Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension.

BACKGROUND & AIMS: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2). METHODS: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 µg twice daily (BID) and 24 µg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/wk vs baseline and ≥3 SBMs/wk for ≥9 weeks, including 3 of the final 4 weeks). RESULTS: 606 patients were randomized to treatment (placebo: n = 202; lubiprostone: n = 404) in study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P = .2245). Both the 12-µg BID and 24-µg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies. CONCLUSIONS: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC but did demonstrate a safety profile similar to that in adults. (ClinicalTrials.gov: Number: NCT02042183; Number: NCT02138136).

Self-Efficacy in Children with Functional Constipation Is Associated with Treatment Success.

OBJECTIVES: To assess the relationship between self-efficacy, the belief that an individual can succeed at a goal, and short-term treatment outcome in children with functional constipation. STUDY DESIGN: Patients with functional constipation age 8-16 years completed the Self-Efficacy for Functional Constipation Questionnaire (SEFCQ), consisting of 14 statements about performing tasks needed for defecation. Patients completed SEFCQ before, immediately after, and 3 weeks after their clinic visit. Treatment success was defined as ≥3 bowel movements into the toilet and no fecal incontinence in the third week. RESULTS: 75% of patients had a successful outcome. Scores were higher in the group that was successful than in those that failed before, immediately after the visit, and 3 weeks later (P < .001). Self-efficacy improved at all time points in the group that was successful (P < .001). In the group that failed, scores improved immediately after clinic visit (P < .01) but were unchanged at follow-up (P > .05). CONCLUSIONS: Improved self-efficacy is associated with successful outcomes in children with functional constipation, thus, it may be beneficial to enhance self-efficacy for defecation during treatment.

Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria.

OBJECTIVE: To assess the prevalence of functional gastrointestinal (GI) disorders in children 0-18 years old according to the newly established Rome IV diagnostic criteria as reported by parents in a representative community sample. STUDY DESIGN: A cross-sectional study in which mothers (n = 1255) of children aged 0-18 years old in the US were recruited to complete an online survey about their child's GI symptoms, quality of life (QoL), and other health conditions. RESULTS: Based on the Rome IV criteria, 24.7% of infants and toddlers aged 0-3 years and 25.0% of children and adolescents aged 4-18 years fulfilled symptom-based criteria for a functional GI disorder. The most common functional GI disorders were infant regurgitation among infants (24.1%) and functional constipation among both toddlers (18.5%) and children and adolescents (14.1%). QoL was diminished in pediatric patients with functional GI disorders (median = 71.69 vs median = 87.60; z = -11.41; P < .001). Children were more likely to qualify for a functional GI disorder if their parent qualified for a functional GI disorder (35.4% vs 23.0%; P < .001). CONCLUSIONS: Based on Rome IV criteria, functional GI disorders are common in pediatric populations of all ages and are associated with decreased QoL.

Childhood Functional Gastrointestinal Disorders: Neonate/Toddler.

In 2006, a consensus concerning functional gastrointestinal intestinal disorders (FGIDs) in infants and toddlers was described. At that time little evidence regarding epidemiology, pathophysiology, diagnostic work-up, treatment strategies and follow-up was available. Consequently the criteria for the clinical entities were more experience than evidence based. In the past decade, new insights have been gained in the different FGIDs in these age groups. Based on those, further revisions have been made to the criteria. The description of infant colic has been expanded to include criteria for the general pediatrician and specific criteria for researchers. The greatest change was the addition of a paragraph regarding the neurobiology of pain in infants and toddlers, including the understanding of the neurodevelopment of nociception and of the wide array of factors that may impact the pain experience.

Biliary Dyskinesia in Children: A Systematic Review.

