Probiotics for treatment of chronic constipation in children.

BACKGROUND: Functional constipation is defined as chronic constipation with no identifiable underlying cause. It is a significant cause of morbidity in children, accounting for up to 25% of visits to paediatric gastroenterologists. Probiotic preparations may sufficiently alter the gut microbiome and promote normal gut physiology in a way that helps relieve functional constipation. Several studies have sought to address this hypothesis, as well as the role of probiotics in other functional gut disorders. Therefore, it is important to have a focused review to assess the evidence to date. OBJECTIVES: To evaluate the efficacy and safety of probiotics for the management of chronic constipation without a physical explanation in children. SEARCH METHODS: On 28 June 2021, we searched CENTRAL, MEDLINE, Embase, CINAHL, AMED, WHO ICTR, and ClinicalTrials.gov, with no language, date, publication status, or document type limitations. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed probiotic preparations (including synbiotics) compared to placebo, no treatment or any other interventional preparation in people aged between 0 and 18 years old with a diagnosis of functional constipation according to consensus criteria (such as Rome IV). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 14 studies (1127 randomised participants): 12 studies assessed probiotics in the treatment of functional constipation, whilst two studies investigated synbiotic preparations. Three studies compared probiotics to placebo in relation to the frequency of defecation at study end, but we did not pool them as there was very significant unexplained heterogeneity. Four studies compared probiotics to placebo in relation to treatment success. There may be no difference in global improvement/treatment success (RR 1.29, 95% CI 0.73 to 2.26; 313 participants; low-certainty evidence). Five studies compared probiotics to placebo in relation to withdrawals due to adverse events, with the pooled effect suggesting there may be no difference (RR 0.64, 95% CI 0.21 to 1.95; 357 participants; low-certainty evidence). The pooled estimate from three studies that compared probiotics plus an osmotic laxative to osmotic laxative alone found there may be no difference in frequency of defecation (MD -0.01, 95% CI -0.57 to 0.56; 268 participants; low-certainty evidence). Two studies compared probiotics plus an osmotic laxative to osmotic laxative alone in relation to global improvement/treatment success, and found there may be no difference between the treatments (RR 0.95, 95% CI 0.79 to 1.15; 139 participants; low-certainty evidence). Three studies compared probiotics plus osmotic laxative to osmotic laxative alone in relation to withdrawals due to adverse events, but it is unclear if there is a difference between them (RR 2.86, 95% CI 0.12 to 68.35; 268 participants; very low-certainty evidence). Two studies compared probiotics versus magnesium oxide. It is unclear if there is a difference in frequency of defecation (MD 0.28, 95% CI -0.58 to 1.14; 36 participants), treatment success (RR 1.08, 95% CI 0.74 to 1.57; 36 participants) or withdrawals due to adverse events (RR 0.50, 95% CI 0.05 to 5.04; 77 participants). The certainty of the evidence is very low for these outcomes. One study assessed the role of a synbiotic preparation in comparison to placebo. There may be higher treatment success in favour of synbiotics compared to placebo (RR 2.32, 95% CI 1.54 to 3.47; 155 participants; low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. One study assessed a synbiotic plus paraffin compared to paraffin alone. It is uncertain if there is a difference in frequency of defecation (MD 0.74, 95% CI -0.96, 2.44; 66 participants; very low-certainty evidence), or treatment success (RR 0.91, 95% CI 0.71 to 1.17; 66 participants; very low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. One study compared a synbiotic preparation to paraffin. It is uncertain if there is a difference in frequency of defecation (MD -1.53, 95% CI -3.00, -0.06; 60 participants; very low-certainty evidence) or in treatment success (RR 0.86, 95% CI 0.65, 1.13; 60 participants; very low-certainty evidence). The study reported that there were no withdrawals due to adverse effects in either group. All secondary outcomes were either not reported or reported in a way that did not allow for analysis. AUTHORS' CONCLUSIONS: There is insufficient evidence to conclude whether probiotics are efficacious in successfully treating chronic constipation without a physical explanation in children or changing the frequency of defecation, or whether there is a difference in withdrawals due to adverse events when compared with placebo. There is limited evidence from one study to suggest a synbiotic preparation may be more likely than placebo to lead to treatment success, with no difference in withdrawals due to adverse events. There is insufficient evidence to draw efficacy or safety conclusions about the use of probiotics in combination with or in comparison to any of the other interventions reported. The majority of the studies that presented data on serious adverse events reported that no events occurred. Two studies did not report this outcome. Future studies are needed to confirm efficacy, but the research community requires guidance on the best context for probiotics in such studies, considering where they should be best considered in a potential treatment hierarchy and should align with core outcome sets to support future interpretation of findings.

