Akshay Batra

Rising incidence of paediatric inflammatory bowel disease (PIBD) in Wessex, Southern England

Background There has been a significant increase in the incidence of paediatric inflammatory bowel disease (PIBD) over the last 25 years although there is no recent data from England. We aimed to analyse changes in incidence within a defined English population over the last decade and compare this to recent and historical incidence data from comparable studies. Methods The new diagnosis incidence of PIBD (age less than or equal to 16 years) was recorded from a prospective database for a geographically defined area within Southern England (2002–2012). Data were analysed for two separate time periods (cohort 1:2002–2006 and cohort 2:2008–2012) and compared to data from the British Paediatric Surveillance Unit (BPSU) survey in 1998/1999. Data were analysed by age, sex and disease type. Results There has been an increase in incidence of PIBD from 6.39/100 000/year during cohort 1 to 9.37/100 000/year during cohort 2 (p=0.0002). This compares with the BPSU incidence data in England (1998–1999) of 5.2/100 000/year. There was no statistically significant difference in median age of diagnosis between cohorts (p=0.46). The incidence of Crohns disease (CD) was 3.8/100 000/year in cohort 1 rising to 5.85/100 000/year in cohort 2 (p=0.001). The incidence of ulcerative colitis (UC) was 2.01/100 000/year in cohort 1 rising to 2.62/100 000/year in cohort 2 (p=0.1458). Overall PIBD incidence is higher in males in cohort 1 (male-to-female ratio 1.35:1) and cohort 2 (male-to-female ratio 1.5:1). Conclusions The incidence of PIBD continues to increase with a rise of almost 50% in the last decade in Southern England. The reasons for this increase remain unclear.

Exome analysis of patients with concurrent pediatric inflammatory bowel disease and autoimmune disease.

Background:Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci in IBD with many genes coding for proteins in key immune pathways. This study looks at autoimmune disease burden in patients diagnosed with PIBD and interrogates exome data of a subset of patients. Methods:Patients were recruited from the Southampton Genetics of PIBD cohort. Clinical diagnosis of autoimmune disease in these individuals was ascertained from medical records. For a subset of patients with PIBD and concurrent asthma, exome data was interrogated to ascertain the burden of pathogenic variants within genes implicated in asthma. Association testing was conducted between cases and population controls using the SKAT-O test. Results:Forty-nine (28.3%) PIBD children (18.49% CD, 8.6% UC, and 21.15% IBDU patients) had a concurrent clinical diagnosis of at least one other autoimmune disorder; asthma was the most prevalent, affecting 16.2% of the PIBD cohort. Rare and common variant association testing revealed 6 significant genes (P < 0.05) before Bonferroni adjustment. Three of these genes were previously implicated in both asthma and IBD (ZPBP2 IL1R1, and IL18R1) and 3 in asthma only (PYHIN1, IL2RB, and GSTP1). Conclusions:One-third of our cohort had a concurrent autoimmune condition. We observed higher incidence of asthma compared with the overall pediatric prevalence. Despite a small sample size, SKAT-O evaluated a significant burden of rare and common mutations in 6 genes. Variant burden suggests that a systemic immune dysregulation rather than organ-specific could underpin immune dysfunction for a subset of patients.

Endoscopic Versus Histological Disease Extent at Presentation of Paediatric Inflammatory Bowel Disease.

Objectives: The Paris classification (PC) of paediatric inflammatory bowel disease categorises disease extent and therefore affects treatment decisions. Histological (microscopic) disease extent is not incorporated, and endoscopic (macroscopic) findings may underrepresent disease extent when compared with histological findings; this study compares disease extent at presentation. Methods: Data were obtained of patients <17 years of age diagnosed with inflammatory bowel disease from 2010 to 2013 at University Hospital Southampton. Data are presented as percentage of patients undergoing endoscopy. PC was performed alongside a modified PC by histological disease location. Results: A total of 172 patients were identified (median age at diagnosis 13.5 years, 115 boys); Crohn disease (CD) 107, ulcerative colitis (UC) 50, inflammatory bowel disease unclassified (IBDU) 15; 159 had undergone upper gastrointestinal (GI) endoscopy, 163 had undergone lower GI endoscopy. Histological disease was more extensive at all points for CD, UC, and IBDU. CD—endoscopic ileal disease in 49% of patients compared with histological disease in 71.3%. Comparing PC—a 10% increase in L3 disease (ileocolonic), a 24% increase in L3 + L4a disease (ileocolonic plus upper GI), and a 27% increase in all of the upper GI involvement if histological disease extent was used. UC—the most common disease location was the rectum (endoscopic 91.5% vs histological 93.6%) and descending colon (endoscopic 89.4% vs histological 95.7%). Comparing PC—a 19% increase in E4 disease (pancolitis) if histological disease extent was used. Conclusions: These data confirm that histological disease extent is greater than endoscopic disease extent. This should be considered when the PC is used. Further study is needed to elucidate which classification would better predict disease outcome.

