World Journal of

WJ C P Clinical Pediatrics
Submit a Manuscript: https://www.f6publishing.com World J Clin Pediatr 2023 June 9; 12(3): 151-161

DOI: 10.5409/wjcp.v12.i3.151 ISSN 2219-2808 (online)

ORIGINAL ARTICLE
Prospective Study
Prevalence of gastroesophageal reflux disease in children with
extraesophageal manifestations using combined-video, multichannel
intraluminal impedance-pH study

Sutha Eiamkulbutr, Termpong Dumrisilp, Anapat Sanpavat, Palittiya Sintusek

Specialty type: Gastroenterology Sutha Eiamkulbutr, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok
and hepatology 10330, Thailand

Provenance and peer review: Termpong Dumrisilp, Department of Pediatrics, Bhumibol Adulyadej Hospital, Bangkok 10220,
Invited article; Externally peer Thailand
reviewed.
Anapat Sanpavat, Department of Pathology, Chulalongkorn University, Bangkok 10330,
Peer-review model: Single blind Thailand

Peer-review report’s scientific Palittiya Sintusek, Thai Pediatric Gastroenterology, Hepatology and Immunology Research
quality classification Unit, King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University,
Bangkok 10330, Thailand
Grade A (Excellent): 0
Grade B (Very good): B Corresponding author: Palittiya Sintusek, MD, PhD, Associate Professor, Thai Pediatric
Grade C (Good): C Gastroenterology, Hepatology and Immunology Research Unit, King Chulalongkorn Memorial
Grade D (Fair): 0 Hospital, Faculty of Medicine, Chulalongkorn University, 1873 Rama IV Road, Pathumwan,
Grade E (Poor): 0 Bangkok 10330, Thailand. [email protected]
P-Reviewer: Lv L, China; Xiao Y,
China
Abstract
Received: February 20, 2023 BACKGROUND
Peer-review started: February 20, Gastroesophageal reflux disease (GERD) might be either a cause or comorbidity in
2023 children with extraesophageal problems especially as refractory respiratory
First decision: April 8, 2023 symptoms, without any best methods or criterion for diagnosing it in children.
Revised: April 13, 2023
AIM
Accepted: May 6, 2023
To evaluate the prevalence of extraesophageal GERD using conventional and
Article in press: May 6, 2023
combined-video, multichannel intraluminal impedance-pH (MII-pH), and to
Published online: June 9, 2023 propose novel diagnostic parameters.

METHODS
The study was conducted among children suspected of extraesophageal GERD at
King Chulalongkorn Memorial Hospital between 2019 and 2022. The children
underwent conventional and/or combined-video MII-pH. The potential para-
meters were assessed and receiver operating characteristic was used for the
significant parameters.

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Eiamkulbutr S et al. Combined-video, MII-pH in extraesophageal GERD

RESULTS
Of 51 patients (52.9% males), aged 2.24 years were recruited. The common problems were cough,
recurrent pneumonia, and hypersecretion. Using MII-pH, 35.3% of the children were diagnosed
with GERD by reflux index (31.4%), total reflux events (3.9%), and symptom indices (9.8%) with
higher symptom recorded in the GERD group (94 vs 171, P = 0.033). In the video monitoring group
(n = 17), there were more symptoms recorded (120 vs 220, P = 0.062) and more GERD (11.8% vs
29.4%, P = 0.398) by symptom indices. Longest reflux time and mean nocturnal baseline
impedance were significant parameters for diagnosis with receiver operating characteristic areas of
0.907 (P = 0.001) and 0.726 (P = 0.014).

CONCLUSION
The prevalence of extraesophageal GERD in children was not high as expected. The diagnostic
yield of symptom indices increased using video monitoring. Long reflux time and mean nocturnal
baseline impedance are novel parameters that should be integrated into the GERD diagnostic
criteria in children.

Key Words: Extraesophageal reflux; pH-impedance; Children; Gastroesophageal reflux; Mean nocturnal
baseline impedance

©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.

Core Tip: This was a retrospective and cross-sectional study with 51 children suspected extraesophageal
gastrointestinal esophageal reflux disease (GERD). This study found the prevalence of GERD in these
pediatric patients was 35.3% by using combined-video, multichannel intraluminal impedance-pH study.
Moreover, longest reflux time and mean nocturnal baseline impedance were depicted as the significant
parameters for GERD diagnosis with satisfied diagnostic value in children.

