurred (mostly anti-GM1 and -GM2), responses were weak and transient. Furthermore, evidence from serologic probing of LOSs of isolates recovered from stools of six volunteers indicated that the isolates had undergone antigenic phase variation in ganglioside mimicry during passage in vivo. Collectively, with the exception of one volunteer with anti-GM2 antibodies at day 60, the results show an absence of persistent antiganglioside antibodies after experimental infection with C. jejuni or following administration of a killed C. jejuni whole-cell oral vaccine, although LOS phase variation occurred.

Discordance among Commercially Available Diagnostics for Latent Tuberculosis Infection

RATIONALE There is uncertainty regarding how to interpret discordance between tests for latent tuberculosis infection. OBJECTIVES The objective of this study was to assess discordance between commercially available tests for latent tuberculosis in a low-prevalence population, including the impact of nontuberculous mycobacteria. METHODS This was a cross-sectional comparison study among 2,017 military recruits at Fort Jackson, South Carolina, from April to June 2009. Several tests were performed simultaneously with a risk factor questionnaire, including (1) QuantiFERON-TB Gold In-Tube test, (2) T-SPOT.TB test, (3) tuberculin skin test, and (4) Battey skin test using purified protein derivative from the Battey bacillus. MEASUREMENTS AND MAIN RESULTS In this low-prevalence population, the specificities of the three commercially available diagnostic tests were not significantly different. Of the 88 subjects with a positive test, only 10 (11.4%) were positive to all three tests; 20 (22.7%) were positive to at least two tests. Bacille Calmette-Guérin vaccination, tuberculosis prevalence in country of birth, and Battey skin test reaction size were associated with tuberculin skin test-positive, IFN-γ release assay-negative test discordance. Increasing agreement between the three tests was associated with epidemiologic criteria indicating risk of infection and with quantitative test results. CONCLUSIONS For most positive results the three tests identified different people, suggesting that in low-prevalence populations most discordant results are caused by false-positives. False-positive tuberculin skin test reactions associated with reactivity to nontuberculous mycobacteria and bacille Calmette-Guérin vaccination may account for a proportion of test discordance observed.