A novel nutritional approach to infants and children with congenital diarrhea due to homozygous DGAT1 mutations.

OBJECTIVES: Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride synthesis. DGAT1 is expressed in human enterocytes and is essential for fat absorption. Homozygous DGAT1 deficiency often presents with severe diarrhea and protein-losing enteropathy (PLE) in the 1st weeks of life. Because severe restriction of fat intake controls diarrhea and decreases PLE, total parenteral nutrition (TPN) was the initial standard therapy in infants and children. We present tertiary center experience managing infants and children with DGAT1 deficiency resulting in the development of a nutritional approach that minimizes the use of TPN. METHODS: From 2014 to 2020, 12 infants with DGAT1 deficiency were treated. Stool output, growth, and development, as well as essential fatty acid status, were monitored. This retrospective experience formed the basis for treatment recommendations, which include an ultralow fat formula with intermittent peripheral intravenous lipid infusions during the 1st year of life. RESULTS: All patients with prolonged intestinal fat exposure had PLE, which resolved when treated with the nutrition protocol. Essential fatty acid status as measured by triene:tetraene ratios normalized in all treated patients. Over time, early genetic diagnosis and prompt initiation of an ultralow fat diet with peripheral intravenous lipid infusions replaced the need for TPN. CONCLUSIONS: Children with DGAT1 deficiency respond to dietary restriction of lipids. Management with a novel nutritional approach provides effective treatment for infants with DGAT1 deficiency, treats diarrhea and PLE, promotes growth and development, avoids TPN dependency, and decreases the potential for essential fatty acid deficiency.

Fatigue in pediatric inflammatory bowel diseases: A systematic review and a single center experience.

OBJECTIVES: We aimed to review the literature on fatigue in pediatric inflammatory bowel diseases (PIBD), to explore how it is measured, and approximate its rate in an inception pediatric cohort. METHODS: Studies on fatigue were systematically reviewed and selected by two authors. Next, we retrieved the two fatigue-related questions of the IMPACT-III questionnaire at 4 and 12 months after diagnosis from a prospectively maintained cohort of PIBD patients, each scoring 0-100 (lower scores imply more fatigue), and 44 healthy controls. RESULTS: The systematic review identified 14 studies reporting fatigue in children, of which nine had fatigue as the primary outcome and only two provided rates of fatigue. No standalone index was identified for measuring fatigue specifically for PIBD. Of 80 children included in the inception cohort, 62 (78%) scored an average of ≤75 on the two IMPACT-III questions (approximating at least mild fatigue), 26 (33%) scored ≤50 (at least moderate fatigue) and nine (11%) scored ≤25 (severe fatigue). In comparison, only four (9%) healthy children scored at least moderate fatigue (p = 0.007). Fatigue rates at 12 months were only slightly and nonsignificantly lower. Fatigue of any severity was reported in 92% children with active disease versus 63% of those in clinical remission (p = 0.01). CONCLUSION: Literature reporting on fatigue in PIBD is scarce, and no PIBD-specific tool is available to measure fatigue. In our cohort, fatigue-related questions were frequently scored low in children with IBD, mainly among children with active disease but also during clinical remission.

Trends and Correlates of Early-Life Exposure to Acid-Suppressant Therapy in Israel (2005-2020).