Citation: Eiamkulbutr S, Dumrisilp T, Sanpavat A, Sintusek P. Prevalence of gastroesophageal reflux disease in

children with extraesophageal manifestations using combined-video, multichannel intraluminal impedance-pH
study. World J Clin Pediatr 2023; 12(3): 151-161
URL: https://www.wjgnet.com/2219-2808/full/v12/i3/151.htm
DOI: https://dx.doi.org/10.5409/wjcp.v12.i3.151

INTRODUCTION
Gastroesophageal reflux (GER) is a physiologic process that commonly occurs in infants. Gastroeso-
phageal reflux disease (GERD) occurs when the refluxates cause troublesome symptoms. The incidence
of GERD has increased in children (0.84 per 1000 persons-year)[1]. Its manifestation varies. Hence, a
high index of suspicion is necessary, especially for extraesophageal manifestations[2]. In clinical
practice, respiratory problems that are refractory to the standard treatment might be from the disease
itself or are extraesophageal manifestations of GERD. Moreover, GERD can be a serious comorbidity
that worsens those respiratory conditions. Consequently, the development of a standard tool to dia-
gnose extraesophageal GERD and its prompt management are crucial.
There are many diagnostic tools for extraesophageal GERD, including pH monitoring, combined
multichannel intraluminal impedance and pH (MII-pH) study, esophagogastroduodenoscopy (EGD)
with biopsies, and laryngoscopy[3]. According to clinical practice guidelines for GERD diagnosis and
management in children (North American Society of Pediatric Gastroenterology, Hepatology, and
Nutrition and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition), the MII-
pH study is the best diagnostic method for esophageal manifestations of GERD[4]. Recent studies in
adults also propose that additional parameters from the MII-pH study, mean nocturnal baseline
impedance (MNBI), and post-reflux swallow-induced peristaltic wave (PSPW), increase the diagnostic
value of this tool[5]. However, there is scarce evidence to support the best method for diagnosing
extraesophageal GERD in children. Further evaluation is necessary. The main purpose of this study is to
determine the prevalence of GERD in children with extraesophageal symptoms using conventional and
combined-video MII-pH studies. The secondary aim is to assess the diagnostic usefulness of combined-
video MII-pH studies for GERD and other diagnostic parameters.

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 Eiamkulbutr S et al. Combined-video, MII-pH in extraesophageal GERD

MATERIALS AND METHODS

Patient selection
The present study is a retrospective and cross-sectional study in children and adolescents with
respiratory symptoms and other extraesophageal manifestations suggestive of GERD. Participants were
treated at King Chulalongkorn Memorial Hospital (KCMH) from February 2019 to December 2021.
Patients who had extraesophageal symptoms (cough, apnea or brief resolved unexplained event,
uncontrolled asthma, recurrent pneumonia, stridor, hoarseness, chronic sinusitis with unknown causes,
allergic rhinitis with difficulty to treatment), and who were between 1 mo and 18 years old were
included in the study. The exclusion criteria were patients who were on proton pump inhibitors or
prokinetics during MII-pH monitoring, unwillingness to participate in the study, and patients who were
already known the other causes that could explain those extraesophageal symptoms.
The Chulalongkorn University Institutional Review Board approved this study (IRB 029/64).
Informed consents and assents were obtained from the patient’s guardians and patients, respectively,
before recruitment to the study.

