CME Exam 1: Whole Food Diet Induces Remission in Children and Young Adults With Mild to Moderate Crohn's Disease and Is More Tolerable Than Exclusive Enteral Nutrition: A Randomized Controlled Trial

Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial

Whole Food Diet Induces Remission in Children and Young Adults With Mild to Moderate Crohn's Disease and Is More Tolerable Than Exclusive Enteral Nutrition: A Randomized Controlled Trial.

OP02 Tasty & Healthy Flexible Diet Induces clinical and biological Remission in Children and Young Adults with Mild-Moderate Crohn's Disease similar to EEN: results from the "TASTI-MM" randomized, physician-blinded, controlled trial

BACKGROUND: Studies have confirmed the efficacy of enteral nutrition for induction of remission in children with Crohn's Disease (CD) and this is first line therapy with the UK. The use of exclusive enteral nutrition can avoid exposure to corticosteroids and associated side effects, but lengthy treatment courses may be daunting and affect adherence, with previous studies identifying this can be a barrier to accepting such treatments. We recently completed a randomised controlled feasibility trial investigating whether the length of treatment with enteral nutrition in paediatric patients impacts on remission rates and withdrawal from therapy. The aim of this element of the trial was to identify barriers to accepting or continuing enteral nutrition for induction of remission of Crohn's disease in children. METHODS: The study was completed in Royal Manchester Children's Hospital, a tertiary paediatric unit within the UK with approximately Patients were randomised to receive 4, 6, 7, 8, or 10 weeks exclusive polymeric enteral nutrition. Patients were interviewed at baseline, 4 and 10 weeks by the principle investigator. They were specifically asked about their views on the therapy, tolerability and compliance issues. The investigator kept a field journal of these interviews. At completion of the study, these notes were analysed by a researcher who had no direct involvement in the study. A thematic analysis using a grounded theory methodology was employed. The analysis proceeded through 3 stages, consisting of open, axial, and selective coding, with constant comparison taking place throughout each phase. Each stage provided categories that could be used to explore the themes of the data in relation to the aims of the study. RESULTS: Analysis of 75 diary entries led to 203 open items coded. Eleven themes were synthesized at the axial level leading to 4 selectively coded themes. The first theme was efficacy. Whilst parents often preferred this to the option of corticosteroids, they were concerned that shorter courses may not be effective. The second theme was tolerability. Children often elected to take corticosteroids rather than exclusive liquid diet, commenting that in particular lengths of therapy would be intolerable. The third theme was adverse events. Parents were very concerned with side effects associated with other medications, whilst children were less concerned with such issue. The final theme was the length of therapy. There was general consensus that shorter lengths of therapy would be extremely beneficial, with more tolerability and acceptability amongst children, but only if efficacy can be demonstrated at shorter durations. CONCLUSIONS: This is the first study to investigate barriers to accepting or continuing enteral nutrition for induction of remission of CD amongst children using a robust qualitative methodology. Parents are keen to use exclusive enteral nutrition as they perceive a lower risk of long term side effects. However, children are very concerned with the tolerability of particularly longer causes, expressing that they would prefer shorter lengths of therapy. Further research to investigate if such shorter courses of therapy are efficacious is needed.

Differences in Outcomes Over Time With Exclusive Enteral Nutrition Compared With Steroids in Children With Mild to Moderate Crohn's Disease: Results From the GROWTH CD Study.