Cholecystectomy rates for biliary dyskinesia in children are rising in the United States, but not in other countries. Biliary dyskinesia is a validated functional gallbladder disorder in adults, requiring biliary colic in the diagnosis. In contrast, most studies in children require upper abdominal pain, absent gallstones on ultrasound, and an abnormal gallbladder ejection fraction (GBEF) on cholecystokinin-stimulated cholescintigraphy for diagnosis. We aimed to systematically review existing literature in biliary dyskinesia in children, determine the validity and reliability of diagnostic criteria, GBEF, and to assess outcomes following cholecystectomy. We performed a systematic review following the PRISMA checklist and searched 7 databases including PubMed, Scopus, Embase, Ovid, MEDLINE, ProQuest, Web of Science, and the Cochrane library. Bibliographies of articles were screened for additional studies. Our search terms yielded 916 articles of which 28 were included. Three articles were manually added from searched references. We reviewed 31 peer-reviewed publications, all retrospective chart reviews. There was heterogeneity in diagnostic criteria and GBEF values. Outcomes after laparoscopic cholecystectomy varied from 34% to 100% success, and there was no consensus concerning factors influencing outcomes. The observational, retrospective study designs that comprised our review limited interpretation of safety and efficacy of the investigations and treatment in biliary dyskinesia in children. Symptoms of biliary dyskinesia overlapped with functional dyspepsia. There is a need for consensus on symptoms defining biliary dyskinesia, validation of testing required for diagnosis of biliary dyskinesia, and randomized controlled trials comparing medical versus surgical management in children with upper abdominal pain.

Rumination Syndrome and Dental Erosions in Children.

Rumination syndrome is the effortless regurgitation of recently ingested food with subsequent reswallowing or spitting out. Dental erosion (DE) affects 2% to 5% of the population. DE is defined as loss of tooth structure by a chemical process that does not involve bacteria. Our objective was to compare the frequency of DE among children with rumination syndrome with healthy controls. We enrolled 30 patients 4 to 21 years of age diagnosed with rumination syndrome, and 30 age- and sex-matched healthy control subjects. Patients were evaluated by pediatric dentists for presence of DE with Taji et al a validated grading system. Patients with rumination were more likely to have DE (P < 0.001). Of patients with rumination syndrome, 23 (77%) had DE, compared with 4 (13%) control subjects. DEs are more frequent in patients with rumination syndrome.

Water Load Test in Children with Chronic Abdominal Pain or Obesity Compared with Nonobese Controls.

OBJECTIVE: Satiety is the perception of satisfied fullness and represents a summation of neural and hormonal influences. Satiety can be assessed by drink tests, including water load. The objective of our study was to confirm the difference in water load volume between nonobese control children and children with functional dyspepsia (FD), children with irritable bowel syndrome (IBS), and obese children. METHODS: A total of 158 children ages 6 to 13 years participated in the study. There were 43 children with FD, 25 with IBS, 44 obese children, and 46 nonobese age-matched control children. Subjects drank as much water as possible in 3 minutes or until their stomachs felt full. RESULTS: Children in the FD and IBS groups drank less water than did the nonobese controls; the obese children drank more water than did the nonobese controls. The water load test demonstrated high specificity but poor sensitivity in predicting children with FD. CONCLUSIONS: A water load test offers a simple, noninvasive research tool to measure satiety. Children with chronic abdominal pain drank less than nonobese control children; however, the water load test did not discriminate between FD and IBS. Obese children drank more water than the other groups, suggesting the possibility of an underlying abnormality in the perception of satiety.

A Randomized Controlled Trial of an Outpatient Protocol for Transitioning Children from Tube to Oral Feeding: No Need for Amitriptyline.

OBJECTIVE: To assess the role of amitriptyline in the effectiveness of an outpatient protocol for weaning medically complicated children from tube to oral feeding. STUDY DESIGN: Twenty-one children seen in multidisciplinary outpatient feeding teams across 4 sites were recruited to a randomized placebo-controlled trial of a 6-month outpatient treatment protocol with behavioral, oral-motor, nutrition, and medication components. RESULTS: All of the children who completed the 6-month program (73%) were weaned to receive only oral feeding, regardless of group assignment. The transition from tube to oral feeding resulted in decreases in body mass index percentile and pain, some improvements in quality of life, and no statistically significant changes in cost. CONCLUSIONS: Amitriptyline is not a key component of this otherwise effective outpatient, interdisciplinary protocol for weaning children from tube to oral feeding. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01206478.

Functional Gastrointestinal Disorders Dominate Pediatric Gastroenterology Outpatient Practice.

