Clare Ceballos

Distinct phenotype of early childhood inflammatory bowel disease

Goals Our goals were to answer 2 questions: (1) Is the presentation of early-onset inflammatory bowel disease (IBD) similar to typical adolescent-onset IBD? (2) Is there variability in familial aggregation in childhood IBD? Background The phenotype of IBD in children under 5 years of age (early-onset) is poorly defined. Clinical and genetic studies of IBD, however, generally assume the phenotype to be homogenous throughout childhood. Study We analyzed data from 413 consecutive pediatric IBD outpatients attending our center between 1995 and 2000. Disease type, anatomic distribution, and family history were compared between children presenting before (early-onset) and after the age of five (5 to 15 y). Results Disease presentation was predominantly colonic in early-onset IBD, most patients presenting with ulcerative colitis (UC). Isolated colonic disease was most frequent in early-onset Crohn disease (colonic 76.5%, ileocolic 24%) compared with ileocolic disease (ileocolic 45.5%, colonic 26%, ileal 19.4%, proximal 6.3%) in the older age group. First-degree family history was highest in early-onset UC 26% versus 11% in the older UC group. Conclusions We describe a distinct phenotype of early childhood onset IBD, with a strikingly high familial aggregation in UC and greater tendency to present with colonic disease. As more genetic heterogeneity is identified in IBD, careful definition of phenotype is required to identify further susceptibility genes. The early-onset form of UC presents an ideal group for further genetic analysis. These phenotype differences also suggest that treatment and outcome may vary in early-onset childhood IBD; prospective studies are required to confirm this.

NOD2/CARD15 variants are associated with lower weight at diagnosis in children with Crohn's disease

OBJECTIVES:NOD2/CARD15 variants have recently been shown to be associated with Crohns disease (CD). No analysis of NOD2/CARD15 gene variants has so far been reported in pediatric patients. Therefore, our aim was to analyze NOD2/CARD15 gene variants in children with CD and to perform genotype-phenotype analyses.METHODS:We studied 101 children with CD and 136 healthy controls. Detailed phenotypic information was obtained from each patient. Patients were genotyped for the three NOD2/CARD15 variants R702W (single nucleotide polymorphism 8 [SNP8]), G908R (SNP12), and L1007fs (SNP13), and genotype-phenotype correlations were performed.RESULTS:We found 33 NOD2/CARD15 mutations in 29 of 101 patients (29%). The frequency of NOD2 variation was 31% in white (n = 87) compared with 11% in controls (χ2= 14; p = 0.0001; OR = 3.7; 95% CI = 1.7–7.8). Four white patients but not control subjects were compound heterozygotes. NOD2/CARD15 variants were significantly associated with ileal disease (χ2= 4.5; p = 0.03; OR = 5; 95% CI = 0.9–35.9). Of the children with NOD2/CARD15 variants, 44% were ≤5th percentile for weight at diagnosis, whereas only 15% of children without mutations were ≤5th percentile (χ2= 8.7; p = 0.003; OR = 4.5; 95% CI = 1.4–14.4). Similar trends were observed for height but they did not reach statistical significance.CONCLUSIONS:Our results demonstrate that: 1) the three NOD2/CARD15 variants confer risk to CD in children; 2) NOD2/CARD15 variants are associated with ileal disease in children as in adults; and 3) NOD2/CARD15 variants are associated with lower weight percentiles at diagnosis in children and a tendency toward lower height percentile, suggesting an association between growth in children with CD.

Home Nasogastric Feeds: Feeding Status and Growth Outcomes in a Pediatric Population.

BACKGROUND Home enteral nutrition (HEN) is a safe method for providing nutrition to children with chronic diseases. Advantages of HEN include shorter hospitalizations, lower cost, and decreased risk of malnutrition-associated complications. Follow-up after hospital discharge on HEN is limited. The purpose of this study was to look at children discharged on nasogastric (NG) feeds to assess follow-up feeding status and impact on growth. METHODS A retrospective chart review was conducted of pediatric patients discharged from Mount Sinai Medical Center on NG feeds between January 2010 and March 2013. RESULTS A total of 87 patients were included. Average age was 1.2 years. The most common diagnoses were congenital heart disease (47%), metabolic disease (17%), neurologic impairment (10%), liver disease (9%), prematurity (8%), and inflammatory bowel disease (6%). At most recent follow-up, 44 (50.6%) were on full oral feeds, 8 (9.2%) were still on NG feeds, 9 (10.3%) had a gastrostomy tube placed, 9 (10.3%) were deceased, and 17 (19.5%) had transferred care or were lost to follow-up. Average time to discontinuation of NG feeds was 4.8 months. Change in body mass index from hospital discharge to follow-up visit 6 to 12 weeks after discharge was statistically significant, from a mean (SD) of 13.78 (2.82) to 14.58 (2.1) (P = .02). Change in weight z score was significant for neurologic impairment (-1.35 to -0.04; P = .03). Height z score change was significant for prematurity (-3.84 to -3.34; P = .02). There was no significant change in height or weight z scores for the other diagnoses. CONCLUSIONS NG feeds can help to improve short-term growth after hospital discharge in children with chronic illnesses.

