Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965.

Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort.

BACKGROUND: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. METHODS: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. RESULTS: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. CONCLUSIONS: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.

Fecal Microbiota Transplantation for Clostridioides difficile Infection in Immunocompromised Pediatric Patients.

OBJECTIVES: We sought to evaluate the safety and effectiveness of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI) in pediatric immunocompromised (IC) patients. METHODS: This is a multicenter retrospective cohort study of pediatric participants who underwent FMT between March 2013 and April 2020 with 12-week follow-up. Pediatric patients were included if they met the definition of IC and were treated with FMT for an indication of recurrent CDI. We excluded patients over 18 years of age, those with incomplete records, insufficient follow-up, or not meeting study definition of IC. We also excluded those treated for Clostridioides difficile recurrence without meeting the study definition and those with inflammatory bowel disease without another immunocompromising condition. RESULTS: Of 59 pediatric patients identified at 9 centers, there were 42 who met inclusion and no exclusion criteria. Included patients had a median age of 6.7 years. Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%). Success rate was 79% after first FMT and 86% after 1 or more FMT. There were no statistically significant differences in patient characteristics or procedural components when patients with a failed FMT were compared to those with a successful FMT. There were 15 total serious adverse events (SAEs) in 13 out of 42 (31%) patients that occurred during the follow-up period; 4 (9.5%) of which were likely treatment-related. There were no deaths or infections with multidrug resistant organisms during follow-up and all patients with a SAE fully recovered. CONCLUSIONS: The success rate of FMT for recurrent CDI in this pediatric IC cohort is high and mirrors data for IC adults and immunocompetent children. FMT-related SAEs do occur (9.5%) and highlight the need for careful consideration of risk and benefit.

Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

INTRODUCTION: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD). METHODS: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets. RESULTS: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not. DISCUSSION: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

Microgranulomas at Diagnosis Are Associated With Need for Antitumor Necrosis Factor Escalation in Pediatric Crohn Disease.

INTRODUCTION: Granulomas are a pathologic hallmark of Crohn disease (CD) although they are found in only a subset of patients. Well-formed granulomas are associated with an aggressive phenotype although it is unknown if microgranulomas confer a similar phenotype. This study sought to define the incidence of microgranulomas in pediatric CD and compare the clinical course with cases with granulomas and those without granulomatous inflammation. METHODS: We performed a single-center, retrospective study of pediatric CD patients who had at least 3 years of follow-up. initial diagnostic biopsies were systematically re-examined by a gastrointestinal pathologist. A priori definitions of granuloma (10+ histiocytes) and microgranuloma (4-9 histiocytes) were used. Disease outcomes of hospitalization, development of complicated disease behavior, perianal disease, and the use of anti-tumor necrosis factor (anti-TNF) therapy were assessed by Kaplan-Meier survival plots. RESULTS: This study included 138 subjects with an average follow-up of 4.6 years. Granulomas were seen in 38 of 138 subjects (27.5%) and an additional 38 subjects (27.5%) had at least 1 microgranuloma (in the absence of granulomas). Escalation to anti-TNF therapy was higher in CD with granulomas (P  = 0.001) and microgranulomas (P  = 0.0001) compared with those without granulomatous inflammation. CONCLUSIONS: A significant subset of pediatric CD patients have microgranulomas (in the absence of well-defined granulomas). Children with CD who have microgranulomas are escalated to anti-TNF therapy more frequently than those without granulomatous inflammation (and at a similar rate to those with granulomas). Pathologists should have a low threshold to report microgranulomas as they may help to predict disease behavior.

The Impact of Vitamin D on Response to Anti-tumor Necrosis Factor-α Therapy in Children With Inflammatory Bowel Disease.

