Clinical Trial: Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: Identification of Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

Brief Summary:

To identify demographic, clinical, genetic, immunologic and/or microbial (i.e., fecal stream characterization) risk factors that influence the likelihood of development of the HAEC phenotype in children who carry the diagnosis of HD. The newly formed HAEC Collaborative Research Group (HCRG) will utilize the 4 participating centers in the current consortia and recruit additional centers to enroll children diagnosed with Hirschsprung disease.

1a: To recruit 200 patients with Hirschsprung disease without HAEC.

1b: To recruit 200 patients with Hirschsprung disease and HAEC using standardized diagnostic criteria by collaborating with participating members of the HAEC Collaborative Research Group[1].

1c: To collect clinical and demographic information from well-characterized HD patients both with and without HAEC.

1d: To collect samples blood for DNA for genome wide association study (GWAS) by high throughput SNP technology and mutational analysis of known HSCR genes.

1e: To collect serum samples at the time of recruitment in a subset cohort (n=50 HD only, n=50 HD + HAEC) for serological immune markers known for inflammatory bowel disease (IBD) including ANCA, ASCA, OMPC, I2, and CBir1 and any newly identified markers.

1f: To collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora in a subset cohort (n=50 HD only, n=50 HD + HAEC) of children (<18 years).

1g: To establish a Centralized Data Coordinating Center for data collection, data quality and detailed data analyses (CSMC) and tissue bank (

Detailed Summary:

Emerging data suggests that the distinct phenotype of HAEC in children with HD may be the result of the complex interplay between host genetics, immune response and environmental triggers. Data suggest that approximately 20-30 percent of patients with HD develop HAEC. Thus, well-designed, multi-disciplinary investigations of genetic, immune and microbial etiologies of HAEC, with sufficient power to detect differences in disease phenotype are critically needed.

The Hirschsprung Disease clinical phenotype of HAEC:

Hirschsprung disease (HD; also known as congenital aganglionic megacolon) affects 1 in 5000 live births [2]. Surgical repair (excision of the aganglionic colon and pull through of the normally ganglionated intestine to the anal canal) is typically performed in infants with HD during the first few months of life [3, 4]. A subgroup of these children with HD will also develop Hirschsprung associated enterocolitis (HAEC), a potentially severe infection of the small bowel and colon[5]. Children who develop HAEC can present with fever, abdominal distention, explosive diarrhea, vomiting, lethargy, and if not diagnosed and treated promptly, can lead to life threatening sepsis and death. HAEC may occur pre- or post-surgery in HD patients. There have been widely varying reports of HAEC incidence ranging from 15-50% pre-surgery to 2-30% post-surgery. A lack of clear definition of HAEC criteria is at least partially responsible for this significant variation in reported incidence[6, 7]. A standardized definition of HAEC was recently developed and published in 2009[1]. The HAEC score consists of the most important clinical diagnostic criteria for HAEC identified from a group of international experts using the Delphi method. Preliminary validation with case scenarios was achieved and the HAEC score can now be used as a standardi
Sponsor: Cedars-Sinai Medical Center

Current Primary Outcome: To identify genetic associations in HD patients who display HAEC phenotype [ Time Frame: 7 years ]

Rationale & hypothesis:

Currently there is no generally accepted pathogenic hypothesis for Hirschsprung Associated Enterocolitis. A number of hypotheses propose the role of host genetics, host immune responses, and environmental factors such as microbial triggers, including in particular, enteric flora, resulting in disease susceptibility and development. These factors (host immune/inflammatory cells, intestinal epithelia and microbial flora) and their interactions may also be important determinants of disease phenotype and disease progression. Therefore we hypothesize that there are identifiable immunologic, genetic, enteric flora profiles along with clinical risk factors that influence development of HAEC phenotype.



Original Primary Outcome: Same as current

Current Secondary Outcome: To identify immunological markers in HD patients who display HAEC phenotype [ Time Frame: 8 years ]

There is recent evidence that some HD patients who were thought to have refractory HAEC, actually developed IBD. Levin, DN et al. JPGN 2012. This aim is to explore the possibility that there may be similarities between the immune mechanisms involved in HAEC and IBD.


Original Secondary Outcome: Same as current

Information By: Cedars-Sinai Medical Center

Dates:
Date Received: July 9, 2014
Date Started: February 2010
Date Completion: December 2025
Last Updated: August 10, 2016
Last Verified: August 2016