Lee ALH, Varjavandi V, Lemberg DA, et al. Does Combined Multichannel Intraluminal Impedance and pH (MII-pH) Testing Improve Clinical Outcomes in Children With Gastroesophageal Reflux Disease? J Ped Gastroenterology and Nutrition: Nov 2020.V.71:5(596-603).


: Lee A.L.H.  / Varjavandi V. / Lemberg D.A. / Ooi C.Y.  / Gupta N. / Krishnan U.


Does Combined Multichannel Intraluminal Impedance and pH (MII-pH) Testing Improve Clinical Outcomes in Children With Gastroesophageal Reflux Disease?

Lee, Adrian L.H.1,2, Varjavandi, Vincent2,3, Lemberg, Daniel A.2,4, Ooi, Chee Y.2,4,
Gupta, Nitin2,4, Krishnan, Usha3,4



1 Faculty of Medicine
2 School of Women's and Children's Health, University of New South Wales
3 Department of Pediatric Surgery
4 Department of Pediatric Gastroenterology, Sydney Children's Hospital, Sydney, Australia.

Address correspondence and reprint requests to Dr. Usha Krishnan, Department of Pediatric Gastroenterology, Sydney Children's Hospital, High Street, Randwick, NSW, Australia 2031 (e-mail: z5032967@ ad.unsw.edu.au).


ABSTRACT

Objectives: The aim of the study was to investigate the role of combined multichannel intraluminal impedance and pH (MII-pH) testing in clinical management of children with gastroesophageal reflux disease (GERD) by exploring the impact of treatment changes made based on MII-pH testing results on symptoms and quality of life outcomes.

Methods: All patients (<18 years) referred to the Sydney Childrens Hospital for MII-pH testing were recruited. Patients were classified by acid suppression therapy (AST) status (on AST and off AST) and changes in medical and surgical management were evaluated. Validated questionnaires (Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire and Infant Gastroesophageal Reflux Questionnaire Revised) were administered at baseline at the time of MII-pH testing, and 4 weeks after treatment changes were made and questionnaire scores were compared.

Results: Of the 45 patients recruited, 24 patients (53.3%) were off AST and 21 patients (46.7%) were on AST. MII-pH testing led to medication changes in 30 patients (66.7%). This included 15 of 24 (62.5%) in those off AST and 15 of 21 (71.4%) in those on AST. More than 98% of patients who had treatment changes showed a significant improvement in both symptoms and quality of life scores.

Conclusions: Our study is one of the first pediatric studies to evaluate the clinical validity of MII-pH testing in the pediatric population referred for suspected GERD, and its ability in guiding clinical management. Our study has shown that treatment decisions guided by and based on results of MII-pH testing led to a significant improvement in symptoms and quality of life in infants and children with GERD.

Key Words: acid suppression therapy, combined multichannel intraluminal impedance and pH testing, quality of life, standardized questionnaire, symptom scores, treatment change

(JPGN 2020;71: 596603)


What Is Known
  • Combined multichannel intraluminal impedance and pH testing has better diagnostic validity than conventional pH monitoring alone.
  • No pediatric studies have yet been performed which convincingly showed that the results of multichannel intraluminal impedance and pH testing influenced clinical outcomes
What Is New
  • Multichannel intraluminal impedance and pH testing results guided clinical management and prevented unnecessary treatment.
  • Majority of patients with treatment changes showed a significant improvement in health and quality of life scores in standardized questionnaires across all age groups.
  • The diagnostic yield and treatment changes were similar in both the on and off acid suppression therapy groups.



Multichannel intraluminal impedance and pH (MII-pH) testing has emerged as a widely used tool for investigation of gastroesophageal reflux disease (GERD). It detects reflux episodes by measuring the changes in electrical resistance between the electrodes in combination with a pH sensor. It is superior to pH monitoring due to its ability to detect nonacid reflux in addition to acid reflux, to determine the temporal association between symptoms and reflux episodes, and to measure the degree of proximal migration of refluxate within the esophagus (16).

