Comparing Effectiveness of a Generic Oral Nutritional Supplement With Specialized Formula in the Treatment of Active Pediatric Crohn's Disease.

BACKGROUND: Exclusive enteral nutrition (EEN) is the recommended induction treatment of mild to moderate active pediatric Crohn's disease (CD). This study compared outcomes of 2 proprietary polymeric formulas. Treatment effectiveness was examined along with practical aspects of formula delivery and differences in estimated treatment costs. METHODS: Data were retrospectively collected from patients with CD who received a generic oral nutritional supplement (Fortisip) across 2 centers (RCH, Melbourne and RHSC, Edinburgh). This was compared with a prospective cohort (RHC, Glasgow) that used a specialized formula (Modulen IBD). The data collected included patient demographics, remission rates, biochemical markers, administration method, and anthropometrics. The estimated treatment cost was performed by comparing price per kcal between each formula. RESULTS: One hundred seventy-one patients were included (106 Fortisip, 65 Modulen IBD, 70 female; median age 13.3 yrs). No difference was demonstrated in remission rate (Fortisip n = 67 of 106 [63%] vs Modulen IBD n = 41 of 64 [64%], P = .89), nonadherence rate (Fortisip n = 7 of 106 [7%] vs Modulen IBD 3 of 64 [5%], P = .57) or method of administration (NGT Fortisip use n = 16 of 106 [12%] vs Modulen IBD 14 of 65 [22%]; P = .31). There was no difference in reduction of biochemical disease markers between the groups (C-reactive protein , P = .13; erythrocyte sedimentation rate, P = .49; fecal calprotectin, P = .94). However, there was a cost-saving of around £500/patient/course if the generic oral nutritional supplement was used. CONCLUSIONS: The generic oral nutritional supplement and specialized formulas both had similar clinical effectiveness in induction of remission in pediatric CD. However, there is considerable cost-saving when using a generic oral nutritional supplement.

Percutaneous endoscopic gastrostomy placement in paediatric Crohn's disease patients contributes to both improved nutrition and growth.

AIM: This paper describes the outcomes of gastrostomy feeding in patients with Crohn's disease (CD). METHODS: Patients with CD who attended the Royal Hospital for Children, Glasgow and received gastrostomy feeding for at least two years between 2003 and 2010 were identified from the clinical database. The data recorded included the anthropometric data, CD phenotype, the surgical technique that was used, complications, medication, feed type, median feed, calories, volume and clinical outcomes. RESULTS: The study identified 16 patients (14 male) who had a gastrostomy inserted using a pull technique at a median age of 12.6 years. Of these two required laparoscopic placement. Short-term complications lasting less than one month were experienced by nine (56%) patients and one (6%) experienced long-term complications. Anthropometry significantly improved at follow-up compared to baseline: at 12 months, the body mass index z-score was 1.11 (p = 0.005) and the weight z-score was 0.19 (p < 0.05). At 24 months, the height z-score was -1.03 (p = 0.04). The daily median volume and calories from feeds increased significantly from baseline to post-PEG insertion, from 400 to 738 mL and 705 to 860 kcal/day (p ≤ 0.01). CONCLUSION: Gastrostomy feeding for paediatric patients with CD was associated with improved nutrition, weight gain and growth outcomes.

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care

The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;1. Patient populations involved in AYP transition. 2. Risks of failing transition or poor transition. 3. Models of AYP transition. 4. Patient and carer/parent perspective in AYP transition. 5. Surgical perspective.(AU)

Anti-TNF therapy for paediatric IBD: the Scottish national experience.

BACKGROUND AND AIMS: Biological agents are being increasingly used in the UK for paediatric-onset inflammatory bowel disease (PIBD) despite limited evidence and safety concerns. We evaluated effectiveness and safety in the clinical setting, highlighting drug cost pressures, using our national Scottish PIBD biological registry. METHODS: Complete usage of the biological agents, infliximab (IFX) and adalimumab (ADA) for treatment of PIBD (in those aged <18 years) from 1 January 2000 to 30 September 2010 was collated from all treatments administered within the Scottish Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN) national managed service network (all regional PGHAN centres and paediatric units within their associated district general hospitals). RESULTS: 132 children had biological therapy; 24 required both agents; 114 had Crohn's disease (CD), 16 had ulcerative colitis (UC) and 2 had IBD Unclassified (IBDU). 127 children received IFX to induce remission; 61 entered remission, 49 had partial response and 17 had no response. 72 were given maintenance IFX and 23 required dose escalation. 18 had infusion reactions and 27 had adverse events (infections/other adverse events). 29 had ADA to induce remission (28 CD and 1 UC), 24 after IFX; 10 entered remission, 12 had partial response and 7 had no response. All had maintenance; 19 required dose escalation. 12 children overall required hospitalisation due to drug toxicity. No deaths occurred with either IFX or ADA. CONCLUSIONS: Complete accrual of the Scottish nationwide 'real-life' experience demonstrates moderate effectiveness of anti tumour necrosis factor agents in severe PIBD but duration of effect is limited; significant financial issues (drug cost-need for dose escalation and/or multiple biological usage) and safety issues exist.

