Clinical characteristics and influence of postoperative Hirschsprung-associated enterocolitis: retrospective study at a tertiary children's hospital.

PURPOSE: To explore the influence of postoperative Hirschsprung-associated enterocolitis (post-HAEC) on long-term outcomes and to identify risk factors of post-HAEC. METHODS: The medical records of 304 eligible patients diagnosed with Hirschsprung's disease (HSCR) were reviewed. We analyzed the clinical characteristics of post-HAEC and its influence on long-term outcomes. Furthermore, risk factors for early and recurrent HAEC were identified separately. RESULTS: The overall incidence of post-HAEC was 29.9% (91/304). We categorized early HAEC as occurring within postoperative 3 months (n = 39) and recurrent HAEC as occurring ≥ 3 episodes within postoperative 6 months (n = 25). Patients with early HAEC were more likely to experience worse nutritional status, defecation function, and quality of life compared to those with late or no episodes (P < 0.05). Similarly, the adverse influences of recurrent HAEC on these outcomes were also significant (P < 0.05). The risk factors for early HAEC included preoperative undernutrition, long-segment HSCR, and postoperative Grade 3-4 complications within 30 days. For recurrent HAEC, risk factors were preoperative malnutrition, non-parental caregivers, long-segment HSCR, and postoperative Grade 3-4 complications within 30 days. CONCLUSION: Classification of post-HAEC based on the first episode time and frequency was necessary. The earlier or more frequent episodes of post-HAEC have detrimental influences on long-term outcomes. Furthermore, risk factors for early and recurrent HAEC were different.

Children with Hirschsprung disease exhibited alterations in host-microbial co-metabolism after pull-through operation.

PURPOSE: This study aims to compare the fecal metabolome in post pull-through HD with and without HAEC patients and healthy young children using nuclear magnetic resonance (NMR) spectroscopy. METHODS: Fresh fecal samples were collected from children under 5 years of age in both post-pull-through HD patients and healthy Thai children. A total of 20 fecal samples were then analyzed using NMR spectroscopy. RESULTS: Thirty-four metabolites identified among HD and healthy children younger than 5 years were compared. HD samples demonstrated a significant decrease in acetoin, phenylacetylglutamine, and N-acetylornithine (corrected p value = 0.01, 0.04, and 0.004, respectively). Succinate and xylose significantly decreased in HD with HAEC group compared to HD without HAEC group (corrected p value = 0.04 and 0.02, respectively). Moreover, glutamine and glutamate metabolism, and alanine, aspartate, and glutamate metabolism were the significant pathways involved, with pathway impact 0.42 and 0.50, respectively (corrected p value = 0.02 and 0.04, respectively). CONCLUSION: Differences in class, quantity, and metabolism of protein and other metabolites in young children with HD after pull-through operation were identified. Most of the associated metabolic pathways were correlated with the amino acids metabolism, which is required to maintain intestinal integrity and function.

Impact of Colorectal Nurse Specialist supervised parental administration of rectal washouts on Hirschsprung's disease outcomes: a retrospective review.

PURPOSE: To highlight the utility of Colorectal Nurse Specialist (CNS) supervised parental administration of rectal washouts in the management of Hirschsprung's disease (HD). METHODS: Retrospective case note review of HD patients treated at a tertiary children's hospital in United Kingdom from January 2011 to December 2022. Data collected included demographics, complications, enterocolitis, obstructive symptoms and stomas. Primary pull-through (PT) is done 8-12 weeks after birth. Parental expertise in performing rectal washouts at home is ensured by our CNS team before and after PT. RESULTS: PT was completed in 69 of 74 HD patients. Rectal washouts were attempted on 63 patients before PT. Failure of rectal washout efficacy necessitated a stoma in four patients (6.4%). Of the 65 patients who had PT and stoma closed, three (4.5%) required a further stoma over a mean follow-up period of 57 months (Range 7-144 months). Two of these had intractable diarrhoea due to Total Colonic Aganglionosis (TCA). One patient (1.5%) had unmanageable obstructive symptoms requiring re-diversion. Hirschsprung-associated enterocolitis (HAEC) requiring hospital admission occurred in 14 patients (21%). CONCLUSION: Our stoma rates are lower compared to recent UK data. This could potentially be due to emphasis on parental ability to perform effective rectal washouts at home under CNS supervision.

Prognostic factors of postoperative Hirschsprung-associated enterocolitis: a cohort study.