Previous studies have shown that MII-pH testing has an increased diagnostic yield in children with symptoms of GERD compared to pH testing alone (79). A study by our group showed that GERD was detected in an additional 42.8% of older children and 62.8% of infants by MII-pH compared to pH testing alone (8). There has, however, been limited evidence on the impacts of MII-pHtesting on the clinical management of children with GERD. The 2018 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition - European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines stated that no pediatric studies have yet been performed which convincingly showed that the results of MII-pH testing influenced clinical outcomes (10).

To date, only 2 pediatric studies have looked at the impact of MII-pH testing in clinical management of children with GERD. A prospective study by Rosen et al (11) concluded that MII-pH testing results changed the clinical management in 62% of children, which was 22% higher than that with pH monitoring alone. A study by Rossi et al (12) found that the majority of children with an abnormal study (47%), who were treated in accordance with North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition GERD guidelines, were responsive to medical antireflux therapy. This is the only published study which used standardized questionnaire to evaluate the impacts of treatment changes. The details of symptoms and quality of life (QOL) scores were, however, not provided (12).

Hence our study is one of the first prospective pediatric studies to evaluate the clinical validity of MII-pH testing in management of infants and children with presumed GERD and the impacts on patient outcomes using validated symptom and QOL questionnaires.
METHODS
Patients referred to the Sydney Childrens Hospital for MII-pH testing were recruited between March 2018 and June 2019. This study was approved by Sydney Childrens Hospital Networks Human Research Ethics Committee.

At the time of testing, the Validated Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire (PGSQ) was administered to children aged 9 to 17 years, and to parents for children aged 2 to 8 years. For infants aged 0 to 2 years, the Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) was administered to the parents. For the PGSQ, the scores are presented as the sum of the scores for each item, which range from 0 (never) to 4 (always). The total score for each subscale is included in the table in brackets. In the PGSQ a decrease in score represents better symptom and QOL outcomes. Similarly the I-GERQ-R is presented as the total score and subscores, and a decrease in total score indicates better symptom and QOL outcomes.

Exclusion criteria included software or catheter malfunction leading to uninterpretable results, study lasted <20 hours, and presence of primary motility disorder such as achalasia.

Medical information was collected from patients medical records. Demographic information collected included: height and weight, sex, age, underlying comorbidities, feeding route, previous surgeries, and endoscopy results. Indication for MII-pH testing was classified into typical esophageal symptoms (TES), extraesophageal symptoms (EES), or both. TES symptoms included regurgitation, vomiting, heartburn, nausea, and epigastric pain. EES included chronic cough, wheezing, recurrent chest infections, hoarseness, dysphonia, and recurrent otitis media (13). Medication status at the time of impedance testing was recorded. It was categorized into 3 main categories: on acid suppression therapy (AST) including proton pump inhibitors (PPIs) and/or H2-receptor antagonists, on both AST and prokinetic, and not on any treatment. Patients off treatment had stopped their medication at least 4 weeks before the date of MII-pH testing.

Based on the criteria of the German Pediatric Impedance Group (7), MII-pH testing was categorized as abnormal when patients met one or more of the following criteria: abnormal acid reflux index (ARI), abnormal number of retrograde bolus movement (RBM), or hypersensitive esophagus (HE). ARI was considered abnormal if patients aged <1 year had an ARI ⩾10% or if patients ⩾1 year had an ARI of ⩾5%. Abnormal RBM was classified when patients aged <1 year had >100 RBM episodes or those aged ⩾1 year had >70 RBM episodes. HE was classified as when patients had normal ARI and RBM but positive symptoms index (⩾50%) and/or symptom association probability (⩾95%).

All patients were reviewed by their treating physician and based on the MII-pH testing results appropriate treatment changes were made. The same symptom and QOL questionnaire were completed by patients/parents at baseline and 4 weeks post treatment and changes in scores were compared to determine whether there was significant improvement in symptom and QOL scores in patients. No other medication changes were made other than the changes in reflux treatment during the 4 weeks period. Informed consent was obtained from patients and parents.

The health and QOL outcomes were evaluated using the PGSQ and I-GERQ-R.

PGSQ was used for 2 different age groups: age 9 to 17 and age 2 to 8. It was developed as 2 versions because of age-related differences in symptoms, developmental considerations, and the necessity of guardians reporting for younger children (14).

The results of PGSQ were categorized into 3 major modules: total symptoms, total impacts, and school. Total symptoms score was further categorized into heartburn, regurgitation, extraesophageal, and sleep (14).

