The Utility of Contrast Enhanced Ultrasound and Elastography in the Early Detection of Fibro-Stenotic Ileal Strictures in Children with Crohn's Disease.

Purpose: Crohn's disease (CD) is a chronic, idiopathic bowel disorder that can progress to partial or complete bowel obstruction. At present, there are no reliable diagnostic tests that can readily distinguish between acute inflammatory, purely fibrotic and mixed inflammatory and fibrotic. Our aim is to study the utility of contrast enhanced ultrasound (CEUS) in combination with shear wave elastography (SWE) to differentiate fibrotic from inflammatory strictures in children with obstructive CD of the terminal ileum. Methods: Twenty-five (19 male) children between 2016-2021 with CD of the terminal ileum were recruited into the study. Among these patients, 22 had CEUS kinetic measurements of tissue perfusion, including wash-in slope (dB/sec), peak intensity (dB), time to peak intensity (sec), area under the curve (AUC) (dB sec), and SWE. In total, 11 patients required surgery due to bowel obstruction. Histopathologic analysis was performed by a pathologist who was blinded to the CEUS and SWE test results. Results: Patients that underwent surgical resection had significantly higher mean area under the curve on CEUS compared to patients responsive to medical therapy (p=0.03). The AUC also correlated with the degree of hypertrophy and the percent fibrosis of the muscularis propria, as determined by histopathologic grading (p<0.01). There was no difference in the mean elastography measurements between these two patient groups. Conclusion: CEUS is a useful radiological technique that can help identify pediatric patients with medically refractory obstructive fibrotic strictures of the terminal ileum that should be considered for early surgical resection.

Design of a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of prucalopride in pediatric patients with functional constipation.

Background: A previous phase 3 trial of prucalopride in pediatric patients (6 months-18 years old) with functional constipation (FC) demonstrated no efficacy versus placebo. We designed an additional phase 3 trial to further assess the efficacy, long-term safety and tolerability of prucalopride in children and adolescents. Methods: This multicenter trial (ClinicalTrials.gov identifier: NCT04759833; EudraCT number: 2022-003221-22) comprises a 12-week, randomized, double-blind, placebo-controlled phase, followed by a 36-week, double-blind, safety extension phase. Approximately 240 toilet-trained patients aged 3-17 years will be randomized 1:1:1 to receive low- (0.04 mg/kg) or high-dose (0.08 mg/kg) prucalopride, or placebo once daily. Fifteen non-toilet-trained patients ≥6 months old with FC will be included in an exploratory efficacy and safety analysis. Discussion: The efficacy endpoints used in this study will differ from those used in adults and in the previous pediatric phase 3 trial; they have been adapted to be more suitable for a wider age range of pediatric patients. Both study phases will be longer than in the previous pediatric study, providing a longer time period in which to assess the efficacy and safety of prucalopride. Study participants will be identified using the modified Rome IV criteria for FC, instead of the Rome III criteria, and non-toilet-trained patients will be included, which will broaden the population of pediatric patients assessed. Patients will undergo fecal disimpaction before randomization and undergo standardized continuous behavioral therapy throughout the trial. This pediatric study of prucalopride will aim to demonstrate the efficacy and long-term safety of this treatment.

Seizure During Infliximab Infusion in a Child With Crohn's Disease: An Illustration of a Neurologic Adverse Event Associated With Drug Antibodies.

Antitumor necrosis factor (anti-TNF) therapy has proven efficacy in the induction and maintenance of remission in children with Crohn's disease (CD). With the increased use of these medications, several adverse events have been associated, including the emergence of neurologic side effects. While demyelinating conditions and neuropathy associated with anti-TNF therapy have been reported in adults, seizures have been anecdotally described in case reports. We describe a case of an adolescent boy who experienced an infliximab-associated seizure during an infusion and the potential role that medication antibody levels may have played in this adverse event.

Pediatric bowel preparation: Sodium picosulfate, magnesium oxide, citric acid vs polyethylene glycol, a randomized trial.