PURPOSE: To identify prognostic factors of postoperative Hirschsprung-associated enterocolitis (HAEC). METHOD: A retrospective cohort study of Hirschsprung patients between 2006 and 2021 was conducted. Patients with anorectal malformation and non-definitive surgery were excluded. Associated factors for postoperative HAEC were reported with hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Forty-nine patients were excluded due to concurrent anorectal malformation and incomplete data. Of 274 patients, 75 patients (27.4%) had at least one episode of postoperative HAEC. There were 28 patients (37.3%) who had multi-episodes of HAEC. The total episodes of post-operative HAEC in this study were 121 episodes (36.8%). In multivariable survival analysis, significant factors associated with postoperative HAEC were the aganglionic level above sigmoid colon (HR = 3.47, p = 0.023, 95% CI 1.19-10.09), and total colonic aganglionosis (HR = 14.83, p = 0.004, 95% CI 2.33-94.40). The patients who experienced clinical enterocolitis before 2 weeks after surgery significantly developed more postoperative HAEC (HR = 5.32, p = 0.038, % CI 1.09-25.92). The incidence of postoperative HAEC was increase in patients with postoperative obstructive symptoms (48.0%). One patient died due to severe sepsis from postoperative HAEC, while three others required intensive care. CONCLUSIONS: The long involvement of aganglionic segment and early postoperative HAEC was significantly associated with postoperative HAEC. Frequent follow-up, parental education, and early treatment are recommended in these individuals, particularly in the first year after surgery.

Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis.

Despite the significant progress that has been made in terms of understanding the pathophysiology and risk factors of Hirschsprung-associated enterocolitis (HAEC), the morbidity rate has remained unsatisfactorily stable, and clinical management of the condition continues to be challenging. Therefore, in the present literature review, we summarized the up-to-date advances that have been made regarding basic research on the pathogenesis of HAEC. Original articles published between August 2013 and October 2022 were searched in a number of databases, including PubMed, Web of Science, and Scopus. The keywords "Hirschsprung enterocolitis", "Hirschsprung's enterocolitis", "Hirschsprung's-associated enterocolitis", and "Hirschsprung-associated enterocolitis" were selected and reviewed. A total of 50 eligible articles were obtained. The latest findings of these research articles were grouped into gene, microbiome, barrier function, enteric nervous system, and immune state categories. The present review concludes that HAEC is shown to be a multifactorial clinical syndrome. Only deep insights into this syndrome, with an accrual of knowledge in terms of understanding its pathogenesis, will elicit the necessary changes that are required for managing this disease.

Prevalence of Hirschsprung-associated enterocolitis in patients with Hirschsprung disease.

PURPOSE: Hirschsprung's associated enterocolitis (HAEC) is a complication of Hirschsprung's Disease (HD) with considerable morbidity and mortality. The variability in presentation leads to a wide variety of the reported prevalence pre-and postoperatively. This systematic review aimed to clarify the prevalence of HAEC in short-(S-HD), long (L-HD), TCA and the type of operation used. METHODS: A systematic literature-based search for relevant cohorts was performed using Pubmed/Medline, Cochrane Library from its inception to May 2021. Studies reporting on pre-and postoperative enterocolitis, segment length, and surgical procedure (Soave, Swenson, Duhamel) were included. Pooled prevalence and subgroup analysis have been calculated for pre-and postoperative HAEC. RESULTS: 4738 articles were identified from the literature search, among which 57 studies, including 9744 preoperative and 8568 postoperative patients, were included. The groups were sorted by length of the aganglionic segment for further analysis. The pooled prevalence for preoperative HAEC was 18.3% for all types, 15.2% for S-HD and 26.1% for TCA. The pooled prevalence for postoperative HAEC was in total 18.2% for all segment lengths and used techniques. Subgroup analysis showed no significant difference in the occurrence of postoperative enterocolitis between the three techniques. CONCLUSION: The prevalence of preoperative HAEC increases with segment length. However, pooled data suggest that the postoperative risk for developing HAEC, independently of the employed method and segment length, is comparable to the preoperative risk.

High intestinal vascular permeability in a murine model for Hirschsprung's disease: implications for postoperative Hirschsprung-associated enterocolitis.

