Rachel J. van der Pol

Efficacy of proton-pump inhibitors in children with gastroesophageal reflux disease: A systematic review

INTRODUCTION: Use of proton-pump inhibitors (PPIs) for the treatment of gastroesophageal reflux disease (GERD) in children has increased enormously. However, effectiveness and safety of PPIs for pediatric GERD are under debate. OBJECTIVES: We performed a systematic review to determine effectiveness and safety of PPIs in children with GERD. METHODS: We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for randomized controlled trials and crossover studies investigating efficacy and safety of PPIs in children aged 0 to 18 years with GERD for reduction in GERD symptoms, gastric pH, histologic aberrations, and reported adverse events. RESULTS: Twelve studies were included with data from children aged 0–17 years. For infants, PPIs were more effective in 1 study (compared with hydrolyzed formula), not effective in 2 studies, and equally effective in 2 studies (compared with placebo) for the reduction of GERD symptoms. For children and adolescents, PPIs were equally effective (compared with alginates, ranitidine, or a different PPI dosage). For gastric acidity, in infants and children PPIs were more effective (compared with placebo, alginates, or ranitidine) in 4 studies. For reducing histologic aberrations, PPIs showed no difference (compared with ranitidine or alginates) in 3 studies. Six studies reported no differences in treatment-related adverse events (compared with placebo or a different PPI dosage). CONCLUSIONS: PPIs are not effective in reducing GERD symptoms in infants. Placebo-controlled trials in older children are lacking. Although PPIs seem to be well tolerated during short-term use, evidence supporting the safety of PPIs is lacking.

Efficacy and Safety of Histamine-2 Receptor Antagonists

IMPORTANCE Histamine-2 receptor antagonists (H2RAs) are frequently used in the treatment of gastroesophageal reflux disease (GERD) in children; however, their efficacy and safety is questionable. OBJECTIVE To systematically review the literature to assess the efficacy and safety of H2RAs in pediatric GERD. EVIDENCE REVIEW PubMed, EMBASE, and the Cochrane database were searched for randomized clinical trials investigating the efficacy and safety of H2RAs in pediatric GERD. Two reviewers independently extracted data from the included articles. The quality of the evidence was assessed using the Grades of Recommendations, Assessment, Development, and Evaluation approach. When possible, infants and children were analyzed separately. FINDINGS Eight studies with a total of 276 children (0-15 years of age) were included. Compared with the placebo, H2RAs were more effective in the reduction of symptoms in terms of histologic healing and increasing gastric pH and had a larger overall treatment effect. In infants, H2RAs were only more effective in terms of histologic healing. Comparing H2RAs with antacids, H2RAs were more effective in symptom reduction in only 1 study. H2RAs compared with proton pump inhibitors were not significantly different in any of the outcome measures. For safety analysis, data were not reported in a quantitative manner and for all outcomes, the quality of evidence was very low. CONCLUSIONS AND RELEVANCE Evidence to support the efficacy and safety of H2RAs in infants and children is limited and of poor quality. Well-designed placebo-controlled trials are needed before thorough conclusions can be drawn.

Diagnostic accuracy of tests in pediatric gastroesophageal reflux disease.

OBJECTIVE To systematically review the literature evaluating the diagnostic accuracy of commonly used diagnostic tests over conventional history taking and physical examination in children ≤ 18 months and >18 months suspected of gastroesophageal reflux disease (GERD). STUDY DESIGN We searched Medline, Embase, and the Cochrane database for studies assessing the diagnostic accuracy of pH-metry, pH-impedance, esophagogastroscopy, barium contrast study, scintigraphy, and empirical treatment as diagnostic tools. Quality was assessed according to Quality Assessment of Studies of Diagnostic Accuracy Included in Systematic Reviews criteria. RESULTS Of the 2178 studies found, 6 studies were included, containing 408 participants (age 1 month-13.6 years) and 145 controls (age 1 month-16.9 years). Studies included children with GERD symptoms; 1 included an atypical presentation. In all the studies, the diagnostic accuracy of pH-metry was investigated, and in 2 studies esophagogastroscopy was investigated as well. Sensitivity and specificity were calculated in 3 studies. The range of reported sensitivity and specificity was broad and unreliable because of poor methodological quality according to Quality Assessment of Studies of Diagnostic Accuracy Included in Systematic Reviews criteria and inadequate study design. CONCLUSION Diagnostic accuracy of tests in children suspected of GERD remains unclear and implications for practice are hard to give. There is an urgent need of well-designed randomized controlled trials where the effect of treatment according to specific signs and symptoms will be compared with the effect of treatment based on the results of additional diagnostic tests, for patient relevant outcomes.

Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux.

Objective: Multichannel intraluminal impedance (MII) directly evaluates esophageal bolus transport. There is a good correlation between MII and manometry in healthy adults, but there are no reports concerning children. The aim of the present study was to determine normal values of esophageal motility using only impedance measurements in healthy children and in a pediatric population with gastroesophageal reflux (GER). Patients and Methods: We described in the present study 60 children submitted to pH-MII for 24 hours for suspected GER. Patients were divided into 2 different groups on the basis of their pH-MII report. Group 1 patients showed acid GER, whereas group 2 patients had negative pH-MII analysis for GER despite symptoms. We described impedance reflux and motility parameters on 10 standardized swallows: number of reflux, mean acid clearing time, median bolus clearing time, bolus presence time, total bolus transit time, segmental transit time, and total propagation velocity. Results: In group 1, the median mean acid clearing time was 151 seconds, whereas the median mean bolus clearing time was 25 seconds. In group 2 patients, all of the reflux parameters were normal. In group 1 the median bolus presence time at each measuring site, the median total bolus transit time, and the median segmental transit time were significantly greater and total propagation velocity lower than values reported in group 2 (P < 0.001), if compared with those described for adult patients. Conclusions: The pH-MII is an ideal test in children because it studies GER with its characteristics and motility pattern. Our report summarizes for the first time impedance motility parameters in healthy children.

Outcomes of endoscopy and novel pH-impedance parameters in children: is there a correlation?

Objectives: Discordance exists between outcomes of endoscopy, multichannel intraluminal impedance monitoring (pH-MII), MII baselines, and gastroesophageal reflux symptoms. The aim of the present study was to determine the association between endoscopy, pH-MII and MII baselines, in children with gastroesophageal reflux symptoms. Methods: Endoscopies were graded for reflux esophagitis (RE). Biopsies of the distal esophagus were assessed for signs suggestive of esophagitis. Reflux index (RI), symptom association probability (SAP), number of reflux episodes, and mean baseline values were calculated. pH-MII was considered positive in children when RI was ≥3% and/or SAP was ≥95% and for infants when RI was ≥10% and/or SAP was ≥95%. Baselines were manually calculated and compared with an automated analysis. For MII baselines, patients were divided in 3 groups: normal endoscopy and negative overall pH-MII; normal endoscopy and an overall positive pH-MII; and RE. Results: A total of 26 children and 14 infants were included, median age: 26.5 months (2 months–16.2 years). Thirteen (32.5%) had RE. A significant negative association was found for RI and MII baselines (P = 0.009) and between SAP and RE (P = 0.039, odds ratio 1.018). MII baseline values were predictive for neither conventional pH-MII parameters nor RE. Manual analysis and automated calculation of MII baselines showed a perfect correlation. Distal MII baselines were significantly lower in children with a positive overall pH-MII outcome compared with the proximal esophagus (P = 0.049). No significant changes were found in baselines among the different groups 1 to 3. Conclusions: Acid-related parameters are significantly related to MII baselines. A perfect correlation between manual- and automated analysis of MII baselines was found. Large prospective studies are needed to confirm the exact role of endoscopy and MII baselines.

Follow-up after pH-metry and pH impedance in pediatric gastroesophageal reflux disease.

