Philip K. Frykman

Hirschsprung-associated enterocolitis: prevention and therapy

Hirschsprung-associated enterocolitis remains the greatest cause of morbidity and mortality in children with Hirschsprung disease. This chapter details the various approaches used to treat and prevent this disease process. This includes prevention of complications, such as stricture formation, prophylaxis with rectal washouts, and identification of high-risk individuals. The chapter also details approaches to diagnose Hirschsprung-associated enterocolitis as well as to exclude other etiologies.

Characterization of bacterial and fungal microbiome in children with Hirschsprung disease with and without a history of enterocolitis: A multicenter study

Development of potentially life-threatening enterocolitis is the most frequent complication in children with Hirschsprung disease (HSCR), even after definitive corrective surgery. Intestinal microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to compare the fecal bacterial and fungal communities of children who developed Hirschsprung-associated enterocolitis (HAEC) with HSCR patients who had never had enterocolitis. Eighteen Hirschsprung patients who had completed definitive surgery were enrolled: 9 had a history of HAEC and 9 did not. Fecal DNA was isolated and 16S and ITS-1 regions sequenced using Next Generation Sequencing and data analysis for species identification. The HAEC group bacterial composition showed a modest reduction in Firmicutes and Verrucomicrobia with increased Bacteroidetes and Proteobacteria compared with the HSCR group. In contrast, the fecal fungi composition of the HAEC group showed marked reduction in diversity with increased Candida sp., and reduced Malassezia and Saccharomyces sp. compared with the HSCR group. The most striking finding within the HAEC group is that the Candida genus segregated into “high burden” patients with 97.8% C. albicans and 2.2% C. tropicalis compared with “low burden” patients 26.8% C. albicans and 73% C. tropicalis. Interestingly even the low burden HAEC group had altered Candida community structure with just two species compared to more diverse Candida populations in the HSCR patients. This is the first study to identify Candida sp. as potentially playing a role in HAEC either as expanded commensal species as a consequence of enterocolitis (or treatment), or possibly as pathobioants contributing to the pathogenesis of HAEC. These findings suggest a dysbiosis in the gut microbial ecosystem of HAEC patients, such that there may be dominance of fungi and bacteria predisposing patients to development of HAEC.

Advances in Hirschsprung Disease Genetics and Treatment Strategies: An Update for the Primary Care Pediatrician

Hirschsprung disease (HSCR) is a multigenic condition with variable presentation. Most commonly, it presents in the neonatal period as a functional intestinal obstruction secondary to failure of caudal migration of the enteric nervous system. Classically, this manifests as dilated proximal bowel and constricted distal bowel with absent ganglia and hypertrophic nerve trunks. When recognized early, medical and surgical therapies can be instituted to minimize associated morbidity and mortality. This article reviews current understanding of the etiology of HSCR, its multigenic associations, the historical evolution of HSCR diagnosis and treatment, and current HSCR therapies.

Murine model of Hirschsprung-associated enterocolitis. I: Phenotypic characterization with development of a histopathologic grading system

PURPOSE The aim of the study was to characterize enterocolitis in the Ednrb-null (Ednrb-/-) mouse with aganglionosis of the colon and to develop and validate a semiquantitative histopathologic grading system to assess enterocolitis. METHODS We isolated colon and ileal specimens of Ednrb-/- and control mice (Ednrb+/+) and performed histochemical staining (H&E) on tissue sections. After establishing inflammation grading criteria, 2 blinded pathologists independently assessed the severity and depth of inflammation of proximal colon segments on 2 separate occasions. Interclass correlations (ICCs) and coefficient of variation (CV) were calculated to determine interrater and intrarater agreement. We then prospectively applied the enterocolitis grading system to Ednrb-/- mice that became clinically ill. A cohort of Ednrb-/- mice were observed until they developed clinical illness, at which time they were euthanized and had multiple organ homogenates cultured for bacteria, and colon and small bowel were histopathologically graded for enterocolitis. Spearmans rank correlations comparing enterocolitis scores with level of bacteremia were performed. RESULTS Intra- and interrater ICCs of the histologic scoring system were satisfactory (0.61 and 0.94, respectively), as were intra- and interrater CVs (18% and 9%, respectively). Of the Ednrb-/- mice, 65% developed bacteremia. Those with bacteremia had significantly higher enterocolitis scores than those without bacteremia (P < .01). Ednrb-/- mice that developed bacteremia showed a strong positive correlation between total enterocolitis scores and number of bacterial colony forming units in peritoneal lavage, liver, kidney, and aerobic spleen. CONCLUSIONS The Ednrb-/- mouse with aganglionosis develops enterocolitis and has features similar to Hirschsprung-associated enterocolitis in humans. Our grading system is a reliable way to assess enterocolitis. By performing microsurgical pull-through, we can now perform controlled, hypothesis-driven, mechanistic studies to evaluate etiologic factors affecting enterocolitis in the Ednrb-/- mouse.