PURPOSE: Intestinal vascular permeability (VP) in a murine model for Hirschsprung's disease (HD) and postoperative Hirschsprung-associated enterocolitis (HAEC) were investigated. METHODS: Intestinal VP was determined using a Miles assay using 1% Evans blue injected into a superficial temporal vein of newborn endothelin receptor-B KO HD model (KO) and syngeneic wild-type (WT) mice (n = 5, respectively). Extravasated Evans blue in normoganglionic ileum (Ng-I), normoganglionic proximal colon (Ng-PC) and aganglionic distal colon (Ag-DC) was quantified by absorbance at 620 nm. Quantitative polymerase chain reaction (qPCR) for Vascular Endothelial Growth Factor A (VEGF-A), VEGF-B, CDH5, SELE and CD31, and immunofluorescence for CD31 were performed. RESULTS: VP was significantly higher in Ng-I, Ng-PC, and Ag-DC from KO than WT (p < 0.01, p < 0.05, and p < 0.05, respectively). qPCR demonstrated upregulated VEGF-A in Ng-I and Ag-DC, VEGF-B in Ng-I, and SELE in Ng-I and Ng-PC (p < 0.05, p < 0.05, p < 0.05, p < 0.01 and p < 0.05, respectively), and downregulated CDH5 in Ng-I and Ng-PC from KO (p < 0.05, respectively). Expression of CD31 mRNA in Ng-I and Ag-DC from KO was significantly higher on qPCR (p < 0.05) but differences on immunofluorescence were not significant. CONCLUSIONS: VP may be etiologic for postoperative HAEC throughout the intestinal tract even after excision of aganglionic bowel.

Reducing Underdiagnosis of Hirschsprung-Associated Enterocolitis: A Novel Scoring System.

BACKGROUND: Hirschsprung-Associated Enterocolitis (HAEC) is a life-threatening and difficult to diagnose complication of Hirschsprung Disease (HSCR). The goal of this study was to evaluate existing HAEC scoring systems and develop a new scoring system. METHODS: Retrospective, multi-institutional data collection was performed. For each patient, all encounters were analyzed. Data included demographics, symptomatology, laboratory and radiographic findings, and treatments received. A "true" diagnosis of HAEC was defined as receipt of treatment with rectal irrigations, antibiotics, and bowel rest. The Pastor and Frykman scoring systems were evaluated for sensitivity/specificity and univariate and multivariate logistic regression performed to create a new scoring system. RESULTS: Four centers worldwide provided data on 200 patients with 1450 encounters and 369 HAEC episodes. Fifty-seven percent of patients experienced one or more episodes of HAEC. Long-segment colonic disease was associated with a higher risk of HAEC on univariate analysis (OR 1.92, 95% CI 1.43-2.57). Six variables were significantly associated with HAEC on multivariate analysis. Using published diagnostic cutoffs, sensitivity/specificity for existing systems were found to be 38.2%/96% for Pastor's and 56.4%/86.9% for Frykman's score. A new scoring system with a sensitivity/specificity of 67.8%/87.9% was created by stepwise multivariate analysis. The new score outperformed the existing scores by decreasing underdiagnosis in this patient cohort. CONCLUSIONS: Existing scoring systems perform poorly in identifying episodes of HAEC, resulting in significant underdiagnosis. The proposed scoring system may be better at identifying those underdiagnosed in the clinical setting. Head-to-head comparison of HAEC scoring systems using prospective data collection may be beneficial to achieve standardization in the field.

Impact of Botulinum Toxin on Hirschsprung-Associated Enterocolitis After Primary Pull-Through.

BACKGROUND: Hirschsprung-associated enterocolitis (HAEC) is a serious potential complication after primary pull-through surgery for Hirschsprung's disease (HSCR). Administration of anal botulinum toxin (BT) injection may improve obstructive symptoms at the internal anal sphincter, leading to improved fecal passage. The timing of administration and effects on delay or prevention of HAEC are unknown. We hypothesized that BT administration increased the postoperative time to HAEC and aimed to investigate whether anal BT administration after primary pull-through surgery for HSCR is associated with increased time to inpatient HAEC admission development. METHODS: We performed a retrospective cohort study examining children with HSCR at US children's hospitals from 2008 to 2018 using the Pediatric Health Information System database with an associated primary pull-through operation performed before 60 d of age. The intervention assessed was the administration of BT concerning the timing of primary pull-through, and two groups were identified: PRO (received BT at or after primary pull-through, before HAEC) and NOT (never received BT, or received BT after HAEC). The primary outcome was time from pull-through to the first HAEC admission. The Cox proportional hazards model was developed to examine the BT administration effect on the primary outcome after controlling for patient-level covariates. RESULTS: We examined a total of 1439 children (67 in the PRO and 1372 in the NOT groups). A total of 308 (21.4%) developed at least one episode of HAEC, including 76 (5.3%) who had two or more episodes. Between 2008 and 2018, the frequency of BT administration has increased from three to 20 hospitals with a frequency of administration between 2.2% and 16.2%. Prophylactic BT (PRO) was not associated with increased time to HAEC event on adjusted analysis. CONCLUSIONS: Among children with HSCR undergoing primary pull-through surgery, prophylactic BT administration did not demonstrate increased time to first HAEC event. A better-powered study with prophylactic BT is required to determine the effect on HAEC occurrence and timing. LEVEL OF EVIDENCE: Level II (retrospective cohort study).

