Faculty Bibliography

Introduction: Previous studies have demonstrated that exposure to anti-TNFa medications or immunomodulators (IMM) does not increase the risk of new or recurrent cancer in patients with inflammatory bowel disease (IBD) and a previous history of cancer. There is little data regarding this risk after the use of newer biologics such as ustekinumab and vedolizumab. In this study, we assessed whether patients with IBD and a history of previous cancer who are exposed to these newer agents have an increased risk of developing subsequent cancer.
Method(s): We performed a retrospective cohort study of patients with IBD and cancer from a single academic medical center between January 2013 and December 2020. We recorded information on demographics, cancer type and treatment, and IBD characteristics and drug exposures. The primary exposure was type of IBD monotherapy after a cancer diagnosis. The primary outcome was development of new or recurrent cancer.
Result(s): Of 401 patients with IBD and a history of cancer, 37 subsequently received vedolizumab, 14 ustekinumab, 31 IMM, 41 anti-TNF, 11 combination anti-TNF with an IMM, and 267 were not exposed to any immunosuppression following a cancer diagnosis (Table 1). There were no differences in duration of IBD, median age at cancer diagnosis, or smoking history. During a total median follow-up of 52 months, 81 (20%) patients developed incident cancer including 6 (16%) exposed to vedolizumab, 2 (14%) to ustekinumab, 3 (10%) to IMM, 12 (29%) to anti-TNF, 2 (18%) to combination anti-TNF with an IMM, and 56 (21%) with no immunosuppression (P = 0.41). Sensitivity analyses assessing any history of exposure to vedolizumab or ustekinumab, inclusive of both single and multiple biologic exposures, also did not reveal an increased rate of incident cancer.
Conclusion(s): In this single-center study, vedolizumab or ustekinumab monotherapy in patients with IBD and a history of cancer was not associated with an increase in new or recurrent cancer compared with anti-TNF, IMM, or no immunosuppression. Prospective studies are needed to confirm this conclusion

Introduction: Acute diarrhea is common in solid organ transplant (SOT) recipients. Although immunosuppression regimens overlap among transplant organ types, it is not known whether particular organ transplants are at higher risk for infectious diarrhea. We compared rates of enteric infection as detected by stool multiplex gastrointestinal PCR panel (GI panel) testing among multiple types of SOT recipients.
Method(s): We performed a cross-sectional study at two academic institutions of inpatient and outpatient recipients of single solid organ transplantation who underwent stool testing with a FilmArray GI panel during an acute episode of diarrhea over 3 years. Patients were stratified by transplant type and the primary outcome was infectious diarrhea by GI panel.
Result(s): Of 300 subjects, there were 58 (19%) heart, 65 (22%) liver, 68 (23%) lung, and 109 (36%) renal single transplant recipients. Use of mTOR inhibitors was less common in lung and renal transplant patients (P<0.001). Lung transplant patients were more likely to be on more immunosuppressive agents (P<0.001; Table) - especially steroids (P<0.001) - and more likely to be on antimicrobial prophylaxis for opportunistic infections (OI). A positive GI panel was identified in 118 (39%) patients, and was more common in renal transplant recipients (54% renal vs. 41% heart vs. 28% liver vs. 25% lung, P<0.001). Bacterial infection was less common in lung transplant recipients (8.8% lung vs. 34% renal vs. 22% heart vs. 22% liver, P=0.002). Hospitalization for acute diarrhea was more common in lung transplant recipients and less common in renal transplant recipients (78% lung vs. 58% renal vs. 68% liver vs. 76% heart, P=0.019). In the multivariate analysis controlling for age, sex, race, comorbidities, prophylaxis, recent hospitalization, and transplant age, use of mTOR inhibitors (Odds Ratio [OR] 3.7, 95% Confidence Interval [CI] 1.1-15), hospitalization (OR 2.3, 95% CI 1.3-4.3), and lung transplant (OR 2.5, 95% CI 1.0-6.4) predicted negative GI panel (Figure 1).
Conclusion(s): In SOT recipients with acute diarrhea, lung transplant patients - who receive more immunosuppression and OI prophylaxis - are more likely to be hospitalized and have a negative GI panel. Lung transplantation, hospitalization, and mTOR inhibitor use independently predict negative GI panel. Transplant and immunosuppression type should be accounted for during the management of acute diarrhea in SOT recipients.