I-GERQ-R is recommended to be presented as the total score and was used to evaluate the symptoms of GERD (15,16).

Questionnaire scores were presented as sum of scores in each item and decrease in score indicates an improvement in symptom and QOL.

Statistical analysis was conducted using IBM SPSS 25. The differences in questionnaire scores were compared using pairedsample t test. Significance was established at P<0.05. The relationship between questionnaire score improvement and possible predictive factors were analyzed through multivariate analysis.
RESULTS
Demographics

A total of 45 patients were recruited. The mean age of patients was 6.6 years. Ten patients were infants (age ⩽1 year) and 35 were older children (age 117 years). There were 25 boys. The indication for MII-pH testing was TES in 9 patients, EES in 7 patients, and 29 patients had both TES and EES. 18 patients (40%) had comorbidities. Table 1 shows the details of patient demographics and endoscopy results.

Multichannel Intraluminal Impedance and pH Results

Thirty-three patients (73.3%) had abnormal MII-pH testing results. 10 (22.2%) had abnormal ARI, 2 (4.4%) had abnormal number of RBM, and 21 (46.7%) had HE. 12 patients (26.7%) had functional or nonreflux-related symptoms. Abnormal endoscopy results did not have a statistically significant association with MII-pH results (P=0.152).

The findings of MII-pH testing are summarized in Table 2. The group on AST had a significantly lower median of acid RBM and of proximal acid RBM when compared to the group off AST.

Treatment Changes

There were treatment changes in 30 of 45 (66.7%) patients. This included starting, increasing, or switching AST; starting or switching prokinetic; and starting neuromodulator, with some overlapping. Two patients were referred for fundoplication. Three patients had a change in feeding mode, which included either changing from bolus to continuous gastric feeds or changing from continuous gastric to jejunal feeds. There were no changes made to the diet, such as special milk formulas and/or exclusion diet during the study period.



Fifteen patients (33.3%) had no changes to their medical management. In this group, 9 patients were not on antireflux treatment at the time of study. Six patients continued with the same treatment as before the study. See Table, Supplemental Digital Content 1, which shows summary of medication changes.

In the whole cohort, changes in medical management occurred in 10 patients (100%) with abnormal ARI, 2 patients (100%) with abnormal RBM, 14 patients (66.7%) with HE, and 4 patients (33.3%) with normal results. Patients with abnormal MII-pH results were significantly more likely to have changes in treatment compared to those with normal MII-pH results (relative risk=2.25; 95% confidence interval; P=0.001).

Results on Patients off Acid Suppression Therapy

Twenty-four patients (53.3%) were off AST at the time of MII-pH testing. Eighteen patients (75%) had abnormal results, which included 6 with abnormal ARI, 2 with abnormal RBM, and 10 with HE. Six patients had normal results. Fifteen patients (62.5%) with abnormal MII-pH results had medication change. Patients with abnormal MII-pH results were significantly more likely to have a change in medication compared to those with normal results (P=0.004). Only AST was started in patients with ARI. All patients with abnormal ARI and RBM had medication changes, which included starting AST prokinetic.

In the 10 patients with HE, 5 started on AST only and 2 started on both AST and prokinetic. Three patients with positive symptom association probability did not commence on antireflux treatment. Patients with normal MII-pH results were not commenced on antireflux treatment. See Figure, Supplemental Digital Content 2, which summarizes the treatment changes in the off AST group.

Results in Patients on Acid Suppression Therapy

Twenty-one patients (46.7%) were on AST at the time of MII-pH testing. Fifteen patients (71.4%) had abnormal results, which included 4 with abnormal ARI and 11 with HE. Six patients (28.9%) had normal results.

Fifteen patients (71.4%) had treatment changes. The commonest change was starting prokinetic which occurred in 7 patients with abnormal MII-pH results. In the 4 patients with abnormal ARI, all of them had changes in management which included starting prokinetic and switching prokinetic switching of AST.

In the 11 Patients who had HE, 5 started on prokinetic, 1 had increased dose of prokinetic. Three patients with adequate acid suppression of current treatment had no changes to their antireflux treatment.

