R. Mark Beattie

Guidelines for the management of inflammatory bowel disease in children in the United Kingdom.

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Next generation exome sequencing of paediatric inflammatory bowel disease patients identifies rare and novel variants in candidate genes

Background Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. Objective To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. Design DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. Results Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohns disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. Conclusion For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

Current pharmacological management of gastro-esophageal reflux in children: an evidence-based systematic review

Gastro-esophageal reflux (GER) is a common phenomenon, characterized by the regurgitation of the gastric contents into the esophagus. Gastro-esophageal reflux disease (GERD) is the term applied when GER is associated with sequelae or faltering growth.The main aims of treatment are to alleviate symptoms, promote normal growth, and prevent complications. Medical treatments for children include (i) altering the viscosity of the feeds with alginates; (ii) altering the gastric pH with antacids, histamine H2 receptor antagonists, and proton pump inhibitors; and (iii) altering the motility of the gut with prokinetics, such as metoclopramide and domperidone.Our aim was to systematically review the evidence base for the medical treatment of gastro-oesophageal reflux in children. We searched PubMed, AdisOnline, MEDLINE, and EMBASE, and then manually searched reviews from the past 5 years using the key words ‘gastro-esophageal’ (or ‘gastroesophageal’), ‘reflux’, ‘esophagitis’, and ‘child

Body composition in childhood inflammatory bowel disease

’ (or ‘infant’) and ‘drug

Therapy of Crohn's disease in childhood.

’ or ‘therapy’. Articles included were in English and had an abstract. We used the levels of evidence adopted by the Centre for Evidence-Based Medicine in Oxford to assess the studies for all reported outcomes that were meaningful to clinicians making decisions about treatment. This included the impact of clinical symptoms, pH study profile, and esophageal appearance at endoscopy.Five hundred and eight articles were reviewed, of which 56 papers were original, relevant clinical trials. These were assessed further. Many of the studies considered had significant methodological flaws, although based on available evidence the following statements can be made. For infant GERD, ranitidine and omeprazole and probably lansoprazole are safe and effective medications, which promote symptomatic relief, and endoscopic and histological healing of esophagitis. Gaviscon® Infant sachets are safe and can improve symptoms of reflux. There is less evidence to support the use of domperidone or metoclopramide. More evidence is needed before other anti-reflux medications can be recommended. For older children, acid suppression is the mainstay of treatment. The largest evidence base supports the early use of H2 receptor antagonists or proton pump inhibitors.

Anaemia and iron deficiency in children with inflammatory bowel disease

BACKGROUND & AIMS Little is known about the impact of disease and treatment on the pattern of growth in children with Inflammatory Bowel Disease (IBD). Significant deficits in height and weight in children with Crohns disease have been reported but changes in fat and fat free mass are less well defined. This study aims to describe the height, weight and body composition of a cohort of children with IBD. METHODS Height, weight, skinfold thicknesses and bioelectrical impedance analysis was performed. Disease activity was assessed with clinical scoring systems. RESULTS 55 children, median age 13.7 years (range 6.5-17.7) were studied. Median (25th, 75th percentile) Standard Deviation Score for BMI, Height and Weight were - 0.3 (- 0.97, 0.65), - 0.56 (- 1.42, 0.06), - 0.62 (- 1.43, 0.19). In Crohns disease, using multiple regression analysis disease activity measured by PCDAI was significantly inversely related to fat free mass (β - 0.2, 95% CI -0.17, -0.03, p 0.005). CONCLUSIONS Children with IBD were both under and overweight. Nutritional deficits were more common in Crohns disease. Fat free mass was related to disease activity in children with Crohns disease regardless of changes in weight. Weight or BMI may mask deficits in lean tissue in the presence of normal or increased proportions of body fat.

