Faculty Bibliography

Introduction: The etiology of acute diarrhea in solid organ transplant (SOT) recipients requires rapid diagnosis to avoid severe infection or graft loss, especially for those requiring hospitalization. We aimed to characterize factors associated with hospitalization for enteric infection as detected by multiplex gastrointestinal PCR panel (GI panel) stool testing in SOT recipients.
Method(s): We performed a cross-sectional study at two academic institutions of inpatient and outpatient SOT recipients who underwent stool testing over 3 years with a FilmArray GI panel during an acute episode of diarrhea. A multivariate analysis was performed to identify factors predictive of hospitalization.
Result(s): Of 300 SOT recipients with an acute episode of diarrhea, 68% (n=204) were hospitalized at the time of sample collection (Table 1). On univariate analysis, hospitalized patients were less likely to have a pathogen identified on the GI panel compared to non-hospitalized patients (33% vs 53%, p, 0.001) - specifically, fewer viral enteric infections (14% vs 27%, P=0.007). Hospitalized patients were more likely to have fever (29% vs 6.3%, p< 0.001) and had a higher 30-day mortality than those not hospitalized (16.9% vs 4.2%; P=0.002). The number of immunosuppressive agents was not associated with hospitalization (P=0.913). In the multivariate analysis adjusting for age, sex, race, Charlson's comorbidity index, antimicrobial prophylaxis, recent hospitalization, transplant type, degree of immunosuppression, and transplant age, fever (odds ratio [OR] 6.8; 95% confidence interval [CI] 2.9- 19), nausea/vomiting (OR 2.5; 95% CI 1.2-5.4) and negative GI panel (OR 2.0; 95% CI 1.1-3.7) were associated with hospitalization. Compared to other organs, renal transplant (OR 0.318, 95% CI 0.133- 0.723) was associated with lower likelihood of hospitalization.
Conclusion(s): In SOT recipients presenting with acute diarrhea, symptoms of severe illness, such as fever and emesis, and a negative GI Panel, were associated with hospitalization. Renal transplant was inversely associated with hospitalization. Diarrheal illness in SOT patients may be caused by pathogens not identified on the GI panel or from non-infectious causes such as immunosuppressive, antimicrobial, or bowel regimen medications. Further elucidation of these non-infectious diarrheal etiologies in SOT recipients hospitalized for acute diarrhea may potentially avoid major complications, such as graft loss, severe infection, and death.

The microbial populations in the gut microbiome have recently been associated with COVID-19 disease severity. However, a causal impact of the gut microbiome on COVID-19 patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. Antibiotics and other treatments during COVID-19 can potentially confound microbiome associations. We therefore first demonstrate that the gut microbiome is directly affected by SARS-CoV-2 infection in a dose-dependent manner in a mouse model, causally linking viral infection and gut microbiome dysbiosis. Comparison with stool samples collected from 97 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, paralleling our observations in the animal model. Specifically, we observed blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species in hospitalized COVID-19 patients. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data obtained from these patients suggest that bacteria translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID 19.

Background/UNASSIGNED:Early life exposures impact immune system development and therefore the risk of immune-mediated diseases, including inflammatory bowel disease (IBD). We systematically reviewed the impact of pre-, peri‑, and postnatal exposures up to the age of five years on subsequent IBD diagnosis. Methods/UNASSIGNED:We identified case-control and cohort studies reporting on the association between early life environmental factors and Crohn's disease (CD), ulcerative colitis (UC), or IBD overall. Databases were search from their inception until May 24th, 2019 until July 14th, 2020. We conducted meta-analyses for quantitative review of relevant risk factors that were comparable across studies and qualitative synthesis of the literature for a wide range of early life exposures, including maternal health and exposures during pregnancy, perinatal factors, birth month and related-factors, breastfeeding, hygiene-related factors and social factors, immigration, antibiotics, offspring health, including infections, and passive smoking. PROSPERO registration: CRD42019134980. Findings/UNASSIGNED:Prenatal exposure to antibiotics (OR 1.8; 95% CI 1.2-2.5) and tobacco smoke (OR 1.5; 95% CI 1.2-1.9), and early life otitis media (OR 2.1; 95% CI 1.2-3.6) were associated with IBD. There was a trend towards an association between exposure to antibiotics in infancy and IBD (OR: 1.7, 95% CI 0.97, 2.9), supported by positive data on population-based data. Breastfeeding was protective against IBD. Other early life risk factors had no association with IBD, but data were limited and heterogenous. Interpretation/UNASSIGNED:Early life is an important period of susceptibility for IBD development later in life. Tobacco smoke, infections and antibiotics were associated positively, and breastfeeding was associated negatively with IBD. Our findings offer an opportunity to develop primary prevention strategies. Funding/UNASSIGNED:This study did not receive any funding.

