Francisco A. Sylvester

Dyspepsia in children and adolescents: a prospective study.

BACKGROUND Dyspepsia is poorly characterized in the pediatric population. The goal of the current study was to describe the clinical constellation and natural history of dyspepsia in children and adolescents seen in a pediatric gastroenterology practice. METHODS A standardized questionnaire was administered by a pediatric gastroenterologist to all subjects 5 or more years of age (and their parents or guardians) treated in a referral pediatric gastroenterology practice for 1 month or more of abdominal pain or discomfort, nausea, or vomiting. Subjects with dyspepsia and dyspepsia subtypes (ulcer-like, dysmotility-like) were identified by using previously defined adult criteria. Evaluation and treatment were performed at the discretion of the attending pediatric gastroenterologist. RESULTS During a 1-year period, 257 patients were screened with 127 subjects fulfilling criteria for dyspepsia (59% girls, 85% white; median age, 11.7 years; median duration of symptoms, 8 months). Symptoms were ulcer-like in 26% and dysmotility-like (nausea predominance) in 15% of subjects. In those with dyspepsia, irritable bowel syndrome and gastroesophageal reflux were noted in 24% and 43%, respectively. Esophagogastroduodenoscopy and biopsy were performed in 56 subjects with 21 (38%) having mucosal inflammation (Helicobacter pylori in 5). The remaining 35 subjects (62%) were considered to have functional dyspepsia. Duration of symptoms less than 1 year and vomiting were risk factors for mucosal inflammation. Follow-up at 6 months to 2 years revealed 70% of subjects were either asymptomatic or much improved regardless of the cause of dyspepsia. CONCLUSION Most children and adolescents with dyspepsia do not have serious disease. In our referral population H. pylori infection was unusual, and no peptic ulceration was found. Most subjects with functional dyspepsia have improvement of symptoms over time.

Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease.

Background: In children with inflammatory bowel disease (IBD) it is not known whether reductions in bone mineral density (BMD) are a consequence of bone turnover alterations and if BMD improves with treatment. Methods: In a cohort of children with IBD, we prospectively measured indicators of bone remodeling, body mass index (BMI), disease activity, intact parathyroid hormone, serum IL‐6, and insulin‐like growth factor‐I at diagnosis and then every 6 months for 2 years. BMD was determined annually using dual x‐ray absorptiometry (DXA). BMD Z‐scores were calculated using height/age. Baseline measurements and calcium intake were compared with a group of age‐ and sex‐matched healthy children. Results: We observed that at diagnosis total body BMD Z‐score (mean ± SD) was −0.78 ± 1.02 for Crohns disease (CD, n = 58), −0.46 ± 1.14 for ulcerative colitis (UC, n = 18), and −0.17 ± 0.95 for control (CL, n = 49) (P < 0.01, CD versus CL). In CD, a BMD Z‐score <−1.0 was associated with lower BMI and higher serum IL‐6. Patients with CD and UC had low bone turnover. Activation of bone formation paralleled clinical improvement, but BMC gain was less than expected over the 2‐year study period, especially in CD. Prednisone use did not correlate with low BMD. Conclusions: Decreased bone turnover occurs in children newly diagnosed with IBD. Although indicators of osteoblast activity increase with clinical improvement, bone mineral accrual does not accelerate. Children with low BMI may be considered for BMD screening, since they are at risk for low bone mass.

Clinical efficacy of probiotics: review of the evidence with focus on children.

Probiotics are marketed in several countries and widely used by pediatric health care providers. Although probiotics can be helpful for specific disorders, they have been broadly prescribed for disorders without clear evidence to support their use. Furthermore, in certain specific conditions, probiotics cause clinical deterioration. This report is a review and evaluation of the evidence or lack thereof to support a beneficial effect of probiotic agents in a variety of pediatric conditions and to review the safety and potential adverse events that may be encountered when using probiotics. It is also important to emphasize that probiotics are highly heterogeneous with differences in composition, biological activity, and dose among the different probiotic preparations.

Cloning and variation of ground state intestinal stem cells

Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, ‘ground state’ stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine.