The fungal microbiota of de-novo paediatric inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterised by an inappropriate chronic immune response against resident gut microbes. This may be on account of distinct changes in the gut microbiota termed as dysbiosis. The role of fungi in this altered luminal environment has been scarcely reported. We studied the fungal microbiome in de-novo paediatric IBD patients utilising next generation sequencing and compared with adult disease and normal controls. We report a distinct difference in fungal species with Ascomycota predominating in control subjects compared to Basidiomycota dominance in children with IBD, which could be as a result of altered tolerance in these patients.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease.

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Detailed assessment of nutritional status and eating patterns in children with gastrointestinal diseases attending an outpatients clinic and contemporary healthy controls.

BACKGROUND/OBJECTIVES: In the era of modern multidisciplinary clinical management, very little is known about the prevalence and presentation of malnutrition in children with gastrointestinal disorders (GastroD) particularly employing composite, global measures of nutritional status. SUBJECTS/METHODS: Anthropometry, body composition, dietary intake, eating habits and grip strength were assessed with bedside methods in 168 patients from outpatient gastroenterology clinics (n, median (IQR) years; Crohn's disease (CD): n=53, 14.2 (11.6:15.4); ulcerative colitis (UC): n=27, 12.2 (10.7:14.2); coeliac disease: n=31, 9.3 (7.5:13.6); other GastroD: n=57, 9.8 (7.2:13.8)) and compared with 62 contemporary healthy controls (n, median (IQR): 9.8 (6.9:13.8)) and the results of the recent UK, National Diet and Nutritional Survey (NDNS). RESULTS: Children with CD had lower BMI z-scores than controls (median (IQR): -0.3 (-0.9:0.4) vs 0.3 (-0.6:1.4); P=0.02) but only 2% were classified as thin (BMI z-score <-2 s.d.). The prevalence of obesity in children with UC was 19%, 6% in CD, 11% in children with other GastroD and 15% in controls. No difference was found in grip strength measurement between groups. Except for CD children, the proportion of patients with suboptimal micronutrient intake was similar to that of controls and the cohort of children from the latest NDNS. A higher proportion of children with CD had suboptimal intake for riboflavin, vitamin B6 and calcium and consumed significantly more meat products, juices (including carbonated drinks), spreads/jams and crisps and savoury snacks and significantly fewer portions of dairy, fish, fruits and vegetables compared with healthy controls. CONCLUSIONS: GastroD affect children's body composition, growth, strength, dietary intake and eating habits, particularly CD, but to a lesser extent than expected.

Pathophysiology and management of abnormal growth in children with chronic inflammatory bowel disease.

Many children with a variety of chronic diseases suffer from a variable component of chronic inflammation and often have co-existing growth retardation. The aetiology of this growth retardation may be multifactorial and in a condition such as inflammatory bowel disease it includes the effects of the disease on nutrition as well as the effect of drugs such as glucocorticoids. Growth is primarily regulated through the endocrine and paracrine component of the GH/IGF-1 axis which may be modulated by other factors such as sex steroids. There is increasing evidence that this axis may be affected in children with chronic inflammation. An improved understanding of the GH/IGF-1 axis and how it is affected in chronic inflammation will lead to an improved rationale for developing therapeutic regimens that can improve growth in those children whose growth does not improve despite optimal management of the disease. This review will illustrate these aspects by concentrating primarily on the pathophysiology of growth retardation in inflammatory bowel disease and possible interventions for improving growth.

Clinical progress in the two years following a course of exclusive enteral nutrition in 109 paediatric patients with Crohn's disease.

BACKGROUND: Exclusive enteral nutrition (EEN) is an effective first line treatment for active paediatric Crohn's disease (CD). AIM: To examine the effect of EEN on short- and long-term clinical outcome together with anthropometric measurements. METHODS: Retrospective case-note review in newly diagnosed CD (<16 years) who completed 8 weeks of EEN. Demographics, anthropometry, disease characteristics and inflammatory markers were collected at EEN initiation and at 1, 2, 6, 12 & 24 months post treatment initiation. EEN response was determined by a patient global assessment. RESULTS: One hundred and nine patients were included (Males 68; Median age: 11.2 years). After 8 weeks EEN, 65 were in remission, 32 improved and 12 had no improvement. By 4 weeks, mean weight/BMI z-score (s.d.) increased (P < 0.02) and between 4 and 8 weeks (P < 0.05). Baseline inflammatory markers all improved significantly by week 4 (albumin, CRP and platelets; all P < 0.01) and ESR (P < 0.00001). 63/109(58%) relapsed during follow-up. 44/63(70%) patients completed a second course of EEN with similar response rate, but lower weight gain (3.3 vs. 5.1 kg, P < 0.05). Height z-score did not change significantly over the 24 months. Introduction of azathioprine within 6 months of diagnosis did not improve height outcomes at 24 months. CONCLUSIONS: Weight and BMI z-score improved with EEN and changes are sustained to 2 years, but height z-score did not. Seventy per cent of patients who relapsed during 2-year follow-up managed a 2nd course of EEN. The optimal therapeutic strategies for length of EEN course and to improve linear growth are awaited.

