Athos Bousvaros

Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment

BackgroundThe inflammatory bowel diseases (IBD) Crohns disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status.ResultsFirmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohns disease was notable for increases in virulence and secretion pathways.ConclusionsThis inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.

2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America.

Background: Studies of pediatric inflammatory bowel disease (IBD) have varied in the criteria used to classify patients as having Crohn disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Patients undergoing an initial evaluation for IBD will often undergo a series of diagnostic tests, including barium upper gastrointestinal series with small bowel follow-through, abdominal CT, upper endoscopy, and colonoscopy with biopsies. Other tests performed less frequently include magnetic resonance imaging scans, serological testing, and capsule endoscopy. The large amount of clinical information obtained may make a physician uncertain as to whether to label a patient as having CD or UC. Nevertheless, to facilitate the conduct of epidemiological studies in children, to allow the entry of children into clinical trials, and to allow physicians to more clearly discuss diagnosis with their patients, it is important that clinicians be able to differentiate between CD and UC. Methods: A consensus conference regarding the diagnosis and classification of pediatric IBD was organized by the Crohns and Colitis Foundation of America. The meeting included 10 pediatric gastroenterologists and 4 pediatric pathologists. The primary aim was to determine the utility of endoscopy and histology in establishing the diagnosis of CD and UC. Each member of the group was assigned a topic for review. Topics evaluated included differentiating inflammatory bowel disease from acute self-limited colitis, endoscopic and histological features that allow differentiation between CD and UC, upper endoscopic features seen in both CD and UC, ileal inflammation and “backwash ileitis” in UC, patchiness and rectal sparing in pediatric IBD, periappendiceal inflammation in CD and UC, and definitions of IC. Results: Patients with UC may have histological features such as microscopic inflammation of the ileum, histological gastritis, periappendiceal inflammation, patchiness, and relative rectal sparing at the time of diagnosis. These findings should not prompt the clinician to change the diagnosis from UC to CD. Other endoscopic findings, such as macroscopic cobblestoning, segmental colitis, ileal stenosis and ulceration, perianal disease, and multiple granulomas in the small bowel or colon more strongly suggest a diagnosis of CD. An algorithm is provided to enable the clinician to differentiate more reliably between these 2 entities. Conclusions: The recommendations and algorithm presented here aim to assist the clinician in differentiating childhood UC from CD. We hope the recommendations in this report will reduce variability among practitioners in how they use the terms “ulcerative colitis,” “Crohn disease,” and “indeterminate colitis.” The authors hope that progress being made in genetic, serological, and imaging studies leads to more reliable phenotyping.

Efficacy of Probiotic Use in Acute Diarrhea in Children: A Meta-Analysis

Our objective was to determine the efficacy of probiotic use in reducing the duration of increased stool output in children with acute diarrheal illness. Eligible studies were limited to trials of probiotic therapy in otherwise healthy children <5 years old with acute-onset diarrhea. The main outcome variable was difference in diarrhea duration between treatment and control groups. Our meta-analysis of 18 eligible studies suggests that coadministration of probiotics with standard rehydration therapy reduces the duration of acute diarrhea by ∼1 day [random-effects pooled estimate = −0.8 days (−1.1, −0.6), P < 0.001]. Differences in treatment effect between studies was assessed by calculating the Q statistic (Q = 204.1, P < 0.001). In subsequent analyses limited to studies of hospitalized children, to double-blinded trials, and to studies evaluating lactobacilli, the pooled estimates were similar (−0.6 to −1.2 days, P < 0.001). In conclusion, bacterial probiotic therapy shortens the duration of acute diarrheal illness in children by approximately one day.

A randomized, double-blind trial of lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease

&NA; Probiotics are widely used by patients with Crohns disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo‐controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6‐mercaptopurine, azathioprine, and low‐dose alternate day corticosteroids. Seventy‐five children (age range, 5‐21 yr) with CD in remission were randomized to either LGG (n = 39) or placebo (n = 36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P = 0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P = 0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.

Executive Summary: 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host

An international panel of experts prepared an evidenced-based guideline for vaccination of immunocompromised adults and children. These guidelines are intended for use by primary care and subspecialty providers who care for immunocompromised patients. Evidence was often limited. Areas that warrant future investigation are highlighted.

Allergic esophagitis in children: a clinicopathological entity.