Altered fecal short chain fatty acid composition in children with a history of Hirschsprung-associated enterocolitis

PURPOSE Children with Hirschsprung disease (HD) who have a history of enterocolitis (HAEC) have a shift in colonic microbiota, many of which are necessary for short chain fatty acid (SCFA) production. As SCFAs play a critical role in colonic mucosal preservation, we hypothesized that fecal SCFA composition is altered in children with HAEC. METHODS A multicenter study enrolled 18 HD children, abstracting for history of feeding, antibiotic/probiotic use, and enterocolitis symptoms. HAEC status was determined per Pastor et al. criteria (12). Fresh feces were collected for microbial community analysis via 16S sequencing as well as SCFA analysis by gas chromatography-mass spectrometry. RESULTS Nine patients had a history of HAEC, and nine had never had HAEC. Fecal samples from HAEC children showed a 4-fold decline in total SCFA concentration vs. non-HAEC HD patients. We then compared the relative composition of individual SCFAs and found reduced acetate and increased butyrate in HAEC children. Finally, we measured relative abundance of SCFA-producing fecal microbiota. Interestingly, 10 of 12 butyrate-producing genera as well as 3 of 4 acetate-producing genera demonstrated multi-fold expansion. CONCLUSION Children with HAEC history have reduced fecal SCFAs and altered SCFA profile. These findings suggest a complex interplay between the colonic metabolome and changes in microbiota, which may influence the pathogenesis of HAEC.

Late onset of necrotizing enterocolitis in the full-term infant is associated with increased mortality: Results from a two-center analysis

PURPOSE The effect of timing of onset of necrotizing enterocolitis (NEC) on outcomes has not been determined for the full-term infant. In this study we aimed to characterize the full-term NEC population and to evaluate onset of NEC. METHODS We performed a two-center retrospective review of all full-term infants (≥ 37weeks) with a diagnosis of NEC between 1990 and 2012. Patients were identified by ICD-9 and age. Early onset for NEC was ≤7days and late onset after 7days of life. Demographics, comorbidities, maternal factors, clinical factors, surgical intervention, complications, and mortality were evaluated. Wilcoxons test was performed on continuous variables and Fishers exact test on categorical data. A p-value<0.05 was considered significant. Univariate outcomes with a p-value<0.1 were selected for multivariable analysis. RESULTS Thirty-nine patients (24 boys, 15 girls) with median EGA of 39weeks were identified. Overall mortality was 18%. Univariate predictors of mortality included congenital heart disease and placement of an umbilical artery (UA) catheter. Multivariate analysis revealed late onset of NEC to be an independent predictor of mortality (OR 90.8, 95% CI 2.6-3121). CONCLUSION Full-term infants who develop NEC after 7days of life, have congenital heart disease, and/or need UA catheterization have increased mortality.

Murine model of Hirschsprung-associated enterocolitis II: Surgical correction of aganglionosis does not eliminate enterocolitis

BACKGROUND Hirschsprung disease (HD) results from aganglionosis of the colon, is linked to acute and chronic enterocolitis (known as Hirschsprung-associated enterocolitis) despite successful corrective surgery, and can lead to bacteremia and even death. The genetic and molecular mechanisms underlying these disorders are largely unknown. METHODS We developed a microsurgical corrective pull-through procedure in mice, and applied that to Ednrb(-/-) mice, which manifest aganglionic megacolon that is very similar to HD. Wild-type littermates (Ednrb(+/+)) also underwent identical surgery. At prespecified time points postoperatively, mice were sacrificed, and histopathologic analyses of intestinal inflammation were performed. Mice of both genotypes were sacrificed after the postoperative recovery period to determine if corrective surgery itself caused inflammation. Stooling patterns were assessed as well to determine if intestinal function normalized after surgery. RESULTS There was no difference in histopathological enterocolitis scores after recovery from surgery. Stooling patterns in Ednrb(-/-) and Ednrb(+/+) mice were similar postoperatively, suggesting normalization of intestinal function. However, with time, approximately 40% of Ednrb(-/-) mice developed clinical illness consistent with enterocolitis. No control (Ednrb(+/+)) mice developed clinical enterocolitis. Histopathological enterocolitis scores in the 40% of Ednrb(-/-) mice that developed clinical enterocolitis postoperatively were significantly worse than those of healthy postoperative Ednrb(-/-) mice. In contrast, none of the Ednrb(+/+) control mice exhibited postoperative long-term inflammation. CONCLUSIONS Microsurgical pull-through operation in Ednrb(-/-) mice produces a mouse model that closely resembles key features of Hirschsprung-associated enterocolitis, enabling controlled study of genetic and molecular mechanisms in Ednrb(-/-) mice and other genotypes that produce similar phenotypes.