16S sequencing and functional analysis of the fecal microbiome during treatment of newly diagnosed pediatric inflammatory bowel disease

Abstract The human microbiome is of considerable interest to pediatric inflammatory bowel disease (PIBD) researchers with 1 potential mechanism for disease development being aberrant immune handling of the intestinal bacteria. This study analyses the fecal microbiome through treatment in newly diagnosed PIBD patients and compares to cohabiting siblings where possible. Patients were recruited on clinical suspicion of PIBD before diagnosis. Treatment-naïve fecal samples were collected, with further samples at 2 and 6 weeks into treatment. Samples underwent 16S ribosomal ribonucleic acid (RNA) gene sequencing and short-chain fatty acids (SCFAs) analysis, results were analyzed using quantitative-insights-into-microbial-ecology. Six PIBD patients were included in the cohort: 4 Crohn disease (CD), 1 ulcerative colitis (UC), 1 inflammatory bowel disease (IBD) unclassified, and median age 12.6 (range 10–15.1 years); 3 patients had an unaffected healthy sibling recruited. Microbial diversity (observed species/Chao1/Shannon diversity) was reduced in treatment-naïve patients compared to siblings and patients in remission. Principal coordinate analysis using Bray–Curtis dissimilarity and UniFrac revealed microbial shifts in CD over the treatment course. In treatment-naïve PIBD, there was reduction in functional ability for amino acid metabolism and carbohydrate handling compared to controls (P = .038) and patients in remission (P = .027). Metabolic function returned to normal after remission was achieved. SCFA revealed consistent detection of lactate in treatment-naïve samples. This study adds in-depth 16S rRNA sequencing analysis on a small longitudinal cohort to the literature and includes sibling controls and patients with UC/IBD unclassified. It highlights the initial dysbiosis, reduced diversity, altered functional potential, and subsequent shifts in bacteria from diagnosis over time to remission.

Epidemiology, management and outcome of ultrashort bowel syndrome in infancy

Ultrashort bowel syndrome (USBS) is a group of heterogeneous disorders where the length of small bowel is less than 10 cm or 10% of expected for the age. It is caused by massive loss of the gut which in the neonatal period can be a result of vanishing gastroschisis or surgical resection following mid-gut volvulus, jejunoileal atresia and/or extensive necrotising enterocolitis. The exact prevalence of USBS is not known although there is a clear trend towards increasing numbers because of increased incidence and improved survival. Long-term parenteral nutrition (PN) is the mainstay of treatment and is best delivered by a multidisciplinary intestinal rehabilitation team. Promoting adaptation is vital to improving long-term survival and can be achieved by optimising feeds, reducing intestinal failure liver disease and catheter-related bloodstream infections. Surgical techniques that can promote enteral tolerance and hence improve outcome include establishing intestinal continuity and bowel lengthening procedures. The outcome for USBS is similar to patients with intestinal failure due to other causes and only a small proportion of children who develop irreversible complications of PN and will need intestinal transplantation. In this review, we will summarise the available evidence focusing particularly on the epidemiology, management strategies and outcome.