In the 6 patients with normal MII-pH results, 3 patients had changes to their treatment made. In 2 of these patients, these changes included increasing AST switching prokinetic and in one patient a neuromodulator was started for their functional/nonreflux symptoms. Three patients did not have changes in treatment as their reflux was well controlled on AST. See Figure, Supplemental Digital Content 3, which summarizes the treatment changes in the on AST group.

Results in Patients With Esophageal Atresia/Tracheoesophageal Fistula

Fifteen patients (33.3%) in our study had esophageal atresia/tracheoesophageal fistula (EA-TEF). Ten (66.6%) of these had abnormal MII-pH results, which included 1 patient with abnormal ARI and 9 patients with HE.

Five of 15 patients (33.3%) were off AST. In these patients 2 patients had normal MII-pH results (including 1 patient with prior fundoplication) and were not commenced on AST. Three patients who had HE were started on PPI.

Ten of 15 patients (66.7%) were on AST at time of testing. Four of whom had prior fundoplication with gastrostomy. Of these 10 patients, 1 had abnormal ARI, 6 had HE, and 3 had normal results. A prokinetic was started in 4 of the 6 patients with HE and 1 patient with abnormal ARI. Ten of 15 patients (66.6%) had treatment changes, including 3 patients in 9 to 17 age group, 4 patients in 2 to 8 age group, and 3 patients in 0 to 2 age group. See Figure, Supplemental Digital Content 4, which summarizes the treatment changes in the EA/TEF group.

Among those with treatment changes in the 9 to 17 age group, there was a significant improvement in all subscores except for sleep. In those with treatment changes in the 2 to 8 age group, there was a significant improvement across all subscores.

In those with treatment changes in the 0 to 2 age group, there was a significant improvement in the I-GERQ-R total score, and the subscores spitting up, refusal, or stopping feeding, crying and fussing, and hiccups. In the 5 patients without treatment changes, there were no significant improvements in all subscores across all 3 age groups. Results are shown in Table 3.



Results in Patients With Previous Fundoplication

Six patients had prior history of fundoplication, of whom 3 patients were in the 2 to 8 age group and 3 patients were in the 9 to 17 age group. Four patients (66.7%) had normal MII-pH results and 2 patients (33.3%) had HE. No treatment changes were made in patients with normal MII-pH results, whereas in 1 of the HE patients a prokinetic was added to the AST. In this patient post treatment change, there was a significant improvement in the total symptoms, regurgitation, and extraesophageal scores in the PGSQ (28 years). In the 5 patients without treatment changes, there were no significant improvement in all subscores across in both the 2 to 8 and 9 to 17 age groups.

Symptoms and Quality of Life Questionnaire Results

Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire (Age 917)

There were 19 patients (42.2%) in this group. Within the group the results were divided into 2 groups: With treatment changes (n=13) versus no treatment changes (n=6). The results are summarized in Table 4.



In the group in which treatment changes were made, the results revealed a significant improvement in total symptoms, heartburn, regurgitation, extraesophageal, total impacts, and school. Only sleep remained non-significant. Total symptoms and total impacts had the greatest difference in means before and after MII-pH testing when treatment changes were made. In the group with no treatment changes, the score changes in each module were all, not significant.

Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire (Age 28)

Thirteen patients (28.9%) were in the age group 2 to 8. The results of 2 groups: With treatment changes (n=8) and without treatment changes (n=5) are shown in Table 5.



Similar to the age 9 to 17 group, total symptoms and total impacts had the greatest difference before and after MII-pH testing, when treatment changes were made. In the group without treatment changes, the score changes in all modules were all not significant.

Infant Gastroesophageal Reflux Questionnaire Revised (Age 02)

Thirteen patients (28.9%) were in the age group 0 to 2. The results of the group with treatment changes (n=9) and without treatment changes (n=4) are shown in Table 6.



In the group with treatment changes made, the results showed a significant difference with improvement in I-GERQ-R total score, as well as the subscores spitting up, refusal or stopping feeding, and crying and fussing. The normal score for I-GERQ-R is ≤15 (15). At the baseline, 3 patients had a normal I-GERQ-R. All of them did not have treatment changes. At 4 weeks post treatment changes, 9 patients had a normal I-GERQ-R. This included, 6 patients with abnormal I-GERQ-R at baseline who now had a normalized score post treatment changes and the 3 who had normal scores at baseline and whose scores remained normal after 4 weeks without any changes to treatment. Patients with treatment changes were more likely to improve and have a normal I-GERQ-R score compared to those without treatment changes (P=0.003).

