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Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract(1). This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence virulence of invading pathogens(2). Here, we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut, the enterococci, enhances fitness and pathogenesis of C. difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogram C. difficile metabolism. Enterococci provide fermentable amino acids, including leucine and ornithine, which increase C. difficile fitness in the antibiotic perturbed gut. Parallel depletion of arginine by enterococci through arginine catabolism provides a metabolic cue for C. difficile that facilitates increased virulence. Evidence of microbial interaction between these two pathogenic organisms is observed in multiple mouse models of infection and C. difficile-infected patients. These findings provide mechanistic insights into the role that pathogenic microbiota have in susceptibility to and severity of C. difficile infection.

Background and Aims Dysbiosis of the gut microbiota is a well-known correlate of the pathogenesis of inflammatory bowel disease [IBD]. However, few studies have examined the microbiome in very early-onset [VEO] IBD, which is defined as onset of IBD before 6 years of age. Here we focus on the viral portion of the microbiome—the virome—to assess possible viral associations with disease processes, reasoning that any viruses potentially associated with IBD might grow more robustly in younger subjects, and so be more detectable. Methods Virus-like particles [VLPs] were purified from stool samples collected from patients with VEO-IBD [n = 54] and healthy controls [n = 23], and characterized by DNA and RNA sequencing and VLP particle counts. Results The total number of VLPs was not significantly different between VEO-IBD and healthy controls. For bacterial viruses, the VEO-IBD subjects were found to have a higher ratio of Caudovirales vs to Microviridae compared to healthy controls. An increase in Caudovirales was also associated with immunosuppressive therapy. For viruses infecting human cells, Anelloviridae showed higher prevalence in VEO-IBD compared to healthy controls. Within the VEO-IBD group, higher levels of Anelloviridae DNA were also positively associated with immunosuppressive treatment. To search for new viruses, short sequences enriched in VEO-IBD samples were identified, and some could be validated in an independent cohort, although none was clearly viral; this provides sequence tags to interrogate in future studies. Conclusions These data thus document perturbations to normal viral populations associated with VEO-IBD, and provide a biomarker—Anelloviridae DNA levels—potentially useful for reporting the effectiveness of immunosuppression.

Food is essential for life. Yet, poor food choices may cause poor health. Dietary manipulation is frequently integrated into the management of common chronic pediatric conditions. Parents seek dietary information to have more control over child's condition and to avoid side effects of medicine. This article reviews selected diets for a few common pediatric disorders including eczema, attention deficit hyperactivity disorder, headache and migraine, non-celiac gluten sensitivity, and irritable bowel syndrome.

Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Summary Children with inflammatory bowel diseases (IBD) are particularly vulnerable to infection with Clostridioides difficile (CDI). IBD and IBD + CDI have overlapping symptoms but respond to distinctive treatments, highlighting the need for diagnostic biomarkers. Here, we studied pediatric patients with IBD and IBD + CDI, comparing longitudinal data on the gut microbiome, metabolome, and other measures. The microbiome is dysbiotic and heterogeneous in both disease states, but the metabolome reveals disease-specific patterns. The IBD group shows increased concentrations of markers of inflammation and tissue damage compared with healthy controls, and metabolic changes associate with susceptibility to CDI. In IBD + CDI, we detect both metabolites associated with inflammation/tissue damage and fermentation products produced by C. difficile. The most discriminating metabolite found is isocaproyltaurine, a covalent conjugate of a distinctive C. difficile fermentation product (isocaproate) and an amino acid associated with tissue damage (taurine), which may be useful as a joint marker of the two disease processes.

Objective Serious pediatric illness places great stress on families. Parents who learn coping skills may better manage these stressors. This study sought to develop and refine a stress coping intervention for parents of hospitalized children, assess the intervention acceptability among these parents, and gather preliminary data on stress, negative and positive affect, anxiety, depression, and self-efficacy. Methods We conducted an observational study in 2 phases, enrolling parents of children who were inpatients with serious illness, 10 in Phase 1 and 40 in Phase 2. All parents completed at baseline measures of stress and psychological well-being and were introduced to the Coping Kit for Parents. Follow-up interviews were conducted at 1 week (all parents) and 1 month (Phase 2 parents only) regarding the acceptability of the intervention. Results At baseline, parents reported that stressful situations were frequent (mean = 30.6, standard deviation [SD] = 6.8) and difficult (mean = 26.2, SD = 7.1) and revealed elevated levels of negative affect (mean = 27.3, SD = 7.7), depression (mean = 8.5, SD = 3.7), and anxiety (mean = 11.3, SD = 3.1) and moderate levels of self-efficacy related to their child's illness (mean = 3.3, SD = 0.5). The majority of parents used the kit regularly and on a scale of 1 to 7 agreed that the kit was helpful (mean = 6.0, SD = 0.9), interesting (mean = 5.7, SD = 1.3), practical (mean = 5.7, SD = 1.4), enjoyable (mean = 6.0, SD = 1.3), and they would recommend it to other parents (mean = 6.4, SD = 0.9). Conclusions The Coping Kit for Parents is an acceptable stress management intervention that could be made available to parents of children with serious illness at pediatric hospitals with minimal staff training or time commitment.

