Systematic Review with Meta-Analysis: Fecal Microbiota Transplantation for Severe or Fulminant Clostridioides difficile.

BACKGROUND: Severe and fulminant Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality. While fecal microbiota transplantation (FMT) has proved to be a highly effective treatment for recurrent CDI, its efficacy in severe or fulminant CDI remains uncertain. AIMS: To perform a systematic review with meta-analysis evaluating clinical outcomes and safety of FMT in severe and fulminant CDI. METHODS: A systemic review with meta-analysis was performed through comprehensive search of Embase, Medline (Ovid), trial registers, and conference abstracts through January 2020. Studies on FMT in severe and fulminant CDI were included. Meta-analysis was done with random effects models given heterogeneity to estimate rates of cure, mortality, and colectomy. Publication bias was assessed using Egger's test. RESULTS: Sixteen studies comprised of one randomized controlled trial, four cohort studies, and eleven case series were analyzed. In total, 676 patients underwent FMT for severe or fulminant CDI. The overall rate of clinical cure after single FMT was 61.3% (95% CI 43.2-78.0%) with 10.9% (95% CI 0.2-30.2%) of patients experiencing major adverse events. The overall pooled colectomy rate after FMT was 8.2% (95% CI 0.1-23.7%) with a pooled all-cause mortality rate after FMT of 15.6% (95% CI 7.8-25.0%). CONCLUSION: Low-quality data support the use of fecal microbiota transplantation in patients with severe and fulminant Clostridioides difficile infection.

Fecal Microbiota Transplantation for Clostridioides difficile in High-Risk Older Adults Is Associated with Early Recurrence.

BACKGROUND: Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridioides difficile infection (CDI). CDI disproportionately affects the elderly; however, there is a paucity of data on FMT effectiveness in older adults, especially subpopulations at highest risk for CDI-related morbidity and mortality. AIM: To assess the efficacy and safety of FMT for CDI in older adults. METHODS: A retrospective, long-term follow-up study was performed. The high-risk subpopulation included patients who were immunocompromised, patients with inflammatory bowel disease, and patients presenting with severe or fulminant colitis. Outcome measures included primary cure rates, early (< 12 weeks) and late (> 12 weeks) recurrence rates, adverse events, and subgroup analysis of higher-risk populations. RESULTS: Our cohort included 75 patients (72% female) with a mean age of 76.4 and Charlson comorbidity index score of 5.4. There were 34 patients in our higher-risk subpopulation as defined above with an adjusted recurrence rate of 32.1%. FMT was performed for severe or fulminant disease in 30.6% of patients with a 3-month survival rate of 73.9%. Overall, the adjusted primary cure rate was 67.2% and the adjusted CDI recurrence was 29.9% in our cohort (90% of recurrences occurred early). Most adverse events in our study were rehospitalizations for recurrent CDI. CONCLUSION: Compared with previous studies of FMT efficacy, our cohort had a lower primary cure rate and higher CDI recurrence rate than previously reported, likely driven by our higher-risk subpopulations. Nevertheless, FMT should be considered early to prevent progression of CDI severity and recurrence, especially in patients who present with severe and fulminant disease.

Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis.

Approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases are caused by mutant superoxide dismutase type 1 (mtSOD1). Although the mechanisms of mtSOD1-induced toxicity remain poorly understood, evidence suggests that accumulation of misfolded SOD1 is fundamental to its toxicity and the death of motor neurons. Misfolded mtSOD1 can accumulate inside the endoplasmic reticulum (ER), leading to ER stress, with activation of the unfolded protein response (UPR). We have previously carried out genetic studies focused on PERK (which is an eIF2α kinase that is rapidly activated in response to ER stress and leads to a repression in translation) and GADD34 (which participates in the dephosphorylation of eIF2α). We reported that mtSOD1 transgenic mice that are haploinsufficient for PERK have a significantly accelerated ALS disease, while mtSOD1 mice that are mutated for GADD34 have a remarkably ameliorated disease. Guanabenz, a centrally acting oral drug approved for the treatment of hypertension, enhances the PERK pathway by selectively inhibiting GADD34-mediated dephosphorylation of eIF2α. We have now treated G93A mtSOD1 transgenic mice with guanabenz and found a significant amelioration of disease with a delay in the onset and prolongation of the early phase of disease and survival. Guanabenz-treated G93A mice have less accumulation of mtSOD1 and an enhanced phosphorylation of eIF2α at endstage. This study further emphasizes the importance of the PERK pathway in the pathogenesis of FALS and as a therapeutic target in ALS, and identifies guanabenz as a candidate drug for the treatment of ALS patients.

