The Variable Response to Teduglutide in Pediatric Short Bowel Syndrome: A Single Country Real-Life Experience.

OBJECTIVES: The glucagon-like peptide-2 analog Teduglutide has been shown to enhance intestinal absorption and decrease parenteral nutrition (PN) requirements in short bowel syndrome (SBS). As data in children is limited, we evaluated nationwide real-life experience and treatment outcome in children with SBS. METHODS: Longitudinal data of children treated with Teduglutide for ≥3 months was collected. Data included demographic and medical background, anthropometrics, laboratory assessments and PN requirements. Treatment response was defined as >20% reduction in PN requirement. RESULTS: The study included 13 patients [54% males, median (interquartile range {IQR}) age of 6 (4.7-7) years]. The most common SBS etiology was necrotizing enterocolitis (38%), and median (IQR) small bowel length was 20 (15-40) cm. Teduglutide treatment ranged between 3 and 51 months [median (IQR) of 18 (12-30) months], with 10 patients (77%) treated >1 year. Response to treatment was observed in 8 patients (62%), with a mean [±standard deviation (SD)] treatment duration of 5.9 (±3.2) months. Among responders, 2 patients were weaned off PN and additional 4 decreased PN needs by >40%. There was a median (IQR) reduction in PN volume/kg of 36% (15%-55%) and in PN energy/kg of 27% (6%-58%). Response was not associated with patients' background, and no correlation was found with bowel length or PN dependency at baseline. CONCLUSIONS: Real-life response to Teduglutide is highly variable among children with SBS. While most patients did reach 20% reduction in PN, less achieved further significant reduction or enteral autonomy. No predictive factors of response to treatment were identified, and large multicenter studies are needed to elucidate predictive factors and long-term outcome.

Monitoring Enables Progress: A Nationwide Quality Improvement Program in Children With Crohn Disease.

OBJECTIVES: In this quality improvement program, named quality in pediatric inflammatory bowel disease, we constructed a nation-wide platform that prospectively recorded clinically important quality indicators in pediatric inflammatory bowel diseases (PIBD), aiming at improving clinical management across the country. METHODS: Representatives of all 21 PIBD facilities in Israel formed a Delphi group to select quality indicators (process and outcomes), recorded prospectively over 2 years in children with Crohn's disease 2-18 years of age seen in the outpatient clinics. Monthly anonymized reports were distributed to all centers, allowing comparison and improvement. Trends were analyzed using the Mann-Kendall test, reporting τ (tau) values. RESULTS: The indicators of 3254 visits from 1709 patients were recorded from September 2017 to September 2019 (mean age 14.7 ±â€Š3.1 years, median disease duration 1.8 years (interquartile range 0.69-4.02)). An increase in three of five process indicators was demonstrated: obtaining drug levels of anti-tumor necrosis factor (TNF) (τ = 0.4; P = 0.005), utilization of fecal calprotectin (τ = 0.38; P = 0.008) and bone density testing (τ = 0.45; P = 0.002). Among outcome indicators, three of nine improved as measured during the preceding year: calprotectin <300 µg/mg (τ = 0.35; P = 0.015), and "resolution of inflammation" defined as a composite of endoscopy, imaging and fecal calprotectin (τ = 0.39; P = 0.007). Endoscopic healing reached borderline significance (τ = 0.28; P = 0.055). An increase in the use of biologics throughout the study was observed (τ = 0.47; P = 0.001) with a concurrent decrease in the use of immunomodulators (τ = -0.47; P = 0.001). CONCLUSIONS: Quality improvement nationwide programs can be implemented with limited resources while facilitating standardization of care, and may be associated with improvements in measured indicators.

The role of Wnt/ß-catenin signaling in enterocyte turnover during methotrexate-induced intestinal mucositis in a rat.