BACKGROUND: Bowel preparation in children can be challenging. AIM: To describe the efficacy, safety, and tolerability of sodium picosulfate, magnesium oxide, and citric acid (SPMC) bowel preparation in children. METHODS: Phase 3, randomized, assessor-blinded, multicenter study of low-volume, divided dose SPMC enrolled children 9-16 years undergoing elective colonoscopy. Participants 9-12 years were randomized 1:1:1 to SPMC ½ dose × 2, SPMC 1 dose × 2, or polyethylene glycol (PEG). Participants 13-16 years were randomized 1:1 to SPMC 1 dose × 2 or PEG. PEG-based bowel preparations were administered per local protocol. Primary efficacy endpoint for quality of bowel preparation was responders (rating of 'excellent' or 'good') by modified Aronchick Scale. Secondary efficacy endpoint was participant's tolerability and satisfaction from a 7-item questionnaire. Safety assessments included adverse events (AEs) and laboratory evaluations. RESULTS: 78 participants were randomized, 48 were 9-12 years, 30 were 13-16 years. For the primary efficacy endpoint in 9-12 years, 50.0%, 87.5%, and 81.3% were responders for SPMC ½ dose × 2, SPMC 1 dose × 2, and PEG groups, respectively. Responder rates for 13-16 years were 81.3% for SPMC 1 dose × 2 and 85.7% for PEG. Overall, 43.8% of participants receiving SPMC 1 dose × 2 reported it was 'very easy' or 'easy' to drink, compared with 20.0% receiving PEG. Treatment-emergent AEs were reported by 45.5% of participants receiving SPMC 1 dose × 2 and 63.0% receiving PEG. CONCLUSION: SPMC was an efficacious and safe for bowel preparation in children 9-16 years, with comparable efficacy to PEG. Tolerability for SPMC was higher compared to PEG.

Contrast-Enhanced Ultrasound and Shear Wave Elastography Evaluation of Crohn's Disease Activity in Three Adolescent Patients.

Characterizing inflammation and fibrosis in Crohn's disease (CD) is necessary to guide clinical management, but distinguishing the two remains challenging. Novel ultrasound (US) techniques: contrast-enhanced US (CEUS) and shear wave elastography (SWE) offer great potential in evaluating disease activity in pediatric patients. Three patients ages 16 to 20 with known CD underwent CEUS and SWE to characterize bowel wall inflammation and fibrosis. Magnetic resonance enterography, endoscopy, or surgical pathology findings are also described when available. The patients' disease activity included acute inflammation, chronic inflammation with stricture formation, and a fibrotic surgical anastomosis without inflammation. CEUS was useful in determining the degree of inflammation, and SWE identified bowel wall fibrosis. Used together these techniques allow for better characterization of the degree of fibrosis and inflammation in bowel strictures. With further validation CEUS and SWE may allow for improved characterization of bowel strictures and disease flares in pediatric patients suffering from CD.

Diagnosis of congenital and acquired focal lesions in the neck, abdomen, and pelvis with contrast-enhanced ultrasound: a pictorial essay.

Contrast-enhanced ultrasound (CEUS) is a versatile imaging modality that improves the diagnostic potential of conventional ultrasound. It allows for portable imaging at the bedside. In this paper, we illustrate how CEUS can be used in evaluating several focal lesions in the pediatric population, including liver hemangioma, telangiectasias, splenic hamartomas, and bladder lesions. We describe the ultrasound findings and contrast enhancement patterns associated with these lesions. Findings are correlated with MRI, CT, and/or pathology when available. This paper demonstrates the value of CEUS in improving characterization of many focal lesions in the pediatric population. CONCLUSION: CEUS is a valuable bedside technique for use in the pediatric population to evaluate focal lesions in various organs, and will allow for safe, more efficient diagnostic imaging. What is Known: • CEUS offers many advantages over CT and MRI and is underutilized in the United States. • It is only FDA approved for vesicoureteral reflux and liver in the pediatric population. However, off label uses are well described. What is New: • This pictorial essay describes ultrasound findings and contrast enhancement patterns associated with liver hemangioma, liver telangiectasia, splenic hamartoma, hemorrhagic ovarian cyst, urachal remnant, spinning top urethras, and kaposiform hemangioendothelioma. • We demonstrate the utility of CEUS in expanding the diagnostic potential of conventional ultrasound.