Anti-inflammatory Effects of Ganoderma lucidum Triterpenoid in Human Crohn's Disease Associated with Downregulation of NF-κB Signaling.

Background:Crohns disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Current medications have potentially serious side effects. Hence, there is increasing interest in alternative therapies. We previously demonstrated the anti-inflammatory effects of Food Allergy Herbal Formula-2 in vitro on peripheral blood mononuclear cells (PBMCs) and mucosa from CD subjects. Here, we investigated the anti-inflammatory effects of a bioactive compound isolated from Ganoderma lucidum (G. lucidum), a key herbal constituent of Food Allergy Herbal Formula-2, in CD in vitro. Methods:Triterpene ganoderic acid C1 (GAC1) was isolated from G. lucidum. Stimulated RAW 264.7 macrophages were treated with GAC1. Human PBMCs and colonic biopsies were obtained from children with CD and cultured with or without GAC1. TNF-&agr; and other proinflammatory cytokine levels were measured in the culture supernatant. NF-&kgr;B signaling was investigated in PBMCs and colonic mucosa treated with GAC1 by In-Cell Western and Western blot analysis. Results:GAC1 decreased TNF-&agr; production by macrophages and PBMCs from CD subjects. GAC1 significantly decreased TNF-&agr;, IFN-&ggr;, and IL-17A production by inflamed colonic biopsies from CD subjects. These effects were due to downregulation of the NF-&kgr;B signaling pathway. Conclusions:GAC1 inhibited production of TNF-&agr; and other proinflammatory cytokines by PBMCs and inflamed CD colonic mucosa due to blockage of NF-&kgr;B activation. GAC1 is a key beneficial constituent in G. lucidum and the Food Allergy Herbal Formula-2 in suppressing the inflammatory cytokines found in CD and warrants clinical investigation for the treatment of CD.

Analysis of current treatments used in clinical practice in a pediatric summer camp population for children with inflammatory bowel disease

Background: Many treatment options exist for children with inflammatory bowel disease (IBD), yet the lack of clinical guidelines for management has lead to great variation in care. The purpose of this project was to evaluate current treatment modalities in children from the Northeast US who applied to the 2010 session of Camp Oasis, a Crohns and Colitis Foundation of America (CCFA)‐sponsored camp for children ages 8–17 with medically stable IBD. Methods: Patient demographics, medical history, and current medications were entered into the camp database. The subjects were divided into two groups; Crohns disease (CD) or ulcerative colitis/indeterminate colitis (UC/IC). In all, 164 applicants were included, 121 (74%) with CD and 43 (26%) with UC/IC. Results: There were no significant differences between the two groups with respect to median age at the time of camp, median age at diagnosis, or median length of illness. Of the 121 applicants with CD, 13 (10.7%) were on an antibiotic, 56 (46.3%) were on a 5‐aminosalicylate (5‐ASA), 10 (8.3%) were on corticosteroids, 57 (47.1%) were on immunomodulators, and 44 (36.4%) were on a biologic agent. Six (5%) were on both an immunomodulator and a biologic agent. Of the 43 subjects with UC/IC, 27 (62.7%) were on a 5‐ASA, two (4.7%) were on corticosteroids, 13 (30.2%) were on an immunomodulator, and four (9.3%) were on a biologic agent. The groups were similar with regard to surgery (20.7% for CD and 18.6% for UC/IC). Conclusions: Identifying current treatment patterns may serve to highlight variations in care among this pediatric IBD population. (Inflamm Bowel Dis 2012)

Growth and early onset inflammatory bowel disease.

In pediatrics, growth is considered one of the most important markers of overall well-being. This study looked at growth in children diagnosed with inflammatory bowel disease before they were 5 years old from a single center. The Childrens Inflammatory Bowel Disease Center at Mount Sinai maintains a database of 1,150 children followed at the center. Ninety-three children were included in this study, 58% boys and 42% girls. The average age at diagnosis was 3.2 years. Sixty-two percent had ulcerative colitis and 38% had Crohn disease. Height was recorded at initial presentation and at the most recent visit to the center; from this, a height percentile and z score were calculated. A target adult height was calculated for each child on the basis of mid-parental height. This target height was compared to the actual height the children achieved or the percentile they were growing along. Ten percent of children in the study presented with growth failure. For children with early onset ulcerative colitis, 58% achieved or exceeded their projected height percentile. For children with early onset Crohn disease, 38% achieved or exceeded their projected height percentile. Fifty-nine percent of the entire group either maintained their presentation percentile or increased their height percentiles over time, with an increase in z score ranging from 0.093 to 4.137.

