Dan Turner

Pediatric modification of the Montreal classification for inflammatory bowel disease: The Paris classification†‡

Background: Crohns disease and ulcerative colitis are complex disorders with some shared and many unique predisposing genes. Accurate phenotype classification is essential in determining the utility of genotype‐phenotype correlation. The Montreal Classification of IBD has several weaknesses with respect to classification of children. The dynamic features of pediatric disease phenotype (change in disease location and behavior over time, growth failure) are not sufficiently captured by the current Montreal Classification. Methods: Focusing on facilitating research in pediatric inflammatory bowel disease (IBD), and creating uniform standards for defining IBD phenotypes, an international group of pediatric IBD experts met in Paris, France to develop evidence‐based consensus recommendations for a pediatric modification of the Montreal criteria. Results: Important modifications developed include classifying age at diagnosis as A1a (0 to <10 years), A1b (10 to <17 years), A2 (17 to 40 years), and A3 (>40 years), distinguishing disease above the distal ileum as L4a (proximal to ligament of Treitz) and L4b (ligament of Treitz to above distal ileum), allowing both stenosing and penetrating disease to be classified in the same patient (B2B3), denoting the presence of growth failure in the patient at any time as G1 versus G0 (never growth failure), adding E4 to denote extent of ulcerative colitis that is proximal to the hepatic flexure, and denoting ever severe ulcerative colitis during disease course by S1. Conclusions: These modifications are termed the Paris Classification. By adhering to the Montreal framework, we have not jeopardized or altered the ability to use this classification for adult onset disease or by adult gastroenterologists. (Inflamm Bowel Dis 2011)

ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents

Background: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. Methods: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. Results: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. Conclusions: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease

Children and adolescents with Crohns disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohns and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Management of Pediatric Ulcerative Colitis: Joint ECCO and ESPGHAN Evidence-based Consensus Guidelines

Background and Aims: Pediatric ulcerative colitis (UC) shares many features with adult-onset disease but there are some unique considerations; therefore, therapeutic approaches have to be adapted to these particular needs. We aimed to formulate guidelines for managing UC in children based on a systematic review (SR) of the literature and a robust consensus process. The present article is a product of a joint effort of the European Crohns and Colitis Organization (ECCO) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). Methods: A group of 27 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to ESPGHAN and ECCO members. A list of 23 predefined questions were addressed by working subgroups based on a SR of the literature. Results: A total of 40 formal recommendations and 68 practice points were endorsed with a consensus rate of at least 89% regarding initial evaluation, how to monitor disease activity, the role of endoscopic evaluation, medical and surgical therapy, timing and choice of each medication, the role of combined therapy, and when to stop medications. A management flowchart, based on the Pediatric Ulcerative Colitis Activity Index (PUCAI), is presented. Conclusions: These guidelines provide clinically useful points to guide the management of UC in children. Taken together, the recommendations offer a standardized protocol that allows effective, timely management and monitoring of the disease course, while acknowledging that each patient is unique.

The Diagnostic Approach to Monogenic Very Early Onset Inflammatory Bowel Disease

Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohns disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.

The minimal detectable change cannot reliably replace the minimal important difference

OBJECTIVE We compared the minimal important difference (MID) with the minimal detectable change (MDC) generated by distribution-based methods. STUDY DESIGN Studies of two quality-of-life instruments (Chronic Respiratory Questionnaire [CRQ] and Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ]) and two physician-rated disease-activity indices (Pediatric Ulcerative Colitis Activity Index [PUCAI] and Pediatric Crohns Disease Activity Index [PCDAI]) provided longitudinal data. The MID values were calculated from global ratings of change (small change for CRQ and RQLQ; moderate for PUCAI and PCDAI) using receiver-operating characteristic (ROC) curve and mean change. Results were compared with five distribution-based strategies. RESULTS Of the methods used to calculate the MDC, the 95% limits of agreement and the reliable change index yielded the largest estimates. In the patient-rated psychometric instruments, 0.5 SD was always greater than 1 standard error of measurements (SEM), and both fell between the mean change and the ROC estimates, on two of four occasions. The reliable change index came closest to MID of moderate change. CONCLUSION For patient-rated psychometric instruments, 0.5 SD and 1 SEM provide values closest to the anchor-based estimates of MID derived from small change, and the reliable change index for physician-rated clinimetric indices based on moderate change. Lack of consistency across measures suggests that distribution-based approaches should act only as temporary substitutes, pending availability of empirically established anchor-based MID values.