Bone health in children and adolescents with chronic diseases that may affect the skeleton: The 2013 ISCD pediatric official positions

The aim of this Task Force was to review the use of dual-energy X-ray absorptiometry (DXA) in children and adolescents with underlying chronic diseases that pose risk factors for compromised bone health, such as inflammation, glucocorticoid therapy, or decreased mobility. The Task Force systematically analyzed more than 270 studies, with an emphasis on those published in the interval since the original 2007 Position Statements. Important developments over this period included prospective cohort studies demonstrating that DXA measures of areal bone mineral density (aBMD) predicted incident fractures and the development of robust reference data and strategies to adjust for bone size in children with growth impairment. In this report, we summarize the current literature on the relationship between DXA-based aBMD and both fracture (vertebral and non-vertebral) outcomes and non-fracture risk factors (e.g., disease characteristics, ambulatory status, and glucocorticoid exposure) in children with chronic illnesses. Most publications described the aBMD profile of children with underlying diseases, as well as the cross-sectional or longitudinal relationship between aBMD and clinically relevant non-fracture outcomes. Studies that addressed the relationship between aBMD and prevalent or incident fractures in children with chronic illnesses are now emerging. In view of these updated data, this report provides guidelines for the use of DXA-based aBMD in this setting. The initial recommendation that DXA is part of a comprehensive skeletal healthy assessment in patients with increased risk of fracture is unchanged. Although the prior guidelines recommended DXA assessment in children with chronic diseases at the time of clinical presentation with ongoing monitoring, this revised Position Statement focuses on the performance of DXA when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture and when the DXA results will influence that management.

Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study

BACKGROUND Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohns disease. Validated models to predict risk for complications are not available, and the effect of treatment on risk is unknown. METHODS We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohns disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. FINDINGS Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohns disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51-82) and specificity of 63% (55-71), with a negative predictive value of 95% (94-97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio [HR] 0·30, 95% CI 0·10-0·89; p=0·0296) but not stricturing complication (1·13, 0·51-2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12-2·57; p=0·0120). When this gene signature was included, the models specificity improved to 71%. INTERPRETATION Our findings support the usefulness of risk stratification of paediatric patients with Crohns disease at diagnosis, and selection of anti-TNFα therapy. FUNDING Crohns and Colitis Foundation of America, Cincinnati Childrens Hospital Research Foundation Digestive Health Center.

Skeletal health of children and adolescents with inflammatory bowel disease.

Current evidence points to suboptimal bone health in children and adolescents with inflammatory bowel disease (IBD) when compared with their healthy peers. This compromise is evident from diagnosis. The clinical consequences and long-term outcome of this finding are still unknown. The mechanism of suboptimal bone health in children and adolescents with IBD lays mainly in reduced bone formation, but also reduced bone resorption, processes necessary for bone growth. Factors contributing to this derangement are inflammation, delayed growth and puberty, lean mass deficits, and use of glucocorticoids. We recognize that evidence is sparse on the topic of bone health in children and adolescents with IBD. In this clinical guideline, based on current evidence, we provide recommendations on screening and monitoring bone health in children and adolescents with IBD, including modalities to achieve this and their limitations; monitoring of parameters of growth, pubertal development, and reasons for concern; evaluation of vitamin D status and vitamin D and calcium intake; exercise; and nutritional support. We also report on the current evidence of the effect of biologics on bone health in children and adolescents with IBD, as well as the role of bone active medications such as bisphosphonates. Finally, we summarize the existing numerous gaps in knowledge and potential subjects for future research endeavors.

A Two-Year Longitudinal Study of Persistent Lean Tissue Deficits in Children With Crohn's Disease

