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Background/Objective– Heterogeneity and chronicity of Crohn’s disease (CD) make prediction of outcomes difficult. To date, no longitudinal measure can quantify burden over a patient’s disease course, preventing assessment and integration into predictive modelling. Here, we aimed to demonstrate the feasibility of constructing a data driven, longitudinal disease burden score.Methods– Literature was reviewed for tools used in assessment of CD activity. Themes were identified to construct a paediatric CD morbidity index (PCD-MI). Scores were assigned to variables. Data were extracted automatically from the electronic patient records at Southampton Children’s Hospital, diagnosed from 2012 to 2019 (inclusive). PCD-MI scores were calculated, adjusted for duration of follow up and assessed for variation (ANOVA) and distribution (Kolmogorov-Smirnov).Results– Nineteen clinical/biological features across five themes were included in the PCD-MI including blood/faecal/radiological/endoscopic results, medication usage, surgery, growth parameters and extraintestinal manifestations. Maximal score was 100 after accounting for follow-up duration.PCD-MI was assessed in 66 patients, mean age 12.5 years. Following quality filtering, 9528 blood/faecal test results and 1309 growth measures were included. Mean PCD-MI score was 14.95 (range 2.2-32.5), data were normally distributed (p=0.2) with 25% of patients having a PCD-MI Conclusions– PCD-MI is a calculatable measure for a cohort of patients diagnosed over an 8-year period, integrating a wide-range of data with potential to determine high or low disease burden. Future iterations of the PCD-MI require refinement of included features, optimised scores and validation on external cohorts.

Background and Aims Crohn’s disease [CD] arises through host-environment interaction. Abnormal gene expression results from disturbed pathway activation or response to bacteria. We aimed to determine activated pathways and driving cell types in paediatric CD. Methods We employed contemporary targeted autoimmune RNA sequencing, in parallel to single-cell sequencing, to ileal tissue derived from paediatric CD and controls. Weighted gene co-expression network analysis [WGCNA] was performed and differentially expressed genes [DEGs] were determined. We integrated clinical data to determine co-expression modules associated with outcomes. Results In all, 27 treatment-naive CD [TN-CD], 26 established CD patients and 17 controls were included. WGCNA revealed a 31-gene signature characterising TN-CD patients, but not established CD, nor controls. The CSF3R gene is a hub within this module and is key in neutrophil expansion and differentiation. Antimicrobial genes, including S100A12 and the calprotectin subunit S100A9, were significantly upregulated in TN CD compared with controls [p = 2.61 x 10-15 and p = 9.13 x 10-14, respectively] and established CD [both p = 0.0055]. Gene-enrichment analysis confirmed upregulation of the IL17-, NOD- and Oncostatin-M-signalling pathways in TN-CD patients, identified in both WGCNA and DEG analyses. An upregulated gene signature was enriched for transcripts promoting Th17-cell differentiation and correlated with prolonged time to relapse [correlation-coefficient-0.36, p = 0.07]. Single-cell sequencing of TN-CD patients identified specialised epithelial cells driving differential expression of S100A9. Cell groups, determined by single-cell gene expression, demonstrated enrichment of IL17-signalling in monocytes and epithelial cells. Conclusions Ileal tissue from treatment-naïve paediatric patients is significantly upregulated for genes driving IL17-, NOD- and Oncostatin-M-signalling. This signal is driven by a distinct subset of epithelial cells expressing antimicrobial gene transcripts.