Predictive factors for the development of postoperative Hirschsprung-associated enterocolitis in children operated during infancy.

PURPOSE: The risk factors for postoperative Hirschsprung-associated enterocolitis (HAEC) are still incompletely understood, especially age at which surgery is performed. Therefore, the aim of this study was to identify the risk factors for the development of postoperative HAEC in children operated during infancy. METHODS: Thirty-five children who had undergone radical surgery for Hirschsprung disease (HD) during infancy were included in the study. They were divided into two groups; those who developed postoperative HAEC (HAEC, 14 patients) and those who did not (no HAEC, 21 patients). Their medical records were retrospectively reviewed for clinical details. RESULTS: Developing postoperative HAEC was significantly associated with long-segment HD (p = 0.020) and the age at radical surgery (p = 0.0241). No other factors had a significant association with postoperative HAEC. In the patients who developed postoperative HAEC (n = 14), those with Trisomy 21 had significantly longer hospitalizations than those without. Patients with long-segment HD had a higher hospitalization rate than those with short-segment HD. CONCLUSION: This study clearly showed that long-segment HD and older age at radical surgery are risk factors for developing postoperative HAEC.

The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling.

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

Does Hirschsprung-Associated Enterocolitis Differ in Children With and Without Down Syndrome?

BACKGROUND: Children with Hirschsprung disease (HD) and Down syndrome (DS) are reported to experience a higher incidence of Hirschsprung-associated enterocolitis (HAEC) than those without DS, although whether their individual episodes are more severe is unknown. METHODS: A single-institution retrospective cohort study was performed on all patients with HD admitted with HAEC between 2009 and 2017. Patients were divided into two groups based on an associated diagnosis of DS, and demographics, clinical characteristics at presentation, and clinical outcomes were compared. RESULTS: Of 86 admissions for HAEC over the study period, 12 (14%) were for patients with DS. Patients admitted with and without DS were similar in terms of age (3.0 versus 2.6 y, P = 0.72), male gender (58% versus 77%, P = 0.17), and proportion with disease proximal to the left colon (9% versus 12%, P = 0.70). Patients admitted with DS were more likely to be tachycardic (75% versus 19%, P ≤ 0.001) and hypotensive (33% versus 7%, P = 0.01) at presentation and presented for treatment after a longer duration of symptoms than those without DS (84 versus 24 h, P = 0.001). Patients admitted with DS were more likely to require intensive care unit admission (58% versus 12%, P = 0.006) and received a longer course of antibiotics (13 d versus 7 d, P = 0.02). The length of stay was similar (6 versus 4 d, P = 0.34). CONCLUSIONS: The results of our study suggest that patients with DS experience more severe episodes of HAEC. Ongoing study is needed to identify preventive strategies to decrease the morbidity of HAEC in children with HD and DS.

Medical alert card: a valuable tool in the management of Hirschsprung's-associated enterocolitis from parental perspective.

PURPOSE: Awareness of Hirschsprung's-associated enterocolitis (HAEC) among patient's families and medical staff can lead to prompt recognition of symptoms and earlier implementation of management. We designed an HAEC medical alert card to raise awareness of HAEC among medical staff and carers of children with Hirschsprung's disease (HD). Our aim was to investigate parental opinion on the utility of this tool. METHODS: All patients diagnosed with HD in two institutions over a period of 14 years received an HAEC alert card and were invited to answer a 1-year follow-up structured questionnaire. RESULTS: A total of 123 patients received an HAEC card. The response rate for the follow-up questionnaire was 62% (n = 76). The majority 96% (n = 73) of the responders considered the card useful. A total of 89% (n = 68) of patients or parents stated that they carry the card with them, while 39% (n = 30) of them have used it on 57 occasions. The majority (83%; n = 25) of these declared that, when presented, the card increased awareness among medical staff and on 53% (n = 16) occasions prompted contact with the tertiary centre. CONCLUSION: The HAEC medical card was found useful by most parents of HD patients. This tool increased awareness of HAEC and improved communication between peripheral hospitals and tertiary paediatric institutions. Therefore, we feel the HAEC alert card may be used in institutions with high HD addressability.