Predictive Factors for Questionnaire Score Improvement

For the whole cohort, the relationship between questionnaire score improvement and possible predictive factors was explored on a multivariate analysis. Factors explored included height and weight z score, sex, age, MII-pH results, symptom indication, prior fundoplication, comorbidities, feeding mode, medication status, and medication change. MII-pH results (P=0.027) and medication change (P<0.001) were significantly associated with score improvement after adjustment. The results are summarized in Table 5.

DISCUSSION
To date, there is a dearth of literature on the clinical validity of MII-pH testing in improving patient related outcomes in the pediatric population. Only 2 previous pediatric studies have focused on whether MII-pH testing changed clinical management of patients with GERD (11,12). Our study is the first to look at the effect of treatment changes on symptoms and QOL using validated symptom questionnaires with details on each of the subdomains of the questionnaire being explored.

In our study, 73.3% of patients had abnormal MII-pH results. MII-pH testing increased the diagnostic yield of GERD by 29% compared to using traditional pH testing alone. This is similar to the 45% additional yield by MII-pH compared to pH testing alone in the study of 700 children with presumed GERD by Pilic et al (7). This finding is in line with the previous pediatric studies, which also showed an increased diagnostic yield for MII-pH testing compared to pH testing alone (79).

Changes to medical management were made in 30 out of 45 patients (66.7%) in our study. Patients with abnormal MII-pH results were 2.25 times more likely to have treatment changes. Our findings were similar to those from the Boston study, where changes in medical management were made in 62% of patients (11). It was also in line with a previous adult study where MII-pH testing resulted in a change in medical or surgical management in >50% of patients (17).

Clinicians could potentially have made empiric changes to antireflux therapy in patients with presumed GERD symptoms without objectively evaluating the etiology of these symptoms with MII-pH testing. In our study if this, however, had been done, 25% of children off AST and 14% of children on AST would have been commenced on AST or had alterations made to their antireflux therapy, respectively, or perhaps even referred for fundoplication despite their symptoms not being due to GERD as shown by their normal results on MII-pH testing. Although our study did not have a control group where treatment changes were made without use of MII-pH testing, potentially 54% of our study cohort who were not on PPI could have been exposed to empirical PPI therapy which was not indicated if treatment changes had been made based on presence of GERD symptoms alone. This is especially important in light of growing evidence of risks associated with long-term use of PPI therapy in infants and children (1820).

Whether MII-pH testing should be done on or off AST has been debated in pediatrics. Adult guidelines have recommended the performance of MII-pH off AST on patients with suspected GERD (21). There is, however, a dearth of pediatric studies evaluating whether MII-pH testing should be performed on or off acid suppression (22). The pediatric study by Rosen et al (11) showed that performing the testing on or off AST had no significant impact in changes made to clinical management in children whose GERD symptoms were evaluated with MII-pH testing (11). Similarly, in our study there was no significant additional diagnostic yield off AST (75% abnormal) compared to on AST (71% abnormal). More patients had treatment changes made in the on AST cohort (71%) including optimization of antireflux medication, 2 referrals for fundoplication, and a change in feeding mode in 3 patients when compared to the treatment changes done in 62.5% of patients in whom the MII-pH study was done off AST, although this difference was not statistically significant. Our results suggest that the recommendation of performing MII-pH testing on or off AST therapy is less clear in pediatrics (11).

More than 98% of patients with treatment changes showed a significant improvement in the health and quality and life scores based on the questionnaire results. In the groups PGSQ (917) and PGSQ (28), the most significant improvements were seen in the total symptoms score and total impacts score. Patients with normal MII-pH results who had no treatment changes showed no improvement in scores. This makes it less likely that the placebo effect of MII-pH testing and evolution of time resulted in improved symptoms. The fact that the significant improvements in symptoms and QOL scores and subscores including in TES and EES across all age groups only occurred in the group where treatment changes were made based on MII-pH results supports the role and clinical validity of MII-pH testing in children with GERD. The only nonsignificant subscore in the age group (917) was sleep. This could be an important finding, as pediatric patients with sleep disturbances are often thought to have GERD and commenced on PPI therapy empirically (23). Young children in the age 0 to 2 group had a significant improvement in I-GERQ-R scores including subscores of crying and fussing after treatment changes were made based on MII-pH results. This is an especially important finding as GERD is difficult to diagnose in infants and young children due to the nonspecific nature of the symptoms, and these children are often empirically commenced on antireflux therapy often with no significant improvement in symptoms. The consistency of score improvement in those with treatment changes across all age groups also supported the accuracy of MII-pH testing across all age groups in the pediatric population.