Introduction: Multiplex gastrointestinal pathogen panels (GI PCR) for the detection of enteric infection offer advantages in turnaround time and sensitivity compared to conventional modalities of stool testing. Previous research on GI PCR has focused almost exclusively on hospitalized patients, however, most cases of gastroenteritis are managed in the outpatient setting. Our aim was to compare GI PCR to conventional stool testing in outpatients with gastroenteritis and evaluate the impact on clinical decision-making and management.
Method(s): We performed a retrospective study of outpatients presenting with acute gastrointestinal symptoms at an academicmedical center from September 2015 to April 2019 who received stool testing with GI PCR, and from February 2009 to April 2012 who received stool culture and ova and parasite exam ("conventional testing"). Patients who received GI PCR were matched by age and sex to patients who received conventional testing. We recorded pathogens isolated, demographic data, presenting symptoms, risk factors, antibiotic therapy, and downstream associated healthcare utilization including abdominal imaging, endoscopy, emergency room visits, hospitalizations, and abdominal surgeries. Univariate and multivariate linear regression was used to estimate the effect of testing on empiric antibiotic therapy.
Result(s): We identified 1,018 outpatients who received GI PCR or conventional stool testing. (n = 509 each). A pathogen was isolated in 208 (41%) patients with GI PCR and 49 (10%, P< 0.01, Table 1) with conventional culture. There were no significant differences in overall rates of antibiotic therapy or average duration of therapy, but GI PCR was associated with less empiric therapy (47% vs 70%, P < 0.01), and higher rates of narrowing (13 vs 4%) and discontinuation (3 vs 0%, P < 0.01) of empiric antibiotics after the initial visit, with a 1.6-fold lower likelihood (95% CI 1.04-2.57, P= 0.04) of initiating empiric antibiotics on multivariable analysis. There were no significant differences in other outcomes.
Conclusion(s): GI PCR testing detected more pathogens compared to conventional stool testing, without a significant increase in antibiotics prescribed. PCR testing was associated with changes in prescribing patterns for antibiotics, with a shift towards less empiric therapy

Introduction: Postoperative recurrence (POR) of Crohn's disease (CD) following ileocecal resection (ICR) is common. Endoscopic CD activity guides postoperative management. Histologic activity precedes endoscopic activity. In patients in endoscopic remission, the influence of histologic activity on risk of subsequent POR is unknown. We aimed to assess the impact of histologic activity on subsequent endoscopic POR in CD individuals in endoscopic remission following ICR.
Method(s): Adult CD patients who underwent ICR between the years 2009 to 2020 with no active disease (Rutgeerts' i0) on index colonoscopy with biopsies of the neoterminal ileum or anastomosis were included. Those without a follow up after the first endoscopy were excluded. The rate of composite POR, including endoscopic (>=i2b disease), radiologic, surgical, and pharmacologic recurrence (i.e. change in treatment), was compared between patients with histologic activity versus quiescence using chi-square and Kaplan-Meier survival analysis curves. Cox proportional hazard modeling was used to compare histologic activity to high-risk features of surgical recurrence and use of postoperative biologic prophylaxis.
Result(s): There were 79 CD patients (Mean age 34 years, 49.4% ileocolonic disease, 71.2% stricturing, 34.5% >=1 prior ICR, 27.8% active smoking, and 25.3% treated with postoperative biologic prophylaxis) with i0 disease and random endoscopic biopsies after ICR that were included. Overall composite recurrence rate was 58.2% over median follow up of 1242 days. Histologic activity was not associated with composite POR (P=0.49) including endoscopic (P=0.50), radiologic (0.99), surgical (0.78), or pharmacologic recurrences (Biologic: P=0.59; Immunomodulator: P=0.99; Steroid POR: P=0.54). Composite POR was not significantly different by histologic activity group (P=0.29) (Figure 1). Adjusting for high risk predictive factors of POR, histologic activity was not associated with composite POR (HR 1.71 (0.92-3.21); P=0.09). While active smoking was significantly associated (HR 2.29 (1.11-4.72); P=0.025) with composite POR, postoperative biologic prophylaxis was protective (HR 0.41 (0.20-0.81); P=0.01) (Table 1).
Conclusion(s): Histologic activity in endoscopically normal exam is not associated with endoscopic, radiologic, surgical, and pharmacologic postoperative recurrences. Future studies are required to assess the utility of endoscopic biopsies in CD patients with i0 disease to better guide the management of postoperative CD