BACKGROUND/AIMS: Intestinal mucositis is a common side-effect in patients who receive aggressive chemotherapy. The Wnt signaling pathway is critical for establishing and maintaining the proliferative compartment of the intestine. In the present study, we tested whether Wnt/ß-catenin signaling is involved in methotrexate (MTX)-induced intestinal damage in a rat model. METHODS: Non-pretreated and pretreated with MTX Caco-2 cells were evaluated for cell proliferation and apoptosis using FACS analysis. Adult rats were divided into three experimental groups: Control rats; MTX-2 animals were treated with a single dose of MTX given IP and were sacrificed on day 2, and MTX-4 rats were treated with MTX similar to group B and were sacrificed on day 4. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation, and enterocyte apoptosis were measured at sacrifice. Real Time PCR and Western blot was used to determine the level of Wnt/ß-catenin related genes and protein expression. RESULTS: In the vitro experiment, treatment with MTX resulted in marked decrease in early cell proliferation rates following by a 17-fold increase in late cell proliferation rates compared to early proliferation. Treatment with MTX resulted in a significant increase in early and late apoptosis compared to Caco-2 untreated cells. In the vivo experiment, MTX-2 and MTX-4 rats demonstrated intestinal mucosal hypoplasia. MTX-2 rats demonstrated a significant decrease in FRZ-2, Wnt 3A Wnt 5A, ß-catenin, c-myc mRNA expression and a significant decrease in ß-catenin and Akt protein levels compared to control animals. Four days following MTX administration, rats demonstrated a trend toward a restoration of Wnt/ß-catenin signaling especially in ileum. CONCLUSIONS: Wnt/ß-catenin signaling is involved in enterocyte turnover during MTX-induced intestinal mucositis in a rat.

Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat.

Toll-like receptor 4 (TLR-4) is crucial in maintaining intestinal epithelial homeostasis, participates in a vigorous signaling process and heightens inflammatory cytokine output. The objective of this study was to determine the effects of glutamine (GLN) on TLR-4 signaling in intestinal mucosa during methotrexate (MTX)-induced mucositis in a rat. Male Sprague-Dawley rats were randomly assigned to one of four experimental groups of 8 rats each: 1) control rats; 2) CONTR-GLN animals were treated with oral glutamine given in drinking water (2%) 48 hours before and 72 hours following vehicle injection; 3) MTX-rats were treated with a single IP injection of MTX (20 mg/kg); and 4) MTX-GLN rats were pre-treated with oral glutamine similar to group B, 48 hours before and 72 hours after MTX injection. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 72 hours following MTX injection. The expression of TLR-4, MyD88 and TRAF6 in the intestinal mucosa was determined using real time PCR, Western blot and immunohistochemistry. MTX-GLN rats demonstrated a greater jejunal and ileal mucosal weight and mucosal DNA, greater villus height in ileum and crypt depth and index of proliferation in jejunum and ileum, compared to MTX animals. The expression of TLR-4 and MyD88 mRNA and protein in the mucosa was significantly lower in MTX rats versus controls animals. The administration of GLN increased significantly the expression of TLR-4 and MyD88 (vs the MTX group). In conclusion, treatment with glutamine was associated with up-regulation of TLR-4 and MyD88 expression and a concomitant decrease in intestinal mucosal injury caused by MTX-induced mucositis in a rat.

Increased Toll-like receptor 9 expression by B cells from inflammatory bowel disease patients.

BACKGROUND: Toll-like receptors (TLRs) are important mediators of the innate immune response. Our aim was to evaluate TLR9 expression in peripheral B cells, taken from inflammatory bowel disease (IBD) patients before and after anti-inflammatory treatment. Nineteen patients with IBD (12-crohn's disease, 7-ulcerative colitis) and 18 healthy controls were included in the study. Disease severity was assessed using the Pediatric/Adults crohn's disease activity index and the ulcerative colitis activity index as needed. Accordingly, patients were classified as mild, moderate or severe disease. Peripheral B cells isolated from IBD patients, before and after anti-inflammatory treatment, and from the control group, were cultured for 24 h with and without CpG oligodeoxynucleotides (ODN-CpG) 0.5 µM. TLR9 expression by memory B cells (CD19+CD27+) was assessed by flow cytometry. RESULTS: We found that TLR9 expression by peripheral B cells was significantly higher in IBD patients than that in healthy controls (12.42 ± 9.5 MFI vs. 6.0 ± 2.6 MFI p = 0.02). The addition of ODN-CpG to B cells resulted in a significantly increase of TLR9 expression in B cells from healthy controls (6.5 ± 3.2 MFI vs. 8.8 ± 4.2 MFI p = 0.007). On the contrary, B cells from IBD patients only partly respond to the addition of ODN-CpG after anti-inflammatory treatment (6.3 ± 3.8 vs. 7.3 ± 3.7, p = 0.1). TLR9 expression was positively correlated with IBD disease severity (r = 0.681, p < 0.0001). CONCLUSIONS: TLR9 expression in memory B from IBD patients is elevated and associated with disease severity.

