Anna Löf Granström

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.

The Immune Response of the Human Brain to Abdominal Surgery

Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic‐to‐brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short‐ and long‐term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function.

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.

Maternal Risk Factors and Perinatal Characteristics for Hirschsprung Disease.

BACKGROUND AND OBJECTIVES: Hirschsprung disease (HSCR) is a congenital defect of the enteric nervous system characterized by a lack of ganglion cells in the distal hindgut. The aim of this study was to assess the birth prevalence, perinatal characteristics, and maternal risk factors in HSCR patients in Sweden. METHODS: This was a nationwide, population-based, case-control study of all children born in Sweden between 1982 and 2012 and registered in the Swedish Medical Birth Register. Cases were identified in the Swedish National Patient Register and data on potential maternal risk factors and patient characteristics were collected from the Swedish National Patient Register and the Swedish Medical Birth Register. Five age- and sex-matched controls were randomly selected for each case. The association between studied risk factors and HSCR was analyzed using conditional logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI). RESULTS: The study population comprised 600 HSCR cases and 3000 controls with a male-to-female ratio of 3.7:1. The birth prevalence of HSCR was 1.91/10 000. Maternal obesity was associated with an increased risk for the child to have HSCR (OR 1.74; CI 1.25–2.44). Children with HSCR were born at an earlier gestational age (OR 1.60; CI 1.18–2.17) than control children. Associated malformations were identified in 34.5% of the cases. CONCLUSIONS: This study showed that the Swedish birth prevalence of HSCR was 1.91/10 000. Children with HSCR disease were born at a lower gestational age than controls. Maternal obesity may increase the risk for the child to have HSCR.

Adult outcomes after surgery for Hirschsprung's disease: Evaluation of bowel function and quality of life.

BACKGROUND AND AIMS Hirschsprungs disease (HSCR) is treated surgically. There is a risk for faecal incontinence and constipation postoperatively. The long-term bowel functional outcome in adults and quality of life are sparsely studied. The aim of this study was to assess bowel function and quality of life in patients who had undergone surgery for HSCR during childhood. METHODS All patients treated between 1969 and 1994 at St. Görans Childrens Hospital in Stockholm were invited to participate in the study. After consent, the patients received questionnaires containing general questions, validated questions on bowel function, questions about urinary function, SF-36 health survey (SF-36) and the Gastrointestinal Quality of Life Index (GIQLI). Clinical data were extracted from the case records. Controls matched for sex and age were randomly selected from the National Swedish Population Register. RESULTS 48 of 60 (80%) invited patients responded to the questionnaires. Nine patients were excluded since the HSCR diagnosis could not be confirmed. The median age of the included patients was 28 (20-43) years. Most patients had undergone Soaves operation (73.4%) and two patients had a stoma at the time of follow-up. The bowel function was impaired in the HSCR group compared to controls, especially problems with flatulence, need to strain at defecation and several defecations for emptying. Patients in the HSCR group also had significantly more problems with faecal incontinence than controls. Quality of life according to SF-36 did not differ significantly between patients and controls, but the GIQLI score showed a significantly worse outcome in the HSCR group compared to the controls. CONCLUSION General quality of life in adults treated for HSCR during childhood is comparable to controls. However, they have impaired bowel function and gastrointestinal quality of life.

Laparoscopic-assisted pull-through for Hirschsprung's disease, a prospective repeated evaluation of functional outcome

AIM OF THE STUDY To evaluate the functional outcome of laparoscopic-assisted endorectal pull-through (LAP) for Hirschsprungs disease (HSCR) over time. METHODS Thirty-five children with HSCR underwent laparoscopic-assisted pull-through at our institution between 1998 and 2009. The diagnosis was histologically confirmed in all cases. Clinical data was extracted from the case records. A prospective assessment of the functional outcome was performed in 2009 and 2012. Exclusion criteria were a follow-up of less than 6 months after treatment (1 case) and total colonic aganglionosis (1 case). An independent examiner, not involved in the clinical care of the patients, performed interviews using a semi-structured questionnaire. Four patients could not be traced for the first interview. Two cases were lost for the second interview. Altogether twenty-seven patients completed the study. Data from the two interviews were compared. The regional ethical review board approved the study. MAIN RESULTS The median patient age was 4 years old (range 2-16) at the time of the first interview and 7 years old (range 5-19) at the time of the second interview . There were 23 males and 4 females in the study group. The median age at laparoscopic-assisted pull-through was 104 days old (range 29 days-8 years). In the first interview 11 patients reported constipation, 18 patients reported soiling more frequently than once per week when they had loose stools and 16 patients when they had solid stools. Laxatives or irrigations were used by 13 of the patients. In the second interview 4 patients reported constipation, 16 patients reported soiling when they had loose stools and 15 patients reported soiling when they had solid stools. Eight patients used laxatives or irrigations. The decrease in constipation was statistically significant (p=0,023). CONCLUSIONS Our study shows a statistically significant reduction of constipation over time. There is a high risk of incontinence after laparoscopic-assisted pull-through, with few signs of short-term improvement.