Prevalence of Functional Gastrointestinal Disorders in Children and Adolescents: Comparison Between Rome III and Rome IV Criteria.

OBJECTIVES: To assess the prevalence of functional gastrointestinal disorders (FGIDs) in children using Rome IV criteria and to compare the prevalence of FGIDs using Rome IV with Rome III criteria. STUDY DESIGN: This was a cross-sectional study using the same methods as our previous study on FGIDs in Colombia. The Questionnaire of Pediatric Gastrointestinal Symptoms Rome IV version was translated into Spanish, followed by reverse translation. Terms were adjusted to children's language by using focus groups of children. School children aged 8-18 years completed the Spanish version of the Questionnaire of Pediatric Gastrointestinal Symptoms Rome IV. Data were compared with Rome III data. RESULTS: In total, there were 3567 children (from 6 cities): 1071 preadolescents (8-12 years) and 2496 adolescents (13-18 years). Average age 13.7 ± 2.4 years (56.5% girls). A total of 21.2% of children had at least 1 FGID. Prevalence was significantly lower than Rome III (P = .004). Similar to Rome III, disorders of defecation were the most common, followed by abdominal pain, and disorders of nausea and vomiting. Prevalence of abdominal migraine decreased (P = .000) and functional dyspepsia increased (P = .000). The new diagnoses functional vomiting and functional nausea were present in 0.7% of all children. CONCLUSIONS: The application of the Rome IV criteria resulted in a significantly lower prevalence of FGIDs; however, the relative frequency of each subgroup of disorders did not change. New diagnoses of the Rome IV criteria were present in a small percentage of children.

Does surgical approach matter in the treatment of pediatric ulcerative colitis?

BACKGROUND: This study aims to compare the morbidity of open versus laparoscopic colectomy or proctocolectomy for pediatric patients with ulcerative colitis (UC) using national readmission outcomes. MATERIALS AND METHODS: The 2010-2014 Nationwide Readmissions Database was used to identify patients < 18 years (excluding newborns) who underwent colectomy or proctocolectomy for UC. Patients with planned readmissions for staged procedures were excluded from readmission analysis. Demographics, hospital factors, and outcomes were compared by operative approach (open vs. laparoscopic) using standard statistical analysis. Results were weighted for national estimates. RESULTS: There were 1922 patients (51% female, age 13 ± 3 years) with UC who underwent colectomy or proctocolectomy during index admission. Most cases were performed open (54%) and as elective admissions (64%). Compared to open approach, laparoscopy was associated with shorter index hospital length of stay (8 [5-17] days vs. 9 [6-18] days, p = 0.015), fewer surgical site infections (< 2% vs. 2%, p = 0.022), and less post-operative gastrointestinal dysfunction (5% vs. 8%, p = 0.008). After stratifying to control for elective and unplanned index admissions, laparoscopic approach was associated with fewer small bowel obstructions during index hospitalizations in both elective (9% vs. 15%, p = 0.003) and unplanned (5% vs. 16%, p<0.001) settings. Readmission for surgical site infection was also less common following laparoscopic approach in both elective (0% vs. 7%, p = 0.008) and unplanned (0% vs. < 7%, p = 0.017) settings. CONCLUSIONS: In pediatric patients with ulcerative colitis, laparoscopic colectomy or proctocolectomy is associated with shorter hospital length of stay, less post-operative complications, and improved readmission outcomes.

Disparities in utilization of laparoscopic colectomies in pediatric Crohn's disease✰.

PURPOSE: Pediatric patients with Crohn's disease often require colectomies. The laparoscopic approach is considered safe, but there is little national data on outcomes and readmissions in this population. METHODS: The Nationwide Readmissions Database was queried from 2010 to 2014 for patients ≤ 18 years who underwent colectomy for Crohn's disease during index admission. Patients were stratified by operative approach: laparoscopic versus open. Outcomes were compared with standard statistical methods. RESULTS: There were 2833 patients (47% female) who underwent a colectomy via laparoscopic (58%) vs. open (42%) approach. Index admissions were elective 55% of the time. Most operations were right hemicolectomy (86%), followed by total colectomy (8%). Of the study population, 489 (17%) were diverted with an ostomy. Readmission rates at 30 days and 1 year were 9% and 18%, respectively. The most common diagnoses at readmission were intra-abdominal infection (16%), small bowel obstruction (16%), and surgical site infection (9%). Laparoscopy was more commonly performed during elective admissions (63% vs. 44%), for patient with private insurance (72% vs. 39%), and for patients in the highest income quartile (66% vs. 48% in the lowest income quartile), all p<0.001. Length of stay was longer on index admission for open colectomy (8[5-12] days vs. 6[4-11] days, p<0.001), while cost was similar ($17,754[$12,375-$30,625] vs. $17,017[$11,219-$27,336], p = 0.104). There were no differences in readmission rate, intraabdominal infection or small bowel obstruction. CONCLUSION: In pediatric patients, laparoscopic colectomy for Crohn's disease is safe and is associated with shorter hospitalization and equivalent hospital costs compared to the open procedure. Socioeconomic disparities in laparoscopic utilization exist and warrant future investigation. LEVEL OF EVIDENCE: Level III.