Background & aims: Nutritional assessment in paediatric inflammatory bowel disease (IBD) is key to supporting growth whilst minimising adiposity. Bedside assessment using bioelectrical impedance spectroscopy (BIS) has previous identified patients with declining cellular and nutritional health. We aimed to assess BIS measures in stable paediatric IBD patient. Methods: Stable IBD patients were recruited at routine hospital visits. All patients underwent BIS, anthropometry and disease activity assessment. Multivariable regression and receiver operator curve (ROC) analyses were undertaken to assess the utility of BIS phase angle 50 KHz (PA-50) and 200/5 KHz impedance ratio (IR) in nutritional assessment. Results: There were 140 study visits from 97 patients, mean age 14.49 years, 62.9% Crohn's disease. Mean BMI Z-score (BMIZ) was 0.31 (range −2.97 to 3.99), 33% of patients were overweight (BMIZ>1) and 13.8% of patients were underweight (BMIZ < −1). Crohn's disease patients had a lower mean BMIZ score 0.14, compared to ulcerative colitis, 0.68, p = 0.007. There was no relationship between PA-50 and BMIZ or disease activity. IR was not related to disease activity but was negatively related to BMIZ in a multivariable regression, accounting for age, sex and disease subtype (beta −0.331, p = 0.001). ROC analyses did not identify a clinically useful cut off for either PA-50 or IR to identify patients with active disease, biologic use or BMIZ>1 or < -1. Conclusion: BIS appears to have limited added value in nutritional assessment of stable paediatric IBD patients. Nearly 1/3 patients were overweight and personalised approach to supplementation is vital to avoid overnutrition.

Background The first wave of the COVID-19 pandemic in the UK severely restricted our regional paediatric GI outpatient services affecting our ability to assess patients in hospital, further compounded by distance of travel of patients (An audit form 2019 showed 70% of patients endoscoped were from outside the local, rather than Southampton area). The issue was further compounded by some DGH’s, who stopped offering the calprotectin test due to COVID-19 infection risk to the staff. Although home based calprotectin kits are also available, families using them have reported their use cumbersome and difficult to process tests at home. In addition, calprotectin results from other laboratories may be difficult to access. These limitations led to the development of a new regional service, in which samples taken at home are posted to the hub hospital laboratory (where the IBD clinic is based) for Calprotectin testing. Aim To study the benefits of offering a service for posting faecal samples for calprotectin testing to a hub laboratory. Methods Children (0–18 years) with IBD in the Wessex region, UK needing a calprotectin test were given postal faecal calprotectin packs (PFCP), either by hand in clinic or posted to their home. Each PFCP contained a labelled specimen bottle with immunology request form, bio-packaging box, sealable return bag (UN3373 compliant) with attached freepost label and instruction sheet. A Calprotectin cut off level of Results 63 patients (M=34, 54% & F=29, 46%) were given PFCP between 27th July & 5th of Nov 2020 with 52.4% posted PFCP and 47.6% given PFCP by hand in the paediatric GI clinic. The patients resided at a mean distance of 41.6 miles (1 SD = 24.1 miles) as the crow flies from the hospital. A mean of 25 days (1SD = 10 days) were taken from posting/handing of PFCP to the lab test result being obtained. The PFCP was returned by 50 patients (79.4% compliance) with a diagnosis of Crohn’s disease 34.9%, UC 28.6%, IBDU 7.9%, oral ulcers 4.8% and 23.8% of patients referred for endoscopy with IBD like symptoms. 30% of the patients with IBD (15/50) posting the PFCP had an abnormal test result. This led to a change in management in 40% of the patients. In the patient group referred with suspected IBD only 1/15 patients had an abnormal calprotectin test. 70% of patients with a normal test were able to be reassured without further investigation. Conclusion This is the first reported series, offering to a large region a robust method for samples to be taken at home and posted to a central hub laboratory for calprotectin testing during the COVID-19 pandemic. Test results were readily available, being performed in the same hospital site as the IBD clinic. Compliance with the new PFCP remains high with 80% using the new PFCP service, with value in early identification of patients who may not have much in terms of symptoms and avoidance of endoscopy in others with a normal calprotectin.

