Multiomic features associated with mucosal healing and inflammation in paediatric Crohn's disease.

BACKGROUND: The gastrointestinal microbiota has an important role in mucosal immune homoeostasis and may contribute to maintaining mucosal healing in Crohn's disease (CD). AIM: To identify changes in the microbiota, metabolome and protease activity associated with mucosal healing in established paediatric CD METHODS: Twenty-five participants aged 3-18 years with CD, disease duration of over 6 months, and maintenance treatment with biological therapy were recruited. They were divided into a low calprotectin group (faecal calprotectin <100 µg/g, "mucosal healing," n = 11), and a high calprotectin group (faecal calprotectin >100 µg/g, "mucosal inflammation," n = 11). 16S gene-based metataxonomics, 1 H-NMR spectroscopy-based metabolic profiling and protease activity assays were performed on stool samples. RESULTS: Relative abundance of Dialister species was six-times greater in the low calprotectin group (q = 0.00999). Alpha and beta diversity, total protease activity and inferred metagenomic profiles did not differ between groups. Pentanoate (valerate) and lysine were principal discriminators in a machine-learning model which differentiated high and low calprotectin samples using NMR spectra (R2 0.87, Q2 0.41). Mean relative concentration of pentanoate was 1.35-times greater in the low calprotectin group (95% CI 1.03-1.68, P = 0.036) and was positively correlated with Dialister. Mean relative concentration of lysine was 1.54-times greater in the high calprotectin group (95% CI 1.05-2.03, P = 0.028). CONCLUSIONS: This multiomic study identified an increase in Dialister species and pentanoate, and a decrease in lysine, in patients with "mucosal healing." It supports further investigation of these as potential novel therapeutic targets in CD.

Systematic review: Body composition in children with inflammatory bowel disease.

BACKGROUND: Paediatric inflammatory bowel disease (IBD) is associated with weight loss, growth restriction and malnutrition. Bone mass deficits are well described, little is known about other body composition compartments. AIMS: To define the alterations in non-bone tissue compartments in children with IBD, and explore the effects of demographic and disease parameters. METHODS: A systematic search was carried out in the PubMed (www.ncbi.nlm.nih.gov/pubmed) and Web of Science databases in May 2014 (limitations age <17 years, and composition measurements compared with a defined control population). RESULTS: Twenty-one studies were included in this systematic review, reporting on a total of 1479 children with IBD [1123 Crohn's disease, 243 ulcerative colitis], pooled mean age 13.1 ± 3.2 years, and 34.9% female. Data were highly heterogeneous, in terms of methodology and patients. Deficits in protein-related compartments were reported. Lean mass deficits were documented in 93.6% of Crohn's disease and 47.7% of ulcerative colitis patients when compared with healthy control populations. Lower lean mass was common to both sexes in Crohn's disease and ulcerative colitis, deficits in females with persisted for longer. Fat-related compartment findings were inconsistent, some studies report reductions in body fat in new diagnosis/active Crohn's disease. CONCLUSIONS: It is clear that almost all children with Crohn's disease and half with ulcerative colitis have reduced lean mass, however, body fat alterations are not well defined. To understand what impact this may have on health and disease in children with IBD, further studies are needed to identify in which tissues these deficits lie, and to quantify body fat and its distribution.

Recognition, assessment and management of eosinophilic oesophagitis.

Eosinophilic oesophagitis (EO) is a chronic immune/antigen-mediated oesophageal disease, with the immune reaction most likely directed to foods but on occasion also to aeroallergens. Clinically, it is characterised by symptoms of oesophageal dysfunction in subjects who typically have other indicators of an atopic tendency. Older children (and adults) frequently present with dysphagia and can have strictures (which may require dilatation). The diagnosis is dependent on an eosinophil-predominant oesophageal inflammation, with 15 or more eosinophils per high-powered field, now generally accepted as a necessary cut-off level of infiltration, which together with other clinical data (eg, oesophageal pH/impedance studies) can help discriminate EO from other potential causes of symptoms such as gastro-oesophageal reflux disease. Recommended therapies, which may need to be long term, are dietary antigen exclusion (with elemental feeds or an exclusion diet) and/or topical corticosteroids.