Phenotypic instability between the near isogenic substrains BALB/cJ and BALB/cByJ.

Closely related substrains of inbred mice often show phenotypic differences that are presumed to be caused by recent mutations. The substrains BALB/cJ and BALB/cByJ, which were separated in 1935, have been reported to show numerous highly significant behavioral and morphological differences. In an effort to identify some of the causal mutations, we phenotyped BALB/cJ and BALB/cByJ mice as well as their F1, F2, and N2 progeny for behavioral and morphological phenotypes. We also generated whole-genome sequence data for both inbred strains (~3.5× coverage) with the intention of identifying polymorphic markers to be used for linkage analysis. We observed significant differences in body weight, the weight of the heart, liver, spleen and brain, and corpus callosum length between the two substrains. We also observed that BALB/cJ animals showed greater anxiety-like behavior in the open field test, less depression-like behavior in the tail suspension test, and reduced aggression compared to BALB/cByJ mice. Some but not all of these physiological and behavioral results were inconsistent with prior publications. These inconsistencies led us to suspect that the differences were due to, or modified by, non-genetic factors. Thus, we did not perform linkage analysis. We provide a comprehensive summary of the prior literature about phenotypic differences between these substrains as well as our current findings. We conclude that many differences between these strains are unstable and therefore ill-suited to linkage analysis; the source of this instability is unclear. We discuss the broader implications of these observations for the design of future studies.

Clostridioides Difficile Infection Is a Rare Cause of Infectious Pouchitis.

INTRODUCTION: The true incidence of Clostridioides difficile infection (CDI) in patients with an ileal pouch is unknown, and there is little published on its associated risk factors. OBJECTIVE: We aimed to evaluate the rate and risk factors of CDI in pouch patients. METHODS: This was a retrospective review conducted at a single tertiary care inflammatory bowel disease (IBD) center. All ulcerative colitis or IBD-unspecified (IBD-U) patients who underwent total proctocolectomy with ileal pouch anal anastomosis for medically refractory disease or dysplasia between 2008 and 2017 were identified. Symptomatic patients tested for CDI were included. Demographic, disease, and surgical characteristics were collected. Nonparametric methods were used to compare continuous outcomes, and χ2 and Fisher's exact tests were used to compare patients with and without CDI as appropriate. RESULTS: A total of 154 pouch patients had postoperative C. difficilestool testing for symptoms of fever, urgency, increased stool frequency, hematochezia, incontinence, and abdominal and/or pelvic pain. CDI was diagnosed in 11 (7.1%) patients a median of 139 days (IQR 34-1,170) after the final surgical stage. Ten patients (90.9%) received oral vancomycin for 10 days and 1 patient (9.1%) received oral metronidazole for 2 weeks. Ten patients (90.9%) reported improvement in symptoms at completion of therapy. Nine patients (81.8%) were retested for CDI for recurrent symptoms and found to be negative. No patient had CDI recurrence. There was no significant difference in demographic and surgical characteristics, previous antibiotic or proton pump inhibitor use, or previous hospital admission among the patients with and without CDI. CONCLUSIONS: CDI is a rare cause of infectious pouchitis and treatment with oral vancomycin improves symptoms.

Inflammatory Pouch Conditions Are Common After Ileal Pouch Anal Anastomosis in Ulcerative Colitis Patients.