OBJECTIVES: Symptom-based diagnostic criteria have improved recognition and standardization of pediatric functional gastrointestinal disorders (FGIDs). We used Rome 3 diagnostic criteria to determine the prevalence of FGIDs in pediatric gastroenterology clinic. In the process, we developed a diagnostic questionnaire for infants and toddlers. METHODS: We enrolled new patients ≤18 years referred during 19 months to a pediatric gastroenterology clinic. Subjects or parents completed a demographic survey and a the Questionnaire on Pediatric Gastrointestinal symptoms, Rome 3 Version (if ≥4 years, or a new infant-toddler questionnaire) before their appointment. RESULTS: We acquired data from 976 subjects: 476 boys, 592 white. Of 332 subjects <4 years, 172 (52%) met diagnostic criteria for ≥1 FGIDs. Of 644 subjects ≥4 years, 486 (75%) met diagnostic criteria for ≥1 FGIDs. Thirty one (9%) subjects <4 years and 170 (26%) subjects ≥4 years met the criteria for ≥2 FGIDs. Of the total sample of subjects <4 years, common FGIDs included functional constipation (29%), infant regurgitation (13%), and cyclic vomiting syndrome (10%). Of the total sample of subjects ≥4 years, common FGIDs included irritable bowel syndrome (36%), abdominal migraine (19%), functional constipation (17%), cyclic vomiting syndrome (8%), functional abdominal pain syndrome (7%), aerophagia (7%), and functional dyspepsia (7%). CONCLUSIONS: More than half of new pediatric gastrointestinal clinic patients met the Rome 3 criteria for ≥1 FGIDs. Satisfying the criteria may facilitate diagnosis on the first visit.

Age of Onset of Functional Constipation.

In a review of 538 children with functional constipation, we analyzed ages of presentation and onset, symptom duration, and behavioral/developmental problems. We divided the subjects into quartiles (Q1-Q4) based on age of onset. Median onset age was 2.3 years. The oldest group had the shortest symptom duration before referral at 1.8 ±â€Š1.8 years (compared with Q3 to Q1, P = 0.039, P = 0.001, P < 0.001, respectively). Of the Q4 subjects, 22% had a behavioral/developmental problem (P < 0.001 compared with Q1-Q3). We conclude that most children develop functional constipation as infants and toddlers, but those with later onset are more likely to have behavioral/developmental issues and see a specialist sooner.

Development and Validation of a Rome III Functional Gastrointestinal Disorders Questionnaire for Infants and Toddlers.

OBJECTIVE: Functional gastrointestinal disorders (FGIDs) in infants and toddlers are common, but no questionnaire is available for use in clinic and research. The purpose of the present study was to develop and validate a questionnaire assessing symptoms associated with FGIDs in infants and toddlers. METHODS: Questions were developed based on the Rome III diagnostic criteria for FGIDs. A group of parents of children with FGIDs and experts in FGID reviewed the questionnaire for content, understandability, and completeness (face validity). Initial content validity was established by comparing physician and questionnaire diagnoses in a group of 332 consecutive new patients at a tertiary care clinic. RESULTS: Ten parents and 8 experts identified no major problems, indicating good face validity. Of 332 consecutive new patients, age 1 month to 4 year of age, 172 subjects (52% of the sample) qualified for a FGID by parent responses to the questionnaire (mean age = 1.23 year, 53% girls). All of these subjects also received an FGID diagnosis by their physician. Agreement between parent and doctor was fair to substantial (κ = 0.18-0.76), except for infant rumination and functional diarrhea in infants, which showed poor overlap. CONCLUSIONS: The newly developed Rome III questionnaire for infants and toddlers had good initial face and content validity. This questionnaire will be an important addition to clinical care and research of infant/toddler FGIDs. Replication of these findings in primary care is needed.

Prevalence of functional gastrointestinal disorders in infants and toddlers.

OBJECTIVES: To determine the prevalence of gastrointestinal symptoms suggestive of an infant/toddler functional gastrointestinal disorder (FGID) as reported by parents in a representative community sample. STUDY DESIGN: Mothers (n = 320) of children aged 0-3 years old were recruited in the US and completed a questionnaire about their child's and their own gastrointestinal symptoms. RESULTS: By Rome criteria, 27% of infants/toddlers qualified for FGIDs. Infant regurgitation was the most common disorder in infants and functional constipation in toddlers. No age, sex, or race differences were found in FGID diagnoses. Compared with those who did not meet Rome criteria, toddlers with FGID had lower quality of life (M = 80.1 vs M = 90.3, P < .001), increased medical visits (M = 0.38 vs 0.14; P < .05), mental health visits (M = 0.29 vs 0.06; P < .05), and hospital stays (M = 0.35 vs 0.06; P < .01). A child was more likely to suffer from hard stools if the parent also reported hard stools (P = .02), but similar association was not found with loose stools. CONCLUSIONS: FGIDs are common in infants and toddlers and can be identified in the general population. They do not vary with sex and race. Quality of life is reduced in those with FGIDs. More research is needed into these largely neglected conditions as it may improve the lives of a significant number of young children.