Update of the management of inflammatory bowel disease.

Up to 25% of patients with Crohn's disease and ulcerative colitis present before the age of 18 years. Although the pathophysiology of inflammatory bowel disease presenting in childhood does not differ fundamentally from that presenting in adulthood, managing these younger patients requires special consideration in light of growth and the potential long term consequences of both the disease and its treatments. Therapeutic approaches have changed in recent years, and there is a fuller appreciation of the role (and risks) of anti-tumour necrosis factor monoclonal therapy.

Blood tests and histological correlates in children with eosinophilic oesophagitis.

AIM: To determine the relationship between blood tests and oesophageal histology in Eosinophilic oesophagitis (EoE). METHODS: All children diagnosed with EoE at one hospital from 2000 to 2009 were considered for inclusion in this study. Three blood test results were analysed, blood eosinophil count, serum total immunoglobulin E (IgE) and radioallergosorbent tests (RAST) to common food allergens. Oesophageal histology was prospectively re-reviewed, and mean eosinophil counts were enumerated. Blood test results were correlated with oesophageal eosinophil counts using Spearman's rank test. RESULTS: Forty children (70% boys) were included in this study, median age at diagnosis 6.5 years (range 0-15). At the time of diagnosis, 78% of children had a raised blood eosinophil count, 90% had a raised serum total IgE and 83% had one or more positive RAST tests. The mean oesophageal eosinophil count was significantly correlated with both blood eosinophil count (p=0.008) and serum total IgE level (p=0.008). CONCLUSION: This study shows that blood tests are often abnormal in children with EoE at the time of diagnosis. Our data demonstrate an association between histological abnormalities and blood test results in children with EoE.

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.

UK incidence of achalasia: an 11-year national epidemiological study.

AIM: To determine the incidence and examine the epidemiology of achalasia before the age of 16 years in the UK from 1998 to 2008. METHODS: 25 regional paediatric surgery referral centres were asked to provide demographic and epidemiological data on cases of childhood achalasia from 1998 to 2008. Incidence rates were calculated from national population estimates. The data collection method was validated in one centre. RESULTS: 228 patients from 24 centres were diagnosed with achalasia before 16 years in the UK from 1998 to 2008. The mean incidence from 1998 to 2008 was 0.18/10(5) children/year. Where additional data was provided (69-81% of cases) 56% of children were male and the mean age of diagnosis was 10.9 years. Logistic regression analysis showed a rising incidence, with an OR of 1.12 (95% CI 1.06 to 1.16) for having achalasia in each successive year. The validation of this methodology showed that 95% of true cases and no false cases were identified. CONCLUSIONS: The mean incidence of childhood achalasia in the UK from 1998 to 2008 is at least 0.18/10(5) children/year; this has risen over the last 11 years and compared to the only other study published in 1988.

Systematic review of the evidence base for the medical treatment of paediatric inflammatory bowel disease.

OBJECTIVE: To systematically review the evidence base for the medical (pharmaceutical and nutritional) treatment of paediatric inflammatory bowel disease. METHODS: Key clinical questions were formulated regarding different treatment modalities used in the treatment of paediatric (not adult-onset) IBD, in particular the induction and maintenance of remission in Crohn disease and ulcerative colitis. Electronic searches were performed from January 1966 to December 2006, using the electronic search strategy of the Cochrane IBD group. Details of papers were entered on a dedicated database, reviewed in abstract form, and disseminated in full for appraisal. Clinical guidelines were appraised using the AGREE instrument and all other relevant papers were appraised using Scottish Intercollegiate Guidelines Network methodology, with evidence levels given to all papers. RESULTS: A total of 6285 papers were identified, of which 1255 involved children; these were entered on the database. After critical appraisal, only 103 publications met our criteria as evidence on medical treatment of paediatric IBD. We identified 3 clinical guidelines, 1 systematic review, and 16 randomised controlled trials; all were of variable quality, with none getting the highest methodological scores. CONCLUSIONS: This is the first comprehensive review of the evidence base for the treatment of paediatric IBD, highlighting the paucity of trials of high methodological quality. As a result, the development of clinical guidelines for managing children and young people with IBD must be consensus based, informed by the best-available evidence from the paediatric literature and high-quality data from the adult IBD literature, together with the clinical expertise and multidisciplinary experience of paediatric IBD experts.