Management of Chronic Functional Constipation in Childhood

Crohn’s disease in childhood is a chronic relapsing and remitting condition that can significantly impact on normal growth and development. This influences the choice of both initial and ongoing management. The goal of therapy is to induce and maintain remission with minimal side effects. Enteral nutrition as the sole therapy for active disease is effective in some children, thus avoiding the use of corticosteroids. In disease that is resistant to conventional treatment, immunosuppression or anti-tumour necrosis factor therapy is indicated. We review the use of these treatments and discuss the new therapies being developed, including antibodies, cytokines and probiotics.

No relation between disease activity measured by multiple methods and REE in childhood Crohn disease

BACKGROUND AND AIMS Anaemia and iron deficiency are common in children with Inflammatory Bowel Disease (IBD) however it is not known if the prevalence of anaemia and iron deficiency alters following diagnosis. METHODS Laboratory results from diagnosis, and at follow up one and two years later were recorded retrospectively in children with IBD recruited from a tertiary centre. Anaemia was defined using WHO standards and iron deficiency defined using published guidelines. RESULTS 46 children (16 girls) with Crohns disease and 34 children (18 girls) with UC were studied. 75% of children with IBD were anaemic at diagnosis, 30% were anaemic at follow up two years later. 90% of children with Crohns and 95% of children with Ulcerative Colitis (UC) were iron deficient at diagnosis. At follow up two years later 70% of children with Crohns and 65% of children with UC were iron deficient. CONCLUSIONS Persistent anaemia and iron deficiency are common in childhood IBD, prevalence alters with duration of time from diagnosis.

Cow’s milk allergy in children

Chronic functional constipation is a common problem in childhood, with soiling a significant issue. The morbidity is high and the treatment is complex. There is a very poor evidence base for the drug treatments used and there are considerable differences in practice in different units.The key to successful management is early diagnosis and prompt treatment with an emphasis on holistic care with multidisciplinary support where needed. For example, the practical approach in our unit at the Southampton General Hospital, Southampton, England emphasizes the non-drug aspects including patient education and behavioral modification and uses stimulant laxatives, usually in a high dose as first-line therapy.There is an urgent need for prospective comparative studies to investigate different treatment regimens and for longitudinal studies to examine the long-term outcome of chronic constipation and the factors that determine it. The lack of a significant evidence base for the use of the most widely used agents proves a significant challenge in the production of evidence-based guidelines and highlights the paucity of data for most of the widely used treatments for childhood constipation.

Therapy of Crohn’s Disease in Childhood

Background and Aims: Increased resting energy expenditure (REE) unmatched by dietary intake is implicated as a cause of poor nutrition in childhood inflammatory conditions. Adequate description of disease activity and correction of REE data for body composition are important to reach reliable conclusions about changes in REE associated with disease. The present study aimed to determine the effect of disease activity measured by clinical status, systemic and stool inflammatory markers on REE in children with Crohn disease using appropriate correction for confounding factors. Methods: Sixty children with Crohn disease were recruited from the regional paediatric gastroenterology unit and studied on 1 occasion. REE was measured by indirect calorimetry. Fat-free mass (FFM) was estimated by skinfold thickness. Disease activity was measured using systemic (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) and faecal markers of inflammation (lactoferrin, calprotectin) and clinical scores (Paediatric Crohn Disease Activity Index). Results: Using a multiple regression model, there was no significant change in REE from active or inactive disease (&bgr; = 0.03, P = 0.7) nor from CRP (&bgr; = −0.05, P = 0.52), ESR (&bgr; = −0.07, P = 0.43), faecal calprotectin (&bgr; = −0.07, P = 0.38), and faecal lactoferrin (&bgr; = 0.01, P = 0.88). REE/kg FFM0.5 was not associated with the Paediatric Crohn Disease Activity Index (r = 0.1, P = 0.44), CRP (r = −0.3, P = 0.84) or ESR (r = 0.12, P = 0.4), faecal calprotectin (r = 0.04, P = 0.97), or faecal lactoferrin (r = 0.02, P = 0.87). Conclusions: REE corrected for physiologically relevant confounders is not associated with degree of disease activity using clinical tools or systemic and local inflammatory markers, and therefore is an unlikely mechanism for poor nutritional state.