Effect of colon transection on spontaneous and meal-induced high-amplitude--propagating contractions in children.

BACKGROUND: After Hirschsprung disease (HD) surgery, many children experience fecal incontinence caused by increased number of high-amplitude-propagating contractions (HAPCs) through the neorectum to the anal verge. The aim of this study was to determine whether children with HD have more HAPCs than children with colon transections for reasons other than HD. METHODS: We reviewed 500 colon manometries. Children (age 7.6 ±â€Š5.1 years, 275 boys) with functional constipation (n = 237, age 7.4 ±â€Š5.0 years, 126 boys) and chronic abdominal pain (n = 48, age 9.8 ±â€Š5.8 years, 25 boys) served as controls compared with subjects with HD (n = 56, age 6.9 ±â€Š4.1 years, 44 boys) and colon transection for other reasons (n = 24, age 6.1 ±â€Š5.8 years, 12 boys). We excluded 139 subjects without HAPCs. We documented HAPCs during 1-hour fasting and 1-hour postprandial. Results are in mean ±â€ŠSD. RESULTS: During fasting, HD subjects had more HAPCs (2.2 ±â€Š3.4/hour) versus functional constipation (0.8 ±â€Š2.2/hour, P = 0.0004) and chronic pain (0.5 ±â€Š1.1/hour, P = 0.001), but not more than colon transection (1.9 ±â€Š3.2/hour, P = 1.0). HD showed more postprandial HAPCs (4.0 ±â€Š5.4/hour) than functional constipation (1.5 ±â€Š2.5/hour, P < 0.0001) and chronic pain (0.9 ±â€Š1.6/hour, P < 0.0001), but not more than colon transection (2.4 ±â€Š3.0/hour, P = 0.6). There were more HAPCs fasting and postprandial after colon transection (1.9 ±â€Š3.2/hour and 2.4 ±â€Š3.0/hour) than functional constipation (0.8 ±â€Š2.2/hour, P = 0.3 and 1.5 ±â€Š2.5/hour, P = 1.0) and chronic pain (0.5 ±â€Š1.1/hour, P = 1.0 and 0.9 ±â€Š1.6, P = 1.0). HD subjects were divided by chief complaint: fecal incontinence or constipation. HD subjects with incontinence (n = 23) only had more HAPCs fasting (P = 0.01) and postprandial (P = 0.01) than HD subjects with constipation (n = 28) only. CONCLUSIONS: Increased HAPCs followed colon transection, regardless of a cause. HD subjects with incontinence had more HAPCs than subjects with colon transection for other reasons.

Disability in Children and Adolescents With Irritable Bowel Syndrome and/or Fibromyalgia.

To compare disability and emotional health in individuals with irritable bowel syndrome (IBS), fibromyalgia, or both, patients completed the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III, childhood Functional Disability Inventory (FDI), and the Behavior Assessment System for Children, Second Edition. Patients' (age range 8-18 years, 19 IBS, 12 fibromyalgia, and 12 both) FDI scores showed greater disability than scores from historically healthy patients. Fibromyalgia (FDI 22.5 ±â€Š12.7, P = 0.018) and patients with both (FDI 26.2 ±â€Š13.8, P = 0.001) averaged greater disability than those with IBS (FDI 10.6 ±â€Š7.9). Disability was correlated with anxiety and depression symptoms. Disability and psychological symptoms are important when evaluating individuals with fibromyalgia and IBS.

Psychotropic medications for pediatric functional gastrointestinal disorders.

We describe the use of psychotropic medications in the treatment of functional gastrointestinal disorders (FGIDs) in children based on available data. We address their safety and efficacy. Most pediatric gastroenterologists do not or are not able to collaborate with child psychiatrists, so it may be beneficial for pediatric gastroenterologists to have a working knowledge of off-label psychotropic drugs to improve functional symptoms. We recommend that efforts be made to involve both the children and their families from the beginning, adverse effects be mentioned, and the treatment plan be explained.

Assessment of abdominal pain through global outcomes and recent FDA recommendations in children: are we ready for change?