Reduced quality of life in children with gastro-oesophageal reflux disease.

AIM: To assess self-reported Quality of life (QoL) in children with Gastro-oesophageal reflux disease (GORD) aged 5-18 and compare this with both disease and healthy control children in a prospective consecutive sample. METHODS: All children attending a tertiary paediatric gastroenterology clinic from February 2009 to May 2009 with GORD, chronic constipation and inflammatory bowel disease (IBD) were asked to complete the validated PedsQL generic QoL assessment (self-report) at their clinic appointment. The PedsQL considers physical, emotional, social and school domains and is scored from 0 to 100. Healthy children were also recruited from the same site. Groups were compared using the independent samples Student's t-test. RESULTS: A total of 184 children completed the assessment [103 (56%) male, mean age 10.7 years +/- 3.3] including 40 children with GORD, 44 with chronic constipation, 59 with IBD and 41 healthy children. QoL was significantly lower in the GORD group compared with both children with IBD (74 vs. 82) and healthy children (74 vs. 84), and was comparable to that of children with chronic constipation (74 vs. 74). CONCLUSIONS: Self-reported QoL in children with GORD attending a tertiary paediatric gastroenterology clinic is significantly reduced compared with both healthy children and children with IBD.

Cow's milk protein-specific T-helper type I/II cytokine responses in infants with necrotizing enterocolitis.

Enteral feeding, in particular with formula feeds, is associated with necrotizing enterocolitis (NEC). In this study, we have examined, in the systemic and mucosal immune compartments, for evidence of bovine milk antigen sensitization in infants with NEC. Eleven newborns with Bell's staging 2-3 NEC [median post-conceptional age 31 wk (range 27-41 wk)], 21 neonatal controls [33 (28-40) wk] and 15 infants undergoing intestinal resection or mucosal biopsy for non-inflammatory conditions [39 (34-42) wk] were studied. Spontaneous and antigen or mitogen elicited interferon-gamma (IFN-gamma) [T-helper type I (Th1)], interleukin (IL)-4 and IL-5 [T-helper type II (Th2)] responses were enumerated using single-cell enzyme-linked immunospot (ELISPOT) assay in peripheral blood (PBMC) or lamina propria mononuclear cells. NEC infants, compared with controls, showed a significant elevation in baseline PBMC cytokine secreting cells, vigorous mitogen responses (20- to 120-fold increase) for IFN-gamma, IL-4 and IL-5 (p < 0.001), strong responses to beta-lactoglobulin (betalg) (IFN-gamma > IL-4/IL-5, p < or = 0.001), and somewhat smaller casein responses. Similarly, in the lamina propria, a small but significant increase in spontaneous cytokine-secreting cells was detected in NEC infants (p < 0.01), with an IFN-gamma/IL-4 predominant phytohemagglutinin (PHA)/concanavalin-A (ConA) response. Three of nine NEC infants (but no controls) also showed a positive ELISPOT response to betalg (IFN-gamma only) but none to casein. We have thus demonstrated significant cow's milk protein (CMP) sensitization in NEC, at least in the systemic compartment (mixed Th1/Th2), with minimal mucosal activation in some cases. These novel findings provide a potential mechanism for a direct contributory role of CMP in the pathogenesis of NEC.

Inflammatory bowel disease.