Background: Ustekinumab has been recently approved for the treatment of moderately to severely active ulcerative colitis (UC). The registry trials for ustekinumab in UC demonstrated efficacy and safety, but data on real-world outcomes are limited. We describe the effectiveness and safety of ustekinumab in patients with UC from 2 US tertiary inflammatory bowel disease centers. Methods: Patients with moderately to severely active UC treated with ustekinumab at NYU Langone Health (New York, New York) and University of Chicago Medical Center (Chicago, Illinois) between January 2016 and March 2020 were retrospectively included. The primary outcome was clinical remission at 3 and 12 months, defined as a partial Mayo score of ≤2, with a combined rectal bleeding and stool frequency subscore of ≤1. Results: Sixty-six UC patients were included. Ninety-two percent of patients had prior exposure to biologics or tofacitinib. Forty-three percent and 45% of patients achieved clinical remission by 3 and 12 months, respectively. Anti-TNF nonresponse and endoscopic Mayo score of 3 were negative predictors of clinical remission. Thirty-three percent of those followed for a year achieved concurrent endoscopic and histologic healing, which was significantly associated with lower partial Mayo score (P < 0.01) and lower stool frequency (P = 0.02). Serious adverse events occurred in 4 (6%) patients (3 UC exacerbations, 1 vasculitis). Conclusions: In this cohort of mostly biologic-refractory UC patients, treatment with ustekinumab achieved remission in nearly half of them at 12 months, and was associated with an overall favorable safety profile. These results are modestly better than the pivotal trials.

The inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract. Imbalance in the gut microbial community, or dysbiosis, and the subsequent immune response, represent the critical relationship between genetic susceptibility, microbes, and environment factors, that result in IBD. Gastrointestinal pathogens - a common cause of dysbiosis - have been implicated as an environmental trigger in new onset IBD, as well as flare of existing IBD. In this article, we systematically review clinical data regarding the association between specific gastrointestinal pathogens and IBD. Numerous bacteria, viruses, fungi, and parasites have been implicated in the pathogenesis of IBD, and exacerbations of existing disease. In this article, we will also specifically discuss the less recognized microbes that have an inverse association with IBD, including certain bacterial pathogens, such as Helicobacter pylori, and parasites, such as Trichuris species. Future prospective and experimental studies are required to establish causality and clarify potential mechanisms of enteric pathogens in modifying the risk and course of IBD.

BACKGROUND:There are concerns that individuals with chronic immune-mediated diseases are at increased risk of COVID-19 and related severe adverse outcome, including intensive care admission or death. We aimed to explore the absolute and relative risk of severe COVID-19 in inflammatory bowel disease (IBD). METHODS:This population-based cohort study used nationwide registers in Sweden, with 67,292 individuals with a diagnosis of IBD 1969-2017 (Crohn's disease, n = 21,599; ulcerative colitis: n = 43,622; IBD-unclassified: n = 2071) and alive on 1 February 2020. Patients with IBD were matched to up to five controls from the general population (n = 297,910). Cox regression estimated hazard ratios (HRs) for (i) hospital admission with laboratory-confirmed COVID-19 as the primary diagnosis, and (ii) severe COVID-19 (composite outcome consisting of (a) COVID-19 intensive care admission, or (b) death from COVID-19 or (c) death within 30 days of COVID-19 hospital admission), were calculated. Analyses were conditioned on age, sex, calendar period, and county and adjusted for other comorbidities. RESULTS:Between 1 February and 31 July 2020, 179 (0.27%) IBD patients and 500 (0.17%) general population controls were admitted to hospital with COVID-19 (adjusted HR [aHR] = 1.43; 95% CI = 1.19-1.72). The corresponding numbers for severe COVID-19 was 65 (0.10%) and 183 (0.06%; aHR = 1.11; 95% CI = 0.81-1.52). Adjusted HRs were similar in Crohn's disease and ulcerative colitis. In a propensity score-matched model taking comorbidity into account until 2016, the increased risk for COVID-19 hospital admission remained (aHR = 1.32; 1.12-1.56), but there was no increased risk of severe COVID-19 (aHR = 1.12; 0.85-1.47). CONCLUSIONS:While individuals with IBD were more likely to be admitted to hospital for COVID-19 than the general population, the risk of severe COVID-19 was not higher.