OBJECTIVES: Experimental studies have shown that vitamin D has an immunomodulatory effect on the innate and adaptive immune systems. Associations between vitamin D deficiency and development or progression of inflammatory bowel diseases (IBDs) are reported, but a cause-and-effect relationship between pretreatment 25 hydroxyvitamin D [25(OH)D] levels and response to anti-tumor necrosis factor-α (anti-TNF) therapy is not established. METHODS: This retrospective study evaluated pediatric IBD patients who had 25(OH)D levels drawn within 3 months of initiating infliximab and/or adalimumab treatment. Demographic features, Paris classification, baseline 25(OH)D levels, disease activity, and laboratory results before and after 3 months of anti-TNF therapy were collected. The interaction between vitamin D insufficiency at induction and lack of response to anti-TNF therapy at 3 months was determined. RESULTS: Of the 383 patients, 76 met inclusion criteria. Sixty-five patients (85.5%) had Crohn disease (CD) and 11 (14.5%) had ulcerative colitis. Seven patients had 25(OH)D levels obtained during both infliximab and adalimumab induction; hence 83 subjects were evaluated (infliximab: 70 patients, adalimumab: 13 patients). 25(OH)D <30 ng/mL was found in 55 of 83 (66.3%) subjects. There were no differences in gender, IBD type, disease activity scores between vitamin D-sufficient and vitamin D-insufficient groups. In CD, proximal gastrointestinal tract inflammation was associated with vitamin D insufficiency (P = 0.019), but other Paris classification parameters and laboratory results were similar in 2 groups. Early termination of anti-TNF therapy was significantly higher in patients who had vitamin D insufficiency (14.5% vs 0%, P = 0.034). CONCLUSIONS: Vitamin D insufficiency before anti-TNF treatment may result in poor response to induction therapy.

Additional Intestinal Mucosal Biopsy Sampling for Research Is Safe During Pediatric Endoscopic Procedures.

Advancing the understanding of inflammatory bowel disease (IBD) pathogenesis has been facilitated by mechanistic studies that require human intestinal tissue. Enrolling pediatric subjects into these studies improves our knowledge of IBD in this underserved population. Given the additional research protections granted to children, institutional review boards (IRBs) must weigh the benefit of obtaining research biopsies against perceived risks. Although obtaining clinical biopsies from children is generally considered safe, there are only limited data on the safety of obtaining research biopsies in children.1-6.

Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Children.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI. METHODS: We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMT at 18 pediatric centers, from February 1, 2004, to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT. RESULTS: Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39-5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26-4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05-4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04-1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations. CONCLUSIONS: Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients-factors associated with success differ from those of adult patients.

Performance of Surveillance MR Enterography (MRE) in Asymptomatic Children and Adolescents With Crohn's Disease.

BACKGROUND: MR enterography (MRE) is the primary modality for evaluating small bowel disease in pediatric Crohn's patients. Standard clinical practice includes imaging patients at diagnosis and during symptomatic recurrence. The role for MRE in surveillance of asymptomatic Crohn's patients has not yet been established. PURPOSE: To determine whether MRE imaging features are associated with clinical recurrence. STUDY TYPE: Retrospective. POPULATIONS: Pediatric Crohn's patients who underwent MRE while asymptomatic, defined by pediatric gastroenterologists using a physician global assessment; 35 MREs were identified. FIELD STRENGTH/SEQUENCE: 1.5T including T2 -weighted single-shot fast spin echo, balanced steady-state free precession, diffusion-weighted, and contrast-enhanced multiphase T1 -weighted gradient recalled echo sequences. ASSESSMENT: MREs were reviewed by three radiologists independently for mural thickening, T2 -weighted hyperintensity, diffusion restriction, hyperenhancement, vasa recta engorgement, and overall assessment of disease activity. Two pediatric gastroenterologists reviewed patient medical records for 6 months following MRE to evaluate for recurrence, defined as Crohn's-related treatment escalation, surgery, or hospitalization. STATISTICAL TESTS: Fisher's exact test, Wald chi-square test, and model selection by Akaike information criterion minimization were used to assess statistical significance of MRE imaging features. RESULTS: Of 35 MREs identified, seven cases demonstrated clinical recurrence at 6 months (20%); 28 cases remained in remission (80%). Imaging features of active disease were present in 86% of patients with recurrence compared to 29% of patients in remission (P = 0.01). Wall thickening, T2 -weighted hyperintensity, hyperenhancement, and diffusion restriction were significantly associated with recurrence. Multivariate regression analysis determined diffusion restriction to be the best predictor of recurrence within 6 months (P = 0.001, area under the curve 0.786). DATA CONCLUSION: MRE performed on young asymptomatic Crohn's patients can identify patients who have a high probability of developing clinical recurrence in a 6-month period, indicating a potential role for surveillance imaging to assess for subclinical active disease. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;50:1955-1963.