Colonic Angioectasia in an Adolescent Boy with Hoyeraal-Hreidarsson on Long-Term Anabolic Steroid Therapy.

Androgen therapy has proven efficacy in treating patients with bone marrow failure who are not candidates for bone marrow transplantation. Herein, we report on a case of colonic angioectasia secondary to oxymetholone use in an adolescent patient with Hoyeraal-Hreidarsson syndrome (HHS). A 13-year-old Caucasian male with HHS characterized by cerebellar hypoplasia, developmental delay, microcephaly, esophageal strictures and myelodysplasia presented with severe hematochezia from colonic angioectasia secondary to long-term oxymetholone therapy. These vascular lesions resolved spontaneously once this anabolic steroid was discontinued. While androgen therapy is often recommended for certain anemias and myelodysplastic syndromes, clinicians should be aware of the potential complication in developing these perceived uncommon colonic angioectasias. Moreover, pediatric gastroenterologists should familiarize themselves in identifying these vascular lesions by colonoscopy, especially among the high risk groups on long-term anabolic steroid therapy.

Development of the pediatric daily ulcerative colitis signs and symptoms scale (DUCS): qualitative research findings.

BACKGROUND: The purpose of this study is to develop patient-reported (PRO) and observer-reported (ObsRO) outcome measures of ulcerative colitis (UC) signs/symptoms in children aged 5-17 with mild/moderate UC. The daily ulcerative colitis signs and symptoms scale (DUCS) was developed in two phases. Phase I involved concept elicitation interviews with patients and healthcare providers, review of website posts and item generation. Phase II involved cognitive debriefing and assessment of usability and feasibility of the eDiaries. Participants were recruited from five US clinical sites, a research recruitment agency, and internet advertising. Thematic and content analysis was performed to identify concepts from Phase I. The Phase II cognitive debriefing interviews were analyzed iteratively to identify problems with clarity and relevance of eDiary content. The US Food and Drug Administration (FDA) also reviewed and provided feedback on the eDiaries. RESULTS: Phase I included 32 participants (22 remission; 10 active disease). Phase II included 38 participants (22 remission; 16 active disease). A core set of seven signs and symptoms emerged that were reported by at least 30% of the patients interviewed: abdominal pain, blood in stool, frequent stools, diarrhea, stool urgency, nighttime stools, and tiredness. Participant input influenced changes such as refinement of item wording, revision of graphics, and selection of response scales. Revisions suggested by FDA included simplifying the response scale and adding questions to capture symptoms during sleeping hours. CONCLUSIONS: The findings of instrument development suggest that the DUCS PRO and ObsRO eDiaries are content-valid instruments for capturing the daily signs and symptoms of pediatric patients with mild to moderate UC in a clinical trial setting.

Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis.

BACKGROUND: Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC). AIM: To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC. METHODS: Participants (5-17 years of age; 18-82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model. RESULTS: Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%-45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified. CONCLUSION: Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844.

Predictors of severity in childhood pancreatitis: correlation with nutritional status and racial demographics.

OBJECTIVE: Acute pancreatitis is one of the leading causes of rising pediatric hospitalizations in North America. The aim of this study was to assess the role of nutritional status and racial influences on the severity of acute pancreatitis in children. METHODS: The institutional review board approved this retrospective chart review of children with the diagnosis of acute pancreatitis between the ages of 0 and 18 years hospitalized at the Johns Hopkins Hospital between 1998 and 2008. Parameters studied included biochemical markers associated with pancreatitis, review of severity of illness reflected through the length of stay, and pediatric intensive care unit admission. RESULTS: The length of in-patient hospitalization was longer for children with imaging findings of pseudocyst or pancreatic necrosis (23.1 ± 26.4 days vs 4.4 ± 10.6 days; P = 0.0074) and malnourished children versus normal weight and obese children (16.5 days for malnourished vs 10.6 days for normal weight vs 10.7 days for obese; P = 0.04). There was also a significant difference in the need for pediatric intensive care unit admission across ethnic groups (18% African American vs 7% white) (P = 0.04). CONCLUSIONS: Ethnicity and nutritional status may influence the severity and duration of hospitalization among children with pancreatitis.