Twenty five per cent of inflammatory bowel disease presents in childhood. Growth and nutrition are key issues in the management with the aim of treatment being to induce and then maintain disease remission with minimal side effects. Only 25% of Crohn's disease presents with the classic triad of abdominal pain, weight loss, and diarrhoea. Most children with ulcerative colitis have blood in the stool at presentation. Inflammatory markers are usually although not invariably raised at presentation (particularly in Crohn's disease). Full investigation includes upper gastrointestinal endoscopy and ileocolonoscopy. Treatment requires multidisciplinary input as part of a clinical network led by a paediatrician with special expertise in the management of the condition.

Neonatal inflammatory intestinal diseases: necrotising enterocolitis and allergic colitis.

The occurrence in the neonatal period and into early infancy of two inflammatory conditions, necrotising enterocolitis (NEC), and allergic colitis, that do not occur in later life highlight the peculiar vulnerability of the gastrointestinal tract in the newborn period to otherwise innocuous insults. The pathogenesis of the relatively benign allergic colitis as a mucosal inflammatory process driven by dietary antigens is relatively well characterised, and its treatment with dietary manipulation is well established. For NEC, hypoxic/ischaemic insult, mucosal immaturity, and its interaction with the intestinal microflora are understood to be the main factors in pathogenesis. Thus far, the most productive interventions have been in preventative approaches, in particular feeding strategies, to reduce the incidence of the condition whilst establishing adequate growth and progression onto enteral feeding. For established NEC, supportive medical therapy or surgical intervention remains the mainstay or treatment, although novel therapies, such as platelet-activating factor (PAF) inhibitors and epidermal growth factor (EGF), have shown some promise in animal models of the condition.

Another cause of bloody diarrhoea in infancy: cytomegalovirus colitis in an immunocompetent child.

Although a ubiquitous pathogen, cytomegalovirus (CMV) is very rarely thought to be the cause of significant gastrointestinal infection in the immunocompetent child. We report the case of a 2-month-old infant who presented with bloody diarrhoea and severe dehydration, which was subsequently diagnosed as CMV enterocolitis and resolved spontaneously without antiviral treatment.

Improvement in quality of life of children with acute Crohn's disease does not parallel mucosal healing after treatment with exclusive enteral nutrition.

BACKGROUND: Crohn's disease is a chronic debilitating disorder affecting a child's physical and emotional well-being. Recent emphasis on 'quality of life' (QOL) has led to re-evaluation of available medical treatments. AIM: To assess prospectively change in QOL, clinical disease activity and intestinal mucosal inflammation in active paediatric Crohn's disease after treatment with exclusive enteral nutrition. In addition, we evaluated whether change in QOL could predict changes in paediatric Crohn's disease activity index (PCDAI) and mucosal inflammation (endoscopic and histologic). METHODS: The IMPACT II questionnaire was used prospectively and longitudinally in 26 consecutively recruited children [16 males (67%), median 14 years, s.d. = 1.7 years] with active Crohn's disease (PCDAI > 20). They were treated with a new polymeric enteral feed (ACD004, Nestle) for a period of 8 weeks. All had PCDAI, QOL and endoscopic assessment at the time of diagnosis and after 8 weeks of treatment. RESULTS: Twenty-three of 26 children achieved a clinical remission at 8 weeks, with improvement in the QOL scores (P < 0.05). The change in QOL score after treatment was predictive of achieving a clinical remission, but not of histological improvement. CONCLUSIONS: Although children may find dietary restrictions difficult, this study confirms a clear improvement in QOL after treatment with exclusive enteral nutrition. However, improvement in QOL scores is not reflected by improvement in mucosal inflammation. Whilst improving QOL remains a core principal in patient management, the long-term consequences of ongoing mucosal inflammation must be better understood before relying only on short-term QOL measures to dictate treatment choices.

Effect of enteral nutrition on antioxidant enzyme systems and inflammation in paediatric Crohn's disease.

