Download PDF
Eur J Pediatr Surg 2023; 33(04): 299-309
DOI: 10.1055/a-1889-6355
Original Article

Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study

Michèle Moesch
1   Department of Pediatric Surgery, University Children's Hospital Basel, Basel, BS, Switzerland
,
Jakob Usemann
2   Department of Pediatric Pulmonology, UKBB Ringgold Standard Institution, Basel, BS, Switzerland
,
Elisabeth Bruder
3   Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
,
Philipp Romero
4   Division of Pediatric Surgery, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany
,
Constantin Schwab
5   Institute of Pathology, University Hospital Heidelberg Institute of Pathology Ringgold Standard Institution, Heidelberg, Baden-Württemberg, Germany
,
Beate Niesler
6   Department of Human Molecular Genetics, University Hospital Heidelberg Institute of Human Genetics Ringgold Standard Institution, Heidelberg, Baden-Württemberg, Germany
,
Maria Angeles Tapia-Laliena
7   Department of Pediatric Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Rasul Khasanov
7   Department of Pediatric Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Tauseef Nisar
7   Department of Pediatric Surgery, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
,
Study Group NIG Retro,
Stefan Holland-Cunz
1   Department of Pediatric Surgery, University Children's Hospital Basel, Basel, BS, Switzerland
,
Simone Keck
1   Department of Pediatric Surgery, University Children's Hospital Basel, Basel, BS, Switzerland
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Objective Hirschsprung's disease (HSCR) is a congenital intestinal neurodevelopmental disorder characterized by the absence of enteric ganglion cells in the distal colon. Although Hirschsprung-associated enterocolitis (HAEC) is the most frequent life-threatening complication in HSCR, to date reliable biomarkers predicting the likelihood of HAEC are yet to be established. We established a three-center retrospective study including 104 HSCR patients surgically treated between 1998 and 2019.

Materials and Methods Patient-derived cryopreserved or paraffin-preserved colonic tissue at surgery was analyzed via βIII-tubulin immunohistochemistry. We subsequently determined extrinsic mucosal nerve fiber density in resected rectosigmoid specimens and classified HSCR patients accordingly into nerve fiber-high or fiber-low groups. We compared the distribution of clinical parameters obtained from medical records between the fiber-high (n = 36) and fiber-low (n = 68) patient groups. We assessed the association between fiber phenotype and enterocolitis using univariate and multivariate logistic regression adjusted for age at operation.

Results Enterocolitis was more prevalent in patients with sparse mucosal nerve fiber innervation (fiber-low phenotype, 87%) compared with the fiber-high phenotype (13%; p = 0.002). In addition, patients developing enterocolitis had a younger age at surgery (3 vs. 7 months; p = 0.016). In the univariate analysis, the odds for enterocolitis development in the fiber-low phenotype was 5.26 (95% confidence interval [CI], 1.67–16.59; p = 0.005) and 4.01 (95% CI, 1.22–13.17; p = 0.022) when adjusted for age.

Conclusion Here, we showed that HSCR patients with a low mucosal nerve fiber innervation grade in the distal aganglionic colon have a higher risk of developing HAEC. Consequently, histopathologic analysis of the nerve fiber innervation grade could serve as a novel sensitive prognostic marker associated with the development of enterocolitis in HSCR patients.

Keywords

Hirschsprung-associated enterocolitis - prognostic marker - extrinsic nerve fibers