BACKGROUND & AIMS Deficits in lean body mass have been reported in cross-sectional studies of children with Crohns disease, but no longitudinal data exist from diagnosis. We observed the effects of Crohns disease on body composition and bone mineral content (BMC), beginning at diagnosis and followed prospectively for 2 years. METHODS The study was conducted at 2 tertiary care centers for pediatric inflammatory bowel diseases. At diagnosis we recorded age, weight, height, levels of serum interleukin-6 and insulin-like growth factor-1, sexual maturation stage, disease activity, z scores for body mass index (BMI), fat-free mass (FFM), and bone mineral content (BMC). z Scores were adjusted for height and age, when appropriate. Measurements were made yearly in patients with Crohns disease (n = 42) but only at the start of the study in controls (n = 81). RESULTS BMI and FFM z scores were significantly reduced at the time of diagnosis in children with Crohns disease, compared with controls. During the 2-year study period, the BMI z scores normalized in patients with Crohns disease, but the FFM z scores did not increase significantly. The BMC z scores increased significantly, but they were still lower than control values after 2 years. Changes in BMC during a period of 2 years were associated with increases in FFM (R(2) = 0.318, P < .01). CONCLUSIONS The correction of BMI that is associated with clinical improvement in children with Crohns disease 2 years after diagnosis results from gains in fat mass. Significant FFM deficits might hamper normal acquisition of bone mass in children with Crohns disease because of a lack of mechanical strain.

Slow-release 5-aminosalicylic acid therapy in children with small intestinal Crohn's disease.

Pharmacologic agents effective in the treatment of Crohns disease confined to the small intestine are limited. The therapeutic efficacy of oral mesalazine in small bowel inflammation, although theoretically promising, remains unproven. In an open-labeled initial trial, timed-release 5-aminosalicylic acid (5-ASA), administered al a daily dosage of 30.6 ± 9.0 mg/kg (mean ± SEM) to children with active Crohns disease involving the small intestine, was associated with improvement on the Harvey index in six of 12 patients treated for 8.1 ± 3.9 weeks. In a subsequent prospective, double-blind study 14 children, ages 9.3 to 16.1 years, with active Crohns disease limited radiologically in the small intestine were randomized to receive either timed-release 5-ASA [50 mg/kg/day (maximum 3 g/day)] or placebo for 8 weeks. Following a 4-week washout period, patients crossed over to receive the other study drug for a further 8 weeks. Six children completed the entire 20-week trial. The van Hees index improved among patients receiving 5-ASA for 8 weeks (Δ = - 18 ± 6.4) but deteriorated among patients given placebo (Δ = + 14 ± 4.1) (p < 0.05). Mean Crohns Disease Activity Index (CDAI) decreased marginally after 8 weeks of 5-ASA treatment (Δ = - 48 ± 38.2) but not with placebo (Δ = - 3.0 ± 7.9) (p = 0.31). Of the eight noncompleters, more patients dropped out of the study because of lack of therapeutic response to placebo (n = 5) than to 5-ASA (n = 2). No serious adverse clinical effects were observed during either trial, but one adolescent girl reported mild hair loss that was promptly reversed after the drug was discontinued. These results indicate that timed-release 5-ASA may be beneficial in the medical therapy of children with active small bowel Crohns disease.

Effects of serum from children with newly diagnosed Crohn disease on primary cultures of rat osteoblasts

Objectives We propose that Crohn disease (CD) decreases bone formation via circulating inflammatory mediators. We therefore examined the effects of serum from newly diagnosed, untreated children with CD on osteoblasts in culture and the role of interleukin-6 (IL-6), a cytokine present in excess in active CD that also has direct effects on bone. Methods Bone mineral density was measured by dual x-ray absorptiometry. Primary cultures of rat osteoblasts were treated with serum from patients with CD and healthy controls. We measured expression of osteoblast proliferation, viability, differentiation markers, and mineralized nodule formation. Neutralizing antibodies were used to inhibit the effects of IL-6 present in serum. Results We studied 24 children with CD (14 male) and 31 controls (15 male). Spine bone mineral density was lower in patients with CD (Z score, −0.8 ± 0.9 vs. 0.0 ± 1.0 for controls;P < 0.05). Nodule formation was markedly decreased in osteoblasts treated with CD serum. However, CD serum did not affect osteoblast proliferation or viability. Expression of proteins characteristic of mature osteoblasts—osteocalcin and alkaline phosphatase—was reduced. Unlike our results in a model of intact bone, neutralization of IL-6 did not inhibit the effects of CD serum. Addition of IL-6 to control serum to match serum concentrations in CD had no effect either. Conclusions CD serum affects osteoblast function and probably differentiation in vitro, suggesting a mechanism by which CD may affect bone formation. IL-6 by itself is not sufficient to cause these effects and probably needs a cofactor present in intact bone.