Severe Pediatric Ulcerative Colitis: A Prospective Multicenter Study of Outcomes and Predictors of Response

BACKGROUND & AIMS In a prospective study of children with severe ulcerative colitis (UC), we aimed to assess outcomes and to identify predictors of nonresponse to intravenous corticosteroids. METHODS A total of 128 children (47% males; 12.9 +/- 3.9 y) hospitalized for severe UC were enrolled from 10 pediatric centers. Clinical and laboratory data and the Pediatric UC Activity Index (PUCAI) were recorded throughout the admission. Patients were followed up for 1 year postdischarge. RESULTS Thirty-seven (29%; 95% confidence interval [CI], 22%-37%) children failed intravenous corticosteroids and received, within 10.5 +/- 6.4 days, cyclosporine (n = 1; 3%), colectomy (n = 3; 8%), or infliximab (n = 33; 89%). Several predictors were associated with intravenous corticosteroids failure, but the best model included number of stools, amount of blood, age, and new-onset disease (odds ratio [OR], 1.9; 95% CI, 1.1-3.5; OR, 2.5; 95% CI, 1.3-4.6; OR, 1.2; 95% CI, 1.04-1.36; and OR, 0.27; 95% CI, 0.1-0.7, respectively). The PUCAI, followed closely by the Travis rule, strongly predicted response when compared with other measures (Seo and Lindgren indices, C-reactive protein level, and fecal calprotectin level) (P < .001). Aiming for sensitivity on day 3, a PUCAI greater than 45 screened for patients likely to fail intravenous corticosteroids (negative predictive value, 94%; positive predictive value, 43%; P < .001). Aiming for specificity on day 5, a PUCAI score greater than 70 optimally guided implementation of salvage therapy (positive predictive value, 100%; negative predictive value, 79%; P < .001). Twenty-five of 33 children treated with infliximab responded. The overall cumulative colectomy rate was 9% and 19% by discharge and 1-year, respectively. The day 3 PUCAI score predicted response up to 1 year postdischarge (P < .001; time to salvage therapy). CONCLUSIONS The PUCAI, calculated on days 3 and 5 of steroid therapy, can identify patients requiring salvage therapy. Infliximab is an effective therapy in steroid-refractory pediatric UC.

IL-10R polymorphisms are associated with very-early-onset ulcerative colitis

Background:Interleukin-10 (IL-10) signaling genes are attractive inflammatory bowel disease (IBD) candidate genes as IL-10 restricts intestinal inflammation, IL-10 polymorphisms have been associated with IBD in genome-wide association studies, and mutations in IL-10 and IL-10 receptor (IL-10R) genes have been reported in immunodeficient children with severe infantile-onset IBD. Our objective was to determine if IL-10R polymorphisms were associated with early-onset IBD (EO-IBD) and very-early-onset IBD (VEO-IBD). Methods:Candidate-gene analysis of IL10RA and IL10RB was performed after initial sequencing of an infantile onset-IBD patient identified a novel homozygous mutation. The discovery cohort included 188 EO-IBD subjects and 188 healthy subjects. Polymorphisms associated with IBD in the discovery cohort were genotyped in an independent validation cohort of 422 EO-IBD subjects and 480 healthy subjects. Results:We identified a homozygous, splice-site point mutation in IL10RA in an infantile-onset IBD patient causing a premature stop codon (P206X) and IL-10 insensitivity. IL10RA and IL10RB sequencing in the discovery cohort identified five IL10RA polymorphisms associated with ulcerative colitis (UC) and two IL10RB polymorphisms associated with Crohns disease (CD). Of these polymorphisms, two IL10RA single nucleotide polymorphisms, rs2228054 and rs2228055, were associated with VEO-UC in the discovery cohort and replicated in an independent validation cohort (odds ratio [OR] 3.08, combined P = 2 x 10−4; and OR 2.93, P = 6 x 10−4, respectively). Conclusions:We identified IL10RA polymorphisms that confer risk for developing VEO-UC. Additionally, we identified the first splice site mutation in IL10RA resulting in infantile-onset IBD. This study expands the phenotype of IL10RA polymorphisms to include both severe arthritis and VEO-UC.

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.

Alterations in the gut microbiome of children with severe ulcerative colitis.

Background: Although the role of microbes in disease pathogenesis is well established, data describing the variability of the vast microbiome in children diagnosed with ulcerative colitis (UC) are lacking. This study characterizes the gut microbiome in hospitalized children with severe UC and determines the relationship between microbiota and response to steroid therapy. Methods: Fecal samples were collected from 26 healthy controls and 27 children hospitalized with severe UC as part of a prospective multicenter study. DNA extraction, polymerase chain reaction (PCR) amplification of bacterial 16S rRNA, and microarray hybridization were performed. Results were analyzed in GeneSpring GX 11.0 comparing healthy controls with children with UC, and steroid responsive (n = 17) with nonresponsive patients (n = 10). Results: Bacterial signal strength and distribution showed differences between UC and healthy controls (adjusted P < 0.05) for Phylum, Class, Order, Family, Genus, and Phylospecies levels with reduction in Clostridia and an increase in Gamma‐proteobacteria. The number of microbial phylospecies was reduced in UC (266 ± 69) vs. controls (758 ± 3, P < 0.001), as was the Shannon Diversity Index (6.1 ± 0.23 vs. 6.49 ± 0.04, respectively; P < 0.0001). Steroid nonresponders harbored fewer phylospecies than responders (142 ± 49 vs. 338 ± 62, P = 0.013). Conclusions: Richness, evenness, and biodiversity of the gut microbiome were remarkably reduced in children with UC compared with healthy controls. Children who did not respond to steroids harbored a microbiome that was even less rich than steroid responders. This study is the first to characterize the gut microbiome in a large cohort of pediatric patients with severe UC and describes changes in the gut microbiome as a potential prognostic feature. (Inflamm Bowel Dis 2012)