Laparoscopic Versus Open Treatment of Congenital Duodenal Obstruction: Multicenter Short-Term Outcomes Analysis

BACKGROUND Laparoscopic repair of congenital duodenal obstruction has become popularized over the past decade. Comparative data on outcomes, however, are sparse. We hypothesized that laparoscopic repair of congenital duodenal obstruction could be performed with similar outcomes to traditional open repair. PATIENTS AND METHODS Medical records for all cases of congenital duodenal obstruction from 2005 to 2011 at three academic teaching hospitals were retrospectively reviewed. Patients were excluded from the analysis if they had confounding surgical diseases, did not have duodenoduodenostomy during the first hospital admission, had the repair performed before transfer from a referring hospital, or weighed less than 1.7  kg at the time of surgery. Analysis was performed as intention to treat, with laparoscopic converted to open cases included in the laparoscopic group. RESULTS Sixty-four cases were included in the analysis (44 open, 20 laparoscopic). Baseline characteristics were similar between the two groups with the exception that the open group, on average, underwent repair later than the laparoscopic group (6 days versus 4 days, respectively). Seven laparoscopic cases were converted to an open procedure (35%), most commonly for difficulty in exposing the decompressed distal duodenum. Laparoscopic repair did take significantly longer than open repair (145 minutes versus 96 minutes, respectively), but clinical outcomes were similar. Complications were rare and were similar between methods of repair. Two patients in the laparoscopic group required subsequent open revision. CONCLUSIONS Laparoscopic duodenoduodenostomy for congenital duodenal obstruction is a technically challenging procedure with a steep learning curve. Despite a relatively high conversion rate, clinical outcomes remained similar to the traditional open repair in selected patients.

Distinct phenotypes of children with perianal perforating Crohn's disease ☆

PURPOSE Perianal perforating disease (PF) has been reported in approximately 15% of children with Crohns disease (CD). It is unknown whether children who present with PF at the time of diagnosis have a different course than those that develop PF while on therapy. METHODS From a prospective, single institution observational registry of children diagnosed with CD, we identified children with perianal perforating CD, defined as perianal abscesses and/or fistulae. Patients who presented with perianal perforating CD (PF-CD0) were compared to those who developed perianal perforating CD (PF-CD1) after initial diagnosis. RESULTS Thirty-eight of 215 (18%) children with CD had PF-CD during a median follow up of 4.5 years. Patients with PF-CD0 (n=26) tended to be more likely male (81% vs. 50%, p=0.07) and younger (9.3 yrs vs. 12.5 yrs, p=0.02). PF-CD1 (n=12) patients were more likely to require diverting ileostomy (42% vs. 8%, p=0.02) and colectomy (33% vs. 4%, p=0.03). Multivariable analysis predicted increased rate of diverting ileostomy in the PF-CD1 group (p=0.007, OR 19.1, 95% CI 1.6-234.8). CONCLUSION Pediatric CD patients who develop PF while on therapy for CD have a more severe phenotype and are more likely to require diverting ileostomy or colectomy compared to those who present with PF-CD.

Guidelines for the diagnosis and management of Hirschsprung-associated enterocolitis

BackgroundPatients with Hirschsprung disease are at risk for Hirschsprung-associated enterocolitis (HAEC), an inflammatory disorder of the bowel that represents the leading cause of serious morbidity and death in these patients. The diagnosis of HAEC is made based on clinical signs and symptoms which are often non-specific, making it difficult to establish a definitive diagnosis in many patients. The purpose of this guideline is to present a rational, expert-based approach to the diagnosis and management of HAEC.MethodsThe American Pediatric Surgical Association Board of Governors established a Hirschsprung Disease Interest Group. Group discussions, literature review, and expert consensus were then used to summarize the current state of knowledge regarding diagnosis, management, and prevention of Hirschsprung-associated enterocolitis (HAEC).ResultsGuidelines for the diagnosis of HAEC and its clinical grade, utilizing clinical history, physical examination findings, and radiographic findings, are presented. Treatment guidelines, including patient disposition, diet, antibiotics, rectal irrigations and surgery, are presented.ConclusionsClear, standardized definitions of Hirschsprung-associated enterocolitis and its treatment are lacking in the literature. This guideline serves as a first step toward standardization of diagnosis and management.Level of evidenceV.