Background Management of paediatric Crohn’s disease (CD) presents significant challenges. Escalation of therapy to biologics or a ‘top-down’ approach, with early introduction of biologics, is common. Anti-TNF agents are widely used, but the use of ustekinumab is still limited. Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both IL-12/-23. Ustekinumab has recently emerged as an alternative treatment option in children with failure of response to anti-TNF alpha treatment and those developing intolerable side effects on anti-TNF treatment including psoriasis. Aims Data on ustekinumab efficacy in paediatric IBD are limited. We report our experience on the use of this monoclonal antibody in paediatric IBD at a tertiary GI service in Wessex. Methods Retrospective review of all paediatric patients (≤ 18 years) receiving ustekinumab for the management of their IBD. Data was collected by reviewing patients’ electronic medical records and available results. Only those who had the treatment for at least 26 weeks were included. Steroid free remission were the primary outcomes of this study and resolution of psoriasis (where applicable) as a secondary outcome measure. Results Between November 2017- November 2020, 12 patients (M:F=6:6) patients were identified who were commenced on ustekinumab for the treatment of their IBD; 9 patients with CD and 3 with IBDU- Crohn’s like. One patient was excluded as the duration of treatment was The median duration between diagnosis and initiation of treatment with ustekinumab was 104 weeks and median duration of treatment with ustekinumab at the time of the review was 60 weeks (26–160 weeks). All patients received standard anti-TNF alpha treatment prior to ustekinumab. (All 11 patients received infliximab, 7 patients received both infliximab and adalimumab, and 4 patients were escalated directly from infliximab to ustekinumab). The key indications for considering ustekinumab were primary non-response (N=5, 45%), secondary loss of response (N=3, 27%) and anti-TNF-alpha induced psoriasis. Six patients (54%) developed psoriasis while on treatment with anti-TNF alpha. Three patients (27%) were switched to ustekinumab primarily in view of anti-TNF-alpha induced psoriasis. Steroid-free remission rates were (81%) at 26 weeks (N=9), (90%) at 52 weeks and 100% thereafter in 5 individuals who remained on ustekinumab over 1 year at the last review. No significant side-effects were reported in any patient. 85% of patients (N=5:6) who were identified with psoriasis have shown good response to switching treatment from anti-TNF to ustekinumab. Conclusions This data suggests that ustekinumab is a useful and a safe treatment option in children with IBD refractory to standard monoclonal therapy and in those developing intolerable anti-TNF alpha induced side-effects, psoriasis in particular. Larger studies from multiple centres would be required to develop standardised pathways for the use of this promising monoclonal agent for the management of paediatric IBD.

The precise role of periostin, an extra-cellular matrix protein, in inflammatory bowel disease (IBD) is unclear. Here, we investigated periostin in paediatric IBD including its relationship with disease activity, clinical outcomes, genomic variation and expression in the colonic tissue. Plasma periostin was analysed using ELISA in 144 paediatric patients and 38 controls. Plasma levels were assessed against validated disease activity indices in IBD and clinical outcomes. An immuno-fluorescence for periostin and detailed isoform-expression analysis in the colonic tissue was performed in 23 individuals. We integrated a whole-gene based burden metric ‘GenePy’ to assess the impact of variation in POSTN and 23 other genes functionally connected to periostin. We found that plasma periostin levels were significantly increased during remission compared to active Crohn’s disease. The immuno-fluorescence analysis demonstrated enhanced peri-cryptal ring patterns in patients compared to controls, present throughout inflamed, as well as macroscopically non-inflamed colonic tissue. Interestingly, the pattern of isoforms remained unchanged during bowel inflammation compared to healthy controls. In addition to its role during the inflammatory processes in IBD, periostin may have an additional prominent role in mucosal repair. Additional studies will be necessary to understand its role in the pathogenesis, repair and fibrosis in IBD.

Objectives: The current classification of inflammatory bowel disease (IBD) is based on clinical phenotypes, which is blind to the molecular basis of the disease. The aim of this study was to stratify a treatment-naïve paediatric IBD cohort through specific innate immunity pathway profiling and application of unsupervised machine learning (UML).Methods: In order to test the molecular integrity of biological pathways implicated in IBD, innate immune responses were assessed at diagnosis in 22 paediatric patients and 10 age-matched controls. Peripheral blood mononuclear cells (PBMCs) were selectively stimulated for assessing the functionality of upstream activation receptors including NOD2, toll-like receptor (TLR) 1-2 and TLR4, and the downstream cytokine responses (IL-10, IL-1β, IL-6, and TNF-α) using multiplex assays. Cytokine data generated were subjected to hierarchical clustering to assess for patient stratification.Results: Combined immune responses in patients across 12 effector responses were significantly reduced compared with controls (P = 0.003) and driven primarily by “hypofunctional” TLR responses (P values 0.045, 0.010, and 0.018 for TLR4-mediated IL-10, IL-1β, and TNF-α, respectively; 0.018 and 0.015 for TLR1-2 -mediated IL-10 and IL-1β). Hierarchical clustering generated 3 distinct clusters of patients and a fourth group of “unclustered” individuals. No relationship was observed between the observed immune clusters and the clinical disease phenotype.Conclusions: Although a clinically useful outcome was not observed through hierarchical clustering, our study provides a rationale for using an UML approach to stratify patients. The study also highlights the predominance of hypo-inflammatory innate immune responses as a key mechanism in the pathogenesis of IBD.