A third of the patients in this study had EA-TEF, 66.7% of whom had treatment changes. In those EA-TEF patients with treatment changes across all age groups there was a significant improvement in symptom and QOL scores, whereas no significant change seen in those whom treatment changes were not made. These findings underscore the importance of diagnosing and treating GERD to improve symptoms and QOL in this cohort.

In children with EA-TEF, conditions including esophageal dysmotility, strictures, and eosinophilic esophagitis (EoE) could potentially contribute to their symptoms (24). None of our EA-TEF patients, however, had strictures and no other medical changes were made other than those to their reflux treatment during the 4 weeks period. Hence we felt that the improved symptoms and QOL in the EA-TEF patients was secondary to the changes based on MII-pH results.

In our group of patients with a history of prior fundoplication, there was a significant improvement in symptoms and QOL only in the solitary patient who had treatment changes post-MII-pH testing. This finding highlights the importance of accurately diagnosing and treating reflux recurrence post fundoplication.

The role of MII-pH testing in improving clinical outcomes in children with GERD is also highlighted by the fact that when the relationship between questionnaire score improvement and possible predictive factors was explored on a multivariate analysis, only MII-pH results (P=0.027) and medication change (P<0.001) were significantly associated with score improvement.

There are some limitations to our study. One limitation was the relatively small sample size. Previous pediatrics studies which, however, evaluated MII-pH testing also had a small sample size including the Boston study, which had a similar cohort size of 50 (11). Secondly, this is a single-center study, and our findings reflect the practice pattern of 1 institution. Our hospital is, however, the only tertiary referral institution for MII-pH testing in the state of New South Wales and Canberra which have a combined pediatric population of >2.5 million, and we receive referrals for MII-pH testing from a large number of general pediatricians, surgeons, gastroenterologists, pulmonologists, and otolaryngologists (25).

Although theoretically it could be said that biopsy results of EoE or reflux esophagitis (RE) could have resulted in the same treatment changes and symptom and QOL improvement, we felt that this was not the case in our study. In our study there were only 2 patients with active EoE at time of testing. Both had optimization of their EoE treatment and no additional treatment changes were made based on results of MII-pH testing which was normal. Both did not show an improvement on follow-up in either their symptoms or QOL. Similarly although there were 4 patients with RE in the cohort, the changes of RE were only mild on histology and we felt it was the MII-pH results and not the endoscopy results which influenced the treating clinician into making the treatment changes. This is because of these 4 patients, only in the 2 patients who also had abnormal ARI had optimization of PPI therapy, whereas in the other 2 RE patients who has HE on MII-pH testing, had addition of prokinetics.

