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Inflammatory Bowel Disease Serological Immune Markers Anti-Saccharomyces cerevisiae Mannan Antibodies and Outer Membrane Porin C are Potential Biomarkers for Hirschsprung-associated Enterocolitis

Frykman, Philip K.*; Patel, Deven C.*; Kim, Sungjin; Cheng, Zhi*; Wester, Tomas‡,§; Nordenskjöld, Agneta‡,§; Kawaguchi, Akemi||; Hui, Thomas T.; Ehrlich, Peter F.#; Granström, Anna L.‡,§; Benliyan, Filip** for the HAEC Collaborative Research Group (HCRG)

Journal of Pediatric Gastroenterology and Nutrition: August 2019 - Volume 69 - Issue 2 - p 176–181
doi: 10.1097/MPG.0000000000002358
Original Articles: Gastroenterology: Inflammatory Bowel Disease

Objective: Hirschsprung-associated enterocolitis (HAEC) is the most frequent complication in Hirschsprung disease (HSCR) patients. Currently HAEC is diagnosed clinically, leaving uncertainty in the diagnosis thereby potentially leading to over- or undertreatment of patients. The aim of this study was to identify immune biomarkers to aid in the diagnosis of HAEC.

Methods: From 2012 to 2017, 43 children with HSCR enrolled in a multicenter study, underwent retrospective evaluation of their medical records, and questionnaire-directed parent interviews. HAEC status was determined using HAEC score with cutoff ≥4. Plasma was collected and analyzed by ELISA for the inflammatory bowel disease–associated antibodies: anti-Saccharomyces cerevisiae mannan antibodies (ASCA), outer membrane porin C (OmpC), CBir1, antineutrophil cytoplasmic antibodies. Data were analyzed using t test, univariate, multivariable, and binomial regression models.

Results: Eighteen patients had at least 1 episode of HAEC, 25 had no history of HAEC. The HAEC and NO HAEC groups had similar median ages (3 years) and family histories of HSCR. The HAEC group showed markedly elevated ASCA IgA and OmpC antibody levels compared with the NO HAEC group, whereas CBir1 and antineutrophil cytoplasmic antibodies were similar between the groups. Both univariate and multivariable analysis revealed higher OmpC antibody levels associated with HAEC (odds ratio 1.39, confidence interval 1–1.92, P = 0.048), whereas univariate analysis identified a trend toward elevated IgA and immunoglobulin G ASCA levels with HAEC.

Conclusions: We identified elevated OmpC and ASCA serum antibody levels in HAEC patients, and that increased OmpC antibody levels correlated with HAEC occurrence, suggesting HAEC and Crohn disease share gut microbial-host immune responses. These antibodies may serve as potential biomarkers for HAEC, although prospective study with larger sample size is needed.

*Division of Pediatric Surgery, Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center

Biostatistics and Bioinformatics Research Center at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA

Department of Pediatric Surgery, Astrid Lindgren's Children's Hospital, Karolinska University Hospital

§Department of Women's and Children's Health, Center of Molecular Medicine-CMM, Karolinska Institutet, Stockholm, Sweden

||Department of Pediatric Surgery, University of Texas Health Science Center Houston, Houston, TX

Division of Pediatric Surgery, UCSF Benioff Children's Hospital Oakland, Oakland, CA

#Division of Pediatric Surgery, C.S. Mott Children's Hospital, University of Michigan, Ann Arbor, MI

**F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Address correspondence and reprint requests to Philip K. Frykman, MD, PhD, Pacific Coast Pediatric Surgery, A Professional Corporation, 2190 Lynn Rd, Suite 200, Thousand Oaks, CA 91360 (e-mail:

Received 24 September, 2018

Accepted 22 March, 2019 registration number: NCT02193685: “Identification of Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children with Hirschsprung Disease.”

The study was supported by National Institutes of Health grants to P.K.F.: DK090281, DK104040 and the Lippey Family Fund for Pediatric Surgery Research at CSMC.

The authors report no conflicts of interest.

© 2019 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,