Probiotics for the prevention of Hirschsprung-associated enterocolitis: a systematic review and meta-analysis.

BACKGROUND/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung's disease. HAEC is reported to occur in 6-50% of patients preoperatively and in 2-35% postoperatively. The exact cause of HAEC is not fully understood, but disturbances of intestinal microbiota have recently been reported in patients with HAEC. In recent years, the administration of probiotics has been proposed to reduce the incidence of HAEC. We conducted a systematic review and meta-analysis to determine the effect of probiotics on postoperative HAEC. METHODS: A systematic literature search for relevant articles was performed in four databases using the combinations of following terms "probiotics", "microbiota", "enterocolitis", "Lactobacillus", "Bifidobacterium", "Saccharomyces", "Streptococcus", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 2002 and 2017. The relevant cohorts of the effect of probiotics in postoperative patients were systematically searched for clinical outcomes. Odds ratio (OR) or standard mean difference (SMD) with 95% confidence intervals (CI) were calculated using standardized statistical methodology. RESULTS: The search strategy identified 1274 reports. Overall, five studies met defined inclusion criteria, reporting a total of 198 patients. Two studies were prospective multicenter randomized control trials. Lactobacillus, Bifidobacterium, Streptococcus, and Enterococcus were used as probiotics. The incidence of HAEC with/without probiotics was 22.6 and 30.5%, respectively, but this was not statistically different (OR 0.72; 95% CI 0.37-1.39; P = 0.33). CONCLUSION: This study shows that the administration of probiotics was not associated with a significant reduction in the risk of HAEC. Additional studies are required to understand more fully the role of microbiota and complex interactions that cause HAEC. With increasing knowledge of the role of microbiota in HAEC, we are likely to understand better the potential benefits of probiotics in this disease.

Inflammatory bowel disease in patients with Hirschsprung's disease: a systematic review and meta-analysis.

AIM AND OBJECTIVES: Hirschsprung-associated enterocolitis (HAEC) continues to be an important cause of morbidity in patients with Hirschsprung's disease (HSCR). HAEC can occur at any time during the course of the disease. The reported incidence of HAEC before surgery ranges from 6 to 50%, and after surgery, it ranges from 2 to 35%. HAEC and inflammatory bowel disease (IBD) have similar clinical presentation including diarrhea, hematochezia, and abdominal pain. In recent years, isolated cases of IBD have been reported in patients who had surgical treatment for HSCR. The exact pathogenesis of HAEC or IBD is not known. However, both conditions are characterized by an abnormal intestinal mucosal barrier function, which may be a common pathway. The purpose of this meta-analysis was to determine the clinical presentation and outcome in patients with HSCR who developed IBD after pull-through operation. MATERIALS AND METHODS: A systematic literature search for relevant articles was performed in four databases using the combinations of the following terms "inflammatory bowel disease", "Crohn/Crohn's disease", "ulcerative colitis", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 1990 and 2017. The relevant cohorts of HSCR associated with IBD were systematically searched for clinical presentation and outcomes. RESULTS: 14 studies met defined inclusion criteria, reporting a total of 66 patients who had HSCR associated with IBD. Mean age at first operation for HSCR was 5.8 months, mean age at diagnosis of IBD was 7.7 years, and the majority of patients were male (73%). The extent of aganglionosis was total colonic aganglionosis in 41% of patients, long segment in 45%, and rectosigmoid in 14%. The majority of patients underwent a Duhamel procedure (84%) for HSCR. The distribution of IBD was Crohn's disease in 72.3% of patients, ulcerative colitis in 16.9%, and others in 10.8%. Eight articles (47 patients) reported about HAEC, and 22 patients (47%) had experienced HAEC after surgery for HSCR. CONCLUSION: Male patients with extensive colonic aganglionosis who continue to suffer from postoperative HAEC after a Duhamel procedure are more susceptible to develop IBD. Recognition of IBD may be important in the long-term follow-up of HSCR patients who have had postoperative HAEC.

Guidelines for the diagnosis and management of Hirschsprung-associated enterocolitis.

