Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery.

BACKGROUND & AIMS: Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery. METHODS: We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P < .05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration. RESULTS: A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716-1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793-1.960). Detectable TNFi drug concentration was not associated with any infection or SSI. CONCLUSIONS: Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort.

Coronary artery calcium scoring for cardiovascular risk assessment in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with higher incidence of atherosclerotic cardiovascular disease (ASCVD). Data investigating the role of coronary artery calcium (CAC) scoring in identifying subclinical atherosclerotic disease in IBD patients is scarce. METHODS: Using data obtained from the CLARIFY registry, a prospective study of no-charge coronary artery calcium (CAC) testing at University Hospitals, we reviewed patients with ulcerative colitis (UC) or Crohn's disease (CD) who underwent CAC scoring from 2014 to 2020. We investigated the concordance between CAC risk and 10-year estimated ASCVD risk by AHA/ACC pooled cohort equation using pre-established thresholds for statin prescription (CAC≥100, 10-year ASCVD risk ≥7.5%). We additionally investigated the association between CAC, preventive therapy initiation and Major Adverse Cardiovascular Events (MACE). RESULTS: A total of 369 patients with IBD were included (174 UC, 195 CD), with median age of 60 years. The median CAC score was 14.9 with no significant difference between UC and CD (P = .76). Overall, 151 (41%) had CAC of 0, 108 (29%) had CAC 1-99, 61 (17%) had CAC 100 to 399, and 49 (13%) had CAC ≥400 with no difference in CAC distribution between CD and UC (P = .17). There was no difference in median CAC between IBD or age/sex-matched controls (P = .34). Approximately half of the patients (52%) with IBD had 10-year estimated ASCVD risk of 7.5% or higher. Among patients with ASCVD risk <7.5% (n = 163), 29 (18%) had CAC≥100 and among patients with ASCVD risk ≥7.5% (n = 178), 102 (57%) had CAC <100. There was no difference between CAC<100 vs CAC≥100 with respect to CRP, use of immunosuppressive or amino-salicylate therapy, IBD severity or complications. CAC score (AUROC 0.67 [0.56-0.78]), but not PCE ASCVD risk (AUROC 0.60 [0.48-0.73]), was predictive of MACE. The best cut-off for CAC score was 76 (sensitivity = 60%, specificity = 69%), and was associated with 4-fold increase in MACE (Hazard Ratio 4.0 [2.0-8.1], P < .001). CONCLUSION: Subclinical atherosclerosis, as evaluated by CAC scoring, is prevalent in patients with IBD, and is associated with cardiovascular events. Further studies are needed to understand underlying biological processes of increased atherosclerotic disease risk among adults with IBD.

Role of through-the-scope catheter-based EUS in inflammatory bowel disease diagnosis and activity assessment.

BACKGROUND AND AIMS: Distinguishing Crohn's disease (CD) from ulcerative colitis (UC) may be difficult when the disease is limited to the colon. Transmural healing is an important adjunctive measure of inflammatory bowel disease activity. The aim of this study was to examine the role of EUS in differentiating CD versus UC and evaluating transmural disease activity. METHODS: This prospective cohort study enrolled 20 patients with CD (10 active [aCD], 10 inactive), 20 patients with UC (10 active [aUC], 10 inactive), and 20 control subjects who underwent colonoscopy from 2019 to 2021 at a tertiary care center. Measurements of bowel wall layer thickness from the rectum and cecum were obtained using a through-the-scope US catheter (UM-3R-3; Olympus, Center Valley, Penn, USA) at the time of colonoscopy. RESULTS: Compared with control subjects, patients with aCD had thicker rectal submucosa and total wall layer (submucosa median, 1.80 mm [interquartile range {IQR}, 1.40-2.00] vs .60 mm [IQR, .40-.70]; total wall median, 3.70 mm [IQR, 3.52-4.62] vs 2.10 mm [IQR, 1.70-2.40], respectively; P < .01). Similar significant findings were observed for the cecal wall layers. Compared with control subjects, patients with aUC had thicker rectal mucosa and total wall but not submucosa or muscularis propria layers (mucosa median, 1.35 mm [IQR, 1.12-1.47] vs .60 mm [IQR, .57-.70]; total wall median, 3.45 mm [IQR, 2.85-3.75] vs 2.10 mm [IQR, 1.70-2.40], respectively; P < .01). Patients with aCD compared with those with aUC had a significantly thicker rectal submucosa layer (median, 1.80 mm [IQR, 1.40-2.00] vs .55 mm [IQR, .40-.75], respectively, P < .01). Cutoff values of 1.1 mm for rectal submucosa in CD (sensitivity, 1.0; specificity, 1.0) and 1.1 mm for rectal mucosa in UC (sensitivity, .8; specificity, .9) were found to differentiate active from inactive disease. CONCLUSIONS: EUS measurements of colon wall layers can help diagnose aCD versus aUC and assess transmural disease activity. (Clinical trial registration number: NCT03863886.).