Covering the Cover

BackgroundAdalimumab monotherapy can suppress gut inflammation and induce remission in active Crohn’s disease but has some limitations. Exclusive enteral nutrition (EEN) is recommended for patients with mild to moderate Crohn’s disease (CD), but implementation is challenging.AimTo evaluate the effectiveness of adalimumab combined with partial enteral nutrition (PEN) in the induction therapy for Crohn’s disease.MethodsA prospective cohort study was designed and a total of 56 patients with active CD who met the criteria for enteral nutrition (EN) treatment in our hospital were selected. The baseline data of all patients were collected including age, sex and other general information. The changes in fecal calprotectin, C-reactive protein (CRP), albumin(Alb), hemoglobin (Hb), platelets (Plt), erythrocyte sedimentation rate (ESR), Crohn’s disease activity index score (CDAI), simple endoscopic score (SES-CD) and body mass index (BMI) were compared between the adalimumab combined with enteral nutrition (ADA+EN) group (N = 37) the adalimumab group (ADA) (N = 19) at week 0 (W0) and treatment outcomes at week 12(W12). Additionally, the differences between the two groups before and after treatment were evaluated. Then the ADA+EN group was divided into an adalimumab combined with exclusive enteral nutrition subgroup (ADA+EEN) and an adalimumab combined with partial nutrition subgroup (ADA+PEN) according to enteral nutrition intake. The changes in fecal calprotectin, CRP, Alb, Hb, Plt, ESR and CDAI, SES-CD and BMI were compared between the ADA+EEN group and the ADA+PEN group at week 0 (W0) and treatment outcomes at week 12(W12). The differences between the two groups before and after treatment were evaluated. To evaluate the effectiveness of the two treatments on patients’ quality of life, nutritional recovery and body composition, patients in the ADA+EN group were needed to complete the Inflammatory Bowel Disease Questionnaire (IBDQ), EQ-5D-5L, the EuroQol visual analogue scale (EQ-VAS) and body composition analysis.A total of 28 patients completed all questionnaires and body composition analyses at week 0 and week 12, including 10 patients in the ADA+EEN group and 18 patients in the ADA+PEN group, respectively. The differences of in IBDQ, EQ-5D-5L and body composition analysis were compared between the two groups at week 0 (W0) and treatment outcomes at week 12(W12). Additionally, the differences between the two groups before and after treatment were evaluated.ResultsThese investigated indexes such as calprotectin, Hb, Plt, ESR, Alb, BMI, CRP, CDAI and SES-CD scores were significantly different before and after treatment in the ADA+EN group (p < 0.01). However, fecal calprotectin, Hb, SES-CD scores and Alb in the ADA group were not statistically significantly different from W0 to W12 (p > 0.05). The fecal calprotectin and CDAI scores in the ADA+EN group were significantly lower than those in the ADA group after treatment. The differences in all factors before and after treatment between the ADA+PEN group and the ADA+EEN group were statistically significant (p < 0.05). However, there was no significant difference between the two groups at week 12 (p > 0.05).ConclusionAdalimumab combined with EN are more effective than ADA monotherapy in terms of endoscopy and clinical remission. By comparing the investigated indicators such as calprotectin, Hb, Plt, ESR ,CRP and SES-CD scores, it was proven that adalimumab combined with partial enteral nutrition or exclusive enteral nutrition has the same remission effect in induced Crohn’s disease. The combination of biological agents and partial nutrition can improve medical order compliance, psychological burden and quality of life. Therefore, adalimumab combined with partial nutrition can be used as the first-line treatment for CD induced remission.

BACKGROUND: Liquid diets were first used in Crohn's disease (CD) to provide preoperative nutritional support, but many of these patients unexpectedly went into remission before operation. Subsequent studies have confirmed the efficacy of enteral nutrition for induction of remission in children with CD and this is first line therapy with the UK. The length of treatment varies in the published paediatric studies from 3 to 10 weeks, with treatment continuing to scheduled end regardless of remission status. The use of exclusive enteral nutrition can avoid exposure to corticosteroids and associated side effects, but lengthy treatment courses may be daunting and affect adherence. No study has investigated the impact of the length of treatment in children on remission or relapse rates. Our aim was to complete a randomised controlled feasibility trial investigating whether the length of treatment with enteral nutrition in paediatric patients impacts on remission rates and withdrawal from therapy.&#13;\n&#13;\nMETHODS: The study was completed in Royal Manchester Children's Hospital, a tertiary paediatric unit within the UK with approximately 400 children diagnosed with IBD. Patients aged 8 to 17 years with a diagnosis of CD were considered for inclusion. Exclusion criteria included: Gastrostomy in situ, Severe CD requiring corticosteroids or surgery, treatment with other therapies within 12 weeks prior to randomisation or anti-TNF agents within the last 6 weeks prior to randomisation. Consent was obtained and baseline characteristics collected. Patients were randomised by a concealed, third-party process. Regimens were of 4, 6, 7, 8, and 10 weeks exclusive polymeric enteral nutrition, with predetermined formulations. Outcomes assessed at baseline and 10 weeks included disease activity, health related quality of life, adverse events and withdrawal rates.&#13;\n&#13;\nRESULTS: Thirty-eight patients with flare ups of CD were considered to start polymeric diet within the study period. Twenty-seven were eligible for inclusion and 12 consented for inclusion (Randomised length of therapy 4 Weeks n = 3, 6 weeks n = 3, 7 weeks n = 2, 8 weeks n = 3, 10 weeks n = 1). The most cited reason for not consenting for inclusion were that 10 weeks was too long for therapy (n = 6) and 4 weeks too short (n = 4). All patients who received exclusive enteral nutrition had gained weight at 4 week review (Mean = 4.4 kg) and final 10 week review (Mean = 7.1 kg). There was no difference in rates of remission between patients treated with 4, 6, or 7 weeks therapy. No patients completed 8 or 10 weeks diet. No significant adverse events were encountered. Withdrawal rates were 63% with reasons including lost to follow up (n = 4), need for steroids (n = 2) and patient not willing to stop therapy at predetermined time (n = 1).&#13;\n&#13;\nCONCLUSIONS: This is the first randomised controlled trial investigating the impact of the enteral nutritional therapy for induction of remission in Paediatric Crohn's disease. This feasibility trial has demonstrated the safety of all lengths of therapy, as well as supporting the possible equivalent efficacy of shorter lengths of therapy. A full randomised controlled trial is warranted to investigate further. Difficulties highlighted in this feasibility trial can inform future study design and will be highlighted in detail.