Objectives: It is unclear how diagnostic tests for gastroesophageal reflux disease (GERD) in children relate to the course of symptoms during follow-up. Methods: During 1 year, all children (ages 0–18 years), who underwent pH-metry and/or pH multichannel intraluminal impedance (MII), were included after written informed consent was obtained. pH-metry and pH-MII test characteristics, such as reflux index (RI, % time that esophageal pH < 4), were obtained from the measurements. A questionnaire containing subcategories (medical history, gastrointestinal [GI] symptoms, extraesophageal symptoms, symptom burden, and therapeutic agents) was used; subjects were asked to fill the questionnaire at the time of inclusion and 3, 6, and 12 months afterward. Results: A total of 162 infants and 42 children were included. pH-MII was performed in 15.4% and 57.4% of infants and children, respectively. All of the other subjects underwent pH-metry. Median RI was 2.0% (interquartile range 3.4) in infants and 1.7% (interquartile range 2.3) in children. RI was considered positive in 6.8% and 12.8% of infants and children, respectively. In infants, RI at baseline was significantly associated with symptom burden at baseline and at 3 and 12 months of follow-up. RI at baseline and reported GI symptoms at 3 months were also significantly associated. In infants and children using medication, symptom burden was significantly higher compared with those not using medication. This difference was found at baseline, after 3 and 12 months. Conclusions: In infants, an initial high RI is associated with persistence of GI symptoms at 3 months and a higher burden of symptoms during the course of 1 year. In children there were no such findings.

Berardinelli-Seip syndrome and achalasia: a shared pathomechanism?

AbstractBerardinelli-Seip congenital lipodystrophy (BSCL) is an uncommon autosomal recessive disorder. Patients with BSCL present with a distinct phenotype since subcutaneous fat is largely lacking and musculature has become more prominent. During childhood, diabetes and acanthosis nigricans evolve and female patients may develop hirsutism. Different genes encoding this entity have been described. Achalasia is a rare esophageal motility disorder, characterized by its distinct motility pattern with absent or incomplete lower esophageal sphincter (LES) relaxations. The exact cause of achalasia is yet unknown. Here, we describe a patient with achalasia in the context of BSCL, which might be linked by a shared pathophysiologic background, as evaluated in this case report. Conclusion: In a BSCL patient presenting with gastrointestinal symptoms, a motility disorder of the gastrointestinal tract should be considered.What is Known:• Berardinelli-Seip congenital lipodystrophy (BSCL) and achalasia are both disorders characterized by low prevalence.What is New:• Co-existence of both diseases is described in this report. Linkage by a potential common pathophysiologic background is discussed in this paper.

Intramural pseudodiverticulosis of the esophagus: a case report

Esophageal intramural pseudodiverticulosis (EIPD) is a rare disorder in adults, and even more in infants and children. It is characterized by the dilatation of the submucosal esophageal glands. The exact etiology and pathophysiology of EIPD is, however, unknown. Dysphagia is the predominant presenting symptom in both children and adults. Conclusion: Here, we present a case of a boy with persistent dysphagia who had a thorough diagnostic workup and was eventually diagnosed with EIPD.

842 Pediatric Gastroesophageal Reflux Disease: Acidic and Non-Acidic Gastric Juice Modulates Bronchial Epithelial IL-8 Response