Bronchial reactivity and fractional exhaled NO in Crohn's disease in the era of immunomodulating treatment.

AIM: Our aim was to determine bronchial hyper-responsiveness (BHR) and fractional exhaled NO (FeNO) in a cohort followed and treated for Crohn's disease (CD) in a Pediatric Gastroenterology Unit. METHODS: Consecutive children with CD were referred to the Pediatric Pulmonary Unit. Each patient completed a questionnaire, followed by spirometry, methacholine challenge test (MCT) and determination of FeNO. The control group included patients evaluated for functional cough who had negative MCT. RESULTS: Twenty-three children and young adults (mean age, 17.39 ± 2.96 years) with CD were compared to 24 healthy controls. 20/23 patients received immunomodulating treatment. Forced expiratory volume in 1 sec (FEV1) was significantly lower prior to (93.74 ± 10.81%, p = 0.009) and at the end of (78.91 ± 18.39%, p = 0.001) the MCT in the CD group compared with the control group (102.2 ± 10.477% and 95.33 ± 11.075%, respectively). Bronchial hyper-responsiveness was observed in 30.4% of patients with CD. FeNO levels were 15.37 ± 24.17 in CD and 11.38 ± 5.42 in the control group (p = 0.21). Neither the response to MCT nor FeNO levels were affected by the disease duration or activity index. CONCLUSION: In our series, BHR is less frequent than previously described in children with CD. We hypothesize that our finding could result from immunomodulating treatments or lower disease activity.

Olive oil-based intravenous lipid emulsion in pediatric patients undergoing bone marrow transplantation: a short-term prospective controlled trial.

BACKGROUND & AIMS: Parenteral nutrition (PN) is an important component of the supportive care of children undergoing bone marrow transplantation (BMT). The study aimed to assess short-term safety and metabolic effects of an olive oil-based (OO) lipid emulsion compared with a MCT/LCT (M/L) emulsion in the clinical setting of pediatric BMT. METHODS: Twenty-eight pediatric BMT patients (age 1-18 years) expected to need PN support for at least 2 weeks, were prospectively enrolled and randomly assigned to receive either OO or M/L lipid emulsions within PN. Clinical and routine laboratory parameters, plasma fatty acids profile, vitamin E and peroxidation status were recorded at baseline and after 14 days of PN. RESULTS: No significant differences were found for hematological parameters, liver enzymes, vitamins, plasma peroxidation status, percentage and time to engraftment. Taking into consideration the baseline fatty acids levels, the OO group showed higher oleic acid (p=0.012), linoleic (p=0.012) and arachidonic acid (p=0.002) enrichment but similar eicosapentanoic and docosahexanoic acids levels compared to the M/L group at day 14. Cholesterol levels decreased significantly in the OO group after 14 days on PN (p=0.017). CONCLUSIONS: OO lipid emulsion was well tolerated, maintained essential fatty acids and peroxidation status, and generated a favorable plasma lipid profile. In this study short-term use of OO intravenous lipid emulsions was safe in children who needed PN support during BMT.

Nutritional supplementation with polymeric diet enriched with transforming growth factor-beta 2 for children with Crohn's disease.

BACKGROUND: A polymeric diet rich in transforming growth factor-beta 2 used as a single nutrient has been shown to induce remission in 79% of children with Crohn's disease. OBJECTIVES: To summarize the experience of several pediatric gastroenterology units in Israel using a TGFbeta2-enriched polymeric diet (Modulen IBD) supplementation in children and adolescents with Crohn's disease. METHODS: In a retrospective study we reviewed the charts of 28 children with Crohn's disease (10 girls, 18 boys) who received, in addition to conventional treatment, Modulen IBD as a supplement to their regular nutrition. These children were compared with 18 children supplemented with standard polymeric formula (Ensure Plus) and 18 children without formula supplementation. We recorded clinical manifestations, growth, and the Pediatric Crohn's Disease Activity Index before and after initiation of the polymeric diet. RESULTS: The Modulen-treated children showed a significant decrease in PCDAI from 34.3 to 15.7 (P< 0.0001). A significant decrease in PCDAI was recorded also in the Ensure Plus group, from 35 to 22 (P= 0.02) but not in the non-supplemented group. Significant improvements in body mass index (P = 0.01) and erythrocyte sedimentation rate (P= 0.03) were recorded at follow-up (median 3.4 months) only in the Modulen IBD group. CONCLUSIONS: In this cohort of children with Crohn's disease, supplementation of the diet with Modulen IBD as well as supplementation with Ensure Plus was associated with a decrease in PCDAI. The children supplemented with Modulen IBD also showed improvement in BMI, suggesting an additional advantage of nutritional therapy in children with this disease.