Background and AimExclusive enteral nutrition (EEN) is recognized internationally as the first line of treatment for children with active Crohn's disease (CD). A survey conducted a decade ago demonstrated that 40% of Australian pediatric gastroenterologists did not think EEN to be an appropriate treatment for CD. This study aimed to explore the current attitudes of Australian and New Zealand (NZ) pediatric gastroenterologists toward the use of EEN in children with inflammatory bowel disease (IBD).MethodsAll practicing pediatric gastroenterologists in Australia and NZ were invited via an existing email network to complete an anonymous online questionnaire.ResultsThe questionnaire was completed by 37 respondents (54% response rate), 31 from Australia and 6 from NZ. All respondents felt that EEN definitely or probably has a role in inducing remission for children with newly diagnosed CD. Australian gastroenterologists were more likely to use EEN for relapsed CD or IBD‐unclassified than NZ doctors (P < 0.05). Adherence was reported to be the greatest disadvantage of EEN. Dietitians were believed to play the most crucial role in EEN administration. Variations in EEN protocols included the use of flavorings or fluids during EEN and different patterns of food reintroduction.ConclusionsThese Australia and NZ pediatric gastroenterologists felt that EEN plays an important role in the induction of remission in children with newly diagnosed CD. However, the perceived role of EEN use in other types of IBD varied. EEN protocols varied widely between centers. Attitudes toward the roles of EEN have altered greatly across Australasia over the last decade.

While the short-term benefits of exclusive enteral nutrition (EEN) for induction of remission in children with Crohn's disease (CD) are well documented, the longer-term outcomes are less clear. This retrospective study aimed to ascertain the outcomes for up to 24 months following EEN in a group of children with CD. Children treated with EEN as initial therapy for newly diagnosed CD over a 5-year period were identified. Details of disease activity, growth, and drug requirements over the period of follow-up were noted. Outcomes in children managed with EEN were compared to a group of children initially treated with corticosteroids. Over this time period, 31 children were treated with EEN and 26 with corticosteroids. Twenty-six (84 %) of the 31 children treated with EEN entered remission. Children treated with EEN exhibited lower pediatric Crohn's disease activity index (PCDAI) scores at 6 months (p = 0.02) and received lower cumulative doses of steroids over the study period (p < 0.0001) than the group treated with corticosteroids. Height increments over 24 months were greater in the EEN group (p = 0.01). Although the median times to relapse were the same, the EEN group had a lower incidence of relapse in each time interval and survival curve analysis showed lower risk of relapse (p = 0.008). EEN lead to multiple benefits beyond the initial period of inducing remission for these children, with positive outcomes over 2 years from diagnosis. Of particular clinical relevance to growing children was the reduced exposure to corticosteroids.

Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014–2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6–8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn’s Disease activity index [wPCDAI] < 12.5). Faecal calprotectin (FC) levels (μg/g) decreased significantly after EEN (830 [IQR 500–1800] to 256 [IQR 120–585] p < 0.0001). Patients with wPCDAI ≤ 57.5, FC < 500 μg/g, CRP >15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6–8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn’s disease regardless of the location of disease and disease activity.