MII-pH study and/or video monitoring

According to the protocol, patients had to fast for one to two hours before a nasal impedance catheter
with a pH probe (Pediatric ZandorpH catheter with one antimony and six impedance sensors with 1.5
cm interval, Laborie, The Netherlands) was distributed throughout the esophagus. The Strobel formula
[6] was used to calculate the proper position of the catheter. Chest X-ray was then used to confirm that
the pH probe was located at 2–3 vertebral distance from the diaphragm. During the MII-pH monitoring,
all patients had their regular meals. Video monitoring was conducted simultaneously with MII-pH
monitoring in 17 patients. The total time of monitoring after excluding meal periods was at least 18 h.
The number of reflux events, the reflux index (RI), the symptom index (SI)/symptom sensitivity index
(SSI)/symptom association probability (SAP), longest reflux time (LRT), the MNBI, and PSPW were
recorded.
Pathological reflux is defined according to the position statement by the British Society of Paediatric
Gastroenterology, Hepatology and Nutrition (BSPGHAN) Motility Working Group[6] as RI > 7% in
children aged ≥ 1 year, and > 10% in children aged < 1 year, or if reflux episodes occur ≥ 70 times in
children aged ≥ 1 year, and ≥ 100 times in children aged < 1 year or positive SI/SSI/SAP. Regarding
symptom recoding, SI is calculated as (reflux-related symptom occurrences/total symptom events) ×
100. SI is considered positive if the value is ≥ 50%. SSI is calculated as (number of symptom-associated
reflux/total number of reflux episodes) × 100. If the percentage of SSI is ≥ 10%, it is considered positive.
SAP is calculated by dividing the total measuring time into 2-min intervals, and creating a four-field
contingency table: The number of intervals with and without GER symptoms, number of intervals with
and without GER symptoms, number of intervals without GER and with the symptoms, and number of
intervals without GER and symptoms. Fisher’s exact test was performed for statistical examination of
correlation. A percentage greater than 95% was considered positive.
Regarding the new parameters, MNBI was measured from the most distal impedance channel during
sleep, with three 10-min time intervals that did not interfere with swallowing. The mean of these three
values was then calculated. PSPW was defined as an antegrade 50% drop in impedance originating in
the proximal esophagus within 30 s after the end of a reflux event and reaching the distal lumen. The
PSPW index was calculated by the number of PSPW divided by the total number of refluxes[5,7].

Esophageal gross and histopathology finding

Within three months of the MII-pH study esophagogastroduodenoscopy with biopsy was performed on
selected patients from recruitment according to decisions by the doctors in charge. The Los Angeles
(LA) Classification[8] was routinely used to record endoscopic findings. The esophageal histopathology
finding was reported by a pathologist using the modified Esohisto criteria as described in our previous
study[8]. In short, a calculated severity score of 0–0.25 was considered normal and a score of ≥ 0.5 was
regarded as esophagitis.

Statistical analysis
Data of categorical variables were expressed as percentages or proportions, and continuous variables as
median [interquartile range (IQR)]. These variables were compared using Fisher’s exact test and
Wilcoxon signed ranks test as appropriate. Univariable and multivariable analyses were used to assess
the independent factors of extraesophageal GERD from demographic variables and parameters from
MII-pH analysis. Statistical significance was defined as P value < 0.05. Receiver operating characteristic
analysis with calculation of the area under the curve was used to assess the diagnostic yield of the
potential parameters of extraesophageal GERD. Statistical analysis was performed using SPSS software
version 24.0.0 (SPSS Inc., Chicago, IL, United States) and Stata version 15.1 (Stata Corp, LLC, College
Station, TX, United States).

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RESULTS
Baseline characteristics of children with suspected extraesophageal GERD
There were 83 children with suspected extraesophageal GERD at KCMH from February 2019 to July
2022. Thirty-two participants were excluded from the present study because they received proton pump
inhibitors/prokinetics during the MII-pH study (n = 21), had unwilling guardians (n = 3), and because
they had known causes of respiratory symptoms (n = 8). Consequently, a total of 51 children were
recruited and 17 of them underwent both the MII-pH study and video monitoring. Twenty-five children
underwent upper endoscopy, while 22 underwent esophageal biopsy for histopathology. The median
age of these 51 participants was 2.24 (1.11, 7.67) years and 27 (52.9%) participants were males. Their
underlying diseases were multiple anomalies (47%), respiratory disorders (35.3%), and neurological
disorders (17.7%). The most common extraesophageal symptoms indicated in the MII-pH study were
cough (41.2%), recurrent pneumonia (25.5%), and hypersecretion (11.8%). However, 16 (31.4%)
participants also had concurrent gastrointestinal symptoms. The median duration of MII-pH recording
was 22.09 (20.20, 23.41) h. Only 265 symptoms were recorded by guardians, including cough (n = 109,
41.1%), irritability (n = 54, 20.4%), apparent secretion (n = 24, 9.1%), vomiting (n = 34, 12.8%), and
heartburn (n = 44, 16.6%). In total, 18 (35.3%) participants were diagnosed with GERD using the MII-pH
study. In the subgroup of children who underwent upper endoscopy (n = 25) and 22 of them had
received esophageal tissue biopsy, 18 (72%) and 16 (72.7%), respectively, were diagnosed with GERD
using the LA classification and modified Esohisto, respectively (Figure 1).