Although some studies have used 8 weeks endpoint on studies of acid suppression with PPIs, we decided to evaluate treatment response 4 weeks after changes to treatment had been made. In the GERD guidelines there was no difference in infants in the response irrespective of whether the response was assessed after 2 or 4 weeks of PPI therapy (10). Similarly in older children with and without esophagitis, several studies showed that the greatest symptomatic improvement occurred in the first 2 to 4 weeks of PPI administration (2629), suggesting that this duration may be sufficient as a diagnostic test for GERD in this population (10). We also wanted to ensure that all patients who had the testing done came for the follow-up. Hence for all these reasons we decided to look for treatment efficacy at 4 weeks post changes in therapy.
CONCLUSIONS
Our study is the first prospective pediatric study to look at the effect of treatment changes on symptoms and QOL using validated symptom questionnaires with details on each of the subdomains of the questionnaire being explored. Our results support the clinical validity of MII-pH testing in the pediatric population referred for suspected GERD, and its ability in guiding clinical management. Our results will need to be corroborated with larger multicenter studies.
REFERENCES
  1. Pilic D, Höfs C,Weitmann S, et al. Inter-and intraobserver agreement in 24-hour combined multiple intraluminal impedance and pH measurement in children. J Pediatr Gastroenterol Nutr 2011;53:2559.
  2. Van Wijk MP, Benninga MA, Omari TI. Role of the multichannel intraluminal impedance technique in infants and children. J Pediatr Gastroenterol Nutr 2009;48:212.
  3. Wenzl TG, Benninga MA, Loots CM, et al. Indications, methodology, and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. J Pediatr Gastroenterol Nutr 2012;55:2304.
  4. Loots CM, Van Wijk MP, Blondeau K, et al. Interobserver and intraobserver variability in pH-impedance analysis between 10 experts and automated analysis. J Pediatr 2012;160:441.e16.e1.
  5. Francavilla R, Magistà AM, Bucci N, et al. Comparison of esophageal pH and multichannel intraluminal impedance testing in pediatric patients with suspected gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2010;50:15460.
  6. Salvatore S, Arrigo S, Luini C, et al. Esophageal impedance in children: symptom-based results. J Pediatr 2010;157:949.e254.e2.
  7. Pilic D, Fröhlich T, Nöh F, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group. J Pediatr 2011;158:650.e14.e1.
  8. Safe M, Cho J, Krishnan U. Combined multichannel intraluminal impedance and pH measurement in detecting gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr 2016;63:e98106.
  9. Rosen R, Lord C, Nurko S. The sensitivity of multichannel intraluminal impedance and the pH probe in the evaluation of gastroesophageal reflux in children. Clin Gastroenterol Hepatol 2006;4:16772.
  10. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49:498547.
  11. Rosen R, Hart K, Nurko S. Does reflux monitoring with multichannel intraluminal impedance change clinical decision making? J Pediatr Gastroenterol Nutr 2011;52:404.
  12. Rossi P, Isoldi S, Mallardo S, et al. Combined multichannel intraluminal impedance and pHmonitoring is helpful inmanaging childrenwith suspected gastro-oesophageal reflux disease. Dig Liver Dis 2018;50:9105.
  13. Vakil N, Van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidencebased consensus. Am J Gastroenterol 2006;101:190020.
  14. Kleinman L, Nelson S, Kothari-Talwar S, et al. Development and psychometric evaluation of 2 age-stratified versions of the Pediatric GERD Symptom and Quality of Life Questionnaire. J Pediatr Gastroenterol Nutr 2011;52:51422.
  15. Orenstein SR. Symptoms and reflux in infants: Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) utility for symptom tracking and diagnosis. Curr Gastroenterol Rep 2010;12:4316.
  16. Kleinman L, Rothman M, Strauss R, et al. The Infant Gastroesophageal Reflux Questionnaire Revised: development and validation as an evaluative instrument. Clin Gastroenterol Hepatol 2006;4:58896.
  17. Jodorkovsky D, Price JC, Kim B, et al. Multichannel intraluminal impedancepH testing is clinically useful in the management of patients with gastroesophageal reflux symptoms. Dig Dis Sci 2014;59:181722.
  18. De Bruyne P, Ito S. Toxicity of long-term use of proton pump inhibitors in children. Arch Dis Child 2018;103:7882.
  19. Canani RB, Cirillo P, Roggero P, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and communityacquired pneumonia in children. Pediatrics 2006;117:e81720.
  20. Cohen S, Bueno de Mesquita M, Mimouni FB. Adverse effects reported in the use of gastroesophageal reflux disease treatments in children: a 10 years literature review. Br J Clin Pharmacol 2015;80:2008.
  21. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al., American Gastroenterological Association. American Gastroenterological Association Medical Position Statement on the Management of Gastroesophageal Reflux Disease. Gastroenterology 2008;135:1383.e191.e5.
  22. Rosen R, Vandenplas Y, Singendonk M, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2018;66:51654.
  23. Orr WC, Goodrich S, Robert J, et al. The effect of acid suppression on sleep patterns and sleep-related gastro-oesophageal reflux. Aliment Pharmacol Ther 2005;21:1038.
  24. Kovesi T, Rubin SJC. Long-term complications of congenital esophageal atresia and/or tracheoesophageal fistula. Chest 2004;126: 91525.
  25. Australian Bureau of Statistics 2016, Census of Population and Housing 2016, ABS, Canberra.
  26. Haddad I, Kierkus J, Tron E, et al. Efficacy and safety of rabeprazole in children (1-11 years) with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2013;57:798807.
  27. Baker R, Tsou VM, Tung J, et al. Clinical results from a randomized, double-blind, dose-ranging study of pantoprazole in children aged 1 through 5 years with symptomatic histologic or erosive esophagitis. Clin Pediatr (Phila) 2010;49:85265.
  28. Fiedorek S, Tolia V, Gold BD, et al. Efficacy and safety of lansoprazole in adolescents with symptomatic erosive and non-erosive gastroesophageal reflux disease. J Pediatr Gastroenterol Nut 2005;40:31927.
  29. Tolia V, Ferry G, Gunasekaran T, et al. Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr 2002;35:S30818.