Percutaneous endoscopic gastrostomy tubes in pediatric bone marrow transplant patients

Background and Objectives: Nourishing a child undergoing bone marrow transplant (BMT) is essential, but the optimal method to achieve this is not established. The objectives of the study were to investigate the incidence and risk factors for complications of gastrostomy tubes in patients with BMT. Methods: A retrospective chart review was conducted of pediatric patients who received a percutaneous endoscopic gastrostomy (PEG) either for BMT or for other indications during a 3-year period. Occurrences of complications, absolute neutrophil count (ANC) at time of PEG placement, and ANC at time of complication were reviewed for both BMT and the comparison group. Results: Of the 11 subjects in the BMT group, 4 (36%) had a major complication of infection related to PEG and 3 of those required PEG removal. Two of the 4 subjects who developed a major complication were moderately neutropenic at the time of PEG placement and all subjects were neutropenic at the time of complication. Of the 30 subjects in the comparison group, only 1 (2.8%) had a major complication with cellulitis. There were no statistically significant differences between the 2 groups before PEG placement for age, weight, albumin, or white blood cell count. The incidence of complication in BMT compared with the comparison group was significant (P = 0.01). Conclusions: Our findings support that ANC should be considered before placement of PEG, significant neutropenia may be a contraindication for PEG placement in BMT patients, and other modalities for nutrition support might need to be considered.

Anti-inflammatory Effects of the Chinese Herbal Formula FAHF-2 in Experimental and Human IBD

Background:Crohns disease (CD) is a chronic inflammatory disease with increasing incidence in children. Current medications have potentially serious side effects, hence increasing interest in alternative therapies. We previously developed an herbal formula, FAHF-2, based on a classical traditional Chinese herbal formula Wu Mei Wan that has long been used in China to treat colitis. We investigated FAHF-2s potential anti-inflammatory effects. Methods:FAHF-2 efficacy was tested in vivo in the CD45RbhiRAG1−/− transfer colitis model. Weight loss, colonic histology, and cytokine production from mesenteric lymph nodes were assessed. Human peripheral blood mononuclear cells (PBMCs) and colonic biopsies were obtained from children newly diagnosed with CD and controls and cultured with or without FAHF-2. Cytokine levels were measured by multiplex immunoassay. The effect of FAHF-2 on TNF-&agr;–producing cells was determined by flow cytometry. NF-&kgr;B signaling was investigated in human lamina propria mononuclear cells upon FAHF-2 treatment by In-Cell Western. Results:FAHF-2–treated mice had decreased weight loss, improved histology, and reduced TNF-&agr;, IL-17, IL-6, and IFN-&ggr; production. In vitro treated PBMCs produced less TNF-&agr;, IFN-&ggr;, and IL-12. FAHF-2 reduced the TNF-&agr;–producing monocytes and T cells. Inflamed CD biopsies produced less TNF-&agr;, IL-17, IL-6, and IL-1&bgr;. These effects are because of decreased NF-&kgr;B activation. Conclusions:FAHF-2 inhibited both adaptive and innate immune proinflammatory cytokine responses in PBMCs and inflamed CD mucosa due in part to blockage of NF-&kgr;B activation. FAHF-2 was effective in halting progression of colitis in a murine model. This study shows that FAHF-2 has potential as a novel treatment of CD.

A Traditional Chinese Herbal Formulation - FAHF-2 for the Treatment of Crohnʼs Disease: P-116

and epigenetic characteristics, such as DNA methylation can respond to environmental changes and have been implicated in triggering these diseases. Therefore, we evaluated the relationship between colonic mucosal microbiota and DNA methylation in untreated pediatric IBD METHODS: The mucosal microbiota was studied by 454 pyrosequencing of the bacterial 16S rRNA gene and the fungal small subunit (SSU) ribosomal region in transverse colonic biopsy specimens from 26 controls, 16 untreated pediatric CD (15 treatment naı̈ve), and 6 UC cases (5 treatment naı̈ve). Genome-wide DNA methylation was examined by Infinium HumanMethylation450 BeadChip Kits in a subset of treatment naı̈ve samples (10 controls, 10 CD, and 4 UC). Validation of the DNA methylation results was performed on an independent cohort (12 controls, 5 CD, 5 UC) and by bisulfite-pyrosequencing of select loci. RESULTS: There was no consistent DNA methylation association with CD. However, UC had a large number of significant DNA methylation associations (4302 shared CpG sites between discovery and validation cohort; false discovery rate: FDR<0.01). The UC-linked methylation changes associated with genes involved in cell adhesion and communication, defense and immune responses. UC microbiota separated from controls and CD (P 1⁄4 0.048). The genus Faecal bacterium was increased in UC (U test P 1⁄4 0.013, FDR 1⁄4 0.24). UC associated DNA methylation changes correlated with bacterial taxa abundance at reads with incomplete or uncertain genus assignment belonging to the families Eubacteriaceae and Lachnospiraceae. CONCLUSION(S): UC associated DNA methylation and microbiota changes overlap at select loci and taxa. These findings may have etiologic, diagnostic and therapeutic relevance for IBD.