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.

BACKGROUND:Inflammatory bowel disease (IBD) patients who have Clostridioides difficile infection (CDI) have worse outcomes. AIMS/OBJECTIVE:We aimed to determine whether such outcomes are the result of CDI or whether CDI occurs in patients who have more severe IBD. METHODS:This was a retrospective study of patients hospitalized for ≥ 2 IBD flares from 2010 to 2019. The primary outcome was time to IBD flare between hospitalizations. First, time to flare was compared between patients who were hospitalized for a flare complicated by CDI and subsequently for a CDI-negative flare (cohort A, denoted +/-) versus patients who were hospitalized for two CDI-negative flares (cohort B, -/-). Second, time between flares was compared within the subset of cohort A patients who had three flares (cohort C, -/+/-) before and after CDI. RESULTS:Time between flares was a median of 4 months (IQR 1-9) among 51 cohort A patients versus 12 months (IQR 6-38) among 51 cohort B patients (log-rank P < 0.01). In contrast, the median time between flares was similar within cohort C before and after CDI (log-rank P = 0.54). At time of the second IBD flare, patients in cohort A (+/-) were more likely to have moderate or severe disease compared to patients in cohort B (-/-). CONCLUSIONS:Patients with prior CDI had shorter time to subsequent IBD flare relative to their CDI-negative counterparts. This is not likely due to CDI itself because there was no difference in time between flares before versus after acquiring CDI. Rather, patients who acquire CDI may have more severe IBD.

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:Sacroiliitis is an inflammatory arthritis of the sacroiliac joints and is associated with inflammatory bowel disease (IBD). Yet, sacroiliitis often goes undiagnosed in IBD, and the clinical association between IBD disease activity and sacroiliitis is not well established. Patients with Crohn's disease (CD) often receive magnetic resonance enterography (MRE) to assess disease activity, affording clinicians the opportunity to evaluate for the presence of sacroiliitis. We aimed to identify the prevalence and disease characteristics associated with sacroiliitis in CD patients undergoing MRE. METHODS:All CD patients undergoing MRE for any indication between 2014 and 2018 at an IBD referral center were identified. The MREs were reviewed for the presence of sacroiliitis based on bone marrow edema (BME) and structural lesions. We analyzed demographics, IBD characteristics, clinical and endoscopic disease activity, and management between CD patients with and without sacroiliitis. RESULTS:Two hundred fifty-eight patients with CD underwent MRE during the study period. Overall, 17% of patients had MR evidence of sacroiliitis, of whom 73% demonstrated bone marrow edema. Female gender, back pain, and later age of CD diagnosis were associated with sacroiliitis (P = 0.05, P < 0.001, P = 0.04, respectively). Disease location and CD therapy were not associated with sacroiliitis on MRE. Clinical, endoscopic, and radiographic disease activity were not associated with sacroiliitis on MRE. CONCLUSION/CONCLUSIONS:Sacroiliitis is a common comorbid condition in CD. With limited clinical clues and disease characteristics to suggest sacroiliitis, physicians may utilize MRE to identify sacroiliitis, especially in CD patients with back pain.