Many paediatric healthcare professionals are increasingly concerned about the long-term secondary impact of the COVID-19 pandemic on the care of children and young people (CYP) with chronic conditions. Those of us working in paediatric gastroenterology now lack the ability to provide the same level of diagnostic care and ongoing management to our patients, particularly the large number with inflammatory bowel disease (IBD). With all elective endoscopy cancelled, difficulty in obtaining day-case infusions and telemedicine becoming the norm, many professionals are justifiably uncomfortable. There is little known about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on those CYP with IBD, or on patients with systemic immunosuppression, although the small amount of data derived thus far indicates mild disease in …

Aim: We assessed growth in a paediatric inflammatory bowel disease (PIBD) cohort. Methods: Paediatric inflammatory bowel disease patients were eligible if they were diagnosed at Southampton Children's Hospital from 2011 to 2018. Weight and height standard deviation scores (SDS) were retrieved. Mean SDS values, SDS change and anti-TNF status were analysed at diagnosis and during follow-up. Results: Four hundred and ninety patients were included, 313 with Crohn's disease (CD). CD patients presented with mean height SDS −0.13, −0.1 at 1-year, −0.11 at 2-years and −0.03 at 5 years, reflecting preserved linear growth. There was no significant height-SDS change from diagnosis to 5-year follow-up, +0.12, 95%-CI: 0.48 to −0.24. Mean weight-SDS at diagnosis was −0.39, driven by CD patients (−0.65). Mean weight-SDS approached 0 after 1 year and remained at the 50th centile throughout follow-up. Growth in ulcerative colitis was maintained. In multivariable regression males had worse height growth from diagnosis to transition (P =.036). Anti-TNF treatment (P =.013) and surgical resection (P =.005) were also associated with poorer linear growth. Patients treated with anti-TNF therapy had lower height-SDS compared to those never treated with anti-TNF at 1 year (−0.2 vs −0.01, P =.22), 2-years (−0.27 vs −0.01, P =.07) and 5 years (−0.21 vs 0.25, P =.051). Conclusion: Height was generally maintained in Crohn's disease, and impaired linear growth was rare in this cohort.

OBJECTIVES: Monogenic inflammatory bowel disease (IBD) comprises rare Mendelian causes of gut inflammation, often presenting in infants with severe and atypical disease. This study aimed to identify clinically relevant variants within 68 monogenic IBD genes in an unselected pediatric IBD cohort. METHODS: Whole exome sequencing was performed on patients with pediatric-onset disease. Variants fulfilling the American College of Medical Genetics criteria as "pathogenic" or "likely pathogenic" were assessed against phenotype at diagnosis and follow-up. Individual patient variants were assessed and processed to generate a per-gene, per-individual, deleteriousness score. RESULTS: Four hundred one patients were included, and the median age of disease-onset was 11.92 years. In total, 11.5% of patients harbored a monogenic variant. TRIM22-related disease was implicated in 5 patients. A pathogenic mutation in the Wiskott-Aldrich syndrome (WAS) gene was confirmed in 2 male children with severe pancolonic inflammation and primary sclerosing cholangitis. In total, 7.3% of patients with Crohn's disease had apparent autosomal recessive, monogenic NOD2-related disease. Compared with non-NOD2 Crohn's disease, these patients had a marked stricturing phenotype (odds ratio 11.52, significant after correction for disease location) and had undergone significantly more intestinal resections (odds ratio 10.75). Variants in ADA, FERMT1, and LRBA did not meet the criteria for monogenic disease in any patients; however, case-control analysis of mutation burden significantly implicated these genes in disease etiology. DISCUSSION: Routine whole exome sequencing in pediatric patients with IBD results in a precise molecular diagnosis for a subset of patients with IBD, providing the opportunity to personalize therapy. NOD2 status informs risk of stricturing disease requiring surgery, allowing clinicians to direct prognosis and intervention.