BACKGROUND:There is wide variation in the quality of care of hospitalized patients with inflammatory bowel disease (IBD). Prior studies have demonstrated that a specialized inpatient IBD service improves short-term outcomes. In this study, we assessed the impact of a dedicated IBD service on the quality of care and long-term outcomes. METHODS:This retrospective cohort study included adult patients admitted for a complication of IBD between March 2017 and February 2019 to a tertiary referral center. In March 2018, a dedicated inpatient IBD service co-managed by IBD gastroenterologists and colorectal surgeons was implemented. Quality of care outcomes included C. difficile stool testing, confirmed VTE prophylaxis administration and opiate avoidance. Long-term outcomes were clinical remission, IBD-related surgery, ED visits, and hospital readmissions at 90 days and 12 months. RESULTS:In total, 143 patients were included; 66 pre- and 77 post-implementation of the IBD service. Fifty-two percent had ulcerative colitis and 48% had Crohn's disease. After implementation, there was improvement in C.difficile testing (90% vs. 76%, P = 0.04), early VTE prophylaxis (92% vs. 77%, P = 0.01) and decreases in narcotic use (14% vs. 30%, P = 0.02), IBD-related ED visits at 90 days (7% vs 18%, P = 0.03) and 12 months (16% vs 30%, P = 0.04), and IBD readmissions at 90 days (16% vs. 30%, P = 0.04). There were no differences in rates of clinical remission or surgery. CONCLUSIONS:The creation of a dedicated inpatient IBD service improved quality of IBD care and reduced post-discharge ED visits and readmissions and broader implementation of this strategy may help optimize care of hospitalized IBD patients.

BACKGROUND AND AIMS/OBJECTIVE:Gastrointestinal infections have been linked to changes in the composition and function of gut microbiome and development of inflammatory bowel diseases. We therefore sought to examine the relationship between gastroenteritis and risk of microscopic colitis (MC). METHODS:We conducted a case-control study of all adult MC patients diagnosed between 1990-2016 in Sweden matched to up to 5 general population controls according to age, sex, calendar year, and county. Cases of MC were identified using SNOMED codes from the ESPRESSO study, a cohort of gastrointestinal pathology reports from all 28 pathology centers in Sweden. We used logistic regression modeling to estimate adjusted odds ratios (aORs) and 95% CIs. RESULTS:Through December of 2016, we matched 13,468 MC cases to 64,479 controls. The prevalence of previous diagnosed gastrointestinal infection was 7.5% among MC patients which was significantly higher than in controls (3.0%, Pcomparison <0.001). After adjustment, gastroenteritis was associated with an increased risk of MC (aOR 2.63; 95%CI=2.42-2.85). Among specific pathogens, Clostridioides difficile (aOR 4.39, 95%CI=3.42-5.63), Norovirus (aOR 2.87, 95%CI=1.66-4.87) and Escherichia species (aOR 3.82, 95%CI=1.22-11.58) but not Salmonella species were associated with an increased risk of MC. The association between gastrointestinal infections and risk of MC was stronger for collagenous subtype (aOR 3.23, 95% CI 2.81-3.70) as compared to lymphocytic colitis (aOR = 2.51, 95% CI 2.28-2.76, Pheterogeneity = 0.005). The associations remained significant after adjustment for immune-mediated conditions and polypharmacy and when compared to unaffected siblings. CONCLUSION/CONCLUSIONS:In a nationwide study, we found that gastrointestinal infection, particularly Clostridioides difficile is associated with an increased risk of subsequent MC.

BACKGROUND:Differentiating between enteric infection and relapse of inflammatory bowel disease (IBD) is a common clinical challenge. Few studies have evaluated the impact of multiplex gastrointestinal polymerase chain reaction (GI PCR) pathogen panels on clinical practice compared to stool culture. Our aim was to compare the impact of PCR stool testing to conventional stool testing in outpatients presenting with relapse of IBD. METHODS:In a retrospective cohort study of outpatients with IBD presenting to NYU Langone Health with flare from September 2015 to April 2019, we compared patients who underwent stool testing with GI PCR to age-, sex-, and IBD-subtype-matched patients who underwent culture and ova and parasite exam (conventional testing). The primary outcome was IBD therapy escalation after testing. Secondary outcomes included rates of posttesting endoscopy, abdominal radiography, antibiotics, and IBD-related emergency department visits, hospitalizations, and abdominal surgeries. RESULTS:We identified 134 patients who underwent GI PCR matched to 134 patients who underwent conventional testing. Pathogens were more frequently identified on GI PCR (26 vs 5%; P < 0.01). We found that GI PCR was associated with less escalation in IBD therapy (16 vs 29%; P < 0.01) and fewer posttest endoscopies (10% vs 18%; P = 0.04), with no differences in IBD outcomes. On multivariate analysis, testing with GI PCR was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.84; P = 0.02) for escalation of IBD therapies. CONCLUSIONS:Testing with GI PCR was associated with higher rates of pathogen detection and lower rates of IBD therapy escalation and endoscopy in the outpatient setting. These changes in management were not associated with a difference in IBD outcomes.