Multiple studies confirm complementary and alternative medicine (CAM), or integrative therapy use is common among children with IBD. Pediatric prevalence rates are compatible with or exceed CAM use in adult IBD. Surveys indicate that biologically based therapies are the most frequently utilized modality among the pediatric IBD population. Concurrent use of biologically based CAM, such as herbals and supplements, and prescription medication is common and may cause untoward drug interactions. In this chapter, we review the available evidence for the safety and efficacy of the most commonly used biologically based therapies in IBD. Clinicians ought to appreciate the prevalence of CAM utilization in the pediatric IBD population, parent’s receptivity toward these modalities as adjuvant therapies, and the reticence to disclose utilization. We suggest that the maintenance of a cursory level of understanding and awareness of CAM modalities, including knowledge of efficacy, interactions, and contraindications, are essential to ensure patient safety.

zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies.We identified a patient with Mowat-Wilson syndrome who also developed cholestasis and histopathologic features consistent with biliary atresia, suggesting that mutations involving zfhz1b may lead to biliary developmental anomalies or injury to the biliary tract. We used the zebrafish model system to determine whether zfhx1b has a role in vertebrate biliary development.Using zebrafish we determined that zfhx1b was expressed in the developing liver during biliary growth and remodeling, and that morpholino antisense oligonucleotide-mediated knockdown of zfhx1b led to defects in biliary development. These findings were associated with decreased expression of vhnf1, a transcription factor known to be important in biliary development in zebrafish and in mammals.Our studies underscore the importance of genetic contributions in the etiology of infantile hepatobiliary disorders, including biliary atresia.

Objective: The objectives of the present study were to assess the prevalence, frequency and type of complementary and alternative medicine (CAM) used by children with chronic viral hepatitis infection, and to determine correlates of use and estimates of nondisclosure regarding CAM use. Patients and Methods: In this cross-sectional pilot study, families of 68 children receiving care for chronic viral hepatitis at a tertiary medical center were administered a survey regarding use of CAM. Results: Forty-six percent of these families reported using CAM for their child at least once since diagnosis with chronic viral hepatitis and 31% used CAM monthly or more frequently. Of all of the CAM therapies, biologically based products such as herbals and dietary supplements were used most often. Use of CAM was independently associated with the current or previous use of antiviral medications for viral hepatitis, parent's use of CAM, and child having a nonliver comorbidity. Rates of physician nondisclosure regarding CAM use were >60%. Conclusions: This is the first report of CAM use in children with chronic viral hepatitis. Use of CAM in this population is common, and despite published adult reports, there is infrequent dialogue between patients and pediatric health care providers regarding use of CAM.

Biliary atresia (BA) is a progressive fibro-obliterative disease of the extrahepatic biliary tree that presents with biliary obstruction in the neonatal period. Untreated, BA is a uniformly fatal disease and, yet, even with our existing therapies, at least 50% of children with BA will undergo liver transplantation by the age of 2 years. Current treatment strategies are, at best, palliative; they focus on prompt diagnosis, supportive nutritional care and interventions for sequelae. The purpose of this article is to discuss the current treatment paradigm for BA and to assess the impact these strategies have on outcomes. As more children with BA survive into adulthood with their native liver, it is important to understand which factors predict good and poor outcomes.