OBJECTIVES: To describe trends and correlates of acid-suppressant therapy usage during the first year of life. STUDY DESIGN: A population-based cohort in a large state-mandated health fund in Israel, including members born between 2005 and 2020, was conducted. Acid-suppressant therapy initiation was defined by any purchase within the first year of life. The association between acid-suppressant therapy initiation with medical and sociodemographic characteristics was assessed via logistic regression. RESULTS: Among 595 860 children, acid-suppressant therapy was initiated in 22 412 (37.6 per 1000). The incidence rate increased by 2.8-fold from 18.2 per 1000 in 2005 to 51.0 per 1000 in 2020, furthermore the median age at initiation decreased. Primary care providers accounted for 74.8% of prescribing physicians in 2005 vs 96.1% in 2020, whereas the prevalence of prescribing gastroenterologists decreased from 18.8% to 2.8%. Preterm birth and small weight per gestational age were associated with acid-suppressant therapy usage, with an aOR of 4.23 (95% CI 3.59-4.99), 3.05 (95% CI 2.72-3.42), and 1.65 (95% CI 1.58-1.74) for extreme, very, and moderate preterm vs term birth and aOR 1.22 (95% CI 1.16-1.28) for small weight per gestational age. Birth order was inversely associated with acid-suppressant therapy initiation, with aOR 0.62 (95% CI 0.60-0.65) for third born vs firstborns. High socioeconomic status was linearly associated with initiation, with aOR 1.12 (95% CI 1.11-1.12) per 1-point increase on a 10-point score. CONCLUSIONS: Our analysis demonstrates a substantial increase in early life exposure to acid-suppressant therapy during recent years in Israel. Correlates for initiation in early life were identified to define a population for intervention to reduce potential unnecessary use.

Long COVID-19 Liver Manifestation in Children.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. METHODS: This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. RESULTS: We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative. CONCLUSIONS: We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

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.

The significance of isolated aspartate aminotransferase elevation in healthy paediatric patients.

AIM: Aspartate aminotransferase (AST) is an enzyme expressed in several organs; therefore, AST elevation may reflect outside of liver pathology. AST elevation may also be associated with macro-AST (m-AST). The aim of this study was to evaluate the long-term course of children with prolonged isolated AST elevation and the prevalence of m-AST in our cohort. METHODS: We retrospectively reviewed the medical charts of children diagnosed with prolonged isolated AST elevation and were evaluated for m-AST. RESULTS: Thirty-two patients were included. AST elevation persisted for a median of 66.6 months and ranged from 1.23 to 12-fold upper limit of normal (ULN). Twenty-two percent were m-AST positive and 44% had borderline levels of m-AST. A statistically significant difference was found for age at presentation between the borderline and the positive m-AST groups (31 vs. 69 months, respectively. p = 0.045). None of the patients with elevated AST developed significant liver disease. CONCLUSION: We confirm the benign course of prolonged isolated AST elevation in general and m-AST in particular. A fifth of the patients with isolated AST elevation were m-AST positive. No differences have been found in AST levels between negative, borderline or positive m-AST.

Dietary Therapies Induce Rapid Response and Remission in Pediatric Patients With Active Crohn's Disease.

BACKGROUND & AIMS: Dietary therapies based on exclusion of usual dietary elements induce remission in children with Crohn's disease (CD), whereas re-exposure induces rebound inflammation. We investigated whether a short trial of dietary therapy, to identify patients with and without a rapid response or remission on the diet (DiRe), can be used to predict success or failure of long-term dietary therapy. METHODS: We collected data from the multicenter randomized trial of the CD exclusion diet (CDED). We analyzed data from 73 children with mild to moderate CD (mean age, 14.2 ± 2.7 y) randomly assigned to groups given either exclusive enteral nutrition (EEN, n = 34) or the CDED with 50% (partial) enteral nutrition (n = 39). Patients were examined at baseline and at weeks 3 and 6 of the diet. Remission was defined as CD activity index scores below 10 and response was defined as a decrease in score of 12.5 points or clinical remission. Inflammation was assessed by measurement of C-reactive protein. RESULTS: At week 3 of the diet, 82% of patients in the CDED group and 85% of patients in the EEN group had a DiRe. Median serum levels of C-reactive protein had decreased from 24 mg/L at baseline to 5.0 mg/L at week 3 (P < .001). Among the 49 patients in remission at week 6, 46 patients (94%) had a DiRe and 81% were in clinical remission by week 3. In multivariable analysis, remission at week 3 increased odds of remission by week 6 (odds ratio, 6.37; 95% CI, 1.6-25; P = .008) whereas poor compliance reduced odds of remission at week 6 (odds ratio, 0.75; 95% CI, 0.012-0.46; P = .006). CONCLUSIONS: For pediatric patients with active CD, dietary therapies (CDED and EEN) induce a rapid clinical response (by week 3). Identification of patients with and without a rapid response to diet might help identify those who, with compliance, will be in clinical remission by week 6 of the diet. ClinicalTrials.gov no: NCT01728870.

Hematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalopathy: A single-center experience underscoring the multiple factors involved in the prognosis.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE. PROCEDURE: HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. RESULTS: Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors. CONCLUSIONS: Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.

The Effect of Nutritional Therapy on Bone Mineral Density and Bone Metabolism in Pediatric Crohn Disease.

OBJECTIVES: Both the inflammatory burden of Crohn disease (CD) and corticosteroids have a negative effect on bone density. Exclusive enteral nutrition (EEN) avoids corticosteroids and promotes endoscopic healing. We aimed to explore the effect of nutritional therapy on bone health in pediatric CD. METHODS: This was a planned sub-study of a clinical trial enrolling children with new-onset mild-moderate CD. Children were randomized to either 6 weeks EEN followed by 6 weeks 25% partial enteral nutrition (PEN) or 6 weeks of 50% PEN with a CD exclusion diet followed by 6 weeks of 25% PEN with exclusion diet. Bone formation and resorption were measured at baseline, week 12 and week 24 by serum C-Propeptide of Type I Procollagen (CICP) and type I Collagen N-Telopeptide (NTX), respectively. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry (DXA) scan at baseline and week 24. RESULTS: Median CICP improved from 130 ng/mL (106-189) at baseline to 223 (143-258) at week 12 and 193 (143-252) at week 24 (P = 0.016 for both, n = 29 children). Median NTX remained unchanged (P = 0.45 and P = 0.45). Thirty-six children had DXA scans performed at diagnosis; 81% and 33% had z scores of <-1 and <-2, respectively. DXA z scores did not improve from baseline (adjusted total body less head [TBLH] BMD -1.62 ±â€Š0.87) to week 24 (-1.76 ±â€Š0.75; P = 0.30, n = 21 with both scans). CONCLUSIONS: Low bone density is common in new-onset mild-moderate pediatric CD. CICP, a sensitive marker of bone formation, improved following dietary intervention but this was not associated with improved BMD.

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.

Prolonged abnormal isolated aminotransferase levels in healthy children is a benign condition.

AIM: Hypertransaminasaemia is a common incidental finding in children. It has been demonstrated that even prolonged elevation usually resolves spontaneously without clear aetiology. The aim of this study was to evaluate whether a longer follow-up period, on a larger group, supports the previous findings. METHODS: We retrospectively reviewed medical charts of children diagnosed with prolonged idiopathic hypertransaminasaemia, which spontaneously resolved over the follow-up period. RESULTS: Of the 468 patients screened for elevated transaminases levels, 87 patients younger than 5 years of age were included in the study. An aetiology was found in half of the patients, and the most common aetiologies were fatty liver and cytomegalovirus (CMV) infection. Aminotransferase abnormality persisted for a median of 10 months, and alanine aminotransferase (ALT) levels ranged from 1.5 to 15.9-fold of the upper limit of normal (ULN). After normalisation of transaminase levels, the values remained normal for a documented mean period of 6.4 ± 3.0 years. CONCLUSION: Although idiopathic asymptomatic aminotransferase elevation in healthy children resolves spontaneously in most children, the abnormality may be prolonged. Comprehensive workup finds aetiology only in half of the patients, and the most common aetiologies are fatty liver and CMV hepatitis, which can be diagnosed by non-invasive methods.

The management and course of eosinophilic oesophagitis in Israeli children.