Efficacy of fecal microbiota transplantation in 2 children with recurrent Clostridium difficile infection and its impact on their growth and gut microbiome.

Fecal microbiota transplantation (FMT) is recognized as an alternative therapeutic modality for recurrent Clostridium difficile infection (RCDI); however, data on its efficacy in children are lacking, including its effect on their growth and fecal microbiota. We report on 2 young children (<3 years old) who failed available therapeutics for RCDI, but responded remarkably well to FMT. Besides resolution of clinical features of C difficile infection (CDI), FMT administration led to marked improvement in their growth, along with increased microbiota diversity, especially proportion of Bacteroides. Our 2 cases illustrate the efficacy of FMT in children with RCDI and its positive effect on their growth and gut microbiota.

Acute kidney injury in a girl with ulcerative colitis and cytomegalovirus-induced focal segmental glomerular sclerosis.

BACKGROUND: Mesalamine or 5-aminosalicylic acid (5-ASA) has proven efficacy in treating patients with ulcerative colitis (UC). Although mesalamine is considered safe, it has been associated with acute interstitial nephritis and renal failure. METHODS: Herein we present a case of a child with UC who developed acute renal failure on mesalamine therapy. RESULTS: A 15-year-old African-American girl with well-controlled UC presented to the Johns Hopkins Hospital with a four-day history of high fever, malaise, generalized body aches, and productive non-bloody cough. Over the next three days, she developed acute renal failure with fluid retention, and elevated serum creatinine and blood urea nitrogen. A kidney biopsy showed drug induced acute interstitial nephritis and focal segmental glomerulosclerosis with viral inclusion bodies likely secondary to cytomegalovirus. CONCLUSION: When treating UC patients with a history of underlying renal disease, it is advised to carefully monitor renal function while on mesalamine therapy.

Contribution of higher risk genes and European admixture to Crohn's disease in African Americans.

BACKGROUND: African Americans (AAs) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD. METHODS: Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. Overall, 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 single nucleotide polymorphisms (SNPs) in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry. RESULTS: Mean EA was similar among the CD cases and controls (20.9% and 20.4%, respectively, P = 0.58). No significant admixture differences were observed among 211 to 227 cases stratified by phenotypic subclassifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, P = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, P = 0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (Leu503Phe [10.5% CD, 7.6% Controls, P = 0.05] and g-207c [41.3% CD, 35.7% Controls, P = 0.03], respectively), and IL23R rs2201841 (18.2% CD, 13.8% Controls, P = 0.03), but not IRGM variants, nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (P = 0.05), whereas a more common haplotype isolating g-207c was not. CONCLUSIONS: Specific functional gene variations contribute significantly to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.

6-Mercaptopurine transport in human lymphocytes: correlation with drug-induced cytotoxicity.

OBJECTIVE: 6-mercaptopurine (6-MP) is efficacious in the treatment of inflammatory bowel disease (IBD). However, about one-third of patients respond poorly to therapy. This study aimed to characterize the inherent differences in 6-MP transport that may cotribute to the differences in treatment responses. METHODS: Intracellular 6-MP accumulation was assayed in Epstein-Barr virus (EBV)-transformed lymphocytes from IBD patients, using (14) C-radiolabeled 6-MP. Cell proliferation was determined by methyl thiazolyl tetrazolium (MTT) assay. Apoptosis was assayed based on the activation of caspase 3. The expressions of 15 potential 6-MP transporters were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Intracellular 6-MP accumulation, varying significantly among patients, was carrier-dependent and partially sodium-dependent. 6-MP cytotoxicity was, at least in part, due to apoptosis and correlated with intracellular drug accumulation. The efflux transporters did not appear to contribute to the variability of intracellular drug accumulation between patients, since none correlated with drug accumulation or cytotoxicity. Rather, differential expression of five influx/uptake transporters might be a key contributor to the difference in the accumulation of and susceptibility to the drug. CONCLUSIONS: The heterogeneity of the drug transporters may be the reason for the therapeutic sensitivity of 6-MP in IBD patients. As the 6-MP uptake is a carrier-mediated and partially sodium-dependent process, future studies are necessary to evaluate the role of the putative transporters and their correlation with drug sensitivity in patients.

