Targeted Assessment of Mucosal Immune Gene Expression Predicts Clinical Outcomes in Children with Ulcerative Colitis.

BACKGROUND AND AIMS: We aimed to determine whether a targeted gene expression panel could predict clinical outcomes in paediatric ulcerative colitis [UC] and investigated putative pathogenic roles of predictive genes. METHODS: In total, 313 rectal RNA samples from a cohort of newly diagnosed paediatric UC patients (PROTECT) were analysed by a real-time PCR microfluidic array for expression of type 1, 2 and 17 inflammation genes. Associations between expression and clinical outcomes were assessed by logistic regression. Identified prognostic markers were further analysed using existing RNA sequencing (RNA-seq) data sets and tissue immunostaining. RESULTS: IL13RA2 was associated with a lower likelihood of corticosteroid-free remission (CSFR) on mesalamine at week 52 (p = .002). A model including IL13RA2 and only baseline clinical parameters was as accurate as an established clinical model, which requires week 4 remission status. RORC was associated with a lower likelihood of colectomy by week 52. A model including RORC and PUCAI predicted colectomy by 52 weeks (area under the receiver operating characteristic curve 0.71). Bulk RNA-seq identified IL13RA2 and RORC as hub genes within UC outcome-associated expression networks related to extracellular matrix and innate immune response, and lipid metabolism and microvillus assembly, respectively. Adult UC single-cell RNA-seq data revealed IL13RA2 and RORC co-expressed genes were localized to inflammatory fibroblasts and undifferentiated epithelial cells, respectively, which was supported by protein immunostaining. CONCLUSION: Targeted assessment of rectal mucosal immune gene expression predicts 52-week CSFR in treatment-naïve paediatric UC patients. Further exploration of IL-13Rɑ2 as a therapeutic target in UC and future studies of the epithelial-specific role of RORC in UC pathogenesis are warranted.

Acute liver dysfunction with delayed peak of serum aminotransferase levels as a presentation of ornithine transcarbamylase deficiency in females.

We describe 10 females with ornithine transcarbamylase (OTC) deficiency and liver dysfunction, revealing a unique pattern of hepatocyte injury in which initial hyperammonemia and coagulopathy is followed by a delayed peak in aminotransferase levels. None of the patients required urgent liver transplantation, though five eventually underwent transplant for recurrent metabolic crises. We intend that this novel observation will initiate further investigations into the pathophysiology of liver dysfunction in OTC-deficient patients, and ultimately lead to the development of therapies and prevent the need for liver transplant.

A Pediatric Patient With Ascites, Proteinuria, and Thrombocytopenia: A Rare Presentation for a Common Illness.

ABSTRACT: A 7-year-old female patient presented to our pediatric emergency department with 5 days of fever, sore throat, abdominal pain, vomiting, headache, and 2 days of periorbital swelling. Her initial laboratory evaluation revealed a negative monospot test, neutropenia, atypical lymphocytosis, and thrombocytopenia in addition to transaminitis and proteinuria. An abdominal ultrasound obtained identified hepatosplenomegaly, moderate ascites, acalculous cholecystitis, and a distended appendix with periappendiceal fluid. She was admitted to gastroenterology for further management with antibiotics and surgery and hematology consults. Ultimately, Epstein-Barr virus polymerase chain reaction was positive. This case highlights an atypical presentation of Epstein-Barr virus and the collaborative approach to diagnosis.

Development of Infliximab Target Concentrations During Induction in Pediatric Crohn Disease Patients.

OBJECTIVES: Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders. METHODS: Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (>50% improvement in fecal calprotectin) and maintenance concentrations ≥5 µg/mL were secondary outcomes. RESULTS: We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 µg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 µg/mL (19.5-40) and 14 µg/mL (8.3-24) compared to 18.8 µg/mL (9.1-23, P < 0.001) and 7.8 µg/mL (4-13.2, P < 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 µg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 µg/mL was associated with a start of maintenance concentration >5 µg/mL (AUC 0.85). Independent predictors for infusion 3 levels <18 µg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level <29 µg/mL. CONCLUSIONS: We found that infusion 2 (≥29 µg/mL) and infusion 3 (≥18 µg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.