MII-pH study
According to the diagnostic criteria by the BSPGHAN Motility Working Group[6], 18 participants had
parameters that were compatible with GERD. A comparison between the GERD and non-GERD groups
did not reveal any statistical difference in the baseline characteristics. Besides the parameters from the
MII-pH study that were used for diagnosing GERD (total reflux event, reflux index, and symptom
index), total symptom record (94 vs 171 times, P = 0.033), LRT (1.3 (0, 4.3) vs 17.2 (9.43, 38.55), P < 0.001),
and MNBI (1897.69 (806.89) vs 1300.48 (600.31) ohms, P = 0.008), were significantly different between the
non-GERD and GERD groups, respectively. Meanwhile, PSPW, another novel metric, did not show a
significant difference between the groups [53.57 (27.59) vs 56.11 (15.7), P = 0.721]. In the multivariable
analysis, LRT and MNBI were the independent parameters that were significantly differences in
participants diagnosed with GERD (P < 0.05) (Table 1).

Combined MII-pH study with video monitoring

The MII-pH study with video monitoring was performed in 17 participants. By the novel combined
video-MII-pH study is different from the conventional MII-pH study. The video-MII-pH study had
conducted simultaneously with MII-pH monitoring and given the clinical symptoms recorded by the
investigator that can make more accurate of symptoms in children who cannot even report their
symptoms. Then we compared the symptoms that were recorded by the participants’ guardians
(conventional study) to the symptoms that were recorded by the video monitoring which is the same
participants.
The total number of symptoms recorded from video by an investigator who simultaneously viewed
throughout the recording, was detected higher than from participants’ guardians even though there’s
no statistical significance (220 vs 120, P = 0.062. This led to an increase in the number of participants who
were diagnosed with GERD by using symptom association indices (SI/SSI/SAP) (n = 2, 11.8% vs n = 5,
29.4%, P = 0.398) (Table 2).

Diagnostic value of the novel parameters from MII-pH study

When using the significant parameters from multivariable analysis to identify GERD, longest reflux
duration and MNBI yielded an area under the curve (AUC) of 0.907 (95%CI: 0.802–1) and 0.726 (95%CI:
0.581–0.870), correspondingly. Combining these two parameters yielded an AUC of 0.914 (95%CI:
0.819–1) (Figure 2). A cutoff value of eight minutes for longest reflux duration had a sensitivity of
83.33% and a specificity of 90.91%. A cutoff value of 1466 ohm for MNBI had a sensitivity of 50.0% and a
specificity of 33.33%.

DISCUSSION
The prevalence of extraesophageal GERD was 35.3% by using the MII-pH study in this study.
Interestingly, 31.4% of children who had extraesophageal manifestations of GERD also had gastro-
intestinal symptoms. Total symptom record, LRT, and MNBI were the parameters that were
significantly different between the GERD and non-GERD groups. LRT and MNBI were the independent
parameters from multivariable analysis. Using video monitoring during MII-pH study to depict more
symptom record increases the diagnostic yield of extraesophageal GERD.

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Table 1 Demographic characteristics and parameters from Multichannel intraluminal impedance-pH study in children diagnosed with
extraesophageal gastroesophageal reflux disease and no extraesophageal gastroesophageal reflux disease, n, (%)

P value
No extraesophageal GERD Diagnosed extraesophageal
Characteristics Univariable Multivariable
(n = 33) GERD by MII-pH study (n = 18)
analysis analysis
Age (yr) (median, IQR) 1.67 (0.91, 3.38) 4.58 (1.70, 13.15) 0.174

Age < 1 yr 10 (30.3) 2 (11.1)

Age ≥ 1 yr 23 (69.7) 16 (88.9)