Early performance of voiding cystourethrogram after urinary tract infection in children.

BACKGROUND: Voiding cystourethrogram is performed 3-6 weeks after urinary tract infection. This prolongs the interval of prophylactics, reducing the likelihood of having to perform the procedure. OBJECTIVES: To investigate the yield and potential risks/benefits of early compared to late performance of VCUG after UTI. METHODS: We conducted a prospective study of 84 previously healthy children < 5 years old admitted from October 2001 to November 2002 with first documented UTI. We then divided the 78 patients who had VCUG into two groups and compared them to a control group: group A--49 children in whom VCUG was performed within 10 days, group B--29 children in whom VCUG was performed > 10 days after UTI, and a historical control group C--82 children in whom VCUG was performed > 4 weeks following UTI. RESULTS: VCUG was performed in 48/48 (100%), 6/35 patients (17.1%) and 34/116 patients (29.3%), and vesicoureteral reflux was demonstrated in 38.8%, 37.9% and 39% in groups A, B and C respectively. No significant difference was found between these groups in terms of incidence of VUR and severity and grading of reflux within each group. One case of UTI secondary to VCUG occurred in a patient in whom the procedure was performed 4 months after the diagnosis. CONCLUSIONS: Performing VCUG early does not influence the detection rate, severity of the VUR, or risk of secondary infection; it shortens the period of prophylactic use and increases performance rate of VCUG, thereby minimizing the risk of failure to detect VUR. The traditional recommendation of performing VCUG 3-6 weeks after the diagnosis of UTI should be reevaluated.

Imaging features of posterior mediastinal chordoma in a child.

A 5 1/2-year-old boy presented with repeated episodes of stridor and cough. Chest radiography demonstrated a widened mediastinum. Evaluation by CT revealed a low-density posterior mediastinal mass initially diagnosed as benign tumor. Histopathological analysis of the resected mass disclosed a malignant chordoma. Our radiological results are described with an analysis of the imaging findings in the medical literature. We present our suggestions for preoperative evaluation of posterior mediastinal tumors.

Impaired gastric myolectrical activity in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is frequently associated with gastrointestinal complaints that can be due to gastrointestinal dysmotility. Electrogastrography (EGG) is an attractive, non-invasive procedure to assess gastric electric activity. The aims of our study were to investigate EGG abnormalities in pancreatic sufficient and pancreatic insufficient CF patients, and to examine whether EGG correlates with gastric emptying as assessed by scintigraphy. METHODS: EGG was performed in 23 CF patients (12 pancreatic sufficient patients, 11 pancreatic insuffficient) by using cutaneous recording pre- and postprandialy. Pre- and postpostprandial EGG indexes were compared to 19 healthy control patients. Gastric emptying was assessed simultaneously by gastric scintigraphy in 11 of the 23 CF patients. Six patients underwent a repeated scintigraphy recording following a month of treatment with cisapride. RESULTS: Abnormal patterns of EGG were found in 78.3% of CF patients compared to 31.3% of controls during fasting (p

Adenosine bronchial provocation with computerized wheeze detection in young infants with prolonged cough: correlation with long-term follow-up.

BACKGROUND: Chronic cough in babies is often associated with bronchial hyperreactivity (BHR). The objective documentation of BHR in babies is difficult, and acoustic methods have been described (provocative concentration of a substance causing wheeze) for conducting bronchial provocation tests (BPTs). We conducted a study to evaluate automatic computerized wheeze detection (CWD) in determining BHR in young infants with prolonged cough, and its correlation with the subsequent development of wheezing. METHODS: Infants aged < 24 months with prolonged cough (ie, > 2 months) underwent acoustic BPTs with the response determined by CWD and auscultation by a physician. Telephone interviews with parents were conducted after 1 month and yearly for the next 3 years. RESULTS: A total of 28 infants who were 4 to 24 months old with prolonged cough were included in the study. Twenty of these infants (71.4%) had BHR as determined by a positive acoustic BPT result. In 11 of these 20 tests, the CWD occurred earlier, and in 9 tests it occurred at the same step as auscultation by a physician. Rhonchi or whistles often preceded wheezes. Seventeen of the 20 patients with BHR completed 3 years of follow-up. Of these, 14 had recurrent episodes of wheezing and shortness of breath, and 3 were well. Six of the eight adenosine-negative patients completed 3 years of follow-up and had no symptoms of BHR. CONCLUSIONS: Acoustic BPT is a technically feasible test for the detection of BHR in young infants. CWD provides an earlier detection of wheeze than stethoscope auscultation. In our group of infants, a positive acoustic BPT result had high correlation with symptoms compatible with BHR over the next 3 years.