Genes implicated in thiopurine-induced toxicity: Comparing TPMT enzyme activity with clinical phenotype and exome data in a paediatric IBD cohort

The aim of our study was to assess the utility of next generation sequencing (NGS) for predicting toxicity and clinical response to thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data for 100 patients were assessed against biochemically measured TPMT enzyme activity, clinical response and adverse effects. The TPMT gene and a panel of 15 other genes implicated in thiopurine toxicity were analysed using a gene based statistical test (SKAT-O test). Nine patients out of 100 (Crohn’s disease- 67, ulcerative colitis- 23 and IBDU-10) had known TPMT mutations associated with deficient enzyme activity. A novel and a highly pathogenic TPMT variant not detectable through standard genotyping, was identified through NGS in an individual intolerant to thiopurines. Of the 14 patients intolerant to thiopurines, NGS identified deleterious TPMT variants in 5 individuals whereas the biochemical test identified 8 individuals as intolerant (sensitivity 35.7% and 57.14%; specificity 93.75% and 50% respectively). SKAT-O test identified a significant association between MOCOS gene and TPMT activity (p = 0.0015), not previously reported. Although NGS has the ability to detect rare or novel variants not otherwise identified through standard genotyping, it demonstrates no clear advantage over the biochemical test in predicting toxicity in our modest cohort.

Colectomy in pediatric ulcerative colitis: A single center experience of indications, outcomes, and complications

BACKGROUND/PURPOSE There is a paucity of data on outcomes and complications of colectomy for pediatric ulcerative colitis (UC). This study reports the experience of a regional center for 18years. METHODS Patients were identified from a prospective database and data obtained by note review. Median height/weight-SDS were calculated preoperatively and postoperatively. Data are expressed as median values (range). RESULTS 220 patients with UC (diagnosed <17years) were identified, and 19 (9%) had undergone colectomy. Age at diagnosis was 11.6years (1.3-16.5), and 42% of patients were male. Time from diagnosis to surgery was 2.2years (0.1-13.1). All patients had failed maximal medical therapy. Fifteen patients had urgent scheduled operation, and 4 had emergency procedures, with 2 for (11%) acute-severe colitis (1 Clostridium difficile colitis) and 2 for acute-severe colitis with toxic dilatation. All initial procedures were subtotal-colectomy with ileostomy. Nine patients (47%) had early complications (during initial admission), 7 (37%) requiring reoperation. Six (32%) had late complications, with 5 requiring laparotomy. No patients had both early and late complications. Height-SDS was -0.27 before surgery and -0.23 (maximal follow-up). Weight-SDS was 0.32 and 0.05 (maximal follow-up). CONCLUSION Approximately 1/11 children with UC required colectomy during childhood. Half of patients had acute complications, and 1/3 of patients required another operation during their first admission. 1/3 of patients developed late complications.

Presenting phenotype of paediatric inflammatory bowel disease in Wessex, Southern England 2010-2013.

There has been at least a twofold increase in the incidence of paediatric inflammatory bowel disease (PIBD) over the last 20 years; we report the presenting features from 2010 to 2013 and compare with previous data.

Immuno-genomic profiling of patients with inflammatory bowel disease: a systematic review of genetic and functional in vivo studies of implicated genes.

Background:Over the last 2 decades, there has been an ever-expanding catalog of genetic variants implicated in inflammatory bowel disease (IBD) through genome-wide association studies and next generation sequencing. In this article, we highlight the remarkable developments in understanding the genetic and immunological basis of IBD. The main objective of the study was to perform a systematic review of published literature detailing functional/immunological studies in patients known to harbor genetic variations in the implicated genes. Methods:A panel of 71 candidate genes implicated in IBD was prioritized using 5 network connectivity in silico methods. An electronic search using MEDLINE and EMBASE from 1996 to February 2014 for each of the selected genes was conducted. Only studies describing genotyped IBD cohorts with concurrent in vivo functional studies were included. Results:Between the reviewers, a total of 35,142 potentially eligible publications were identified. Only 8 genes had publications meeting the inclusion criteria. A total of 67 studies were identified across the selected genes. The NOD2 gene had the most number with 41 studies followed by IL-10 with 11 eligible studies. A meta-analysis was not practical given the heterogeneity of the study design and the number of implicated genes with diverse immunological and physiological functions. Conclusions:There is a clear lack of functional studies in humans to assess the in vivo impact of the various genetic variants implicated. A collaborative approach merging genomics and functional studies will help to unravel the obscure mechanisms involved in IBD.

Exome analysis of rare and common variants within the NOD signaling pathway

Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p =  0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis.