Vincent Biank

Pediatric onset crohn's colitis is characterized by genotype-dependent age-related susceptibility

Background: Pediatric onset Crohns disease (CD) is associated with more colitis and less ileitis compared with adult onset CD. Differences in disease site by age may suggest a different genotype, or different host responses such as decreased ileal susceptibility or increased susceptibility of the colon. Methods: We evaluated 721 pediatric onset CD patients from 3 cohorts with a high allele frequency of NOD2/CARD15 mutations. Children with isolated upper intestinal disease were excluded. The remaining 678 patients were evaluated for interactions between age of onset, NOD2/CARD15, and disease location. Results: We found an age‐related tendency for isolated colitis. Among pediatric onset patients without NOD2/CARD15 mutations, colitis without ileal involvement was significantly more common in first‐decade onset patients (P = 4.57 × 10−5, odds ratio [OR] 2.76, 95% confidence interval [CI] 1.72–4.43). This was not true for colonic disease with ileal involvement (P = 0.35), or for isolated colitis in patients with NOD2/CARD15 mutations (P = 0.61). Analysis of 229 patients with ileal or ileocolonic disease and a NOD2/CARD15 mutation disclosed that ileocolitis was more prevalent through age 10, while isolated ileitis was more prevalent above age 10 (P = 0.016). NOD2/CARD15 mutations were not associated with age of onset. Conclusions: In early‐onset pediatric CD, children with NOD2/CARD15 mutations demonstrate more ileocolitis and less isolated ileitis. Young children without NOD2/CARD15 mutations have an isolated colonic disease distribution, suggesting that this phenotype is associated with genes that lead to a specific phenotype of early‐onset disease. (Inflamm Bowel Dis 2007)

Association of Crohn’s Disease, Thiopurines, and Primary Epstein-Barr Virus Infection with Hemophagocytic Lymphohistiocytosis

OBJECTIVE To assess the incidence of hemophagocytic lymphohistiocytosis (HLH) in a well-defined population of children with inflammatory bowel disease (IBD) and evaluate the common clinical and laboratory characteristics of individuals with IBD who developed HLH. STUDY DESIGN We conducted a retrospective study of all children who developed HLH over an 8-year period. The incidence of HLH in patients with IBD was calculated using US census data and a statewide project examining the epidemiology of pediatric IBD. RESULTS Among children in Wisconsin, 20 cases of HLH occurred during the study period; 5 cases occurred in children with IBD. Common characteristics include: Crohns disease (CD), thiopurine administration, fever lasting more than 5 days, lymphadenopathy, splenomegaly, anemia, lymphopenia, and elevated serum triglycerides and ferritin. Of the patients, 4 had primary Epstein-Barr virus infections. The incidence of HLH among all children in Wisconsin was 1.5 per 100 000 per year. The risk was more than 100-fold greater for children with CD (P < .00001). CONCLUSIONS Pediatric patients with CD are at increased risk for developing HLH; primary Epstein-Barr virus infection and thiopurine administration may be risk factors.

DLG5 R30Q Variant Is a Female-Specific Protective Factor in Pediatric Onset Crohn's Disease

OBJECTIVE:A significant association between the DLG5 variant (R30Q) and inflammatory bowel disease (IBD) has been confirmed in several independent adult IBD cohorts. There is growing evidence that gender significantly influences R30Q susceptibility in Crohns disease (CD). Pediatric onset CD features a significantly lower incidence for female children compared with male children. We, therefore, studied the influence of gender on R30Q susceptibility in an exclusively pediatric onset IBD cohort.DESIGN:A total of 281 CD (181 trios) and 479 population-based controls were genotyped for DLG5 R30Q using Taqman assay. Association was tested by case-control and transmission disequilibrium testing analysis. Multivariate logistic regression was performed to investigate gene–gene and gene–gender interactions, as well as genotype–phenotype correlations.RESULTS:Overall allele frequency for R30Q was 8.5% in CD and 10.3% in controls. Logistic regression showed R30Q had no association with CD (OR 0.81, 95% CI 0.55–1.20, P = 0.3) when the cohort was analyzed as a whole. Stratified by gender, a significant negative association was detected for R30Q in female children (OR 0.39, 95% CI 0.2–0.77, P = 0.006), but not in male children. Gender was found to be an effect modifier of the association between R30Q and CD as the odds ratios in female children and male children differed significantly. The gender-specific association of R30Q and CD was independent of additional CD risk factors such as CARD15 and IBD5.CONCLUSIONS:DLG5 has a gender-specific role in the susceptibility of pediatric CD. Specifically, the significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children.

Identifying youth nonadherence in clinical settings: Data-based recommendations for children and adolescents with inflammatory bowel disease†

Background: To examine the validity of patient self‐report of thiopurine adherence in pediatric inflammatory bowel disease (IBD) against an objective electronic monitoring adherence measure, and to investigate the role of youth and maternal involvement in remembering to take daily medications as predictors of medication adherence. Methods: Fifty‐one youths with IBD, ages 11–18 years, participated. Youths completed questionnaire assessments of their own and their maternal caregivers involvement in remembering to take daily medications at baseline, completed monthly interviews assessing thiopurine adherence over the past week for a period of 6 months, and utilized a Medication Events Monitoring System (MEMS) electronic monitor for their thiopurine medication for 6 months. Participants were grouped into adherent (at least 80% of doses taken based on objective MEMS caps) or nonadherent for analyses. Results: Youths who were nonadherent based on electronic monitoring overestimated their adherence by 23%, whereas adherent youths overestimated their adherence by only 2%, and as such patient self‐report offered little utility in identifying youths who were nonadherent. Youths who reported high levels of involvement in remembering to take their medications were nearly eight times less likely to be nonadherent. Conclusions: The current findings provide evidence that clinicians who work with children and adolescents with IBD may benefit from modifying their approach to nonadherence screening. Asking about youth involvement in remembering daily medications may be more informative than asking them to recall their medication‐taking behavior over the last week in identifying those at highest risk for nonadherence. (Inflamm Bowel Dis 2011;)

Genetic variants in the autophagy pathway contribute to paediatric Crohn’s disease

Massey and Parkes ( Gut 2007; 56 :1489–92) recently highlighted the impact of genome-wide association (GWA) studies in generating new insights into the aetiology of Crohn’s disease (CD). We share their enthusiasm. However, the mechanisms underlying childhood-onset CD remain unknown. Phenotypic differences among children, the increased risk of CD among family members with early-onset disease and the attractive strategy of stratifying cases by age of onset to understand further the genetic architecture of CD all justify studying children with CD in genetic association studies. To this end, we tested 11 genetic variants in our paediatric CD population who were recently identified in predominantly adult-onset (mean age of onset ranging from 24 to 27 years) CD GWA studies.1–6 We studied 555 CD-affected children with the mean age of onset of 11.7 years, and 486 disease-free controls. Individuals were self-identified as …

Role of Nutrition in Pediatric Chronic Liver Disease

The liver plays a central role in energy and nutrient metabolism. Malnutrition is highly prevalent among patients with chronic liver disease and leads to increased morbidity and mortality rates. This review addresses the causes of malnutrition, methods used to assess nutrition status, and appropriate treatment strategies in pediatric patients with chronic liver disease.

Paneth cell defects in Crohn’s disease patients promote dysbiosis

BACKGROUND Paneth cell dysfunction has been implicated in a subset of Crohns disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients. METHODS Pediatric CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18 were recruited prior to routine endoscopic biopsy. Ileal mucosal samples were analyzed for Paneth cell phenotypes, mucosal microbiome composition, and RNA transcriptome. RESULTS The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome. CONCLUSION Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop. FUNDING The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohns and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).

HIDA, percutaneous transhepatic cholecysto-cholangiography and liver biopsy in infants with persistent jaundice: can a combination of PTCC and liver biopsy reduce unnecessary laparotomy?

