Antibiotic Cocktail for Pediatric Acute Severe Colitis and the Microbiome : The PRASCO Randomized Controlled Trial

Background: Alterations in the microbiome have been postulated to drive inflammation in IBD. In this pilot randomized controlled trial, we evaluated the effectiveness of quadruple antibiotic cocktail in addition to intravenous-corticosteroids (IVCSs) in acute severe colitis (ASC). Methods: Hospitalized children with ASC (pediatric ulcerative colitis activity index [PUCAI] >= 65) were randomized into 2 arms: the first received antibiotics in addition to IVCS (amoxicillin, vancomycin, metronidazole, doxycycline/ciprofloxacin [IVCS+AB]), whereas the other received only IVCS for 14 days. The primary outcome was disease activity (PUCAI) at day 5. Microbiome was analyzed using 16S rRNA gene and metagenome. Results: Twenty-eight children were included: 16 in the AB + IVCS arm and 12 in the IVCS arm (mean age 13.9 +/- 4.1 years and 23 [82%] with extensive colitis). The mean day-5 PUCAI was 25 +/- 16.7 vs 40.4 +/- 20.4, respectively (P = 0.037). Only 3 and 2 children, respectively, required colectomy during 1-year follow-up (P = 0.89). Microbiome data at time of admission were analyzed for 25 children, of whom 17 (68%) had a predominant bacterial species (>33% abundance); response was not associated with the specific species, whereas decreased microbiome diversity at admission was associated with day-5 response in the IVCS arm. Conclusion: Patients with ASC have alterations in the microbiome characterized by loss of diversity and presence of predominant bacterial species. Quadruple therapy in addition to IVCS improved disease activity on day 5, but larger studies are needed to determine whether this is associated with improved long-term outcomes.Peer reviewe

Mesalamine Enemas for Induction of Remission in Oral Mesalamine-refractory Pediatric Ulcerative Colitis : A Prospective Cohort Study

Background: Paediatric ulcerative colitis [UC] is more extensive than adult disease, and more often refractory to mesalamine. However, no prospective trials have evaluated mesalamine enemas for inducing remission in children. Our goal was to evaluate the ability of mesalamine enemas to induce remission in mild to moderate paediatric UC refractory to oral mesalamine. Methods: This was an open-label arm of a previously reported randomised controlled trial of once-daily mesalamine in active paediatric UC [MUPPIT trial]. Children aged 4-18 years, with a Paediatric Ulcerative Colitis Activity Index [PUCAI] score of 10-55, were enrolled after failing at least 3 weeks of full-dose oral mesalamine. Patients treated with steroids or enemas in the previous month and those with isolated proctitis were excluded. Children received Pentasa (R) enemas 25 mg/kg [up to 1g] daily for 3 weeks with the previous oral dose. The primary endpoint was clinical remission by Week 3. Results: A total of 38 children were enrolled (mean age 14.6 +/- 2.3 years; 17/38 [45%] with extensive colitis). Clinical remission was obtained in 16 [42%] and response was obtained in 27 [71%] at Week 3. Eight children deteriorated and required steroids. There were no differences in baseline parameters between those who entered or failed to enter remission, including disease extent [43% in left-sided and 41% in extensive colitis] and disease activity [44% in mild and 41% in moderate activity]. Conclusion: Clinical remission can be markedly increased in children who are refractory to oral mesalamaine by adding mesalamine enemas for 3 weeks, before commencing steroids.Peer reviewe

Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real-world patient mix.

Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12-month steroid-free remission (SFR) without switching biologics or undergoing surgery. We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate-to-severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2-4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice

The Incidence and Characteristics of Venous Thromboembolisms in Paediatric-Onset Inflammatory Bowel Disease: A Prospective International Cohort Study Based on the PIBD-SETQuality Safety Registry

Background and Aims: Guidelines regarding thromboprophylaxis for venous thromboembolisms [VTEs] in children with inflammatory bowel disease [IBD] are based on limited paediatric evidence. We aimed to prospectively assess the incidence of VTEs in paediatric-onset IBD [PIBD], characterize PIBD patients with a VTE and identify potential IBD-related risk factors. Methods: From October 2016 to September 2020, paediatric gastroenterologists prospectively replied to the international Safety Registry, monthly indicating whether they had observed a VTE case in a patient <19 years with IBD. IBD details [type, Paris classification, clinical and biochemical disease activity, treatment] and VTE details [type, location, treatment, outcome] were collected. To estimate VTE incidence, participants annually reported the number of PIBD patients, data source and catchment area of their centre. A systematic literature review and meta-analysis was performed to calculate the VTE incidence in the general paediatric population. Results: Participation of 129 PIBD centres resulted in coverage of 24 802 PIBD patients. Twenty cases of VTE were identified [30% Crohn's disease]. The incidence of VTEs was 3.72 (95% confidence interval [CI] 2.27-5.74) per 10 000 person-years, 14-fold higher than in the general paediatric population (0.27 [95% CI 0.18-0.38], p < 0.001). Cerebral sinus venous thrombosis was most frequently reported [50%]. All but one patient had active IBD, 45% were using steroids and 45% were hospitalized. No patient received thromboprophylaxis, whereas according to current PIBD guidelines, this was recommended in 4/20 patients. Conclusion: There is an increased risk of VTEs in the PIBD population compared to the general paediatric population. Awareness of VTE occurrence and prevention should be extended to all PIBD patients with active disease, especially those hospitalized