What is known?  Coronavirus disease 2019 (COVID-19) may lead to severe inflammatory response and cytokine storm.  More than 200 patients with multisystem inflammatory syndrome in children and adolescents (MIS-C) temporally related to COVID-19 infection have been reported.  Anti-Tumor necrosis factor-α therapy with infliximab is effective for the induction and maintenance of remission in pediatric Crohn's disease patients. What is new?  Higher levels of pro-inflammatory cytokines can be seen in patients with inflammatory bowel disease and cytokine storm associated with COVID-19 infection than are reported in either inflammatory bowel disease or with COVID-19 alone.  Infliximab therapy can effectively treat both pediatric Crohn's disease and MIS-C temporally associated with COVID-19 infection.

Background: Ustekinumab is an effective therapy for Crohn disease currently approved for adults. Off-label use in the pediatric population is increasing, but its effectiveness in this age group has not been reported. Aims: The aim of the study was to describe real-world experience with ustekinumab at a tertiary care pediatric inflammatory bowel disease (IBD) center. Methods: As part of an ongoing observational cohort study of biologic-treated pediatric IBD patients initiated in October 2014, data on demographics, disease behavior, location and activity, treatment, and surgical history were collected for all patients receiving ustekinumab. Disease activity was assessed using the Harvey Bradshaw index or partial Mayo score. Primary outcome was steroid-free remission at 52 weeks. Descriptive statistics summarized the safety and efficacy outcomes, and univariate analyses were performed to examine associations of clinical characteristics with efficacy. Results: Fifty-two children and young adults initiating ustekinumab were analyzed; 81% Crohn Disease, 8% ulcerative colitis, and 11% IBD-unspecified. Median [IQR] age at induction was 16.8 [14–18] years. Patients were followed for a minimum of 12 months. Most patients (81%) failed >1 anti-TNF, and 37% failed anti-TNF and vedolizumab; 10 patients were biologic-naïve. At week 52, 75% were still on ustekinumab, and 50% (bio-exposed) and 90% (bio-naïve) were in steroid-free remission. Two infusion reactions and neither serious adverse events nor serious infections were observed. Conclusions: Our results suggest that ustekinumab is efficacious and safe in pediatric patients with IBD. Controlled clinical trial data are needed to confirm these observations.

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Background Nontraditional combination of existing therapies is often the only option to avoid surgery in refractory inflammatory bowel disease (IBD) patients. We aim to assess the efficacy and safety of concomitant use of 2 biologic therapies or combination of biologic and tofacitinib in a refractory pediatric IBD cohort. Methods As part of an ongoing single-center observational cohort study of therapeutic outcomes in pediatric IBD patients (younger than 18 years), data were collected for patients receiving dual therapy. Primary outcome was 6 months of steroid-free remission. Secondary outcomes included time to steroid-free remission, change in serum biomarkers (C-reactive protein and erythrocyte sedimentation rate) and albumin between baseline and 6 months, and adverse events. Results Sixteen children (9 ulcerative colitis/IBD-unspecified, 7 Crohn’s disease), with a disease duration of 3 (2.1–5.0) years, initiated dual therapy at an age of 15.9 (13.5–16.8) years after failing ≥2 biologic therapies. Nine (56%) were treated with vedolizumab/tofacitinib, 4 (25%) with ustekinumab/vedolizumab, and 3 (19%) with ustekinumab/tofacitinib. Twelve (75%; 7 ulcerative colitis/IBD-unspecified, 5 Crohn’s disease ) achieved steroid-free remission at 6 months. Erythrocyte sedimentation rate and C-reactive protein decreased (P = 0.021 and P = 0.015, respectively) and albumin increased (P = 0.003) between baseline and 6 months. One patient on 30 mg of vedolizumab/tofacitinib and prednisone daily developed septic arthritis and a deep vein thrombosis. Conclusions Our data suggest that dual therapy may be an option for patients with limited therapeutic options remaining. Safety concerns should always be at the forefront of decision-making, and larger studies are needed to help confirm the preliminary safety data observed.