Outcomes of percutaneous endoscopic gastrostomy in children.

Percutaneous endoscopic gastrostomy (PEG) is a relatively safe and minimally invasive surgical method for providing enteral access in children. In pediatrics, the indications for PEG placement frequently include malnutrition or failure to thrive, as well as oropharyngeal dysphagia, especially in children with neurological impairment (NI). The risk for postoperative complications is low. However, among children with NI, gastroesophageal reflux disease (GERD) may necessitate fundoplication prior to gastrostomy tube placement. Preoperative pH probe testing has not been shown to be an effective screening tool prior to PEG placement among patients with GERD. Laparoscopic gastrostomy tube insertion was introduced in pediatric patients in an attempt to decrease complications associated with PEG. Although outcomes were reported to be similar to or better than PEG alone, future comparative studies are needed to better define the optimal patient demographic for this technique.

Annual update of pediatric digestive diseases.

The 24th Annual Meeting of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition provided a comprehensive overview of pediatric digestive diseases. The meeting and its adjunct events, including a postgraduate course and 1-day symposium, enabled a diverse group of physicians, trainees and nurses to have the opportunity to discuss the latest developments in pediatric gastrointestinal, liver and nutritional disorders.

The genetics of inflammatory bowel disease: diagnostic and therapeutic implications.

BACKGROUND: The genetics of inflammatory bowel diseases (IBD) has brought new insight into the spectrum of disease phenotypes that are collectively labeled as either Crohn's disease or ulcerative colitis. In concert with the pharmacogenomics of drug therapy, it has led clinicians to develop the notion of a more tailored approach to therapy. DATA SOURCES: Articles were searched from PubMed (1995-2010) with key words "inflammatory bowel diseases", "Genetics", "pharmacogenomics". RESULTS: Among all the putative susceptibility loci, the NOD2 gene has been the most studied and linked to an aggressive form of stricturing and perforating disease of the ileum. Other potential gene polymorphisms, including those encoding for the interleukin-23 receptor, have lent themselves to the recent development of potential novel immunosuppressive therapies. While the linkage of a number of autophagy genes with either Crohn's disease or ulcerative colitis has provided insight into the innate adaptive immune pathway's response to commensual intestinal bacteria. Pharmacogenetic polymorphisms of azathioprine metabolism have been shown to predict toxicity to anti-metabolite therapy. Patients with absent thiopurine methyl transferase enzyme activity are at risk for irreversible bone marrow suppression, and are not considered good candidates for either 6-mercaptopurine (6-MP) or azathioprine therapy. CONCLUSIONS: Ultimately, the correlation between these genotypes and clinical phenotype of disease will inevitably lead to an improved understanding of disease natural history and a more tailored approach to therapy. Although there is ongoing debate as to whether these inherent differences in enzyme activity can predict responsiveness to anti-metabolite therapy, some gastroenterologists do find value in 6-MP metabolite testing as a means of monitoring patient compliance and tailoring the dose of anti-metabolite therapy based on a perceived therapeutic window. In the future, patients with IBD will ultimately be categorized based on their genomic imprint to allow for a better delineation of disease phenotype. Furthermore, the application pharmacogenomics of drug therapy into clinical practice will be pivotal in maximizing treatment response while avoiding untoward side-effects.

Rash induced by anti-tumor necrosis factor agents in an adolescent with Crohn's disease.

BACKGROUND: A 17-year-old white male with Crohn's disease who was receiving maintenance infusions of the anti-tumor necrosis factor (TNF) agent, infliximab, presented with a new-onset psoriasiform skin rash. The rash was not responsive to topical or oral corticosteroids and worsened after infliximab infusions and after subsequent administration of a second anti-TNF drug, adalimumab. INVESTIGATIONS: Full medical history and physical examination, including assessment of the morphology of rash and the temporal correlation with administration of anti-TNF agents. DIAGNOSIS: Anti-TNF-agent induced psoriasiform skin rash. MANAGEMENT: Discontinuation of anti-TNF therapy. The patient opted to have his gastrointestinal symptoms treated with oral mesalazine and metronidazole.