Sex, male 17 (51.5) 10 (55.6) 1

Underlying diseases 0.441

Respiratory disorder

Bronchiectasis 1 (3.03) 0

Chronic lung disease 7 (21.21) 2 (11.11)

Congenital hypoventilation 0 2 (11.11)

syndrome

Subglottic stenosis 0 1 (5.56)

Tracheobronchomalacia 1 (3.03) 0

Laryngomalacia 1 (3.03) 0

BRUE 1 (3.03) 0

Chronic cough 1 (3.03) 0

Neurological disorder

Swallowing dysfunction 2 (6.06) 1 (5.56)

Spastic cerebral palsy 2 (6.06) 3 (16.67)

Infantile spasm 1 (3.03) 0

Multiple anomalies

Syndromic disorder 6 (18.18) 2 (11.11)

Non-syndromic disorder 9 (27.27) 7 (38.89)

Indication for evaluation

Extraesophageal symptoms 0.679

Recurrent pneumonia 9 (27.3) 4 (22.2)

Hypersecretion 4 (12.1) 2 (11.1)

Cough 11 (33.3) 10 (55.6)

Glossoptosis 1 (3.0) 0

Tracheobronchomalacia 1 (3.0) 0

Stridor 1 (3.0) 0

Choking 4 (12.1) 1 (5.6)

Chronic rhinosinusitis 0 1 (5.6)

BRUEs 1 (3.0) 0

Apnea 1 (3.0) 0

Esophageal symptoms 0.293

Vomiting 8 (24.2) 6 (38.9)

Heartburn 1 (3.0) 1 (5.6)

None 24 (72.7) 11 (61.1)

Total recorded symptoms 94 171 0.033 0.064

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Eiamkulbutr S et al. Combined-video, MII-pH in extraesophageal GERD

(times, %)

Cough 43 (45.75) 66 (38.60) 0.404

Irritability 32 (34.04) 22 (12.86) 0.754

Apparent secretion 7 (7.44) 17 (9.94) 0.346

GI symptoms (vomiting or 12 (12.77) 66 (38.60) 0.081

heartburn)

Impedance parameters (median,

IQR)

Total time (hours) 22.12 (20.34, 24.04) 21.34 (19.97, 22.62) 0.391
1
Reflux index 0.40 (0, 1.45) 8.4 (4.43, 14.20) 0.001

Longest reflux time (min) 1.3 (0, 4.30) 17.2 (9.43, 38.55) 0.001

Total reflux events1 12 (5.00, 37.50) 28 (18.50, 45.50) 0.032 0.012

Weakly acid reflux events

Acid reflux events 9 (2.50, 27.00) 10 (3.75, 21.75) 0.79

Nonacid reflux events 1 (0, 4.50) 15.5 (8.75, 25.25) 0.001

Symptom indices 0 (0, 4.00) 0 (0,1.00) 0.381 0.212

Symptom index1 0 (0, 0.00) 0 (0, 12.73) 0.208

Symptom sensitivity index1 0 (0, 0.00) 0 (0, 1.40) 0.32

1
Symptom associated index 0 (0, 0.00) 0 (0, 85.63) 0.168

MNBI (ohms) (mean, SD) 1897.69 (806.89) 1300.48 (600.31) 0.008

PSPW (%) (mean, SD) 53.57 (27.59) 56.11 (15.70) 0.721

Diagnosis GERD

Gross finding (n = 25) 8/12 (66.7) 10/13 (76.9) 0.673

Histopathology (n = 22) 6/11 (54.5) 10/11 (90.9) 0.149

1
Significant factors in univariable analysis were not included in the multivariable analysis because of collinearity with criteria diagnosis gastroesophageal
reflux disease using the MII-pH study.
BRUE: Brief resolved unexplained event; MNBI: Mean nocturnal baseline impedance; PSPW: Post-reflux swallow-induced peristaltic wave index; GERD:
Gastroesophageal reflux disease; MII-pH: Multichannel intraluminal impedance-pH; IQR: Interquartile range.