Background: The Paris classification (PC) of paediatric inflammatory bowel disease (PIBD) categorises disease extent and therefore impacts on treatment decisions Histological (microscopic) disease extent is not incorporated and endoscopic (macroscopic) findings may underrepresent disease extent when compared to histological findings; this study compares disease extent at presentation. Methods: Data were obtained of patients below 17 years of age diagnosed with IBD from 2010-13 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: 172 patients were identified (median age at diagnosis 13.5, 115 male); Crohns disease (CD)- 107, Ulcerative Colitis (UC)- 50, Inflammatory Bowel Disease Unclassified (IBDU)- 15; 159 had undergone upper 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 to histological disease in 71.3%. Comparing PC; a 10% increase in L3 disease (ileocolonic), a 24% increase in L3+L4a disease (ileocolonic plus upper gastrointestinal (GI)) and a 27% increase in all 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. Conclusion: This data confirms 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.

Background: anti-tumour necrosis factor-α (anti-TNF) therapy use has risen in paediatric-onset inflammatory bowel disease (PIBD). Whether this has translated into preventing/delaying childhood surgery is uncertain. The Wessex PIBD cohort were analysed for trends in anti-TNF-therapy and surgery. Design: all patients diagnosed with PIBD within Wessex from 1997-2017 were assessed. Prevalence of anti-TNF-therapy and yearly surgery rates (resection and perianal) during childhood (

Discrepancies between inflammatory bowel disease (IBD) endoscopic/histological extent are documented at diagnosis. It is unclear whether these differences persist through disease course, with potential impact on categorization and management. We aimed to analyze the progression of disease over a 3-year period.Patients younger than 17 years, diagnosed between 2010 and 2013 at Southampton Children's Hospital and followed-up for 3 years were eligible. Primary outcome was disease extent at diagnosis and follow-up. Data are presented as percentage of patients undergoing endoscopy. Paris classification (PC) and PC using histological, rather than endoscopic disease, were determined.One hundred and twenty-five patients were included, 66 boys; Crohn's disease (CD) 74, ulcerative colitis (UC) 40, IBD unclassified (IBDU) 11. All had endoscopy at diagnosis. One hundred and two patients underwent ≥1 repeat endoscopies.Disease extent reduced from diagnosis to first follow-up endoscopy for both endoscopic and histological disease extent (CD/UC/IBDU, all P 0.00006). Histological extent remained greater than endoscopic in CD with significant differences in stomach, ileum, and large bowel at all follow-up points (P = 0.045). Endoscopic matched histological extent in UC/IBDU. Applying a modified PC resulted in significant changes for CD (L3 27.4%-53.2%, P = 0.006, L3 + L4A 21%-50%, P = 0.001, and upper gastrointestinal disease 50%-80.6%, P = 0.0006) but not UC. CD height (-0.37 to -0.25) and weight (-1.09 to -0.19) standard deviation scores increased from diagnosis to follow-up.Histological disease is greater than endoscopic extent at diagnosis and during follow-up in CD, although not in UC/IBDU. Classification of disease extent in CD should be based on both endoscopic and histological criteria.

Supplemental Digital Content is available in the text, 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.