Background: Leucine can stimulate insulin release, but the mechanism has remained unclear. Results: Leucine regulates adrenergic ␣2 receptor trafficking. Rapamycin and clonidine together increase the risk of diabetes. Conclusion: mTOR activation by leucine elicits insulin release via adrenergic ␣2 receptors. Rapamycin and clonidine appear to synergistically facilitate new-onset diabetes. Significance: Our findings may have relevance in the clinical management of renal transplant patients.

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Background & Aims The immunosuppressant rapamycin frequently causes non-infectious diarrhea in recipients of organ transplants. We investigated the mechanisms of this process. Methods We performed a retrospective analysis of renal transplant recipients treated with rapamycin from 2003 through 2010 at Albany Medical College, collecting data on serum levels of rapamycin. Levels of the Na+/H+ exchanger 3 (NHE3) were measured in human ileal biopsies from patients who did and did not receive rapamycin (controls), in ileum tissues from rats or mice given rapamycin, and in mice with intestine-specific disruption of Mtor (mTORf/f:Villin-cre mice) or Atg7 (Atg7flox/flox; Villin-Cre). Exchange activity and intestinal water absorption were measured using a pH-sensitive dye and small intestine perfusion, respectively. Results Episodes of non-infectious diarrhea occurred in organ recipients following increases in serum levels of rapamycin. Expression of NHE3 was reduced in the ileal brush border of patients with diarrhea. In rats and mice, continuous administration of low doses of rapamycin reduced levels of NHE3 in intestinal tissues; this effect was not observed in mice with intestinal deletion of ATG7, indicating that autophagy is required for the reduction. Administration of single high doses of rapamycin to mice, to model the spikes in rapamycin levels that occur in patients with severe diarrheal episodes, resulted in reduced phosphorylation of S6 and AKT in ileal tissues, indicating inhibition of the mTOR complex (mTORC1 and mTORC2). Intestines of mice with intestine-specific deletion of mTOR were dilated and contained large amount of liquid stools; they also had reduced levels of total NHE3 and NHERF1, compared with control mice. We observed a significant reduction in Na+/H+ exchange activity in ileum tissues from these mice. Conclusions Rapamycin inhibition of mTOR reduces levels of NHE3 and Na+/H+ exchange activity in intestinal tissues of patients and rodents. This process appears to require the autophagic activity mediated by ATG7. Loss of mTOR regulation of NHE3 could mediate the development of diarrhea in patients undergoing rapamycin therapy.

I n response to the coronavirus disease 2019 ) pandemic, gastrointestinal professional societies initially provided guidance to delay all elective endoscopies and to perform only urgent or emergent procedures. 1 This resulted in endoscopy centers operating at less than 25% of normal volume. 2 In early April, plans to reopen endoscopy units had begun. Because almost half of coronavirus infections are transmitted by asymptomatic or presymptomatic individuals, gastrointestinal societies advised obtaining a negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) molecular test for all patients within 48-72 hours before endoscopy to prevent viral transmission. 3,4 Despite SARS-CoV-2 molecular testing recommendations for endoscopy centers, there is little evidence to support their effectiveness. Stanford University Medical Center reported 1 in 694 ambulatory SARS-CoV-2-positive tests, which is a positive percentage of 0.14% compared with 4.34% in Santa Clara County from April 1 to May 31. 5 In this study, we report on outcomes of universal 48-to 72-hour preprocedure SARS-CoV-2 testing over a 2-month period from May 1, 2020 to June 30, 2020 after reopening an adult and pediatric endoscopy center in New York City, the global epicenter of the pandemic, and to compare those results with the New York City and New York State SARS-CoV-2-positive percentages during that time. MethodsWe conducted a retrospective chart review of all patients undergoing endoscopy and subsequent preprocedure SARS-CoV-2 polymerase chain reaction (PCR) testing at the Mount Sinai Hospital in New York City from May 1, 2020 to June 30, 2020. Almost all testing was performed at the Mount Sinai Hospital. Procedures were postponed at least 14 days for a positive SARS-CoV-2 PCR test, unless classified as emergent. Universal COVID-19 infection prevention precautions were observed for all patients, regardless of testing outcome, in accordance with joint gastrointestinal societal guidance.