Rates of Intestinal Resection and Colectomy in Inflammatory Bowel Disease Patients After Initiation of Biologics: A Cohort Study.

BACKGROUND & AIMS: 50% to 80% Crohn's disease (CD) and 10% to 30% ulcerative colitis (UC) patients require surgery over their lifetime. Biologic therapies may alter this natural history, but data on the effect of biologics on surgery rates in this patient population are mixed. We sought to investigate the influence of biologics on surgery prevalence in CD and UC. METHODS: We used a commercial database (Explorys Inc, Cleveland, OH), which includes electronic health record data from 26 major integrated US healthcare systems. We identified all patients who were diagnosed with CD or UC that were treated with any biologics between 2015 and 2020. The primary outcome was to examine the association between biologics therapy and the prevalence of bowel resection. Also, we identified the factors associated with surgery in IBD patients on biologics. RESULTS: Of 32,904,480 patients in the database, we identified 140,540 patients with CD and 115,260 patients with UC, of whom 25,840 (18%) and 9,050 (7.8%) patients received biologics, respectively. The prevalence of intestinal resection was significantly lower in biologics-treated CD patients (9.3%) compared to those who did not receive biologics (12.1%) (p < .001). Similarly, biologic-treated UC patients were significantly less likely to undergo colectomy (7.3%) compared to UC patients who did not receive biologic therapy (11.0%) (p < .001). Tobacco use, Clostridium difficile infection, and perianal disease were associated with intestinal resection in CD. Colon neoplasm and Clostridium difficile infection were associated with colectomy in UC. CONCLUSIONS: In this study of a large healthcare administrative database, inflammatory bowel disease (IBD) patients treated with biologics were significantly less likely to undergo bowel resection when compared to those who never received biologics. This data suggests that biologics may impact surgical rates in IBD.

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases.

Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease. To inform these clinical guidelines, this technical review was developed in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework for interventional and prognostic studies, and focused on the application of TDM for biologic therapy, specifically anti-tumor necrosis factor-α agents, and for thiopurines. Focused questions address the benefits and risks of a strategy of reactive TDM (in patients with active inflammatory bowel disease) to guide treatment changes compared with empiric treatment changes, and the benefits and risks of a strategy of routine proactive TDM (during routine clinical care in patients with quiescent disease) compared with no routine TDM. Additionally, the review addresses the benefits and risks of routine measurement of thiopurine methyltransferase enzyme activity or genotype before starting thiopurine therapy compared with empiric weight-based dosing and explores the performance of different trough drug concentrations for anti-tumor necrosis factor agents and thiopurines to inform clinical decision making when applying TDM in a reactive setting. Due to a paucity of data, this review does not address the role of TDM for more recently approved biologic agents, such as vedolizumab or ustekinumab.

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

BACKGROUND & AIMS: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities. METHODS: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database). Single-nucleotide polymorphisms (SNPs) associated at P < 5.0 × 10-8 in meta-analysis with a nominal evidence (P < .05) in each scan were considered to have genome-wide significance. RESULTS: We detected SNPs at HLA-DRB1, and African-specific SNPs at ZNF649 and LSAMP, with associations of genome-wide significance for UC. We detected SNPs at USP25 with associations of genome-wide significance for IBD. No associations of genome-wide significance were detected for CD. In addition, 9 genes previously associated with IBD contained SNPs with significant evidence for replication (P < 1.6 × 10-6): ADCY3, CXCR6, HLA-DRB1 to HLA-DQA1 (genome-wide significance on conditioning), IL12B,PTGER4, and TNC for IBD; IL23R, PTGER4, and SNX20 (in strong linkage disequilibrium with NOD2) for CD; and KCNQ2 (near TNFRSF6B) for UC. Several of these genes, such as TNC (near TNFSF15), CXCR6, and genes associated with IBD at the HLA locus, contained SNPs with unique association patterns with African-specific alleles. CONCLUSIONS: We performed a genome-wide association study of African Americans with IBD and identified loci associated with UC in only this population; we also replicated IBD, CD, and UC loci identified in European populations. The detection of variants associated with IBD risk in only people of African descent demonstrates the importance of studying the genetics of IBD and other complex diseases in populations beyond those of European ancestry.

Clonal Parabacteroides from Gut Microfistulous Tracts as Transmissible Cytotoxic Succinate-Commensal Model of Crohn's Disease Complications.

Crohn's disease (CD) has been traditionally viewed as a chronic inflammatory disease that cause gut wall thickening and complications, including fistulas, by mechanisms not understood. By focusing on Parabacteroides distasonis (presumed modern succinate-producing commensal probiotic), recovered from intestinal microfistulous tracts (cavernous fistulous micropathologies CavFT proposed as intermediate between 'mucosal fissures' and 'fistulas') in two patients that required surgery to remove CD-damaged ilea, we demonstrate that such isolates exert pathogenic/pathobiont roles in mouse models of CD. Our isolates are clonally-related; potentially emerging as transmissible in the community and mice; proinflammatory and adapted to the ileum of germ-free mice prone to CD-like ileitis (SAMP1/YitFc) but not healthy mice (C57BL/6J), and cytotoxic/ATP-depleting to HoxB8-immortalized bone marrow derived myeloid cells from SAMP1/YitFc mice when concurrently exposed to succinate and extracts from CavFT-derived E. coli , but not to cells from healthy mice. With unique genomic features supporting recent genetic exchange with Bacteroides fragilis -BGF539, evidence of international presence in primarily human metagenome databases, these CavFT Pdis isolates could represent to a new opportunistic Parabacteroides species, or subspecies (' cavitamuralis' ) adapted to microfistulous niches in CD.

Circulating CD4(+) and CD8(+) T cells are activated in inflammatory bowel disease and are associated with plasma markers of inflammation.

Inflammatory bowel disease (IBD) is characterized by damage to the gut mucosa and systemic inflammation. We sought to evaluate the role of chronic inflammation on circulating T-cell activation in human subjects with Crohn's disease and ulcerative colitis. We studied 54 patients with IBD and 28 healthy controls. T-cell activation and cycling were assessed in whole blood samples by flow cytometry. Levels of lipopolysaccharide (LPS) were measured in serum by Limulus amoebocyte lysate assay, and plasma levels of inflammatory markers and LPS-binding proteins were measured by ELISA. The proportions of circulating CD4(+) and CD8(+) T lymphocytes in cycle (Ki67(+) ) are increased in patients with IBD compared with these proportions in controls. CD8(+) T cells from patients with IBD are also enriched for cells that expressed CD38 and HLA-DR, and proportions of these cells are related to plasma levels of interleukin-6 and C-reactive protein in these patients. Intracellular interleukin-2 and interferon-γ levels were elevated in resting and polyclonally activated CD4(+) and CD8(+) T cells in patients with IBD when compared with levels from healthy controls. Surprisingly, we did not find increased levels of LPS in the serum of patients with IBD. We did, however, find a signature of recent microbial translocation, as levels of LPS-binding protein are increased in the plasma of patients with IBD compared with plasma levels in healthy controls; LPS-binding protein levels are also directly related to proportions of CD38 HLA-DR-expressing CD4(+) and CD8(+) T cells. Local damage to the gastrointestinal tract in IBD may result in systemic inflammation and T-cell activation.

Sweets and Inflammatory Bowel Disease: Patients Favor Artificial Sweeteners and Diet Foods/Drinks Over Table Sugar and Consume Less Fruits/Vegetables.

BACKGROUND: While artificial sweeteners are deemed safe, preclinical studies indicate that artificial sweeteners contribute to gastrointestinal inflammation. Little is known about patients' perceptions and consumption of artificial sweeteners in inflammatory bowel disease (IBD). We surveyed the consumption frequency and beliefs of IBD patients and control participants regarding artificial sweeteners. METHODS: We surveyed 130 individuals (IBD patients, n = 93; control/non-IBD participants, n = 37) among our tertiary hospital population to determine consumption frequency and beliefs regarding artificial sweeteners (Splenda/sucralose, Stevia/stevia, NutraSweet/Equal/aspartame). A 14-question questionnaire surveyed the frequency of 9 dietary habits, preferences, and beliefs on health benefits of commercial artificial sweeteners, using the following as positive and negative control questions: table sugar, water, fruits/vegetables, and coconut-oil, among others. RESULTS: Despite the similarity in yes/no consumption data, artificial sweeteners (Q4 t test P = .023) and diet (low calorie) foods/drinks (Q4 t test P = .023) were consumed more frequently by patients with IBD than by control participants, while no difference in preference for water instead of juices/sodas was observed between IBD patients and control participants. Conversely, patients with IBD consumed table sugar less frequently than control participants (Q1 t test-P = .09), in agreement with their reporting of sugary foods as cause of symptoms (P < .01). A positive correlation was observed between artificial sweeteners and fresh fruits/vegetables among the first 31 IBD patients (Spearman P = .017) and confirmed with 62 new IBD patients (r = 0.232; 95% CI, 0.02-0.43; P = .031), indicating that artificial sweeteners are deemed a healthy habit in IBD. Excluding fresh fruits/vegetables, multivariate analyses to develop surrogate principal component analysis indexes of healthy habits confirmed that artificial sweeteners consumption follows healthy preferences among our IBD patients (adjusted P < .0001). CONCLUSIONS: Consumption of artificial sweeteners correlated with healthy habits, suggesting that our IBD population deemed artificial sweeteners as healthy and/or had preferences for naturally or artificially sweetened flavors and products.

Artificial sweeteners and artificially sweetened (diet, low calorie) foods/drinks are consumed more often by inflammatory bowel disease patients compared with control participants, and inflammatory bowel disease patients deem artificial sweeteners consumption as a healthy habit, when differentiating between table sugar and artificial sweeteners.

High Burden of Obesity and Low Rates of Weight Loss Pharmacotherapy in Inflammatory Bowel Disease: 10-Year Trend.