Paediatric inflammatory bowel disease (PIBD), comprising Crohn’s disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBDU) is a complex and multifactorial condition with increasing incidence. An accurate diagnosis of PIBD is necessary for a prompt and effective treatment. This study utilises machine learning (ML) to classify disease using endoscopic and histological data for 287 children diagnosed with PIBD. Data were used to develop, train, test and validate a ML model to classify disease subtype. Unsupervised models revealed overlap of CD/UC with broad clustering but no clear subtype delineation, whereas hierarchical clustering identified four novel subgroups characterised by differing colonic involvement. Three supervised ML models were developed utilising endoscopic data only, histological only and combined endoscopic/histological data yielding classification accuracy of 71.0%, 76.9% and 82.7% respectively. The optimal combined model was tested on a statistically independent cohort of 48 PIBD patients from the same clinic, accurately classifying 83.3% of patients. This study employs mathematical modelling of endoscopic and histological data to aid diagnostic accuracy. While unsupervised modelling categorises patients into four subgroups, supervised approaches confirm the need of both endoscopic and histological evidence for an accurate diagnosis. Overall, this paper provides a blueprint for ML use with clinical data.

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.

The impact of immunosuppression on interferon-γ release assays and novel cytokine biomarkers of TB infection, mycobacteria-specific IL-2, IP-10 and TNF-α responses was investigated in an ex vivo model. Cytokine responses in standard QuantiFERON-TB Gold in-Tube (QFT-GIT) assays were compared with duplicate assays containing dexamethasone or infliximab. Dexamethasone converted QFT-GIT results from positive to negative in 30% of participants. Antigen-stimulated interferon-γ, IL-2 and TNF-α responses were markedly reduced, but IP-10 responses were preserved. Infliximab caused QFT-GIT result conversion in up to 30% of participants and substantial reductions in all cytokine responses. Therefore, corticosteroids and anti-TNF-α agents significantly impair interferon-γ release assay performance. IP-10 may be a more robust TB biomarker than interferon-γ in patients receiving corticosteroids.

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. (Inflamm Bowel Dis 2014;20:1813–1819)

We present the unique case of a 15 year old boy with upper airway obstruction found to have Crohn's disease in the absence of gastrointestinal symptoms. Laryngeal manifestations of Crohn's disease are extremely rare. Only 11 cases have been reported in the literature, of which only one is in a child. Laryngeal Crohn's disease usually occurs accompanied by gastrointestinal symptoms or in patients with a prior diagnosis of Crohn's disease. The literature on the clinical features and management of laryngeal Crohn's is discussed along with a summary of the reported otolaryngological manifestations and associations with Crohn's disease.

Background: Most cases of inflammatory bowel disease (IBD) are caused by complex host–environment interaction. There are a number of conditions associated with a single-gene mutation, most cases are very early onset (aged < 6 yr), present with a unique form of disease and often have atypical features.Methods: Whole-exome data for 147 pediatric patients with IBD were interrogated for a panel of 51 genes associated with monogenic IBD. Observed variation was categorized according to the American College of Medical Genetics (ACMG) guidelines to identify rare, novel, and known variants that might contribute to IBD.Results: Five hundred seventy-four variants were identified across 51 genes. These were categorized in line with ACMG guidance to remove benign variants and to identify “pathogenic” and “likely pathogenic” variants. In 6 patients, we observed 6 pathogenic variants of which CYBA(c.287+2T>C), COL7A1(c.6501+1G>C), LIG4(p.R814X), and XIAP(p.T470S) were known causative mutations, and FERMT1(p.R271Q) and SKIV2L(c.354+5G>A) were novel. In the 3 patients with XIAP, SKIV2L, and FERMT1 variants, individuals' disease features resembled the monogenic phenotype. This was despite apparent heterozygous carriage of pathogenic variation for the latter 2 genes. The XIAP variant was observed in a hemizygous male.Conclusions: Whole-exome sequencing allows for identification of known and de novo potentially causative mutations in genes associated with monogenic IBD. Although these are rare conditions, it is vital to identify causative mutations early to improve prognosis. We postulate that in a subset of IBD, heterozygous mutations (in genes believed to manifest IBD through autosomal recessive inheritance) may contribute to clinical presentation.

Immunosuppression after organ transplantation is complex and ever evolving. Over the past two decades, newer immunosuppressive agents have been introduced with an aim to provide better patient and graft survival. Improved therapeutic strategies have been developed offering the option to use combinations of drugs with non-overlapping toxicities. There are, however, only a few clinical studies with robust data to rationalize the use of these agents in children. This review will discuss the newer immunosuppressive agents used for solid organ transplant, their current status in post-transplant management and prevention of allograft rejection.