Introduction: With the many alluring features of HRM including superior spatial resolution and rapid recording frequency, interest in manometric evaluation of the pharynx during swallowing has been renewed. However, crucial information about the physiologic variability of pharyngeal peristaltic pressure wave parameters is scarce. These data are vital for developing normative data and correct interpretation of pharyngeal manometry results. The aims of the present study were to determine: 1) the variability of pharyngeal peristaltic pressure wave amplitude and duration between swallows at various distances from the upper esophageal sphincter (UES) and 2) Pharyngeal Contractile Integral(PCI),hypo-pharyngeal intra-bolus pressure(IBP) and nadir UES pressure(N-UESP) for a range of swallowed volumes. Methods: We studied seven healthy individuals (age:51±25 years, 6F) in upright head neutral position using a high resolution manometry catheter with 36 recording sites positioned trans-nasally such that pressure was recorded from the entire pharynx, UES and proximal esophagus. In each subject, we tested three repetitions each of dry and room temperature 0.5,5 and 10ml water at 20-30second intervals. Statistical analysis included ANOVA, Kruskal-Wallis Testing, Bartletts Test of variance, Conovers Squared Rank Test of Variance and the coefficient of variation. Results: Spatial variation of the peak peristaltic pressure wave amplitude showed significant difference in variance across locations 2, 3, 4, 5, 6, 7 and 8cm above the upper margin of the UES high pressure zone (umUESHPZ) for dry(p=0.043), 0.5 (p=0.006) and 5ml (p=0.049)swallows (table). There was significant variability in the peak amplitude between swallows at all sites as seen by the standard deviation bars in the figure (representative example for 5ml swallows). The smallest degree of variability across sites was seen at p6 (6 cm above the umUESHPZ) shown in the figure as circles representing the coefficients of variation. Variance due to volume effects also showed significant differences; however, these difference in variance were confined only to sites 3 (p=0.015), 4 (p=0.020) and 6 (p=0.022) cm above the umUESHPZ. In contrast, PCI and IBP showed similar variability for the tested swallow volumes. Conclusions: 1) Parameters of pharyngeal peristaltic pressure wave vary significantly from one swallow to the other for dry and water swallows,2) this variability is significantly different for different locations across the pharynx. 3) these findings should be taken into account for defining normative data and using pharyngeal manometry for clinical purposes. Supported in part by R01DK025731 and P01DK068051.

Su1252 Gastric Juice Composition and Acid Suppression in Pediatric Gastroesophageal Reflux Disease

INTRODUCTION: Gastric acid suppression is justified to prevent severe gastro esophageal reflux (GER) disease related complications. However, it does not reduce the total amount and proximal extent of GER in the esophagus and non-acid components are able to induce (extra-esophageal) GER symptoms as well. No data on the composition of gastric juice (GJ) in children using gastric acid suppression exists. We therefore aimed to assess whether the composition of gastric juice in children using proton pump inhibitors (PPIs) differs, compared to that of their controls. METHODS: Infants and children (0-18 years) on proton pump inhibitors (PPIs) for at least six weeks and a control group not using anti reflux medication, were included. GJ was obtained through an existing nasogastric or a percutaneous endoscopic gastrostomy tube/ Mic-key gastrostomy. In the collected GJ (5 ml), pH, pepsin activity, bile salts and endotoxin (LPS) levels were determined. Pepsin was measured using a fluorometric assay using 4-Methyl-Coumaryl-7-Amide (MCA) substrate with/without pepstatin. Concentrations of deconjugated and taurine/glycine-conjugated bile salts were assessed by reversephase HPLC. Levels of LPS were determined using the spectrophotometric Limulus Amebocyte Lysate assay. RESULTS: GJ was analyzed from 16 children with (median: 3.8 yrs, range: 17.6 years) and 16 children (4.0 yrs, range: 16.0) without PPI therapy. Median duration of PPI treatment was 24 weeks (range: 514 weeks). Gastric pH was 5.0 (range: 5.0) and 1.0 (range: 4.5) in the PPI and control group respectively (p <0.001). Pepsin, unconjugated bile salts, and endotoxin were not significantly different in the two groups. Total taurine conjugated bile salts, and specifically taurocholate, was significantly higher in the PPI group (p=0.01 and p=0.005). pH and concentration of deconjugated bile and conjugated bile salts were significantly associated (p=0.006 and p=0.02). Endotoxin and bile salts were not significantly associated. CONCLUSION: Taurine conjugated bile acids are significantly higher in children chronically using PPIs compared to controls. Moreover acidity of gastric pH correlated negatively with deconjugated and conjugated bile salts. These findings imply that GJ under chronic proton pump inhibition contains nonacid components potentially harmful to esophageal mucosa and bronchial tissue.