Publication History

Received: 21 November 2021

Accepted: 23 June 2022

Accepted Manuscript online:
01 July 2022

Article published online:
14 October 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Aboagye J, Goldstein SD, Salazar JH. et al. Age at presentation of common pediatric surgical conditions: reexamining dogma. J Pediatr Surg 2014; 49 (06) 995-999
    CrossrefPubMedGoogle Scholar
  • 2 Martucciello G. Hirschsprung's disease, one of the most difficult diagnoses in pediatric surgery: a review of the problems from clinical practice to the bench. Eur J Pediatr Surg 2008; 18 (03) 140-149
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Szylberg L, Marszałek A. Diagnosis of Hirschsprung's disease with particular emphasis on histopathology. A systematic review of current literature. Prz Gastroenterol 2014; 9 (05) 264-269
    PubMedGoogle Scholar
  • 4 Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung disease. Am J Hum Genet 1990; 46 (03) 568-580
    PubMedGoogle Scholar
  • 5 Langer JC, Durrant AC, de la Torre L. et al. One-stage transanal Soave pullthrough for Hirschsprung disease: a multicenter experience with 141 children. Ann Surg 2003; 238 (04) 569-583 , discussion 583–585
    CrossrefPubMedGoogle Scholar
  • 6 Elhalaby EA, Coran AG, Blane CE, Hirschl RB, Teitelbaum DH. Enterocolitis associated with Hirschsprung's disease: a clinical-radiological characterization based on 168 patients. J Pediatr Surg 1995; 30 (01) 76-83
    CrossrefPubMedGoogle Scholar
  • 7 Frykman PK, Short SS. Hirschsprung-associated enterocolitis: prevention and therapy. Semin Pediatr Surg 2012; 21 (04) 328-335
    CrossrefPubMedGoogle Scholar
  • 8 Demehri FR, Halaweish IF, Coran AG, Teitelbaum DH. Hirschsprung-associated enterocolitis: pathogenesis, treatment and prevention. Pediatr Surg Int 2013; 29 (09) 873-881
    CrossrefPubMedGoogle Scholar
  • 9 Thomas DFM, Fernie DS, Malone M, Bayston R, Spitz L. Association between Clostridium difficile and enterocolitis in Hirschsprung's disease. Lancet 1982; 1 (8263): 78-79
    CrossrefPubMedGoogle Scholar
  • 10 Tang W, Su Y, Yuan C. et al. Prospective study reveals a microbiome signature that predicts the occurrence of post-operative enterocolitis in Hirschsprung disease (HSCR) patients. Gut Microbes 2020; 11 (04) 842-854
    CrossrefPubMedGoogle Scholar
  • 11 Frykman PK, Nordenskjöld A, Kawaguchi A. et al; HAEC Collaborative Research Group (HCRG). Characterization of bacterial and fungal microbiome in children with Hirschsprung disease with and without a history of enterocolitis: a multicenter study. PLoS One 2015; 10 (04) e0124172
    CrossrefPubMedGoogle Scholar
  • 12 Yan Z, Poroyko V, Gu S. et al. Characterization of the intestinal microbiome of Hirschsprung's disease with and without enterocolitis. Biochem Biophys Res Commun 2014; 445 (02) 269-274
    CrossrefPubMedGoogle Scholar
  • 13 Li Y, Poroyko V, Yan Z. et al. Characterization of intestinal microbiomes of Hirschsprung's disease patients with or without enterocolitis using Illumina-MiSeq high-throughput sequencing. PLoS One 2016; 11 (09) e0162079
    CrossrefPubMedGoogle Scholar
  • 14 Yildiz HM, Carlson TL, Goldstein AM, Carrier RL. Mucus barriers to microparticles and microbes are altered in Hirschsprung's disease. Macromol Biosci 2015; 15 (05) 712-718
    CrossrefPubMedGoogle Scholar
  • 15 Nakamura H, Tomuschat C, Coyle D, O'Donnel AM, Lim T, Puri P. Altered goblet cell function in Hirschsprung's disease. Pediatr Surg Int 2018; 34 (02) 121-128
    CrossrefPubMedGoogle Scholar
  • 16 Mattar AF, Coran AG, Teitelbaum DH. MUC-2 mucin production in Hirschsprung's disease: possible association with enterocolitis development. J Pediatr Surg 2003; 38 (03) 417-421 , discussion 417–421
    CrossrefPubMedGoogle Scholar
  • 17 Keck S, Galati-Fournier V, Kym U. et al. Lack of mucosal cholinergic innervation is associated with increased risk of enterocolitis in Hirschsprung's disease. Cell Mol Gastroenterol Hepatol 2021; 12 (02) 507-545