Background: The prevalence of obesity and inflammatory bowel disease (IBD) has increased in the last decade. There is a paucity of data on the recent trend of obesity and the utilization of anti-obesity pharmacotherapy in IBD. We aimed to use a population-level database to analyze their trends. Methods: A retrospective analysis of population-level data from 2010 to 2019 was performed among individuals ≥18 years of age using a commercial database, IBM Explorys. The prevalence and trends of obesity, diabetes mellitus type 2 (DM2), essential hypertension, dyslipidemia and/or hyperlipidemia, sleep apnea, and anti-obesity pharmacotherapy were studied. Univariate analysis using chi-square test and trend analysis using the Cochrane Armitage test were performed. Results: Among 39 717 520 adults, 37.3% of IBD patients have a diagnosis of obesity (Crohn's disease 36.9% vs ulcerative colitis 38.5%, P < .0001). The proportion of IBD adults with obesity and metabolic comorbidities increased from 2010 to 2019: obesity (19.7%-30.1%), DM2 (8.3%-12.5%), hypertension (25.1%-33.9%), hyperlipidemia (22.1%-32.2%), and sleep apnea (4.1%-10.8%). All comparisons were statistically significant (P < .0001). Only 2.8% of eligible adults with obesity were prescribed anti-obesity pharmacotherapy in the last 10 years, with trends increasing from 1.4% to 3.6%, 2010-2019. Conclusions: With obesity being a harbinger for metabolic syndrome, the increase in obesity in IBD patients was accompanied by a concomitant increase in the diseases associated with obesity in the past decade. However, this alarming rise in obesity was accompanied by a disproportionately small increase in anti-obesity pharmacotherapy similar to general population.

Predictors of Hospital-related Outcomes of COVID-19 Infection in Patients With Inflammatory Bowel Disease in the Early Pandemic Phase: A Nationwide Inpatient Database Survey.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at higher risk for severe COVID-19 infection. However, most studies are single-center, and nationwide data in the United States are lacking. This study aimed to investigate hospital-related outcomes and predictors of these outcomes in patients with IBD and COVID-19 infection. METHODS: The National Inpatient Sample and National Readmission database were queried for all the patient hospitalizations with IBD with concurrent COVID-19 in the study group and non-COVID-19 related hospitalizations in the control group. For patients under 18 years, elective and trauma-related hospitalizations were excluded. Primary outcomes included mortality, septic shock, mechanical ventilation, and intensive care utilization. Secondary outcomes included length of stay and total hospitalization costs. RESULTS: From this query, 8865 adult patients with IBD and COVID-19 were identified. These patients were relatively older (62.8 vs 57.7 years, P < .01), and the majority were females (52.1% with COVID-19 vs 55.2% without COVID-19). Patients with IBD and COVID-19 had higher mortality (12.24% vs 2.55%; P < .01), increased incidence of septic shock (7.9% vs 4.4%; P < .01), mechanical ventilation (11.5% vs 3.7%; P < .01), and intensive care utilization (12% vs 4.6%; P < .01). These patients also had higher mean length of stay (8.28 days vs 5.47 days; P < .01) and total hospitalization costs ($21 390 vs $16 468; P < .01) than those without COVID-19 infection. CONCLUSIONS: Patients with IBD and COVID-19 have worse outcomes, with a higher incidence of severe COVID-19 disease, leading to higher mortality rates, longer lengths of stay, and increased total hospitalization costs. Encouraging preventive health measures and treating promptly with advanced COVID-19 therapies may improve outcomes and decrease the healthcare burden.

This study used nationwide data to examine hospital-related outcomes in patients with inflammatory bowel disease (IBD) and COVID-19 disease. Patients with IBD and COVID-19 had higher mortality, septic shock, mechanical ventilation, and intensive care utilization rates. They also experienced higher costs and longer hospital stays, highlighting the need for preventive measures and timely treatment to improve outcomes and reduce healthcare burden.