NASPGHAN Clinical Report on Postoperative Recurrence in Pediatric Crohn Disease.

Pediatric Crohn disease is characterized by clinical and endoscopic relapses. The inflammatory process is considered to be progressive and may lead to strictures, fistulas, and penetrating disease that may require surgery. In addition, medically refractory disease may be treated by surgical resection of inflamed bowel in an effort to reverse growth failure. The need for surgery in childhood suggests severe disease and these patients have an increased risk for recurrent disease and potentially more surgery. Data show that up to 55% of patients had clinical recurrence in the first 2 years after initial surgery. The current clinical report on postoperative recurrence in pediatric Crohn disease reviews the risk factors for early surgery and postoperative recurrence, operative risk factors for recurrence, and prevention and monitoring strategies for postoperative recurrence. We also propose an algorithm for postoperative management in pediatric Crohn disease.

Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection.

BACKGROUND: Fecal microbiota transplantation (FMT) has been shown to be safe and effective in treating refractory or relapsing C. difficile infection (CDI), but its use has been limited by practical barriers. We recently reported a small preliminary feasibility study using orally administered frozen fecal capsules. Following these early results, we now report our clinical experience in a large cohort with structured follow-up. METHODS: We prospectively followed a cohort of patients with recurrent or refractory CDI who were treated with frozen, encapsulated FMT at our institution. The primary endpoint was defined as clinical resolution whilst off antibiotics for CDI at 8 weeks after last capsule ingestion. Safety was defined as any FMT-related adverse event grade 2 or above. RESULTS: Overall, 180 patients aged 7-95 years with a minimal follow-up of 8 weeks were included in the analysis. CDI resolved in 82 % of patients after a single treatment, rising to a 91 % cure rate with two treatments. Three adverse events Grade 2 or above, deemed related or possibly related to FMT, were observed. CONCLUSIONS: We confirm the effectiveness and safety of oral administration of frozen encapsulated fecal material, prepared from unrelated donors, in treating recurrent CDI. Randomized studies and FMT registries are still needed to ascertain long-term safety.

MR Enterographic Findings as Biomarkers of Mucosal Healing in Young Patients With Crohn Disease.

OBJECTIVE: The purpose of this study was to investigate the MR enterographic findings that best correlate with mucosal healing assessed with ileocolonoscopy. MATERIALS AND METHODS: Patients with Crohn disease who underwent two ileocolonoscopic examinations and also underwent MR enterography close in time to the second endoscopic examination were included in a retrospective study. Two pediatric gastroenterologists blinded to the imaging findings reviewed the endoscopic examinations to assess for mucosal healing, defined as resolution of inflammation within a bowel segment at subsequent ileocolonoscopy. Two radiologists blinded to endoscopic and clinical data interpreted the MR enterographic images. Sensitivity, specificity, and accuracy for mucosal healing were calculated for several imaging features. RESULTS: A total of 30 patients (15 female patients, 15 male patients; age range, 8-24 years; mean, 17.2 ± 3.2 years) with pediatric-onset Crohn disease were examined. The average time between MR enterography and the second ileocolonoscopic examination was 12.7 ± 7.9 days. A total of 202 bowel segments from the terminal ileum to rectum were evaluated in the 60 ileocolonoscopic examinations. Forty-four bowel segments exhibited mucosal healing, and 37 segments exhibited persistent inflammation. At imaging, the MR index of activity score in mucosal healing segments was 6.6 ± 3.4, compared with 13.7 ± 9.7 in segments without mucosal healing (p = 0.0001). The average bowel wall thickness in healing segments was 2.7 ± 0.9 mm compared with 4.7 ± 3.1 mm in persistently inflamed segments (p = 0.0004). An MR index of activity score less than 8 had the highest accuracy for mucosal healing (accuracy, 74%; sensitivity, 84%; specificity, 62%; p < 0.0001). Mucosal hyperenhancement (72%, 98%, 41%), mesenteric hypervascularity (72%, 98%, 41%), bowel wall edema (72%, 93%, 46%), and bowel wall thickness less than 4 mm (72%, 84%, 57%) were also strongly associated with mucosal healing (p < 0.0003). CONCLUSION: In this study MR enterography was accurate for assessing mucosal healing, an important therapeutic endpoint in pediatric patients with Crohn disease.