The aim of this study was to evaluate rates of clinical remission, endoscopic remission, and mucosal healing after a 6-week treatment period with partial enteral nutrition (PEN) and to compare them to those obtained by standard exclusive enteral nutrition (EEN) treatment in children with active Crohn's disease (CD). Twenty-five patients with active CD (median age 13.6 years, range 3.6-18.0) were recruited to either PEN (n = 12) or EEN (n = 13) treatment groups. The PEN group received 75% of their dietary needs from a polymeric formula plus one meal per day from an anti-inflammatory diet (AID). Patients were assessed at weeks 0, 1, 3, and 6 using clinical and laboratory parameters. Endoscopic assessment was performed at induction and week 6. On intention to treat analysis, clinical remission (Pediatric CD Activity Index < 10) was achieved in 69.2% and 75.0% of EEN and PEN patients, respectively (p = 0.999). The endoscopic remission (Simple Endoscopic Score for CD (SES-CD) ≤ 2) rates were 45.5% in both groups, while mucosal healing rates (SES-CD = 0) were 45.5% with EEN and 27.3% with PEN (p = 0.659).Conclusion: The results of our prospective pilot study suggest that PEN, allowing one meal from AID, could be as effective as EEN in inducing clinical and endoscopic remission in children with active CD. However, larger randomized controlled studies are warranted to confirm our findings.Trial registration: This clinical trial was registered under the number ClinicalTrials.govidentifier: NCT03176875.What is Known:• Exclusive enteral nutrition is a first-line treatment in active pediatric Crohn's disease; however, patients often find it difficult to adhere to.• Exclusive enteral nutrition is more effective than corticosteroids in achieving mucosal healing.What is New:• This is the first prospective study on partial enteral nutrition in active pediatric Crohn's disease, evaluating not only clinical, but also endoscopic remission.• A novel approach of partial enteral nutrition that allows one meal per day from an anti-inflammatory diet was as effective as exclusive enteral nutrition in inducing clinical and endoscopic remission in active Crohn's disease.

Assessment of nutritional habits and nutrition status in patients with Crohn's disease before Exclusive Enteral Nutrition and after gaining remission

Enteral nutrition as a treatment for inflammatory bowel diseases is an ongoing area of interest. Even in the era of biologic agents, exclusive enteral nutrition (EEN) offers a unique, drug-free measure for induction of remission in luminal Crohn's disease. The purpose of this review is to discuss the role of EEN in the evolving therapeutic scheme for Crohn's disease, to report on new evidence for short and long-term efficacy and highlight findings on the mechanisms of the anti-inflammatory effects of EEN in light of current understanding of disease pathogenesis. Recent clinical studies have suggested that EEN has an established advantage over corticosteroids for inducing remission in children with luminal Crohn's disease with comparable clinical efficacy but superior mucosal healing effect as well as better safety profile. Preoperative EEN therapy can also improve postoperative outcome of intestinal resection. Basic research has demonstrated that EEN has direct anti-inflammatory properties, can correct localization of tight junction proteins, alter micro RNAs expression, and profoundly affect the intestinal microbiota. EEN is an effective treatment for induction of remission in pediatric luminal Crohn's disease and should be offered as a first-line treatment. Accumulating evidence suggest that EEN has direct anti-inflammatory properties with an effect on the intestinal microbiota. However, the relationships between these effects and the specific triggers for these changes have yet to be elucidated.

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn’s disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN. Microbiota and metabolites were analyzed by 16S rRNA gene amplicon sequencing and NMR. Selected metabolites were evaluated in relevant model systems. Microbiota and metabolome of patients with CD and controls were different at all time points. Amino acids, primary bile salts, trimethylamine and cadaverine were elevated in patients with CD. Microbiota and metabolome differed between responders and non-responders prior to EEN. EEN decreased microbiota diversity and reduced amino acids, trimethylamine and cadaverine towards control levels. Patients with CD had reduced microbial metabolism of bile acids that partially normalized during EEN. Trimethylamine and cadaverine inhibited intestinal cell growth. TMA and cadaverine inhibited LPS-stimulated TNF-alpha and IL-6 secretion by primary human monocytes. A diet rich in free amino acids worsened inflammation in the DSS model of intestinal inflammation. Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Prior to EEN, microbiota and metabolome are different between responders and non-responders.