AIM: Eosinophilic oesophagitis (EoE) is a chronic inflammatory oesophageal disease, which has become more recognised in the past decade. We wanted to characterise our patients and review their course of disease and response to treatment. METHODS: We retrospectively reviewed the medical records of EoE patients from January 2010 to May 2018 in our Gastroenterology Institute. A hundred and two children were included in this study. We investigated the characteristics of patients and the response to three treatment options: proton pump inhibitors, elimination diet and topical steroids. The response to treatment was analysed according to 3 aspects: clinical, endoscopic appearance and histological features. RESULTS: Clinical improvement was noted in 55%, 75% and 87.5% on PPIs, diet and budesonide, respectively. Endoscopic improvement was noted in 38.4%, 51.4% and 65.4% on PPIs, diet and budesonide, respectively. Histological improvement was noted in 43.7%, 62.2% and 88.5% on PPIs, diet and budesonide, respectively. CONCLUSION: Our findings suggest that Israeli paediatric EoE patients have characteristics that resemble previous reports. Although there is a correlation between symptoms, endoscopic and histological appearance, we cannot rely on patients reports alone, and therefore, repeated endoscopy and biopsies are mandated. Topical steroids seem to be the most effective treatment option.

[ALLERGY PREVENTION AND TREATMENT DURING THE FIRST YEAR].

INTRODUCTION: The effect of the pregnant mother's nutrition and the effect of the baby's nutrition during the first-year on the development of allergy and atopic disease in the baby have been studied extensively in recent years. Key recommendations for healthcare bodies in Europe and the United States include: • Allergy prevention in at-risk infants (parent or sibling with allergy): Currently, there is a consensus of healthcare organizations around the world that the recommended exclusive breastfeeding duration is the first 6 months of life for the overall health benefit of the baby. Allergy prevention in non-breastfed infants at risk: There are studies showing that fully hydrolyzed formula can reduce the risk of allergic reactions, especially atopic dermatitis, in high-risk non-breastfed babies. Some recommendations for high-risk non-breastfed infants support feeding up to 4 to 6 months with hydrolyzed formulas. Further research is needed on this subject. Soy formulas failed to prevent allergy in high-risk infants. • In case of cow's milk allergy symptoms in breastfed babies: Although a small amount of food allergens may be present in the milk, mothers should be encouraged to continue breastfeeding while avoiding consumption of cow's milk and products. • In case of cow's milk allergy symptoms in non-breastfed babies: Under six months of age, extensively hydrolyzed formula is suitable for most cases of cow's milk allergy, except for severe clinical conditions, which require amino acid formulas. Over six months, soy formulas can be considered. Exposure to solid foods: The current recommendations are to start on solids at the age of 4-6 months and there is no recommendation for avoiding known allergens, despite family history. Later introduction of peanut, fish or egg does not prevent, and may even increase, the risk of developing food allergy. In order to provide a professional and appropriate response to infants and parents, it is important to know the latest guidelines, based on research from recent years as clinical recommendations have changed over the past few decades.

Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring.

BACKGROUND & AIMS: Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS: We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 µg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS: The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 µg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS: In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.

Crohn's Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is recommended for children with mild to moderate Crohn's disease (CD), but implementation is challenging. We compared EEN with the CD exclusion diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier. METHODS: We performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7 to 12 (stage 2) (n = 40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7 to 12 (n = 38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed; 16S ribosomal RNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 (pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12. RESULTS: Four patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2 ± 2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P = .002; odds ratio for tolerance of CDED and PEN, 13.92; 95% confidence interval [CI] 1.68-115.14). At week 6, 30 (75%) of 40 children given CDED plus PEN were in corticosteroid-free remission vs 20 (59%) of 34 children given EEN (P = .38). At week 12, 28 (75.6%) of 37 children given CDED plus PEN were in corticosteroid-free remission compared with 14 (45.1%) of 31 children given EEN and then PEN (P = .01; odds ratio for remission in children given CDED and PEN, 3.77; CI 1.34-10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria. CONCLUSION: CDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870.