CT and MRI of Rare Extraintestinal Manifestations of Inflammatory Bowel Disease in Children and Adolescents.

Inflammatory bowel disease (IBD) is associated with a spectrum of extraintestinal manifestations (EIMs) affecting many organ systems. EIMs can occur in more than 40% of patients with IBD and are associated with significant morbidity. They occur at any time point in the course of disease, often during an active phase of bowel inflammation, but sometimes preceding bowel disease. Prompt recognition of EIMs enables timely and more effective therapy. Physicians who image patients with IBD should be aware of the myriad extraintestinal conditions that may be detected on imaging studies, both within and outside of the abdomen, as they may predate the diagnosis of IBD. Cross-sectional imaging of unusual conditions associated with IBD will be presented, including pathology in the hepatobiliary, pancreatic, genitourinary, musculoskeletal, mucocutaneous, vascular, neurologic, and pulmonary systems.

Role of percutaneous abscess drainage in the management of young patients with Crohn disease.

BACKGROUND: Intra-abdominal abscess is a common complication of Crohn disease in children. Prior studies, primarily in adults, have shown that percutaneous abscess drainage is a safe and effective treatment for this condition; however, the data regarding this procedure and indications in pediatric patients is limited. OBJECTIVE: Our aim was to determine the success rate of percutaneous abscess drainage for abscesses related to Crohn disease in pediatric patients with a focus on treatment endpoints that are relevant in the era of biological medical therapy. MATERIALS AND METHODS: We retrospectively reviewed 25 cases of patients ages ≤20 years with Crohn disease who underwent percutaneous abscess drainage. Technical success was defined as catheter placement within the abscess with reduction in abscess size on post-treatment imaging. Clinical success was defined as (1) no surgery within 1 year of drainage or (2) surgical resection following drainage with no residual abscess at surgery or on preoperative imaging. Multiple clinical parameters were analyzed for association with treatment success or failure. RESULTS: All cases were classified as technical successes. Nineteen cases were classified as clinical successes (76%), including 7 patients (28%) who required no surgery within 1 year of percutaneous drainage and 12 patients (48%) who had elective bowel resection within 1 year. There was a statistically significant association between resumption of immunosuppressive therapy within 8 weeks of drainage and both clinical success (P < 0.01) and avoidance of surgery after 1 year (P < 0.01). CONCLUSION: Percutaneous abscess drainage is an effective treatment for Crohn disease-related abscesses in pediatric patients. Early resumption of immunosuppressive therapy is statistically associated with both clinical success and avoidance of bowel resection, suggesting a role for percutaneous drainage in facilitating prompt initiation of medical therapy and preventing surgical bowel resection.

Occult Blood and Perianal Examination: Value Added in Pediatric Inflammatory Bowel Disease Screening.

