Identification and validation of a blood- based diagnostic lipidomic signature of pediatric inflammatory bowel disease.

Improved biomarkers are needed for pediatric inflammatory bowel disease. Here we identify a diagnostic lipidomic signature for pediatric inflammatory bowel disease by analyzing blood samples from a discovery cohort of incident treatment-naïve pediatric patients and validating findings in an independent inception cohort. The lipidomic signature comprising of only lactosyl ceramide (d18:1/16:0) and phosphatidylcholine (18:0p/22:6) improves the diagnostic prediction compared with high-sensitivity C-reactive protein. Adding high-sensitivity C-reactive protein to the signature does not improve its performance. In patients providing a stool sample, the diagnostic performance of the lipidomic signature and fecal calprotectin, a marker of gastrointestinal inflammation, does not substantially differ. Upon investigation in a third pediatric cohort, the findings of increased lactosyl ceramide (d18:1/16:0) and decreased phosphatidylcholine (18:0p/22:6) absolute concentrations are confirmed. Translation of the lipidomic signature into a scalable diagnostic blood test for pediatric inflammatory bowel disease has the potential to support clinical decision making.

Experiences and satisfaction of video follow up of children with paediatric gastrointestinal conditions linking tertiary centre with guardians and clinicians at the local hospital: a cross-sectional study.

BACKGROUND: Children with complicated gastrointestinal conditions are dependent on follow up by tertiary care specialists throughout childhood to prevent and treat complications. In Sweden, paediatric surgical- and intestinal rehabilitation centres are centralised which means that many patients and guardians have to travel long distances to access tertiary referral centres. Our tertiary referral centre has developed a model of shared care with video conferences for follow up with our centre and the patient and guardians attending together with the responsible professionals at the local hospital. This study aimed to investigate the experiences and satisfaction with video follow-up visits (VFV) between a tertiary referral centre and guardians and clinicians at their local hospital. METHODS: Eligible participants were families with children with oesophageal atresia, intestinal failure and intestinal motility disorders and their local clinicians attending VFV with our tertiary referral centre from 2015 to 2020. Questionnaires included fixed-response alternatives, a 6-point Likert scale and open questions. RESULTS: Fifty-seven out of 102 families (56%) and 19 out of 27 local clinicians (70%) responded the questionnaires. In 68% of the VFV, two guardians attended compared to 35% in the physical visits. Of the guardians attending VFV, 82% lost ≤ half a working day and 91% attending physical visits lost ≥ one full working day. Median distance to the tertiary referral centre was 267 km and attending VFV avoided emissions of 7.2 metric tonnes of CO2. Of the guardians, 90% and of the clinicians 95% were satisfied with VFV. Advantages were avoidance of travelling and the participants shared the same information. CONCLUSIONS: VFV is an appropriate alternative to physical visits with a high grade of satisfaction among the guardians and clinicians. VFV was time-saving for the families and reduced CO2 emissions.

Mucosal and Plasma Metabolomes in New-onset Paediatric Inflammatory Bowel Disease: Correlations with Disease Characteristics and Plasma Inflammation Protein Markers.

BACKGROUND AND AIMS: To advance the understanding of inflammatory bowel disease [IBD] pathophysiology, we compared the mucosal and plasma metabolomes between new-onset paediatric IBD patients and symptomatic non-IBD controls, and correlated plasma inflammation markers and disease characteristics with the altered metabolites. METHODS: Paired colonic and ileal biopsies and plasma from 67 treatment-naïve children with incident Crohn's disease [CD; n = 47], ulcerative colitis [UC; n = 9], and non-IBD controls [n = 11] were analysed using ultra-performance liquid chromatography-mass spectrometry [UPLC-MS/MS]. Inflammatory plasma proteins [n = 92] were assessed. RESULTS: The metabolomes in inflamed mucosal biopsies differed between IBD patients and controls. In CD, mucosal levels of several lysophospholipids [lysophosphatidylcholines, lysophosphatidyletanolamines, lysophosphatidylinositols, and lysophosphatidylserines] were decreased, correlating with various plasma metabolites including amino acid analogues and N-acetylated compounds. In both CD and UC, mucosal sphingolipids, including ceramide [d18:2/24:1, d18:1/24:2], lactosyl-N-palmitoyl-sphingosine [d18:1/16:0], behenoyl sphingomyelin [d18:1/22:0], lignoceroyl sphingomyelin [d18:1/24:0], and/or sphingomyelin [d18:1/24:1, d18:2/24:0] were increased, correlating with sphingolipids, bile acids, and/or N-acetylated metabolites in plasma. Among proteins associated with CD, interleukin-24 correlated with plasma metabolites, including lactosyl-N-palmitoyl sphingosine [d18:1/16:0] and phosphatidyletanolamine [18:1/18:1], haemoglobin, and faecal calprotectin. In UC, interleukin-24, interleukin-17A, and C-C motif chemokine 11 correlated with several plasma metabolites, including N-acetyltryptophan, tryptophan, glycerate, and threonate, and with the Paediatric Ulcerative Colitis Activity Index, C-reactive protein, and faecal calprotectin. CONCLUSIONS: Mucosal perturbations of lysophospholipids and sphingolipids characterised the metabolome in new-onset paediatric IBD and correlated with plasma metabolites. By integrating plasma metabolomics data with inflammatory proteins and clinical data, we identified clinical and inflammatory markers associated with metabolomic signatures for IBD.