A Nordic multicenter survey of long-term bowel function after transanal endorectal pull-through in 200 patients with rectosigmoid Hirschsprung disease

OBJECTIVE Transanal endorectal pull-through (ERPT) is the most popular technique to treat Hirschsprung disease (HD). Still, there is limited knowledge on long-term bowel function. This cross-sectional, multicenter study assessed long-term bowel function in a large HD population and examined predictors of poor outcome. METHODS Patients older than four years or their parents filled out a validated questionnaire on bowel function. Clinical details were recorded retrospectively from medical records. RESULTS 73/200 (37%) patients reported absolutely no impaired bowel function, meaning no constipation, fecal accidents, stoma, appendicostomy or need for enemas. Seven (4%) had a stoma, and 33 (17%) used antegrade or rectal colonic enemas. Most disarrangements of fecal control and constipation were significantly less common in older age group, but abnormal defecation frequency and social problems remained unchanged. Syndromic patients (n=31) experienced frequent fecal accidents (46%) more often than nonsyndromic (14%, P<0.001). Having a syndrome (adjusted OR 5.6, 95% CI 2.1-15, P=0.001) or a complete transanal ERPT (adjusted OR 2.4, 95% CI 1.1-5.7, P=0.038) was significantly associated with poor outcome defined as having a stoma, an appendicostomy, daily fecal accidents or need of regular rectal wash outs. CONCLUSION A significant number of HD patients experience bowel problems many years after definite surgery. Fecal control was significantly better in older than younger HD patients, but some continued to have considerable bowel problems also as adults. A total transanal ERPT was associated with poorer outcome. Long-term follow-up of HD patients is warranted. Prognosis Study: Level II.

A novel stop mutation in the EDNRB gene in a family with Hirschsprung’s disease associated with Multiple Sclerosis

PURPOSE We identified a girl with Hirschsprungs disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals. METHODS The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed. RESULTS All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS. CONCLUSION We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.

Laparoscopic Repyloromyotomy following Open Pyloromyotomy for Recurrent Pyloric Stenosis: A Case Report and Review of the Literature

Idiopathic hypertrophic pyloric stenosis (IHPS) is the most common cause of projectile nonbilious vomiting during infancy necessitating surgery. Ramstedt first described extramucosal pyloromyotomy to definitively treat IHPS in 1912 and was first performed laparoscopically by Alain et al in 1991.1 Randomized controlled studies comparing laparoscopic pyloromyotomy (LP) with open pyloromyotomy (OP) have demonstrated shorter postoperative recovery time, reduced analgesic use, and improved cosmesis when performed laparoscopically.2 Recurrent IHPS and incomplete pyloromyotomy are rare, and very few reports in the English literature document their management.3–7 Prior case reports describe treatment with an open reoperation or endoscopic dilatation.4 We report a 15-week-old infant with recurrent IHPS who was successfully treated using laparoscopic repyloromyotomy following an open circumumbilical pyloromyotomy 11 weeks earlier.

Hirschsprung disease—Bowel function beyond childhood

Hirschsprung disease is a developmental defect of the enteric nervous system characterized by lack of enteric neurons in the distal hindgut. There are numerous reports on short-term outcomes indicating that impaired bowel function is common. Recently, several controlled studies show that bowel function outcomes are affected beyond childhood, in adolescents and adults, compared with healthy control subjects. Constipation and fecal incontinence are common. The impaired bowel function appears to have a negative impact on quality of life, although, a majority of patients have adapted to their symptoms. On the other hand, Hirschsprung disease seems to have limited impact on education and occupation in adult life. The aim of this review was to summarize current knowledge of bowel function outcome beyond childhood in patients with Hirschsprung disease.