Table 2 Comparing symptoms recorded by conventional and combined visual data object -monitoring in children who underwent
multichannel intraluminal impedance-pH study (n = 17), n, (%)

Characteristics Conventional MII-pH study Combined video-MII-pH study P value

Total recorded symptoms 120 220 0.062

Cough 31 (25.83) 46 (20.90) 0.259

Irritability 38 (31.67) 101 (45.90) 0.114

Apparent secretion 3 (2.50) 43 (19.55) 0.02

GI symptoms (vomiting or heartburn) 48 (40.00) 33 (15.00) 0.339

Symptom indices (median, IQR)

Symptom index 0 (0–5.00) 0 (0–11.65) 0.306

Symptom sensitivity index 0 (0–2.65) 0 (0–5.80) 0.306

Symptom associated index 0 (0–37.60) 0 (0–93.15) 0.306

Diagnosis GERD using symptom indices 2 (11.76) 5 (29.41) 0.398

GI: Gastrointestinal; GERD: Gastroesophageal reflux disease; MII-pH: Multichannel intraluminal impedance-pH; IQR Interquartile range.

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 Eiamkulbutr S et al. Combined-video, MII-pH in extraesophageal GERD

Figure 1 Recruitment of children with respiratory symptoms suggestive of gastroesophageal reflux disease. EGD: Esophagogastro-
duodenoscopy; GERD: Gastroesophageal reflux disease; MII-Ph: multichannel intraluminal impedance and pH.

Figure 2 Area under the receiver operating characteristic curve of the novel parameters to diagnose extraesophageal gastroesophageal
reflux disease. MNBI: Mean nocturnal baseline impedance; ROC: Receiver operating characteristic curve; GERD: Gastroesophageal reflux disease.

There are several debates over clinical symptoms of extraesophageal reflux disease in children
because of heterogeneity, non-specificity, and unreliability. Moreover, the prevalence of extraeso-
phageal GERD reflects the real burden and depends on the modalities for diagnosis. Hence, finding the
best diagnostic tool for extraesophageal GERD is crucial. Many proposed diagnostic tools, such as
oropharyngeal pH monitoring/salivary pepsin, have been studied with unsatisfactory results[9-11]. As
a result, the present study was designed using MII-pH study and histopathology—which are the gold
standard for diagnosing esophageal GERD—to be the gold standard diagnosis for extraesophageal
GERD. Moreover, combined-video monitoring was performed in 17 participants. The present study