NOD2/CARD15 mutation analysis and genotype-phenotype correlation in Jewish pediatric patients compared with adults with Crohn's disease.

OBJECTIVES: The allelic variants in the NOD2/CARD15 gene G908R, R702W, and 1007fs are strongly and independently associated with susceptibility to Crohn's disease (CD). Our aim was to compare the NOD2/CARD15 genotype and the genotype-phenotype correlation in Jewish pediatric patients with CD (

Nonsyndromic paucity of interlobular bile ducts: report of 10 patients.

OBJECTIVES: Only a few reports of nonsyndromic paucity of interlobular bile ducts (NS-PILBD) have been published. The authors' aim was to outline the clinical and laboratory profile of patients with NS-PILBD diagnosed at a tertiary referral center. METHODS: The authors reviewed all the reports of pediatric liver biopsies performed between 1991 and 2000 at their institution. Upon diagnosis of NS-PILBD, patients' records were examined for clinical, laboratory, and histologic data, and liver biopsy specimens were re-evaluated. RESULTS: Three hundred biopsies were performed in children during the study period, of which 64 were in infants younger than 1 year. NS-PILBD was diagnosed in 10 of 64 (16%) biopsy specimens. Mean age at presentation was 10 days (range, 1 day-6 weeks), and mean follow-up was 4.5 years (range, 1-9 years). An underlying condition was identified in 70% of children with NS-PILBD: namely congenital cytomegalovirus (n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), mitochondrial DNA depletion (n = 1), Niemann-Pick type C (n = 1), and arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC syndrome; n = 1). All children presented with jaundice. Four children had initially acholic stools. At their last follow-up visit, failure to thrive was present in five children, and cholestasis in six children. Mortality was noted only in children with metabolic diseases (n = 2). CONCLUSIONS: In the study, NS-PILBD was common in young children undergoing liver biopsy. Although NS-PILBD is nonspecific, a wide survey for inborn errors of metabolism should be included in the diagnostic work-up of NS-PILBD. In the authors' center, the association of certain metabolic diseases with NS-PILBD carries a grave prognosis.

The effect of early treatment in children with chronic hepatitis.

BACKGROUND: The aim of this study was to compare the efficacy of interferon alpha (IFN) or IFN and ribavirin (IFN+RIB) combination therapy in children with chronic hepatitis C (CHC). Most children were infected during treatment for pediatric malignancies. PATIENTS AND METHODS: We reviewed the charts of 20 patients (11 boys and 9 girls) aged 10.6 +/- 3.7 years with CHC who were treated between 1995 and 2001. Seven patients diagnosed with CHC before 1998 were treated with 3 million units of IFN three times weekly for 6 to 12 months. Thirteen children diagnosed after 1998 were treated with 3 million units of IFN three times weekly plus 15 mg/kg of ribavirin daily for 6 months (IFN+RIB). RESULTS: Demographic and clinical characteristics were not different between the two treatment groups. A sustained complete response defined as serum alanine aminotransferase normalization and hepatitis C virus RNA clearance at 6 and 12 months after termination of treatment occurred in three of seven children (43%) treated with IFN monotherapy compared with 7 of 12 children (54%) in the group treated with IFN+RIB combination therapy (not significant). The only difference between responders and nonresponders was the duration of infection before the initiation of therapy, which was significantly shorter in responders (1 +/- 0.3 vs. 5.6 +/- 2.2; P = 0.001). CONCLUSIONS: In this small cohort of children with CHC, early initiation of antiviral treatment was associated with a sustained response rate independent of treatment type. Regular follow-up of children at risk of acquiring hepatitis C virus infection should assist in the early diagnosis. Early initiation of antiviral treatment may improve the rate of sustained response.