The effects of anti-TNF-α treatment with adalimumab on growth in children with Crohn's disease (CD).

INTRODUCTION: Adalimumab is used to treat children with Crohn's disease (CD), but the effects of adalimumab on growth in CD have not been studied. AIM: To study growth and disease activity over 12 months (6 months prior to (T-6), baseline (T0) and for 6 months following (T+6) adalimumab). SUBJECTS AND METHODS: Growth and treatment details of 36 children (M: 22) who started adalimumab at a median (10th, 90th) age of 14.7 years (11.3, 16.8) were reviewed. RESULTS: Of 36 cases, 28 (78%) went into remission. Overall 42% of children showed catch up growth, which was more likely in: (i) those who achieved remission (median change in height SDS (ΔHtSDS) increased from -0.2 (-0.9, 1.0) at T0 to 0.2 (-0.6, 1.6) at T+6, (p=0.007)), (ii) in those who were on immunosuppression ΔHtSDS increased from -0.2 (-0.9, 1.0) at T0 to 0.1 (-0.8, 1.3) at T+6, (p=0.03) and (iii) in those whose indication for using adalimumab therapy was an allergic reaction to infliximab, median ΔHtSDS increased significantly from -0.3 (-0.9, 1.0) at T0 to 0.3 (-0.5, 1.6) at T+6, (p=0.02). Median ΔHtSDS also increased from -0.4 (-0.8, 0.7) at T0 to 0.0 (-0.6, 1.6) at T+6, (p=0.04) in 15 children who were on prednisolone therapy when starting adalimumab. CONCLUSION: Clinical response to adalimumab therapy is associated with an improvement in linear growth in a proportion of children with CD. Improved growth is more likely in patients entering remission and on immunosuppression but is not solely due to a steroid sparing effect.

Impact of inflammatory bowel disease on pubertal growth.

BACKGROUND: Puberty is thought to be commonly affected in adolescents with inflammatory bowel disease (IBD). AIMS: To determine the impact of Crohn's disease (CD) and ulcerative colitis (UC) on the pubertal growth spurt. METHODS: Retrospective study of 30 boys with CD (CD-M), 11 girls with CD (CD-F), 14 boys with UC (UC-M) and 12 girls with UC (UC-F). Pubertal growth was assessed by calculating peak height velocity SDS (PHV SDS), height SDS at diagnosis (Ht(Diag)) and height SDS at PHV (Ht(PHV)) and age at PHV (Age(PHV)). Systemic markers of disease activity were also collected. RESULTS: Altered parameters of pubertal growth were observed in the CD groups compared to the normal population: in the CD-M group, median Ht(Diag) was -0.56 (p = 0.001) and median Age(PHV) was 14.45 years (p = 0.004), and in the CD-F group, median Ht(Diag) was -1.14 (p = 0.007) and Ht(PHV) was -0.79 (p = 0.039). Individually, 8/30 CD-M cases had one or more parameter affected: 2 boys had Ht(Diag )<-2, 3 boys had Ht(PHV) <-2, 2 boys had an Age(PHV) >2 years above population mean, and 2 boys had a PHV SDS <-2. In the whole group, Age(PHV) showed an association with erythrocyte sedimentation rate (r = 0.4; p = 0.005) and an inverse association with BMI (r = 0.4; p = 0.001). CONCLUSION: Disorders of pubertal growth are more likely to occur in CD and, particularly, in boys.

Evaluating the use of metabolite measurement in children receiving treatment with a thiopurine.