There has been an increase in the incidence of paediatric inflammatory bowel disease (PIBD) over the last 20 years.1 2 We have previously published data from Wessex, England, reporting an incidence of 9.37/100 000/year (2008–2012), which significantly increased from 5.2/100 000/year in 1998–1999, 6.39/100 000/year in 2002–2006, and 7.82/100 000/year in 2003–2008.1 2 We now report the most recent disease incidence figures for Wessex, England (1 January 2013 to 31 December 2017) and analyse them with previously published Wessex data (1 January 2002 to 21 December 2012) demonstrating the most contemporary incidence and the trend over 16 years. The ‘Wessex’ population was estimated from the Office for National Statistics using defined postcodes, based on the contemporary referral area.1 3 Statistical analyses of the data were conducted …

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.All patients diagnosed with PIBD at University Hospitals Southampton from 2010 to 2013 were identified from an in-house database. Data were obtained from paper and electronic notes. Height, weight and BMI SDS are presented as median values (95% CI).One hundred and seventy-two patients were included (median age at diagnosis 13.5, 115 male); Crohn's disease (CD) - 107, UC - 50, inflammatory bowel disease unclassified (IBDU) - 15. The most common presenting features of CD were abdominal pain (86%), diarrhoea (78.5%) and weight loss (56.1%); 42.1% of patients had all three. In UC blood in stool (92%), diarrhoea (92%) and abdominal pain (88%) were the most common; all three in 76% of patients. CD presented with ileocolonic disease in 52.5%. UC presented with pancolitis in 64%. There was growth delay in CD: height -0.37 (-0.60 to -0.14); weight -1.09 (-1.35 to -0.83). Growth was maintained in UC: height 0.53 (0.19 to 0.87); weight 0.14 (-0.20 to 0.48).Paediatric inflammatory bowel disease phenotype remains as extensive despite increasing incidence. Although the classical phenotype is common, a reasonable proportion present with atypical features, normal growth and normal blood markers.

Aims There has been at least a two-fold increase in the incidence of paediatric-onset CD over the last 20 years; there are few recent reports of the presenting phenotype – symptoms, inflammatory markers and disease extent. We report the presenting features of a defined cohort and compare to previous data. Methods Patients diagnosed with CD at University Hospitals Southampton from 2010–2013 were identified from an in-house database. Data were obtained from note review using a standardised proforma and compared to previous UK data. 1 Weight and height at diagnosis are presented as median SDS (95% CI). Results 106 children were included. Median age 13.80 (Range 4.40–17.32 years), 79 male. The most common presenting features are seen in Table 1. The majority of patients presented with ileocolonic disease (51%) or isolated colonic disease (32%). Twenty-eight patients (26.4%) had perianal signs (5.7% abscesses/fistulae). Inflammatory markers were raised at diagnosis-median CRP 18.0 mg/L (8.9–27.1), ESR24.0 mm/hr (19.6–28.4); however normal inflammatory markers were frequently seen-normal CRP 26.4%, ESR 18.2%. Weight SDS was –1.088 (–1.35 to –0.83), 52% patients were below –1 standard deviation (SD). Height SDS was –0.366 (–0.60 to –0.14). 26.5% of patients were between –1 and –2 SD from the median and 4.8% were below –2 SD. Family history (3 rd degree relative or closer) of IBD was seen in 27.6%. Conclusion Despite an increase in incidence of CD there does not appear to be an accrual of milder cases of disease. A significant number of patients will present with both normal growth and normal inflammatory markers. Reference Sawczenko A. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child. 2003;88(11):995–1000

Article first published online 17 April 2015. Supplemental Digital Content is Available in the Text., 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.

Management of bleeding multiple haemangiomata within the gastrointestinal tract is a surgical challenge in this case of Blue Rubber Bleb Naevus Syndrome (BRBNS). Described is a novel use of the laparoscope as a rigid enteroscope in order to provide intraluminal imaging for successful lesional resection from small bowel.