The Role of the Mind-Body Connection in Children with Food Reactions and Identified Adversity: Implications for Integrating Stress Management and Resilience Strategies in Clinical Practice.

Child adversity is often associated with poor quality of life in pediatric gastrointestinal disorders, including non-allergic food reactions (food intolerances), which may be improved using mind-body interventions. We conducted an observational study to (1) describe child adversity (stressors) and resilience factors in children with food intolerances, and (2) explore the association between stressors and self-reported use of integrative modalities. A retrospective chart review of children ≥4-years-old presenting to a pediatric food intolerances clinic from 2017 to 2020 was performed (n = 130). Use of integrative medicine at intake, demographic, illness, and social history data were collected. Qualitative analysis identified exposure to stressors and resilience strategies. Correlation was assessed using a chi-square test. Management of the medical condition was the most common stressor, indicating impact on quality of life. Resilience strategies included themes of self-coping and social support. Individuals with one or more stressors were more likely to be using an integrative modality (most commonly, mind-body interventions) prior to their visit (X2 = 8.1, p = 0.004). Our hypothesis-generating study suggests that screening for child adversity and integrative medicine use may be used to better address quality of life and personalized approaches to treat pediatric food intolerances.

Enterococci enhance Clostridioides difficile pathogenesis.

Enteric pathogens are exposed to a dynamic polymicrobial environment in the gastrointestinal tract1. This microbial community has been shown to be important during infection, but there are few examples illustrating how microbial interactions can influence the virulence of invading pathogens2. Here we show that expansion of a group of antibiotic-resistant, opportunistic pathogens in the gut-the enterococci-enhances the fitness and pathogenesis of Clostridioides difficile. Through a parallel process of nutrient restriction and cross-feeding, enterococci shape the metabolic environment in the gut and reprogramme 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. We find evidence of microbial interaction between these two pathogenic organisms in multiple mouse models of infection and patients infected with C. difficile. These findings provide mechanistic insights into the role of pathogenic microbiota in the susceptibility to and the severity of C. difficile infection.

Multi-omic Analysis of the Interaction between Clostridioides difficile Infection and Pediatric Inflammatory Bowel Disease.

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.

Dynamics of the Stool Virome in Very Early-Onset Inflammatory Bowel Disease.

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.

Development and Pilot Testing of a Coping Kit for Parents of Hospitalized Children.

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.

Integrative Nutrition for Pediatrics.

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.

The inflammatory phenotype of the fibrous plate is distinct from the liver and correlates with clinical outcome in biliary atresia.

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.

Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial.

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.

Intrahepatic biliary anomalies in a patient with Mowat-Wilson syndrome uncover a role for the zinc finger homeobox gene zfhx1b in vertebrate biliary development.

BACKGROUND: zfhz1b is the causative gene for Mowat-Wilson syndrome, in which patients demonstrate developmental delay and Hirschsprung disease, as well as other anomalies. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Our studies underscore the importance of genetic contributions in the etiology of infantile hepatobiliary disorders, including biliary atresia.

Use of complementary and alternative medicine in pediatric chronic viral hepatitis.

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: how medical complications and therapies impact outcome.

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.

Recent advances in biliary atresia: prospects for novel therapies.

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.

Successful revision of portoenterostomy in an infant with 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.

Live virus immunization after orthotopic liver transplantation.

Viral infection is a recognized and potentially serious complication in children following solid organ transplantation. The risks of viral infection are particularly important for infants who may not have completed standard childhood immunizations at the time of transplantation and are therefore at risk for otherwise preventable infections. The general practice of withholding live virus immunization from transplant recipients has been questioned and several small studies have looked at MMR and/or Varivax administration in children following transplantation. This retrospective study analyzes the response to primary MMR and varicella immunization in selected pediatric liver transplant recipients in the largest such study to date. Nineteen of 26 children (73%) developed serologic immunity for measles following MMR (although 18 required multiple doses). Similarly, varicella immunization resulted in seroconversion in 20 of 31 children (64.5%; seven required multiple doses). Only minor adverse effects reported in the general population were observed. Live virus immunization with MMR and Varivax was safe and immunogenic in this selected population of liver transplant recipients.

Does "cystic" biliary atresia represent a distinct clinical and etiological subgroup? A series of three cases.

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.