BACKGROUND: Clinical response to thiopurine medication is related to the concentration of its metabolites. Proxy measures are traditionally used to assess dose adequacy. We present our experience of using tioguanine (previously known/formerly referred to as thioguanine) metabolite measurements in paediatric patients and evaluate their effect on clinical practice. AIMS: To report our experience of using tioguanine metabolite measurements in paediatric patients and to evaluate their effects on clinical practice. METHODS: The 6-tioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) were measured in children prescribed thiopurine medication for at least 3 months. Data were collected on thiopurine methyl transferase (TPMT) genotype, drug dose, laboratory indices and management changes. Therapeutic 6-TGN levels were defined as 235-400 pmol/8 × 10(8) RBCs. Seventy individuals (30 males) with a median age of 15 years. Underlying diagnoses were 'IBD' (68/70) and two cases of eosinophilic colitis. Sixty-three were treated with azathioprine and seven with mercaptopurine. A total of 103 separate measurements were made. RESULTS: On initial measurement, 68% of patients had 6-TGN levels outside therapeutic levels despite standard thiopurine dosing. Initial 6-TGN levels were significantly higher in patients with TPMT mutations. Toxicity occurred in seven cases. The 6-TGN levels were significantly higher in those with signs of marrow toxicity. The 6-TGN level correlated with WBC, leukocyte count, mean corpuscular volume (MCV) and ΔMCV; however, the ability of each of these to predict therapeutic 6-TGN levels was poor. After initial measurement, management was changed in 25/70 cases (36%). CONCLUSIONS: 6-TGN levels were therapeutic in a minority of those patients who were tested. Proxy measures perform poorly in predicting therapeutic 6-TGN levels. Measuring thiopurine metabolites is useful for dosage adjustment in children, and for the detection of potential toxicity.

Cycled enteral antibiotics reduce sepsis rates in paediatric patients on long-term parenteral nutrition for intestinal failure.

BACKGROUND: Long-term parenteral nutrition has transformed the prognosis for children suffering from intestinal failure. However, parenteral nutrition itself is associated with considerable morbidity and mortality including that caused by sepsis. AIM: To examine a strategy of cycled enteral antibiotics in reducing the incidence of sepsis in paediatric intestinal failure patients. METHODS: Retrospective analysis of the incidence of sepsis rates of patients on long-term parenteral nutrition, at a tertiary paediatric hospital. Patients were separated into those who received cycled enteral antibiotics and a control group. Sepsis rates before and during cycled enteral antibiotics were compared with comparable timeframes between the cycled enteral antibiotics and control groups. Central venous catheter removal rates were also compared. RESULTS: Fifteen patients (eight cycled enteral antibiotics, & seven controls) received 9512 parenteral nutrition days, with a total of 132 sepsis episodes. All eight patients of the treatment group demonstrated a decrease in the frequency of episodes of sepsis following the introduction of cycled enteral antibiotics. The cycled enteral antibiotics group had a significant reduction in infection rate during the treatment period (from 2.14 to 1.06 per 100 parenteral nutrition days, P = 0.014: median effect size -1.04 CI 95%-1.93, -0.22), whereas the controls had no significant change (1.91 - 2.36 per 100 parenteral nutrition days P = 0.402: median effect size 0.92 CI 95%-1.96, 4.17). The central venous catheter survival rates increased in the cycled enteral antibiotics group from 0.44 central venous catheter removals per 100 parenteral nutrition days to 0.27 central venous catheter removals per 100 parenteral nutrition days, although this was not statistically significant. CONCLUSIONS: Cycled enteral antibiotics significantly reduced the rate of sepsis in a small group of paediatric intestinal failure patients. Larger well-designed prospective studies are warranted to further explore this finding.

A British Society of Paediatric Gastroenterology, Hepatology and Nutrition survey of the effectiveness and safety of adalimumab in children with inflammatory bowel disease.

BACKGROUND: Adalimumab is efficacious therapy for adults with Crohn's disease (CD). AIM: To summarise the United Kingdom and Republic of Ireland paediatric adalimumab experience. METHODS: British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) members with Inflammatory Bowel Disease (IBD) patients <18 years old commencing adalimumab with at least 4 weeks follow-up. Patient demographics and details of treatment were then collected. Response and remission was assessed using the Paediatric Crohn's Disease Activity Index (PCDAI)/Physicians Global Assessment (PGA). RESULTS: Seventy-two patients [70 CD, 1 ulcerative colitis (UC), 1 IBD unclassified (IBDU)] from 19 paediatric-centres received adalimumab at a median age of 14.8 (IQR 3.1, range 6.1-17.8) years; 66/70 CD (94%) had previously received infliximab. A dose of 80 mg then 40 mg was used for induction in 41(59%) and 40 mg fortnightly for maintenance in 61 (90%). Remission rates were 24%, 58% and 41% at 1, 6 and 12 months, respectively. Overall 43 (61%) went into remission at some point, with 24 (35%) requiring escalation of therapy. Remission rates were higher in those on concomitant immunosuppression cf. those not on immunosuppression [34/46 (74%) vs. 9/24 (37%), respectively, (χ(2) 8.8, P=0.003)]. There were 15 adverse events (21%) including four (6%) serious adverse events with two sepsis related deaths in patients who were also on immunosuppression and home parenteral nutrition (3% mortality rate). CONCLUSIONS: Adalimumab is useful in treatment of refractory paediatric patients with a remission rate of 61%. This treatment benefit should be balanced against side effects, including in this study a 3% mortality rate.