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found that video monitoring increased the value of symptom-reflux association in extraesophageal
GERD. This is congruent with our previous study which depicted a trend of symptom-reflux association
with particular symptoms of GERD in children diagnosed with esophageal atresia[12]. The real-time
video captured in MII-pH monitoring with physician symptom recordings had higher symptom indices.
There were more symptoms recorded including cough, hypersecretion, irritability, and vomiting. There
were also more GERD diagnoses secondary to the symptoms that were more trustworthy than conven-
tional methods. These studies highlight that symptom recording by video monitoring in children
increases the value of symptom association for GERD diagnosis.
Although identifying extraesophageal manifestation of GERD is challenging and needs evaluation
regarding whether it represents true GERD or a mimicker, the present study found concomitant
gastrointestinal symptoms or signs in a majority of these children. Moreover, esophagitis was also
detected in a majority of children with extraesophageal symptoms in the present study. This might
explain the gastrointestinal symptoms they experienced. The reflex theory is a possible explanation
regarding why children with extraesophageal GERD also had gastrointestinal involvement. The theory
suggests that reflux stimulates the vagus nerve in the esophagus leading to cough, bronchoconstriction,
or other extraesophageal symptoms via vagally mediated reflexes[13,14]. However, previous studies
demonstrated a lower prevalence of esophagitis in patients with extraesophageal GERD. A positive
reflux-laryngitis varies from 5% up to 31%[15-18]. Routine upper endoscopy in all children with solely
extraesophageal symptoms might be avoided. This invasive procedure should be preserved for patients
who have both extraesophageal and esophageal manifestations of GERD. To increase the reliability of
symptom assessment, we encourage the physician to have the dedicated history taking or possible video
recording of symptoms during MII-pH study simultaneously with the routine symptom recorded by
patients or their guardians. Upper endoscopy with biopsy is necessary and could increase the yield of
GERD diagnosis in these selected children.
Besides using symptom association to diagnose extraesophageal GERD, we found that acid reflux
was mainly present in the present study in accordance with Borrelli et al’s work. Borrelli et al[19] found
that 66% of cough bursts were related to acid reflux episodes. However, different results were
demonstrated by Zenzeri et al[20] who found predominantly weak acid and nonacid reflux in children
with respiratory problems. Because of the lack of standardized protocol and children’s conditions in
previous studies, a large multicenter study regarding children with different manifestations is necessary
to extend the knowledge and narrow the specific treatment for them. In the present study, a majority of
children had complicated underlying diseases (multiple anomalies, respiratory disease, or neurological
deficit) that increased the risk of esophageal motility disorder and reflux. This could explain the high
predominance of acid reflux.
The pathogenesis of GERD is complex and multifactorial. Though abnormal transient esophageal
relaxation is the main pathogenesis, other factors such as-esophageal mucosal disease, esophageal
dysmotility, gastroparesis, and anatomical defect (hiatal hernia, short segment of abdominal
esophagus)-must be considered as aggravated risk factors of GERD[21]. Children with multiple
comorbidities, especially neurological deficit, usually have sedentary lifestyles or are bedridden, and
this affects gastrointestinal motility. We found that the LRT had statistically significant discriminate
GERD and non-GERD children, reflexes the impairment of esophageal volume clearance as one of the
pathogenesis of GERD[22,23]. However, there was no impairment of chemical clearance as shown by
the insignificant difference in PSPW in both groups. MNBI is another parameter that can discriminate
GERD from non-GERD children. MNBI represents esophageal integrity[5] and has a reasonably low
value in GERD. To the best of our knowledge, PSPW and MNBI are the new impedance-pH parameters
which are integral in the Lyon Consensus criteria for diagnosing GERD in adults[24]. The impact of
PSPW and MNBI on increasing the yield of GERD diagnosis in children is rare. There is only one study
concerning the impact of MNBI in children with GERD by Rosado-Arias et al[25]. That study found that
a low MNBI is associated with a pathological AET. Our study is compatible with the study by Rosado-
Arias et al[25] and confirmed the role of a low MNBI in helping the diagnostic yield of GERD. To the
best of our knowledge, the present study is the first study to evaluate the PSPW parameter between
GERD and non-GERD children. A previous study by Park et al[26] showed impairment of PSPW in
adults with laryngopharyngeal reflux and esophageal GERD, but our study is incongruent with same. It
is possible that the chemical clearance is important for the pathogenesis of extraesophageal GERD in
adults vs in children. Further studies from multicenter or with the higher number of participants about
PSPW and MNBI parameters, are crucial in aiding the diagnosis of GERD in children.
The certain strength of our study is that we integrated video monitoring into MII-pH study for
diagnosing extraesophageal GERD in children. Moreover, the novel parameters (PSPW and MNBI) were
evaluated to increase the yield of GERD diagnosis. However, there are some limitations. Firstly, it was a
small number of children in a single center study. Therefore, the results are specific to the particular co-
morbidities that were present and cannot be extrapolated to children with previously healthy or less co-
morbidities. Secondly, because of the coronavirus disease 2019 pandemic, upper endoscopy was not
performed in all children. Given this, there is the potential for selective bias and a high prevalence of
children with extraesophageal GERD having esophagitis.

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 Eiamkulbutr S et al. Combined-video, MII-pH in extraesophageal GERD

CONCLUSION
In conclusion, the prevalence of GERD was not as high as expected. Employing video monitoring into
conventional MII-pH study increases the diagnostic yield of symptom indices. LRT and MNBI are novel
parameters that should be integrated into the diagnostic criteria for GERD.

ARTICLE HIGHLIGHTS
Research background
Gastroesophageal reflux disease (GERD) might be either a cause or comorbidity in children with
extraesophageal problems especially as refractory respiratory symptoms, without any best methods or
criterion for diagnosing it in children.

Research motivation
Recent studies in adults also propose that additional parameters from the multichannel intraluminal
impedance (MII)-pH study, mean nocturnal baseline impedance (MNBI), and post-reflux swallow-
induced peristaltic wave, increase the diagnostic value of this tool. However, there has been scarce
evidence to support the best method for diagnosing extraesophageal GERD in children.

Research objectives
To study the prevalence of extraesophageal GERD, especially in children who presented with refractory
respiratory problems by using combined video-MII-pH study. Furthermore, to identify other
parameters from MII-pH study that can help the diagnosis of extraesophageal GERD.