    CrossrefPubMedGoogle Scholar
  • 18 Gosain A, Barlow-Anacker AJ, Erickson CS. et al. Impaired cellular immunity in the murine neural crest conditional deletion of endothelin receptor-B model of Hirschsprung's disease. PLoS One 2015; 10 (06) e0128822
    CrossrefPubMedGoogle Scholar
  • 19 Rusmini M, Griseri P, Lantieri F. et al. Induction of RET dependent and independent pro-inflammatory programs in human peripheral blood mononuclear cells from Hirschsprung patients. PLoS One 2013; 8 (03) e59066
    CrossrefPubMedGoogle Scholar
  • 20 Moore SW, Johnson G, Schneider JW. Elevated tissue immunoglobulins in Hirschsprung's disease–indication of early immunologic response. Eur J Pediatr Surg 2000; 10 (02) 106-110
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Kamijo K, Hiatt RB, Koelle GB. Congenital megacolon; a comparison of the spastic and hypertrophied segments with respect to cholinesterase activities and sensitivities to acetylcholine, DFP and the barium ion. Gastroenterology 1953; 24 (02) 173-185
    CrossrefPubMedGoogle Scholar
  • 22 Moore SW, Johnson G. Acetylcholinesterase in Hirschsprung's disease. Pediatr Surg Int 2005; 21 (04) 255-263
    CrossrefPubMedGoogle Scholar
  • 23 Devroede G, Lamarche J. Functional importance of extrinsic parasympathetic innervation to the distal colon and rectum in man. Gastroenterology 1974; 66 (02) 273-280
    CrossrefPubMedGoogle Scholar
  • 24 Payette RF, Tennyson VM, Pham TD. et al. Origin and morphology of nerve fibers in the aganglionic colon of the lethal spotted (ls/ls) mutant mouse. J Comp Neurol 1987; 257 (02) 237-252
    CrossrefPubMedGoogle Scholar
  • 25 Meier-Ruge W, Hunziker O, Tobler HJ, Walliser C. The pathophysiology of aganglionosis of the entire colon (Zuelzer-Wilson syndrome). Morphometric investigations of the extent of sacral parasympathetic innervation of the circular muscles of the aganglionic colon. Beitr Pathol 1972; 147 (03) 228-236
    CrossrefPubMedGoogle Scholar
  • 26 Kapur RP, Reed RC, Finn LS, Patterson K, Johanson J, Rutledge JC. Calretinin immunohistochemistry versus acetylcholinesterase histochemistry in the evaluation of suction rectal biopsies for Hirschsprung disease. Pediatr Dev Pathol 2009; 12 (01) 6-15
    CrossrefPubMedGoogle Scholar
  • 27 Bruder E, Terracciano LM, Passarge E, Meier-Ruge WA. Enzyme histochemistry of classical and ultrashort Hirschsprung's disease [in German]. Pathologe 2007; 28 (02) 105-112
    PubMedGoogle Scholar
  • 28 Garrett JR, Howard ER, Nixon HH. Histochemical diagnosis of Hirschsprung's disease. Lancet 1969; 2 (7617): 436
    CrossrefPubMedGoogle Scholar
  • 29 Garrett JR, Howard ER, Nixon HH. Bowel innervation in Hirschsprung's disease. BMJ 1969; 3 (5672): 718-719
    CrossrefPubMedGoogle Scholar
  • 30 Borovikova LV, Ivanova S, Zhang M. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000; 405 (6785): 458-462
    CrossrefPubMedGoogle Scholar
  • 31 Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 2006; 131 (04) 1122-1130
    CrossrefPubMedGoogle Scholar
  • 32 Di Giovangiulio M, Bosmans G, Meroni E. et al. Vagotomy affects the development of oral tolerance and increases susceptibility to develop colitis independently of the alpha-7 nicotinic receptor. Mol Med 2016; 22: 464-476
    CrossrefPubMedGoogle Scholar
  • 33 Matteoli G, Gomez-Pinilla PJ, Nemethova A. et al. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 2014; 63 (06) 938-948
    CrossrefPubMedGoogle Scholar
  • 34 Bastida G, Beltrán B. Ulcerative colitis in smokers, non-smokers and ex-smokers. World J Gastroenterol 2011; 17 (22) 2740-2747
    CrossrefPubMedGoogle Scholar
  • 35 Payne SC, Furness JB, Burns O. et al. Anti-inflammatory effects of abdominal vagus nerve stimulation on experimental intestinal inflammation. Front Neurosci 2019; 13: 418
    CrossrefPubMedGoogle Scholar