The authors report no conflicts of interest.

Copyright (c) 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

DOI: 10.1097/MPG.0000000000002851


Supplementals

Table, Supplemental Digital Content 1. Summary of treatment change with some overlapping

Treatment Change

N (%)

Start PPI

15 (25.9)

Increase PPI

4 (6.9)

Switch PPI

1 (1.7)

Start H2RA

2 (3.4)

Start prokinetic

11 (19.0)

Increase prokinetic

1 (1.7)

Switch prokinetic

3 (5.2)

Start neuromodulator

1 (1.7)

Fundoplication referral

2 (3.4)

Change of feeding mode

3 (5.2)

Treatment unchanged

15 (25.9)

Anti-reflux treatment unchanged

6 (10.3)

Anti-reflux treatment not commenced

9 (15.6)

PPI: proton pump inhibitors, H2RA: H2 Receptor Antagonist

Abnormal ARI
N=6

Start PPI only

4

Start PPI + start prokinetic

2

Abnormal RBM
N=2

Start AST only

2

Hypersensitive Esophagus
N=10

Start PPI only

5

Start PPI + start prokinetic

2

Anti-reflux treatment not commenced

3



Normal: Functional/Non-reflux N=6

Anti-reflux treatment not commenced

3



Abnormal ARI
N=4

Start prokinetic only

1

Switch prokinetic only

1

Start H2RA + start prokinetic + fundoplication referral

1

Switch PPI + switch prokinetic

1

Hypersensitive Esophagus
N=11

Increase PPI only

2

Start prokinetic only

3

Start prokinetic + fundoplication referral

1

Start H2RA + start prokinetic

1

Increase prokinetic only

1

Change in feeding mode

3

Anti-reflux treatment unchanged

3

Normal: Functional/Non-reflux N=6

Increase PPI only

1

Increase PPI + Switch prokinetic

1

Start neuromodulator

1

Anti-reflux treatment unchanged

3

Figure, Supplemental Digital Content 3. Treatment changes in on AST group


Abnormal ARI N=1


Switch AST + start prokinetic

1

Figure, Supplemental Digital Content 4. Treatment changes in EA/TEF off AST group (N=10)


Hypersensitive Esophagus
N=6

Start prokinetic only

3

Start H2RA + start prokinetic

1

Change in feeding mode

2

Fundoplication referral

1

Anti-reflux treatment unchanged

2

Normal: Functional/Non-reflux N=3

Increase AST only

1

Increase AST + Switch prokinetic

1

Anti-reflux treatment unchanged

1



Table, Supplemental Digital Content 5. Predictive factors and their relationship with score improvement

Predictive factors

P value

Height z score

0.658

Weight z score

0.686

Gender (M vs F)

0.385

Age (Infant vs Older Children)

0.669

MII-pH results (Normal vs abnormal)

0.027

Symptom indication (TES vs EES)

0.379

Prior fundoplication (Yes vs No)

0.742

Comorbidities (Yes vs No)

0.577

Feeding mode (Oral vs non-oral)

0.682

Medication status (On AST vs off AST)

0.385

Medication change (Yes vs No)

P<0.001


MII-pH: multichannel intraluminal impedance and pH, AST: acid suppression therapy

""

. : " ", " -",
" ", " " .

.

 -