10-Year Trend of Abdominal Magnetic Resonance Imaging Compared With Abdominal Computed Tomography Scans in Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) frequently undergo multiple computed tomography (CT) examinations. With the widespread availability of magnetic resonance imaging (MRI), it is unclear whether the use of CTs in IBD has declined. We aimed to analyze the trends of CT and MRI use in a large cohort of IBD patients in a 10-year period. METHODS: We retrospectively analyzed adults ≥18 years of age using a de-identified database, IBM Explorys. Patients with ≥1 CT of the abdomen (± pelvis) or MRI of the abdomen (± pelvis) at least 30 days after the diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were included. We examined the factors associated with patients undergoing multiple CTs (≥5 CTs of the abdomen) and performed a trend analysis from 2010 to 2019. RESULTS: Among 176 110 CD and 143 460 UC patients, those with ≥1 CT of the abdomen annually increased from 2010 to 2019 with mean annual percentage change of +3.6% for CD and +4.9% for UC. Similarly, annual percentage change for patients with ≥1 MRI (CD: +15.6%; UC: +22.8%) showed a rising trend. There was a 3.8% increase in CD patients receiving ≥5 CTs of the abdomen annually compared with a 2.4% increase among UC patients in the 10-year period. Age ≥50 years, men, African Americans, public insurance payors, body mass index ≥30kg/m2, and smoking history were associated with ≥5 CTs. CONCLUSIONS: There is a considerable increase in the number of CT scans performed in IBD patients. Further studies can explore factors influencing the use of CT and MRI of the abdomen in IBD patients.

The proportion of inflammatory bowel disease patients with ≥5 computed tomographies of the abdomen annually has increased by 2.4%-3.8% from 2010 to 2019. Age ≥50 years, men, African Americans, public insurance payors, body mass index ≥30kg/m2, and smoking history were associated with ≥5 computed tomographies of the abdomen annually.

A randomized, double-blind, placebo-controlled pilot study of Lactobacillus reuteri ATCC 55730 for the prevention of antibiotic-associated diarrhea in hospitalized adults.

GOALS: The purpose of the study was to evaluate Lactobacillus reuteri for the prevention of antibiotic-associated diarrhea (AAD) in hospitalized adults. BACKGROUND: AAD is a problem in hospitalized adults, contributing to increased length of stay, cost, and mortality. Probiotics have been proposed as a way to prevent AAD. L. reuteri decreases acute infectious diarrhea in children; however, L. reuteri has never been evaluated for the prevention of AAD. STUDY: In a randomized, double-blind, placebo-controlled pilot study, in-patients receiving antibiotics were given L. reuteri 1×10 colony-forming units twice daily or an identical placebo for 4 weeks. Stool frequency, consistency, and gastrointestinal symptoms were monitored during the 4-week treatment period and during a 2-week follow-up period. RESULTS: A total of 31 patients were enrolled. Eight patients were excluded in the data analysis because of length of study participation less than 14 days. Mean age was 51 ± 18 years; 63% were female and 37% male. Most frequent primary diagnosis was pneumonia (20%), followed by abscess (10%), chronic obstructive pulmonary disease (6.7%), and bronchitis (6.7%). Thirteen patients received L. reuteri and 10 received placebo. Patients treated with L. reuteri had a significantly lower frequency of diarrhea compared with placebo (50% in the placebo group vs. 7.7% in the probiotic group, P=0.02). There were no differences in the frequency or severity of gastrointestinal symptoms. CONCLUSIONS: In this placebo-controlled, pilot study, L. reuteri twice daily for 4 weeks significantly decreased AAD among hospitalized adults. L. reuteri was safe and well tolerated.

Infliximab-Induced Acute Liver Failure in a Patient With Crohn's Disease Requiring Orthotopic Liver Transplantation.

Tumor necrosis factor-alpha inhibitors are not known to have significant liver toxicity; however, a few case reports state otherwise. We report the case of a 25-year-old man with Crohn's disease who was initiated on infliximab. The patient developed severe mixed hepatocellular and cholestatic liver injury that progressed into acute liver failure. Based on clinical history, laboratory findings, and histology, this was presumed because of the development of autoimmune hepatitis secondary to infliximab. He underwent liver transplantation. The mainstay of treatment in this rare condition involves steroid therapy and possible transplantation. Patients must then avoid anti-tumor necrosis factor-alpha therapy for life.