Infiltration of esophageal epithelium by eosinophils is seen in reflux esophagitis and allergic gastroenteritis. This study was performed to identify differences between patients with acid reflux esophagitis and those with non-acid reflux, possibly allergic, esophagitis. Intraepithelial eosinophils were demonstrated in posttherapy esophageal biopsy specimens in 28 children treated for gastroesophageal reflux disease (GERD). These patients were divided into three groups based on their response to treatment and the results of esophageal pH probe monitoring. Eleven patients (Group A) had incomplete clinical response and normal pH probe monitoring results. Ten patients (Group B) had incomplete response but did not have pH probe monitoring. These two groups formed the index population. Seven patients (Group C) had clinical improvement with GERD therapy and abnormal pH probe monitoring characteristic of GERD; they constituted the control population. Clinical, laboratory, and pathologic features were evaluated to detect differences between index and control populations. Dysphagia, food impaction, failure to thrive, peripheral eosinophilia, and abnormal allergen skin test results were detected only in Group A and B patients. Biopsy specimens of the distal 9 cm of the esophagus, after GERD therapy, contained larger numbers of eosinophils in Groups A and B than in Group C as shown on high-power fields (HPF) (A: 31/HPF +/- 19.5; B: 28/HPF +/-23.7; versus C: 5/HPF +/-6.7; p = 0.009). Eosinophil aggregates were identified only in Groups A and B (p = 0.07). Eosinophils located preferentially in the superficial layers of the squamous epithelium were noted only in Groups A and B (p = 0.02). Group A and B patients demonstrated clinical improvement when given antiallergic therapy. The authors identified a group of pediatric patients characterized by an allergic history, lack of adequate response to GERD therapy, normal esophageal pH probe monitoring results, and large numbers of eosinophils in esophageal biopsy specimens obtained after GERD treatment. On the basis of these features, the authors propose that these patients represent examples of allergic esophagitis.

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

Background and Objectives: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. Methods: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. Results: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean ± SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 ± 10.4, 32.2 ± 12.7, and 47.8 ± 14.9, respectively (P < 0.001 for all comparisons). Mean ± SD PCDAI for inactive disease after treatment was 5.2 ± 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of ≥30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of ≥12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. Conclusions: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of ≥30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Serologic Testing with ANCA, ASCA, and Anti-OmpC in Children and Young Adults with Crohn's Disease and Ulcerative Colitis: Diagnostic Value and Correlation with Disease Phenotype

OBJECTIVES:Serologic testing is increasingly being utilized to evaluate children with suspected inflammatory bowel disease (IBD). The aim of this paper was to evaluate the sensitivity and specificity of a currently available panel involving four antibodies: deoxyribonuclease (DNase)-sensitive perinuclear antineutrophil cytoplasmic antibody (DNase-sensitive pANCA), IgA and IgG antibodies to Saccharomyces cerevisiae (IgA and IgG ASCA), and antibody to Escherichia coli outer membrane porin (anti-OmpC). We also wished to determine whether antibody levels correlated with disease activity, and whether a specific antibody pattern correlated with location and outcome of disease in children.METHODS:We studied sera from 81 children with Crohns disease (CD), 54 with ulcerative colitis (UC), and 63 controls. Clinical data, disease activity, and disease diagnosis were gathered at the time of serum sampling, and charts were re-reviewed at time of the study to determine long-term outcome. Enzyme-linked immunosorbent assay was utilized to determine titers of antibodies to ASCA, DNase-sensitive pANCA, and anti-OmpC; the presence of perinuclear staining for ANCA was confirmed by immunofluorescence.RESULTS:We identified ASCA antibodies in 44% of CD patients, 0% of UC patients, and 1 control patient. DNase-sensitive pANCA antibodies were found in 70% of patients with UC, 18% of CD patients (predominantly Crohns colitis), and 3% of controls. Anti-OmpC as an isolated assay had low sensitivity for both CD (24%) and UC (11%), and displayed a 5% false-positive rate. However, anti-OmpC did identify a small number of IBD patients not detected by the other assays. If any one or more of the four antibodies was positive, the overall sensitivity of the four antibody panel was 65% for CD and 76% for UC, with a specificity of 94%. Patients who were ASCA-positive were more likely to have disease of the ileum or ileum and right colon than patients who were ASCA-negative (58% vs 18%, p < 0.001). Patients with ASCA-positive were also more likely to require ileocecal resection (36% vs 13%, p < 0.05).CONCLUSIONS:A currently available commercial antibody panel has good sensitivity and excellent specificity for CD and UC. The ASCA antibodies, while highly specific for CD, identify predominantly the subset of children with disease of the ileum and ascending colon who may be at increased risk of surgery.

Consensus for Managing Acute Severe Ulcerative Colitis in Children: A Systematic Review and Joint Statement From ECCO, ESPGHAN, and the Porto IBD Working Group of ESPGHAN

OBJECTIVES:Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohns and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN.METHODS:A group of 19 experts in pediatric IBD participated in an iterative consensus process including two face-to-face meetings. A total of 17 predefined questions were addressed by working subgroups based on a systematic review of the literature.RESULTS:The recommendations and practice points were eventually endorsed with a consensus rate of at least 95% regarding: definitions, initial evaluation, standard therapy, timing of second-line therapy, the role of endoscopic evaluation and heparin prophylaxis, how to administer second-line medical therapy, how to assess response, surgical considerations, and discharge recommendations. A management flowchart is presented based on daily scoring of the Pediatric Ulcerative Colitis Activity Index (PUCAI), along with 28 formal recommendations and 34 practice points.CONCLUSIONS:These guidelines provide clinically useful points to guide the management of ASC in children. Taken together, the recommendations offer a standardized protocol that allows effective monitoring of disease progress and timely treatment escalation when needed.