UNLABELLED: Crohn's disease is characterized by chronic inflammation of the gastrointestinal mucosa, which can be successfully treated with enteral nutrition. In this study, the activities of the antioxidant metalloenzymes copper/zinc-superoxide dismutase (Cu/Zn-SOD) and selenium-glutathione peroxidase (Se-GPx) were determined in erythrocyte lysates from children with Crohn's disease. Both enzymes exhibited significantly lower activities relative to healthy control subjects: 1.55 +/- 0.33 vs 2.13 +/- 0.75 SOD U mg(-1) protein (p < 0.025) for Cu/Zn-SOD, and 61.9 +/- 17.7 vs 93.6 +/- 28.7 mU mg(-1) protein (p < 0.01) for Se-GPx. Treatment of patients with a specific polymeric diet, CT3211, for a period of 8 wk did not significantly alter the activities of the enzymes. In contrast, clinically, enteral nutritional therapy induced a remission in 13/14 children, and a significant fall in both median serum C-reactive protein and mean serum tumour necrosis factor-alpha levels. CONCLUSION: The results imply that the anti-inflammatory action of enteral nutrition in Crohn's disease is caused by a mechanism other than restitution of these antioxidant enzymes.

Portal vein thrombosis and pancreatic failure.

We report a case of a child with portal vein thrombosis presenting with protein losing enteropathy. He later developed exocrine and endocrine pancreatic failure. This association has not been reported before.

Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn's disease.

BACKGROUND: Although enteral nutrition is a recognized form of treatment for intestinal Crohn's disease, there are persisting problems with feed palatability and only limited data as to its mode of action. AIM: To assess the effects of a specific oral polymeric diet (CT3211; Nestle, Vevey, Switzerland), which is rich in transforming growth factor beta2, on the mucosal inflammatory process. METHODS: Twenty-nine consecutive children with active intestinal Crohn's disease were treated with CT3211 as the sole source of nutrition for 8 weeks. Patients were assessed clinically, and endoscopically, whilst cytokine mRNA was measured in mucosal biopsies before and after treatment by quantitative reverse transcriptase polymerase chain reaction. RESULTS: After 8 weeks 79% of children were in complete clinical remission. Macroscopic and histological healing in the terminal ileum and colon was associated with a decline in ileal and colonic interleukin-1beta mRNA (pre-treatment to post-treatment ratio 0.008 and 0.06: P < 0.001, P = 0.006). In the ileum there was also a fall in interferon gamma mRNA (ratio 0.15, P < 0.001) with a rise in transforming growth factor beta1 mRNA (ratio 10, P = 0.04), whilst in the colon interleukin-8 mRNA fell with treatment (ratio 0.06, P < 0.05). CONCLUSIONS: The clinical response to oral polymeric diet CT3211 is associated with mucosal healing and a down regulation of mucosal pro-inflammatory cytokine mRNA in both the terminal ileum and colon. In the ileum there was also an increase in transforming growth factor beta1 mRNA.

Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children.

AIM: To establish a reference range in the paediatric population for the new glomerular filtration rate (GFR) marker, cystatin C, and to compare it with that of creatinine. METHODS: Cystatin C and creatinine were measured by particle enhanced nephelometric immunoassay (PENIA) and fixed interval Jaff¿e methods, respectively, in 291 children aged 1 day to 17 years, including 30 premature infants with gestational ages ranging from 24 to 36 weeks. RESULTS: In the premature infants, concentrations of both cystatin C and creatinine were significantly raised compared with term infants, with cystatin C concentrations being between 1.10 and 2.06 mg/litre and creatinine between 32 and 135 micromol/litre. In premature infants, there was no significant relation between gestational age and cystatin C or creatinine concentration. Creatinine concentrations fell to a nadir at 4 months of age, rising gradually to adult values by about 15-17 years of age, in contrast to cystatin C, which fell to a mean concentration of 0.80 mg/litre by the 1st year of life, and remained constant throughout adulthood up to the age of 50 years. Neither analyte showed any influence of sex. CONCLUSION: The measurement of cystatin C, rather than creatinine, is more practical for monitoring GFR changes in the paediatric population.