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial.

OBJECTIVES: Growth impairment is common in children with Crohn disease (CD). We aimed to assess the effect of adalimumab (ADL) treatment on linear growth in children with CD in a post-hoc analysis of the Pediatric Crohn's Disease AdalImumab Level-based Optimization Treatment randomized controlled trial. METHODS: Children 6 to 17 years who responded to ADL induction were assessed consecutively for anthropometric parameters. Associations of these parameters with disease characteristics and disease activity were analyzed. RESULTS: Overall, 66 patients completed 72 weeks of follow-up (25% girls, mean age of 15.6 ±â€Š2.5 years). Median (interquartile range [IQR]) height z score improved from -0.6 (-1.6-0.15) at baseline to -0.33 (-1.3-0.5) at week 72 (P = 0.005) with lesser improvement in patients with perianal disease. Similar effect was noted in children with growth potential (boys younger than 16 years, girls younger than 14 years). Median (IQR) height velocity standard deviation was -0.32 (-1.5-0.8) at week 26, and +0.11 (-1.1-1.3) at week 72. Median weight z score increased from -0.54 (-1.2-0.15) to -0.1 (-0.9-0.6), P < 0.001 and body mass index from -0.4 (-1.0-0.5) to 0.0 (-0.8-0.9), P = 0.005. Pediatric CD activity index and erythrocyte sedimentation rate at week 4 correlated negatively with height z score changes (P = 0.043 and P = 0.048, respectively), whereas sustained clinical and biologic remission (week 4-72) were positively associated with changes in height z scores. Significant improvement in linear growth was predicted by lower pediatric CD activity index and erythrocyte sedimentation rate at the end of induction and sustained clinical remission (P = 0.05) and sustained normal C-reactive protein (P = 0.001) at all visits. CONCLUSION: In children with moderate-to-severe CD, ADL treatment had a significant effect on linear growth, with normalization of weight and body mass index (clinicaltrials.gov no: NCT02256462).

Azithromycin and metronidazole versus metronidazole-based therapy for the induction of remission in mild to moderate paediatric Crohn's disease : a randomised controlled trial.

OBJECTIVE: Crohn's disease (CD) pathogenesis associated with dysbiosis and presence of pathobionts in the lumen, intracellular compartments and epithelial biofilms. Azithromycin is active in all three compartments. Our goal was to evaluate if azithromycin-based therapy can improve response and induce remission compared with metronidazole alone in paediatric CD. DESIGN: This blinded randomised controlled trial allocated children 5-18 years with 1012.5 or remission using intention to treat analysis. RESULTS: 73 patients (mean age 13.8±3.1 years) were enrolled, 35 to group 1 and 38 to group 2. Response and remission rates at week 8 were identical 23/35 (66%) in group 1 and 17/38 (45%) and 15/38 (39%) in group 2 (P=0.07 and P=0.025, respectively). The needed to treat for remission was 3.7. Faecal calprotectin declined significantly in group 1 (P=0.003) but not in group 2 (p=0.33), and was lower at week 8 (P=0.052). Additional therapy was required in 6/35(17%) from group 1 versus 16/38(42%) in group 2 (P=0.027) by week 8. Among 12 failures in group 2, open-label azithromycin led to remission in 10/12 (83%). CONCLUSIONS: The combination of azithromycin and metronidazole failed to improve response but was superior for induction of remission and reduction in calprotectin. TRIAL REGISTRATION NUMBER: NCT01596894.

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant.