OBJECTIVES: Irritable bowel syndrome is a multisymptom construct, with abdominal pain (AP) acting as the driving symptom of patient-reported severity. The Food and Drug Administration considers a >30% decrease in AP as satisfactory improvement, but this has not been validated in children. We investigated the correspondence of 2 measures for AP assessment, ≥30% improvement in AP and global assessment of improvement. METHODS: Secondary analysis of data from 72 children who completed a randomized clinical trial for abdominal pain-associated functional gastrointestinal disorders. Children completed daily assessment of AP intensity, functional disability inventory (FDI), question regarding pain's interference with activities, and 2 global assessment questions. We measured the extent to which ≥30% improvement of AP and global assessment questions correlated with each other and with disability. RESULTS: The global questions correlated with each other (r=0.74; P<0.0001) and with a ≥30% improvement in AP (P<0.01). Global outcomes were satisfaction with treatment was inversely related to the child's report of interference with activities (P<0.01) and symptom relief was positively associated with ≥30% improvement in FDI scores (P<0.009). A 30% change in FDI scores was associated with global questions of symptom relief (P=0.009) but not with satisfaction with treatment (P=0.07). The association of AP improvement with interference with activities (P=0.14) or change in FDI scores (P=0.27) did not reach significance. CONCLUSIONS: Currently used global assessments are significantly associated with decreased pain intensity, decreased interference with daily activities, and a ≥30% change in FDI scores, whereas recommended 30% improvement in pain intensity is not as comprehensive.

Lubiprostone for the treatment of functional constipation in children.

OBJECTIVES: Pediatric functional constipation is common; effective, easily administered treatment options are limited. Lubiprostone is an oral chloride channel protein-2 activator that stimulates gastrointestinal fluid secretion, softens stools, and facilitates bowel movements (BMs). We evaluated the safety and effectiveness of lubiprostone in children and adolescents with functional constipation. METHODS: Patients ≥12 kg, 17 years or younger, and with <3 spontaneous BMs (SBMs; ie, BMs that did not occur within 24 hours of rescue medication use) per week were enrolled at 22 US general pediatric and pediatric gastroenterology centers (January 2007-October 2008). Patients received 4 weeks of open-label lubiprostone at doses of 12 µg once daily (QD), 12 µg twice daily (BID), or 24 µg BID based on age and weight. The primary endpoint was SBM frequency during week 1 versus baseline. RESULTS: Of 127 enrolled patients, 124 were treated and analyzed (12 µg QD, n = 27; 12 µg BID, n = 65; 24 µg BID, n = 32), and 109 completed the study. The mean age of treated patients was 10.2 years (range 3-17 years); 65 were boys. Mean SBM frequency significantly increased compared with baseline at week 1 (3.1 vs. 1.5 SBMs/week, P < 0.0001). SBM frequency was improved significantly from baseline overall (P < 0.0001) and for individual dose groups (P ≤ 0.0062) during weeks 2, 3, and 4. Common (≥5%) adverse events included nausea (18.5%), vomiting (12.1%), diarrhea (8.1%), abdominal pain (7.3%), and headache (5.6%). Two patients experienced serious adverse events (unrelated abdominal pain; unrelated sickle cell crisis). CONCLUSIONS: Lubiprostone was efficacious and well tolerated in children and adolescents with functional constipation.

Isolation of Bacteriophages for Clinically Relevant Bacteria.

The isolation of bacteriophages targeting most clinically relevant bacteria is reasonably straightforward as long as its targeted host does not have complex chemical, physical, and environmental requirements. Often, sewage, soil, feces, and different body fluids are used for bacteriophage isolation procedures, and following enrichment, it is common to obtain more than a single phage in a sample. This chapter describes a simple method for the enrichment and isolation of bacteriophages from liquid and solid samples that can be adapted for different clinically important aerobic bacteria.

Diffuse esophageal spasm in children referred for manometry.

Diffuse esophageal spasm (DES) causes chest pain and/or dysphagia in adults. We reviewed charts of 278 subjects 0 to 18 years of age after esophageal manometry to describe the frequency and characteristics of DES in children. Patient diagnoses included normal motility (61%), nonspecific esophageal motility disorder (20%), DES (13%, n=36), and achalasia (4%). Of patients with DES, the most common chief complaint was food refusal in subjects younger than 5 years (14/24, 58%) and chest pain in subjects older than 5 years (4/12, 33%). Comorbid medical conditions, often multiple, existed in 33 subjects. DES should be considered when young children present with food refusal.