OBJECTIVES: Pediatric inflammatory bowel disease (IBD) often presents insidiously and standard blood tests are normal in 20% of patients. We hypothesize that fecal occult blood testing (FOBT) and the perianal examination in addition to blood tests provide important information during the screening process for IBD. The aim of the present study was to measure the diagnostic value of adding FOBT and perianal examination to standard screening laboratories in evaluating children and adolescents for IBD. METHODS: The medical records of consecutive patients undergoing ileocolonoscopy for IBD were reviewed. Laboratory test results, FOBT, and perianal examination before the decision to perform the ileocolonoscopy were recorded. Standard limits of laboratory tests were used. Multivariate logistic regression was performed on a discovery cohort and applied to an independent validation cohort. RESULTS: The discovery cohort included 335 patients (85 IBD and 250 non-IBD). A total of 61.2% had FOBT and perianal examination performed before the decision to perform the ileocolonoscopy. A total of 119 patients had complete blood testing, FOBT, and perianal examination available for full analysis. The sensitivity of the laboratory testing was 80.5% for IBD, and the sensitivity of FOBT with perianal examination was 66.9%. The combined sensitivity of laboratory testing and FOBT with perianal examination was, however, 97.6%. The most predictive model included C-reactive protein, platelet counts, and FOBT with perianal examination and was superior to the laboratory value-only model (P < 0.001) that was validated in a separate cohort. CONCLUSIONS: Perianal examination and FOBT improve sensitivity in screening children for IBD.

Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study.

BACKGROUND: Recurrent Clostridium difficile infection (CDI) with poor response to standard antimicrobial therapy is a growing medical concern. We aimed to investigate the outcomes of fecal microbiota transplant (FMT) for relapsing CDI using a frozen suspension from unrelated donors, comparing colonoscopic and nasogastric tube (NGT) administration. METHODS: Healthy volunteer donors were screened and a frozen fecal suspension was generated. Patients with relapsing/refractory CDI were randomized to receive an infusion of donor stools by colonoscopy or NGT. The primary endpoint was clinical resolution of diarrhea without relapse after 8 weeks. The secondary endpoint was self-reported health score using standardized questionnaires. RESULTS: A total of 20 patients were enrolled, 10 in each treatment arm. Patients had a median of 4 (range, 2-16) relapses prior to study enrollment, with 5 (range, 3-15) antibiotic treatment failures. Resolution of diarrhea was achieved in 14 patients (70%) after a single FMT (8 of 10 in the colonoscopy group and 6 of 10 in the NGT group). Five patients were retreated, with 4 obtaining cure, resulting in an overall cure rate of 90%. Daily number of bowel movements changed from a median of 7 (interquartile range [IQR], 5-10) the day prior to FMT to 2 (IQR, 1-2) after the infusion. Self-ranked health score improved significantly, from a median of 4 (IQR, 2-6) before transplant to 8 (IQR, 5-9) after transplant. No serious or unexpected adverse events occurred. CONCLUSIONS: In our initial feasibility study, FMT using a frozen inoculum from unrelated donors is effective in treating relapsing CDI. NGT administration appears to be as effective as colonoscopic administration. CLINICAL TRIALS REGISTRATION: NCT01704937.

MicroRNA-124 regulates STAT3 expression and is down-regulated in colon tissues of pediatric patients with ulcerative colitis.

BACKGROUND & AIMS: Altered levels and functions of microRNAs (miRs) have been associated with inflammatory bowel diseases (IBDs), although little is known about their roles in pediatric IBD. We investigated whether colonic mucosal miRs are altered in children with ulcerative colitis (UC). METHODS: We used a library of 316 miRs to identify those that regulate phosphorylation of signal transducer and activator of transcription 3 (STAT3) in NCM460 human colonocytes incubated with interleukin-6. Levels of miR-124 were measured by real-time polymerase chain reaction analysis of colon biopsies from pediatric and adult patients with UC and patients without IBD (controls), and of HCT-116 colonocytes incubated with 5-aza-2'-deoxycytidine (5-AZA). Methylation of the MIR124 promoter was measured by quantitative methylation-specific polymerase chain reaction. RESULTS: Levels of phosphorylated STAT3 and the genes it regulates (encoding vascular endothelial growth factor (VEGF), BCL2, BCLXL, and matrix metallopeptidase 9 [MMP9]) were increased in pediatric patients with UC compared with control tissues. Overexpression of miR-124, let-7, miR-125, miR-26, or miR-101 reduced STAT3 phosphorylation by ≥ 75% in NCM460 cells; miR-124 had the greatest effect. miR-124 was down-regulated specifically in colon tissues from pediatric patients with UC and directly targeted STAT3 messenger RNA (mRNA). Levels of miR-124 were decreased, whereas levels of STAT3 phosphorylation increased in colon tissues from pediatric patients with active UC compared with those with inactive disease. In addition, levels of miR-124 and STAT3 were inversely correlated in mice with experimental colitis. Down-regulation of miR-124 in tissues from children with UC was attributed to hypermethylation of its promoter region. Incubation of HCT-116 colonocytes with 5-AZA up-regulated miR-124 and reduced levels of STAT3 mRNA. CONCLUSIONS: miR-124 appears to regulate the expression of STAT3. Reduced levels of miR-124 in colon tissues of children with active UC appear to increase expression and activity of STAT3, which could promote inflammation and the pathogenesis of UC in children.