  • 36 Sinniger V, Pellissier S, Fauvelle F. et al. A 12-month pilot study outcomes of vagus nerve stimulation in Crohn's disease. Neurogastroenterol Motil 2020; 32 (10) e13911
    CrossrefPubMedGoogle Scholar
  • 37 Heuckeroth RO. Nerves make the bowel happy, even when the enteric nervous system is missing!. Cell Mol Gastroenterol Hepatol 2021; 12 (02) 785-786
    CrossrefPubMedGoogle Scholar
  • 38 Müller I, Kym U, Galati V. et al; NIGStudy Group. Cholinergic signaling attenuates pro-inflammatory interleukin-8 response in colonic epithelial cells. Front Immunol 2022; 12: 781147
    CrossrefPubMedGoogle Scholar
  • 39 Chumpitazi BP, Self MM, Czyzewski DI, Cejka S, Swank PR, Shulman RJ. Bristol Stool Form Scale reliability and agreement decreases when determining Rome III stool form designations. Neurogastroenterol Motil 2016; 28 (03) 443-448
    CrossrefPubMedGoogle Scholar
  • 40 Gray JR. What is chronic constipation? Definition and diagnosis. Can J Gastroenterol 2011; 25 (Suppl B): 7B-10B
    CrossrefPubMedGoogle Scholar
  • 41 Elsherbeny M, Abdelhay S. Obstructive complications after pull-through for Hirschsprung's disease: different causes and tailored management. Ann Pediatr Surg 2019; 15: x
    CrossrefPubMedGoogle Scholar
  • 42 Levitt MA, Martin CA, Olesevich M, Bauer CL, Jackson LE, Peña A. Hirschsprung disease and fecal incontinence: diagnostic and management strategies. J Pediatr Surg 2009; 44 (01) 271-277 , discussion 277
    CrossrefPubMedGoogle Scholar
  • 43 Ross E, Munoz FM, Edem B. et al; Brighton Collaboration Failure to Thrive Working Group. Failure to thrive: case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. Vaccine 2017; 35 (48 Pt A): 6483-6491
    CrossrefPubMedGoogle Scholar
  • 44 Batra A, Keys SC, Johnson MJ, Wheeler RA, Beattie RM. Epidemiology, management and outcome of ultrashort bowel syndrome in infancy. Arch Dis Child Fetal Neonatal Ed 2017; 102 (06) F551-F556
    CrossrefPubMedGoogle Scholar
  • 45 Pastor AC, Osman F, Teitelbaum DH, Caty MG, Langer JC. Development of a standardized definition for Hirschsprung's-associated enterocolitis: a Delphi analysis. J Pediatr Surg 2009; 44 (01) 251-256
    CrossrefPubMedGoogle Scholar
  • 46 Meier-Ruge WA, Bruder E. Pathology of chronic constipation in pediatric and adult coloproctology. Pathobiology 2005; 72 (1–2): 1-102
    PubMedGoogle Scholar
  • 47 Swenson O, Bill Jr AH. Resection of rectum and rectosigmoid with preservation of the sphincter for benign spastic lesions producing megacolon; an experimental study. Surgery 1948; 24 (02) 212-220
    PubMedGoogle Scholar
  • 48 Rehbein F, Halsband H. Hirschsprung's disease: Rehbein's intra-abdominal resection technic [in French]. Ann Chir Infant 1970; 11 (01) 92-93
    PubMedGoogle Scholar
  • 49 Duhamel B. New operation for congenital megacolon: retrorectal and transanal lowering of the colon, and its possible application to the treatment of various other malformations [in French]. Presse Med 1956; 64: 2249-2250
    PubMedGoogle Scholar
  • 50 Soave F. A new surgical technique for treatment of Hirschsprung's disease. Surgery 1964; 56: 1007-1014
    PubMedGoogle Scholar
  • 51 De la Torre-Mondragón L, Ortega-Salgado JA. Transanal endorectal pull-through for Hirschsprung's disease. J Pediatr Surg 1998; 33 (08) 1283-1286
    CrossrefPubMedGoogle Scholar
  • 52 Georgeson KE, Cohen RD, Hebra A. et al. Primary laparoscopic-assisted endorectal colon pull-through for Hirschsprung's disease: a new gold standard. Ann Surg 1999; 229 (05) 678-682 , discussion 682–683
    CrossrefPubMedGoogle Scholar
  • 53 Chow CW, Chan WC, Yue PC. Histochemical criteria for the diagnosis of Hirschsprung's disease in rectal suction biopsies by acetylcholinesterase activity. J Pediatr Surg 1977; 12 (05) 675-680
    CrossrefPubMedGoogle Scholar
  • 54 Schofield DE, Devine W, Yunis EJ. Acetylcholinesterase-stained suction rectal biopsies in the diagnosis of Hirschsprung's disease. J Pediatr Gastroenterol Nutr 1990; 11 (02) 221-228