BackgroundHistorically, HIDA is the initial diagnostic test in the evaluation of biliary atresia (BA). Non-excreting HIDA scans can yield false-positive results leading to negative laparotomy.ObjectiveCholestatic infants must be evaluated promptly to exclude biliary atresia (BA) and other treatable hepatic conditions. Intraoperative cholangiogram (IOC) is the gold standard for diagnosing BA, but requires surgical intervention. Percutaneous transhepatic cholecysto-cholangiography (PTCC) and liver biopsy are less invasive and have been described in small case series. We hypothesized that PTCC and liver biopsy effectively exclude BA, thus avoiding unnecessary IOC.Materials and methodsRetrospective review of cholestatic infants who underwent PTCC, biopsy or cholescintigraphy at a tertiary children’s hospital from August 1998 to January 2009. Group differences were evaluated and the receiver operator curve and safety of PTCC determined.ResultsOne-hundred twenty-eight cholestatic infants were reviewed. Forty-six (36%) underwent PTCC. Forty-one out of 46 (89%) had simultaneous PTCC and liver biopsy. PTCC was completed successfully in 19/23 (83%) children despite a small or absent GB on initial US. Negative laparotomy rate was 1/6 (17%) for simultaneous PTCC/liver biopsy. Complications occurred in 4/46 including bleeding (n = 2), fever with elevated transaminases (n = 1) and oxygen desaturations (n = 1).ConclusionPTCC, particularly when performed in combination with simultaneous liver biopsy, effectively excludes BA in cholestatic infants with acceptable morbidity. PTCC can frequently be performed when a contracted gallbladder is seen on initial US exam. Negative laparotomy rate is lowest when PTCC is coupled with simultaneous liver biopsy.

Successful Treatment of Autoimmune Hepatitis With Methotrexate

492 A utoimmune hepatitis (AIH) is a chronic progressive condition of unknown etiology characterized by interface hepatitis, abnormal levels of serum globulins, and autoantibodies (1). AIH is a relatively common condition in the United States affecting 11% to 23% of patients with chronic liver disease (2). In children, AIH can have an aggressive course leading to cirrhosis and liver failure. Fortunately, AIH is usually responsive to immunosuppressive therapy with biochemical response expected in a minimum of 80% of patients and even higher response rates reported by Gregorio et al (3,4). Traditionally, steroids are the established therapy to induce remission in AIH; however, long-term use of steroids is limited by significant adverse effects including linear growth failure and osteoporosis. As a result, additional immunosuppressants or steroid-sparing agents (SSA) have been used to limit a patient’s exposure to steroids. The most frequently used medication is 6-mercaptopurine (6-MP) or its derivative azathioprine (AZA). Although the majority of patients with respond to the above regimen of induction with steroids and 6-MP/AZA as maintenance therapy (5), there are few data on management of 6-MP/AZA therapeutic failures. Specifically, only a few reports have been published evaluating the efficacy of other immunomodulatory agents for those patients who fail 6-MP/AZA maintenance therapy. Other immunomodulating agents reported include cyclosporine (CSA), mycophenolate mofetil (MMF), and tacrolimus (3); however, to date there are no reports identifying the successful treatment of AIH in the pediatric population with methotrexate (MTX). Accordingly, we report 2 steroid-dependent pediatric patients with AIH, who had sustained remission on MTX.

Respiratory syncytial virus and pediatric liver transplant: one center's experience

Respiratory syncytial virus (RSV) is a ubiquitous virus responsible for acute infections of the respiratory tract in patients of all ages. RSV presents significant health risks to immunocompromised patients. Two patients, 1 before a liver transplant and 1 after a liver transplant, died of a severe RSV infection. Because of the high risk of death, we recommend expanding the criteria for palivizumab prophylaxis to 2 types of patients: (1) patients with chronic liver disease or who have received a liver transplant and are 24 months old or less and (2) transplant recipients with underlying pulmonary conditions who are less than 36 months old. Further research is indicated in pediatric solid-organ transplant centers to evaluate the effective management of RSV infection to prevent morbidity.