Re-evaluating Blood Markers as Predictors of Outcome in Multivisceral and Intestinal Transplantation.

BACKGROUND: Multivisceral transplant (MVTx) and isolated intestinal transplant (ITx) are complex surgical procedures. The subsequent proinflammatory state in the immediate postoperative period makes interpretation of blood markers difficult. METHOD: We aimed to establish the course of various blood markers after MVTx/ITx, and to evaluate their use as diagnostic markers of complications. This was a single center prospective cohort. We analyzed blood markers collected preoperatively, on alternate days for the first postoperative week, and then weekly for 4 weeks. This study was in compliance with The Declaration of Helsinki. RESULTS: Over a 16-month period (July 2017-October 2018), 20 subjects aged 2 to 67 years with a median age of 24.5 years received MVTx/ITx. Twelve recipients (60%) had an infection. Neutrophil lymphocyte count ratio (NLCR) was higher than established upper limits of normal, regardless of infection status. NLCR and white blood cell count were useful to identify infected MVTx/ITx recipients, with P values <.05 for 2 and 1 of 7 time points post transplant, respectively. Higher preoperative eosinophil% predicted future acute cellular rejection (P value .023). CONCLUSIONS: This is the first study to extensively track the course of blood markers post MVTx/ITx and identified NLCR and white blood cell count as potential diagnostic blood markers of infection.

Prophylactic colectomy for children with familial adenomatous polyposis: resource utilization and outcomes for open and laparoscopic surgery.

BACKGROUND: Laparoscopic approach for the surgical management of familial adenomatous polyposis (FAP) has become increasingly common for pediatric patients. The purpose of this study was to compare short-term outcomes and resource utilization between open and laparoscopic surgery for prophylactic colectomy in children with FAP. METHODS: The Kids' Inpatient Database (2009 and 2012) was analyzed for children (age ≤20 years) with FAP that underwent prophylactic total colectomy or proctocolectomy. Patient demographics, treating hospital characteristics, hospital charges, and short-term outcomes were compared according to the surgical technique utilized (open versus laparoscopic). RESULTS: Overall, we identified 216 patients with FAP that underwent elective total colectomy, of which 95 cases were performed by open surgery and 121 were done laparoscopically. The majority of patients were treated at large, not-for-profit, urban teaching hospitals, and the median age was equal (16 years) in both groups. Complications that were more common for open procedures included accidental perforation or hemorrhage (4% vs. 0%, P=0.023), reopening of surgical site (3% vs. 0%, P=0.049), and pneumonia (3% vs. 0%, P=0.049). Simultaneous proctectomy was performed more commonly in the open cohort (91% vs. 71%, P<0.001) as well as ileostomy creation (74% vs. 49%, P<0.001). The median length of stay was similar in the open and laparoscopic groups (7 vs. 6 days, P=0.712). Median total hospital charges were also similar ($67,334 vs. $68,717, P=0.080). CONCLUSIONS: A laparoscopic approach for prophylactic colectomy can be safely performed in children with FAP, and total hospital charges are equivalent compared to open surgery. However, simultaneous proctectomy was performed less often with laparoscopic surgery.

A retrospective comparison of outcomes for open vs. laparoscopic surgical techniques in pediatric ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is an aggressive disease in the pediatric population and a cause of significant, lifelong morbidity. The aim of this study is to compare surgical complications in pediatric patients undergoing laparoscopic vs. open surgical treatment for UC. METHODS: We queried the Kids' Inpatient Database (KID) for all cases of UC undergoing surgical treatment in 2009 and 2012. We identified patients who received total colectomy without proctectomy (n=413) or total proctocolectomy (n=196) and performed univariate and multivariate analyses comparing laparoscopic vs. open procedures. RESULTS: In pediatric UC patients undergoing total colectomy without proctectomy, open procedures were associated with more complications than laparoscopic, including fluid and electrolyte disorders (40% vs. 28%), surgical wound dehiscence (6% vs. 2%), septicemia (18% vs. 2%), and gastrointestinal disorders (16% vs. 7%) among others, all P<0.05. Likewise, in patients with UC undergoing total proctocolectomy, there were more complications in open vs. laparoscopic technique, including increased transfusion requirements (25% vs. 7%, P=0.001) and significantly more gastrointestinal upset, including nausea, vomiting, and diarrhea (11% vs. 1%, P=0.003). In multivariate analysis, patients who underwent total colectomy with or without proctectomy had an increased risk of experiencing any complication when their procedure was performed in an open or non-elective fashion (all odds ratio >2.4; all P<0.001). CONCLUSIONS: The laparoscopic approach was associated with significantly lower rates of surgical complications in pediatric patients undergoing total colectomy with or without proctectomy for UC. These findings demonstrate that laparoscopic technique compares favorably, and may be preferable, to the open approach in selected pediatric patients with UC.