Biliary atresia is an inflammatory cholangiopathy of still undetermined etiology. Correlations between histologic findings and clinical outcome in this disease have largely been based on evaluation of liver parenchyma. This study aimed to characterize the pattern of inflammation within the biliary remnant and identify associations between the type and degree of inflammation and clinical outcome as reflected by the transplant-free interval. The inflammation within the fibrous plates and livers of 41 patients with biliary atresia was characterized using immunohistochemical markers and the cell populations were digitally quantified. The type and quantity of cells within the infiltrate were then correlated with length of time from Kasai portoenterostomy until transplant. Histologic and immunohistochemical features of the biliary remnant allowed stratification of patients into "inflammatory plate" and "fibrotic plate" groups. Overall there was no significant difference in transplant-free interval between the two cohorts; however, there was a trend towards a longer time to transplant among patients in the "fibrotic plate" group. In addition, the composition of the inflammatory infiltrate in the fibrous plate was distinctly different from that present in the liver and only the characteristics of the inflammation in the fibrous plate, in particular the number of Foxp3+ T regulatory lymphocytes correlated with clinical outcome. The results of this study support the view of the extra-hepatic biliary tree as the primary site of injury in BA with the changes seen in the liver as secondary manifestations of outflow obstruction. The association between specific inflammatory cell subtypes within the fibrous plate and the length of transplant-free interval also supports the role of the immune system in the initial process of bile duct damage in biliary atresia.

We present a case report of a boy with biliary atresia who, after hepatoportoenterostomy performed on day 21 of life, had immediate resolution of cholestasis and remained anicteric until 3.5 months of age. He then abruptly developed acholic stools. Nuclear medicine imaging study showed no excretion. Broad-spectrum antibiotics and corticosteroids were administered but did not lead to clinical improvement; a surgical revision of the original anastomosis was undertaken at 4 months of age. At 14 months of age, the child is anicteric and growing well. In this case, successful revision of hepatoportoenterostomy averted the need for liver transplantation.

Objectives To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life. Study design Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB Results Fifty percent (68/137) of infants had TB P P P P P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P P Conclusions Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB Trial registration ClinicalTrials.gov: NCT00061828 and NCT00294684.

Identification of children with hepatitis B or hepatitis C requires a heightened awareness of whom to screen, and which tests to obtain. Recent recommendations for hepatitis B case identification include screening of any person born in an area of the world where the prevalence exceeds 2%, or children born in the USA to parents who have emigrated from endemic regions. Chronic hepatitis B is a life-long disease that requires monitoring that is best managed as a partnership between the primary practitioner and the specialist. Vaccination is the best method of preventing hepatitis B transmission and titer measurement post-vaccination is recommended for close contacts. Like hepatitis B, hepatitis C in childhood frequently is undetected without knowing whom to screen. The best method of testing for hepatitis C is determination of antibody (anti-HCV). Children in whom HCV RNA is detected by PCR should be referred for consideration of treatment. Quantitative hepatitis C RNA and genotype testing are helpful in making treatment decisions and determining the likelihood of treatment response. Social aspects of both hepatitis B and C are essential areas of discussion for the practitioner, who should address alcohol use, illicit drugs, and sexual transmission. Family members of children with hepatitis B or hepatitis C should undergo appropriate testing and teaching about strategies to reduce transmission within the home. Children with hepatitis B or hepatitis C should not be excluded from school or extracurricular activities. Universal precautions that should already be in place in these settings are sufficient.

Background: Biliary atresia (BA) is a progressive fibro-obliterative disease of the extrahepatic biliary tree that presents with biliary obstruction before 2 months of age. Untreated BA is a uniformly fatal disease and even with our current therapies only 50% of children with BA will be transplant-free by 2 years of age. Despite descriptions of this disorder dating back to the 1800s our current therapies are palliative. They focus on prompt diagnosis, supportive nutritional care and interventions for sequelae. Objective: To present the literature supporting current treatment strategies and potential future therapies. Method: Each of the aspects of care is described and the literature about nuances of care is provided. Conclusion: Therapies will not improve outcomes until novel treatments are introduced, such as those suggested, which may intervene in the inflammatory or fibrotic steps of the disease process.

We describe a unique series of 3 cases of biliary atresia (BA) associated with a choledochal cyst. All 3 children presented with jaundice at birth and had no other abnormalities. Although these children had a fetal form of BA, their presentation and outcome differed from those of biliary atresia splenic malformation syndrome (BASM), the well-described form of early onset BA. Unlike those with BASM, these children had no other associated malformations, had a normal birth weight, and did not yet require a liver transplant. We believe that the present series of patients and their associated pathology may represent a distinct phenotype with a common, prenatally acquired etiology that is different from other fetal forms of BA, such as BASM, and from patients who present with the classic perinatal form of BA.

Importance Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome. Objective To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver. Design, Setting, and Patients The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013. Interventions Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy. Main Outcomes and Measures The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events. Results The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, −10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group ( P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P = .008). Conclusions and Relevance Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia. Trial Registration clinicaltrials.gov Identifier:NCT00294684