Improved Outcome of Intestinal Failure in Preterm Infants.

OBJECTIVE: The aim of the study was to evaluate the outcome and to identify predictors for survival and enteral autonomy in neonatal intestinal failure (IF). METHODS: A retrospective observational study in a Swedish tertiary centre of children born between 1995 and 2016 with neonatal IF, defined as dependency on parenteral nutrition (PN) ≥60 days, starting with PN before the age of 44 gestational weeks. Data were extracted from medical records and predictors for survival and enteral autonomy were identified by the Cox regression model. Time to death and weaning off PN analysis were performed with Kaplan-Meier curves including log rank test. RESULTS: In total, 105 children were included. Median gestational age was 28 weeks (22-42), 50% were born extremely preterm (<28 gestational weeks). PN started at a median age of 2 days (0-147) with a median duration of 196 days (60-3091). Necrotizing enterocolitis was the dominating cause of IF (61%). Overall survival was 88%, 5 children died of sepsis and 4 of intestinal failure-associated liver disease. Survival increased from 75% during 1995 to 2008 to 96% during 2009 to 2016 (P = 0.0040). Age-adjusted small bowel length of >50% and birth 2009 to 2016 were predictors for survival. Enteral autonomy was achieved in 87%, with positive prediction by small bowel length of >25% of expected for gestational age and remaining ileocecal valve. CONCLUSIONS: Preterm neonates with IF, at high risk of IF-associated morbidity, showed a high overall survival rate. Small-bowel length and being born 2009 to 2016 were predictors for survival and remaining ICV and small-bowel length were predictors for enteral autonomy.

Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome.

BACKGROUND: The composition of the intestinal microbiota seems to be an important factor in determining the clinical outcome in children with short bowel syndrome (SBS). Alterations in the microbiota may result in serious complications such as small bowel bacterial overgrowth (SBBO) and intestinal mucosal inflammation that lead to prolonged parenteral nutrition (PN) dependency with subsequently increased risk of liver failure and sepsis. To date, there are no reported mappings of the intestinal microbiome in children with SBS. Here, we present the first report on the intestinal microbial community profile in children with SBS. FINDINGS: The study includes children diagnosed with SBS in the neonatal period. Healthy siblings served as controls. Fecal samples were collected, and microbial profiles were analyzed by using 16S rRNA gene sequencing on the Illumina MiSeq platform. We observed a pronounced microbial dysbiosis in children with SBS on PN treatment with an increased and totally dominating relative abundance of Enterobacteriacae in four out of five children compared to children with SBS weaned from PN and healthy siblings. CONCLUSIONS: The overall decreased bacterial diversity in children with SBS is consistent with intestinal microbiome mappings in inflammatory bowel diseases such as Crohn's disease and necrotizing enterocolitis in preterm infants. Our findings indicate that intestinal dysbiosis in children with SBS is associated with prolonged PN dependency.

Human enterovirus species B in ileocecal Crohn's disease.

OBJECTIVES: Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD. METHODS: We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis. RESULTS: All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia. CONCLUSIONS: The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.

Manifestations of small bowel disease in pediatric Crohn's disease on magnetic resonance enterography.

BACKGROUND: We report the manifestations of Crohn's disease (CD) observed on magnetic resonance enterography (MRE) in a pediatric population at the time of CD diagnosis. METHODS: MRE of 95 consecutive pediatric patients with inflammatory bowel disease (IBD) examined in 2006-2009 were retrospectively analyzed, with documentation of findings based on type and location of the small bowel (SB) disease. RESULTS: In all, 51 were boys and 44 girls. 54 had CD, 31 non-CD IBD, and 10 no IBD. The most common site of SB involvement in CD was the terminal ileum seen in 29 (53.7%) patients, followed by ileum in 10 (18.5%) and jejunum in 9 (16.7%) patients. Solitary jejunal inflammation (3.7%), SB stenoses (1.9%), fistula formation (0.95%), and abscess (0.95%) were much less common. Perienteric lymphadenopathy was seen in 30 (55.6%) patients and fatty proliferation in 9 (16.7%). The most common manifestation of SB inflammation was increased contrast enhancement of bowel wall (93.5%), thickening of the bowel wall (90.3%), and derangement of bowel shape with saccular formations (25.8%). CONCLUSIONS: MRE in the pediatric population often demonstrates increased contrast uptake, bowel wall thickening, and perienteral lymphadenopathy in CD. More chronic small bowel changes seen commonly in adults and solitary jejunal involvements are less commonly seen.