Fecal transplant for recurrent Clostridium difficile infection in children with and without inflammatory bowel disease.

Ten children at our institution received single-infusion fecal microbiome transplant (FMT) using healthy, related screened donor stool to treat recurrent Clostridium difficile infection (RCDI) via nasogastric tube (2 patients) or colonoscopic delivery. Nine of the 10 (90%) children had resolution of their symptoms after a single-infusion FMT with follow-up of 1 month to 4 years. No concerning related adverse events were recognized during short- or long-term follow-up. Three of these children had concomitant inflammatory bowel disease and 2 of these 3 (66%) patients cleared RCDI with no clinical change in their underlying inflammatory bowel disease clinical activity as assessed by Physician's Global Assessment. All of the patients who had clinical improvement of gastrointestinal symptoms of RCDI while treated with antibiotics had lasting return of baseline health after FMT.

Paediatric Crohn's disease: histologic findings at initial presentation.

BACKGROUND: Diagnosing paediatric Crohn's disease (CD) based on histology can present challenges. We evaluate the histological spectrum of treatment-naïve biopsies from children with CD and assess these findings' diagnostic and predictive value. METHODS: Three cohorts were identified: (1) 137 patients with CD, (2) 116 patients with ulcerative colitis (UC) and (3) 50 patients without inflammatory bowel disease. Biopsies from the gastrointestinal (GI) tract were re-examined for signs of active and chronic inflammation, including lymphocyte-pattern oesophagitis, focal enhancing gastritis and indicators of chronicity. Additionally, granulomas and microgranulomas (defined as clusters of 4-9 epithelioid histiocytes) were evaluated. RESULTS: Lymphocyte-pattern oesophagitis was observed in 15% of patients (n=20). Moderate-to-severe diffuse gastritis was noted in 50.4% of patients (n=68), while focal enhancing gastritis was identified in 11.1% (n=15). In terminal ileal biopsies, 46.1% exhibited activity and 5.3% showed features of chronicity. Active colitis was present in 73% of patients (n=100), with chronic colitis seen in 11.7% (n=16). Granulomas and microgranulomas were observed in 31.4% (43/137) and 48.9% (67/137) of patients, respectively. Notably, 30.7% (42/137) of patients with microgranulomas were without granulomas. Previously undetected microgranulomas were found in 20 of 27 cases. 2.5% of patients with UC and none of the control cohort showed microgranulomas. Lymphocyte-pattern oesophagitis was associated with an increased need for anti-tumor necrosis factor (TNF) therapy (p=0.007). CONCLUSIONS: GI microgranulomas, often overlooked, are specific to CD in the proper clinical context. Oesophageal lymphocytosis may predict a need for more aggressive treatment. The study brings to light under-recognised aspects of CD's histological diagnosis, including the oversight of microgranulomas, the high prevalence of diffuse gastritis and low prevalence of focal enhancing gastritis, the frequent absence of terminal ileitis and the infrequent occurrence of chronic colitis.