PURPOSE: This study aimed to characterize the clinical phenotype, genetic basis, and consequent immunological phenotype of a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease, and no evidence of recurrent or severe infections. METHODS: Trio whole-exome sequencing (WES) was utilized for pathogenic variant discovery. Western blot (WB) and immunohistochemical (IHC) staining were used for protein expression analyses. Immunological workup included in vitro T cell studies, flow cytometry, and CyTOF analysis. RESULTS: WES revealed a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene: c.1590C>A; p.Asn530Lys which co-segregated with the disease in the nuclear family. WB and IHC analyses demonstrated reduced protein levels in patient's cells compared with controls. Moreover, comprehensive immunological workup revealed severely diminished blood-borne regulatory T cell (Treg) frequency and impaired in vitro CD4+ T cell proliferation and Treg generation. CyTOF analysis showed significant shifts in the patient's innate and adaptive immune cells compared with healthy controls and ulcerative colitis patients. CONCLUSIONS: Pathogenic variants in CARMIL2 have been implicated in an immunodeficiency syndrome characterized by recurrent infections, occasionally with concurrent chronic diarrhea. We show that CARMIL2-immunodeficiency is associated with significant alterations in the landscape of immune populations in a patient with prominent gastrointestinal disease. This case provides evidence that CARMIL2 should be a candidate gene when diagnosing children with very early onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

Nutritional regulators of intestinal inflammation.

PURPOSE OF REVIEW: Recent knowledge teaches us that food is one of the most important environmental factors affecting our health from disease prevention to cause. Food is one of the key players in the normal gut microenvironment, affecting microbial composition, function, gut barrier and host immunity. This review aims to summarize the current data on food components as regulators of intestinal inflammation, with particular focus on the inflammatory bowel diseases (IBDs). RECENT FINDINGS: We summarize our current understanding on nutrition as possible cause and treatment for IBD and concentrate on several food components that have an anti-inflammatory role on the intestine (vitamin D, butyrate, resveratrol, curcumin). SUMMARY: The proven efficacy of exclusive enteral nutrition to induce remission in children (and recently adults) with Crohn's disease has totally changed the clinical practice. Food components that have an anti-inflammatory role on the intestine (vitamin D, butyrate, resveratrol, curcumin) may now serve as an adjuvant to treatment. While our understanding has expanded in recent years, there remain many aspects of the interactions between nutrition and the gut that remain to be elucidated. Further focused research may lead to advances in understanding of disease pathogenesis and also result in new improved therapeutic interventions.

Transient Exocrine Pancreatic Insufficiency in Children: An Existing Entity?

OBJECTIVES: Pancreatic insufficiency in children is usually associated with diseases such as cystic fibrosis, Shwachman-Diamond syndrome, or chronic pancreatitis. Fecal elastase-1 is a reliable laboratory test for the diagnosis of exocrine pancreatic insufficiency (EPI). Transient pancreatic insufficiency has been rarely described and data on this entity are lacking in the medical literature. In this retrospective study we report 17 cases of transient pancreatic insufficiency presented mainly with failure to thrive and/or diarrhea. METHODS: We followed 43 children (age range 1 month-18 years) with low fecal elastase-1 in our institution between the years 2009 and 2017. We followed growth and laboratory results (particularly, complete blood count, albumin, transaminases, celiac serology, sweat test, and fat-soluble vitamins). Elastase levels <200 mg/g were considered as pancreatic insufficiency. RESULTS: Twenty-six were excluded due to missing data, a comorbidity or being syndromatic. Enrolled children (17) were all otherwise healthy.The median age at diagnosis was 3 years (range 0.2-15 years), 11 girls and 6 boys. Their main presenting symptoms were failure to thrive and/or diarrhea. Median fecal elastase-1 levels were 71 mg/g (range 18-160). Median time for normalization was 6 months (range 1-48 months). Abdominal sonography, celiac serology, and sweat test were normal for all patients. Most patients were treated with pancreatic enzymes until resolution. CONCLUSIONS: Transient EPI without clear etiology should be in the differential diagnosis of EPI after ruling out known etiologies. The resolving course pattern may be attributed to an unidentified infectious agent. Further studies to assess the etiology are mandated.