    CrossrefPubMedGoogle Scholar
  • 55 Muller PA, Schneeberger M, Matheis F. et al. Microbiota modulate sympathetic neurons via a gut-brain circuit. Nature 2020; 583 (7816): 441-446
    CrossrefPubMedGoogle Scholar
  • 56 Vincent C, Miller MA, Edens TJ, Mehrotra S, Dewar K, Manges AR. Bloom and bust: intestinal microbiota dynamics in response to hospital exposures and Clostridium difficile colonization or infection. Microbiome 2016; 4: 12
    CrossrefPubMedGoogle Scholar
  • 57 Wiles TJ, Jemielita M, Baker RP. et al. Host gut motility promotes competitive exclusion within a model intestinal microbiota. PLoS Biol 2016; 14 (07) e1002517
    CrossrefPubMedGoogle Scholar
  • 58 Husebye E, Hellström PM, Sundler F, Chen J, Midtvedt T. Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats. Am J Physiol Gastrointest Liver Physiol 2001; 280 (03) G368-G380
    CrossrefPubMedGoogle Scholar
  • 59 Rolig AS, Mittge EK, Ganz J. et al. The enteric nervous system promotes intestinal health by constraining microbiota composition. PLoS Biol 2017; 15 (02) e2000689
    CrossrefPubMedGoogle Scholar
  • 60 Mederer T, Schmitteckert S, Volz J. et al. A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet 2020; 16 (11) e1009106
    CrossrefPubMedGoogle Scholar
  • 61 Amiel J, Sproat-Emison E, Garcia-Barcelo M. et al; Hirschsprung Disease Consortium. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet 2008; 45 (01) 1-14
    CrossrefPubMedGoogle Scholar
  • 62 Tilghman JM, Ling AY, Turner TN. et al. Molecular genetic anatomy and risk profile of Hirschsprung's disease. N Engl J Med 2019; 380 (15) 1421-1432
    CrossrefPubMedGoogle Scholar
  • 63 Haricharan RN, Seo JM, Kelly DR. et al. Older age at diagnosis of Hirschsprung disease decreases risk of postoperative enterocolitis, but resection of additional ganglionated bowel does not. J Pediatr Surg 2008; 43 (06) 1115-1123
    CrossrefPubMedGoogle Scholar
  • 64 Aworanti O, Hung J, McDowell D, Martin I, Quinn F. Are routine dilatations necessary post pull-through surgery for Hirschsprung disease?. Eur J Pediatr Surg 2013; 23 (05) 383-388
    Article in Thieme ConnectPubMedGoogle Scholar
  • 65 Frykman PK, Patel DC, Kim S. et al; HAEC Collaborative Research Group (HCRG). Inflammatory bowel disease serological immune markers anti-saccharomyces cerevisiae mannan antibodies and outer membrane porin C are potential biomarkers for Hirschsprung-associated enterocolitis. J Pediatr Gastroenterol Nutr 2019; 69 (02) 176-181
    CrossrefPubMedGoogle Scholar
  • 66 Dariel A, Grynberg L, Auger M. et al. Analysis of enteric nervous system and intestinal epithelial barrier to predict complications in Hirschsprung's disease. Sci Rep 2020; 10 (01) 21725
    CrossrefPubMedGoogle Scholar
  • 67 El-Sawaf M, Siddiqui S, Mahmoud M, Drongowski R, Teitelbaum DH. Probiotic prophylaxis after pullthrough for Hirschsprung disease to reduce incidence of enterocolitis: a prospective, randomized, double-blind, placebo-controlled, multicenter trial. J Pediatr Surg 2013; 48 (01) 111-117
    CrossrefPubMedGoogle Scholar
  • 68 Melendez E, Goldstein AM, Sagar P, Badizadegan K. Case records of the Massachusetts General Hospital. Case 3-2012. A newborn boy with vomiting, diarrhea, and abdominal distention. N Engl J Med 2012; 366 (04) 361-372
    CrossrefPubMedGoogle Scholar
  • 69 Chumpitazi BP, Fishman SJ, Nurko S. Long-term clinical outcome after botulinum toxin injection in children with nonrelaxing internal anal sphincter. Am J Gastroenterol 2009; 104 (04) 976-983
    CrossrefPubMedGoogle Scholar
  • 70 Takiishi T, Fenero CIM, Câmara NOS. Intestinal barrier and gut microbiota: shaping our immune responses throughout life. Tissue Barriers 2017; 5 (04) e1373208
    CrossrefPubMedGoogle Scholar
  • 71 Medina-Contreras O, Geem D, Laur O. et al. CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice. J Clin Invest 2011; 121 (12) 4787-4795
    CrossrefPubMedGoogle Scholar