BACKGROUND: Total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) is the gold standard surgery for ulcerative colitis (UC) patients with medically refractory disease. The aim of this study was to report the rates and risk factors of inflammatory pouch conditions. METHODS: This was a retrospective review of UC or IBD unspecified (IBDU) patients who underwent TPC with IPAA for refractory disease or dysplasia between 2008 and 2017. Pouchoscopy data were used to calculate rates of inflammatory pouch conditions. Factors associated with outcomes in univariable analysis were investigated in multivariable analysis. RESULTS: Of the 621 patients more than 18 years of age who underwent TPC with IPAA between January 2008 and December 2017, pouchoscopy data were available for 386 patients during a median follow-up period of 4 years. Acute pouchitis occurred in 205 patients (53%), 60 of whom (30%) progressed to chronic pouchitis. Cuffitis and Crohn's disease-like condition (CDLC) of the pouch occurred in 119 (30%) patients and 46 (12%) patients, respectively. In multivariable analysis, female sex was associated with a decreased risk of acute pouchitis, and pre-operative steroid use and medically refractory disease were associated with an increased risk; IBDU was associated with chronic pouchitis; rectal cuff length ≥2 cm and medically refractory disease were associated with cuffitis; age 45-54 at colectomy was associated with CDLC. Rates of pouch failure were similar in chronic pouchitis and CDLC patients treated with biologics and those who were not. CONCLUSIONS: Inflammatory pouch conditions are common. Biologic use for chronic pouchitis and CDLC does not impact the rate of pouch failure.

Faecal microbiota transplant decreases mortality in severe and fulminant Clostridioides difficile infection in critically ill patients.

BACKGROUND: Severe and fulminant Clostridioides difficile infection is associated with high mortality rates. While faecal microbiota transplant has been shown to be effective for recurrent C difficile infection, there is little data on the utility of faecal microbiota transplant in severe or fulminant C difficile infection. AIM: To compare the outcomes of antibiotics and faecal microbiota transplantation vs antibiotics alone (standard of care) in critically ill patients with severe or fulminant C difficile infection. METHODS: This was a retrospective, matched cohort study in one urban tertiary academic care centre including 48 patients hospitalised with severe or fulminant C difficile infection who required care in intensive care unit. RESULTS: Patients who received faecal microbiota transplantation (n = 16) had a 77% decrease in odds for mortality (OR 0.23, 95% CI 0.06-0.97) with a number needed to treat of 3 to prevent one death. CONCLUSIONS: Faecal microbiota transplantation provides mortality benefit over standard of care for severe and fulminant C difficile infection and should be considered in critically ill patients.

Endoscopic activity in asymptomatic patients with an ileal pouch is associated with an increased risk of pouchitis.

BACKGROUND: The significance of endoscopic activity in asymptomatic ulcerative colitis (UC) patients with an ileal pouch is unknown. AIM: To investigate the association of endoscopic pouch activity in asymptomatic patients with the subsequent development of pouchitis. METHODS: We analyzed a retrospective cohort of patients with UC or IBD-unspecified who underwent a total proctocolectomy with ileal pouch anal anastomosis (IPAA). Asymptomatic patients with a Pouchitis Disease Activity Index (PDAI) symptom sub-score of zero who underwent an index surveillance pouchoscopy were included. Endoscopic pouch body activity was graded as 0: normal, 1: mucosal inflammation, or 2: mucosal breaks (ulcers and/or erosions). The primary outcome was primary acute idiopathic pouchitis defined as PDAI score ≥ 7 with symptoms lasting less than four weeks and responsive to standard antibiotics, not otherwise meeting criteria for secondary pouchitis. The secondary outcome was chronic idiopathic pouchitis defined as PDAI score ≥ 7 with symptoms lasting greater than four weeks despite standard antibiotics. Predictors of pouchitis were analyzed using Kaplan-Meier and Cox regression methods with hazard ratios (HR) and 95% confidence intervals (CI) reported. RESULTS: 143 asymptomatic pouch patients were included. Index endoscopic pouch body activity was 0 in 86 (60.1%) patients, 1 in 26 (18.2%) and 2 in 31 (21.7%). The median length of follow-up after index surveillance pouchoscopy was 3.03 [IQR 1.24-4.60] years. Primary acute idiopathic pouchitis occurred in 44 (31%) patients and chronic idiopathic pouchitis in 12 (8.4%). Grade 2 endoscopic pouch activity was associated with the development of acute pouchitis (HR 2.39, 95% CI 1.23-4.67), although not chronic pouchitis (HR 1.76, 95% CI 0.53-5.87). Histologic inflammation in endoscopically normal pouch mucosa was not associated with acute or chronic pouchitis. CONCLUSIONS: Mucosal breaks are present in nearly a quarter of asymptomatic patients with IPAA and are associated with an increased risk of acute pouchitis.