Research methods
Children with respiratory symptoms and other extraesophageal manifestations suggestive of GERD
were enrolled to participate in the present study. MII-pH study and/or video monitoring and/or upper
endoscopy with esophageal histopathology were performed. The prevalence of extraesophageal GERD
and the novel diagnostic parameters to diagnose extraesophageal GERD were analyzed.

Research results
The prevalence of extraesophageal GERD was 35.3% by using the MII-pH study and 31.4% of children
who had extraesophageal manifestations of GERD also had gastrointestinal symptoms. Total symptom
record, longest reflux time (LRT), and MNBI were the parameters that were significantly different
between the GERD and non-GERD groups. LRT and MNBI were the independent parameters from
multivariable analysis. Using video monitoring during MII-pH study to depict more symptom record
increases the diagnostic yield of extraesophageal GERD.

Research conclusions
In conclusion, the prevalence of GERD was not as high as expected. Employing video monitoring into
conventional MII-pH study increases the diagnostic yield of symptom indices. LRT and MNBI are novel
parameters that should be integrated into the diagnostic criteria for GERD.

Research perspectives
The diagnostic test for extraesophageal GERD in children is limited and there have been a few data
support the favorable treatment outcome in these children. Hence, the extensive investigations in these
difficult cases are needed and other mimic causes should be ruled out. Further study in aspect of
esophageal manometry combined with video-MII-pH study and histopathology in various present-
ations of GERD should be initiated to extend the knowledge about the pathogenesis of GERD and
hopefully, could tailor therapy for these patients.

ACKNOWLEDGEMENTS
We are grateful to all participants and their guardians in the present study; Voranush Chongsrisawat,
Chomchanat Tubjareon, Sittichoke Prachuapthunyachart, Atikan Sirichoompun, Nattakoon
Potjalongsin, all physician and nurses for the great care to our patients.

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Eiamkulbutr S et al. Combined-video, MII-pH in extraesophageal GERD

FOOTNOTES
Author contributions: Eiamkulbutr S, Dumrisilp T and Sintusek P performed the upper endoscopy and MII-pH
study; Eiamkulbutr S, Dumrisilp T collected all the data; Sanpavat A analyzed and interpreted the histopathological
data; Eiamkulbutr S recorded all symptoms from video recording; Eiamkulbutr S and Sintusek P analyzed and
interpreted the MII-pH study and wrote the manuscript; Sintusek P was responsible for designing, editing, and
revising the manuscript; Sintusek P edited the intellectual content in the manuscript; all approved for the final
version of the manuscript.

Supported by The Ratchadapiseksompotch Fund, Chulalongkorn University's Faculty of Medicine, King

Chulalongkorn Memorial Hospital's Department of Pediatrics, and Chulalongkorn University's Faculty of Medicine
(GA64/48).

Institutional review board statement: The study was reviewed and approved by the Chulalongkorn University
Institutional Review Board approved this study (IRB 029/64).

Clinical trial registration statement: This study is registered at

https://www.thaiclinicaltrials.org/show/TCTR20210829001. The registration identification number is
TCTR20210829001.

Informed consent statement: All study participants, or their legal guardian, provided written consent prior to study
enrollment.

Conflict-of-interest statement: The authors of this manuscript having no conflict of interest to disclose.

Data sharing statement: Data will be shared when investigators contact the corresponding author.

CONSORT 2010 statement: The authors have read the CONSORT 2010 statement, and the manuscript was prepared
and revised according to the CONSORT 2010 statement.

Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by
external reviewers. It is distributed in accordance with the Creative Commons Attribution-NonCommercial (CC BY-
NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license
their derivative works on different terms, provided the original work is properly cited and the use is non-
commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin: Thailand

ORCID number: Termpong Dumrisilp 0000-0001-7110-0664; Anapat Sanpavat 0000-0002-6425-3379; Palittiya Sintusek 0000-
0003-4441-0151.

Corresponding Author's Membership in Professional Societies: American Association for the Study of Liver Diseases,
174508; European Society of Pediatric Gastroenterology, Hepatology and Nutrition, 1135.

S-Editor: Ma YJ
L-Editor: A
P-Editor: Ma YJ

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