Low-Grade Appendiceal Mucinous Neoplasm in an Adolescent Patient With Untreated Crohn's Disease.

Appendiceal mucinous neoplasms are rarely diagnosed in pediatric patients. We present a 16-year-old adolescent boy with severe Crohn's disease who was not on maintenance medication for his underlying diagnosis. He was referred for nutritional optimization and small bowel obstruction. An emergent laparoscopic ileocecectomy with primary ileocolonic anastomosis was carried out secondary to acute peritonitis. Small bowel pathologic findings were consistent with Crohn's disease with low-grade appendiceal mucinous neoplasm (LAMN) of the appendix.

Open Versus Laparoscopic Right Hemicolectomies in Pediatric Patients with Crohn's Disease.

Introduction: Surgery remains an important treatment modality for the management of pediatric Crohn's disease (CD). The objective of this study was to perform a comparative analysis of open right hemicolectomy (ORH) and laparoscopic right hemicolectomy (LRH) for the management of pediatric CD. Materials and Methods: The Kids' Inpatient Database (KID) was queried (2009-2012) for ICD-9 procedure codes for ORH (45.73) and LRH (17.33) in patients with CD (ICD-9 codes: 555.0, 555.1, 555.2, 555.9). Open and laparoscopic procedures were compared using propensity score (PS)-matched analysis (PSMA) of 41 variables. Results: Overall 889 patients were identified and after PS matching, there were 380 ORHs and 380 LRHs. There were zero in-hospital deaths (0/821). ORH patients were more likely to have septicemia, respiratory compromise, pneumonia, perforation and/or laceration, complications, and require blood transfusions (all, P < .05). Although LRH patients were more likely to develop postoperative nausea/vomiting/diarrhea (P < .0001), they had a shorter hospital length of stay (P < .0001) and lower overall hospital charges and cost (P < .001). Conclusion: ORH and LRH in KID have similar low in-hospital mortality in pediatric CD. However, ORH was associated with higher morbidity including an increased risk for respiratory complications, surgical complications, need for blood transfusions, and increased resource utilization than patients who had laparoscopic procedures. In select patients, LRH is safe, feasible, and potentially superior to ORH.

Cryptosporidium diagnosed on endoscopic biopsy in a paediatric patient with inflammatory bowel disease.

Cryptosporidium, a parasitic infection commonly associated with diarrhoea, may be difficult to differentiate from a flare in patients with inflammatory bowel disease and can lead to unnecessary therapy and increase in morbidity and mortality. We report the case of a paediatric patient who had substantial stool output requiring significant fluid resuscitation and who was later diagnosed with cryptosporidium on endoscopic biopsy. Diagnostic work up for cryptosporidium should be strongly considered when a patient presents with a flare involving massive stool output.

Atypical protein kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells.

Atypical protein kinase iota (PKCiota) is a key organizer of the apical domain in epithelial cells. Ezrin is a cytosolic protein that, upon activation by phosphorylation of T567, is localized under the apical membrane where it connects actin filaments to membrane proteins and recruits protein kinase A (PKA). To identify the kinase that phosphorylates ezrin T567 in simple epithelia, we analyzed the expression of active PKC and the appearance of T567-P during enterocyte differentiation in vivo. PKCiota phosphorylated ezrin on T567 in vitro, and in Sf9 cells that do not activate human ezrin. In CACO-2 human intestinal cells in culture, PKCiota co-immunoprecipitated with ezrin and was knocked down by shRNA expression. The resulting phenotype showed a modest decrease in total ezrin, but a steep decrease in T567 phosphorylation. The PKCiota-depleted cells showed fewer and shorter microvilli and redistribution of the PKA regulatory subunit. Expression of a dominant-negative form of PKCiota also decreased T567-P signal, and expression of a constitutively active PKCiota mutant showed depolarized distribution of T567-P. We conclude that, although other molecular mechanisms contribute to ezrin activation, apically localized phosphorylation by PKCiota is essential for the activation and normal distribution of ezrin at the early stages of intestinal epithelial cell differentiation.