BACKGROUND: Patients 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. METHODS: The 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). RESULTS: Guidelines 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. CONCLUSIONS: Clear, 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 EVIDENCE: V.

Guidelines for the management of postoperative obstructive symptoms in children with Hirschsprung disease.

Although most children with Hirschsprung disease ultimately do well, many experience a variety of ongoing problems after pull-through surgery. The most common include obstructive symptoms, soiling, enterocolitis and failure to thrive. The purpose of this guideline is to present a rational approach to the management of postoperative obstructive symptoms in children with Hirschsprung disease. The 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 causes, methods of diagnosis, and treatment approaches to children with obstructive symptoms following pull-through for Hirschsprung disease. Causes of obstructive symptoms post-pull-through include mechanical obstruction; persistent or acquired aganglionosis, hypoganglionosis, or transition zone pull-through; internal sphincter achalasia; disordered motility in the proximal intestine that contains ganglion cells; or functional megacolon caused by stool-holding behavior. An algorithm for the diagnosis and management of obstructive symptoms after a pull-through for Hirschsprung disease is presented. A stepwise, logical approach to the diagnosis and management of patients experiencing obstructive symptoms following pull-through for Hirschsprung disease can facilitate treatment. Level of evidence V.

Altered expression of IL36γ and IL36 receptor (IL1RL2) in the colon of patients with Hirschsprung's disease.

PURPOSE: Hirschsprung's disease associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in Hirschsprung's disease (HSCR). Altered intestinal epithelial barrier function and abnormal microbiota are implicated in the pathogenesis of HAEC. IL-36γ, a member of the IL-1 superfamily, is involved in host defense and contributes to proinflammatory responses and development of inflammatory diseases. The IL36 receptor (IL1RL2) is an important mediator molecule in the inflammatory response. Animal data suggests that IL1RL2 is involved in mucosal healing. We designed this study to investigate the hypothesis that the IL-36γ axis is altered in HSCR. METHODS: We investigated IL-36γ and IL1RL2 expression in ganglionic and aganglionic bowel of HSCR patients (n = 10) and controls (n = 10). qPCR, Western blotting and confocal immunofluorescence were performed. MAIN RESULTS: qPCR and Western blot analysis revealed that IL-36γ is strongly expressed in the aganglionic and ganglionic colon of patients with HSCR. ILR1L2 expression was significantly decreased in HSCR specimens compared to controls (p < 0.05). Confocal microscopy revealed a markedly increased expression of IL36γ in the colonic epithelium of patients with HSCR compared to controls. IL1RL2 was localized in the colonic epithelium and showed a markedly decreased expression in all HSCR specimens. CONCLUSION: To our knowledge, we report for the first time the expression of IL36γ and ILRL2 in the colon of patients with HSCR. The increased expression of IL36γ and the markedly decreased expression of IL1RL2 in the aganglionic and ganglionic bowel in HSCR may result in an increased inflammatory response and altered mucosal response healing leading to the susceptibility to develop HAEC.

Increased Act1/IL-17R expression in Hirschsprung's disease.

PURPOSE: Hirschsprung's disease -associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in Hirschsprung's disease (HSCR). Altered intestinal epithelial barrier function is implicated in the pathogenesis of HAEC. IL-17 is a proinflammatory cytokine that plays a crucial role in host defense against microbial organisms in the development of inflammatory diseases. Act1 is an essential adaptor molecule required for the IL-17-mediated inflammatory responses via interaction with IL-17 receptor (IL-17R). We designed this study to investigate the hypothesis that Act1/Il-17R expression is upregulated in HSCR. METHODS: We investigated Act1 and IL17R expression in ganglionic andaganglionic bowel of HD patients (n = 10) and controls (n = 10). qPCR, Western blotting and confocal immunofluorescence were performed. MAIN RESULTS: qPCR and Western blot analysis revealed that Act1 and IL17R are strongly expressed in the aganglionic and ganglionic colon of patients with HSCR. Act1 and IL17R expression was significantly increased in HSCR specimens compared to controls (p < 0.05). Confocal microscopy revealed a markedly increased expression of Act1 and IL17R in the colonic epithelium of patients with HSCR compared to controls. CONCLUSION: To our knowledge, we report, for the first time, the expression of Act1 in the human colon. The increased expression of Act1 and Il-17 in the aganglionic and ganglionic bowel in HSCR may result in IL-17-mediated increased inflammatory response leading to the development of HAEC.