(2024) 24:538
Gan et al. BMC Pediatrics
https://doi.org/10.1186/s12887-024-04975-w

BMC Pediatrics

RESEARCH

Open Access

24 h combined esophageal multichannel
intraluminal impedance and pH monitoringin children with chronic coughYi Gan1, Xiaoqin Zhou1, Zhaoxuan Huang1, Shan Gao1, Guirong Wang1, Li Gu1, Di Zhang1, Lingzhi Yan1,
Shanshan Shang1, Junhua Shu1* and Danna Tu1*

Abstract
Background Chronic cough in children is closely related to gastroesophageal reflux (GER). However, this association
has not been adequately studied due to a lack of diagnostic tools. Combined esophageal multichannel intraluminal impedance and pH (MII-pH) monitoring is considered the most accurate method for evaluating the association
between symptoms and reflux, but data on its use in children with chronic cough are still lacking. We aimed to assess
the association between chronic cough and GER in children through MII-pH monitoring.
Methods Children with chronic cough (> 4 weeks) who were suspected gastroesophageal reflux disease(GERD) wereselected to undergo 24 h MII-pH monitoring at our hospital. Patients were divided into groups according to theirage, body position, reflux index (RI) or total reflux events, and the differences between the groups were analyzed.
Then the significance and value of 24 h pH and impedance monitoring in chronic cough and the relationshipbetween chronic cough and reflux were discussed.
Results Overall, 426 patients were included. The median age was 12 months (interquartile range: 6–39.5 months),
129 (30.3%) patients had RI > 7% detected by pH-metry, and 290 (68.1%) patients had positive diagnosis basedon the impedance data. GER predominantly occurred in the upright position and mostly involved weakly acidic refluxand mixed gas–liquid reflux. There were 14.1% of children in non-acid GER group were SAP positive showing no difference in acid GER group 13.2% (P = 0.88), whereas patients with SAP > 95% in MII positive group (47[16.2%]) is higher
than in MII negative group (P < 0.05).
Conclusion Twenty four hour MII-pH monitoring is safe, well tolerated in children, but also has a higher detection rate of gastroesophageal reflux. It can find identify weakly acidic reflux, weakly alkaline reflux and reflux eventswith different physical properties, which can explain the relationship between GER and chronic cough more comprehensively. It provides new approach for exploring the etiology, diagnosis and treatment of children with chronic
cough.
Keywords Pediatrics, Children, Chronic cough, Gastroesophageal reflux*Correspondence:
Junhua Shu
sfysjh2011@163.com
Danna Tutdn_tutu@163.com
Full list of author information is available at the end of the article

Introduction
For children aged ≤ 14 years, chronic cough is definedas cough that persists for > 4 weeks [1]. Previous epidemiological studies have suggested an association between
GERD and chronic cough [2]. Often, children with
GERD do not have typical symptoms of regurgitation,© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc-​nd/4.​0/.

Gan et al. BMC Pediatrics(2024) 24:538

heartburn, vomiting, failure to thrive, abdominal pain,and dysphagia.
GERD has not been commonly identified as the causeof pediatric cough due to the lack of accurate diagnostic
tools for pediatric GERD [3]. The various objective methods for diagnosing GERD include endoscopy, pH-metry(also known as pH monitoring), and MII-pH monitoring[4]. pH monitoring was developed in the 1990s, and for along time, it was regarded as the best technique for measuring reflux [5]. However, this technique cannot detect
all gastroesophageal reflux events, particularly when little or no acid is present in the refluxate. MII-pH monitoring has been recommended as a valuable alternativefor detecting and evaluating gastroesophageal reflux, as
it can effectively analyze the characteristics and components of refluxates, identify liquid and gas reflux, and differentiate between acid and non-acid reflux [6]. However,
due to the high cost of MII-pH monitoring and its poor
compliance in children, it has not been widely used inpediatrics.
Therefore, in the present study, we aimed to assess theassociation between chronic cough and gastroesophageal
reflux detected through 24 h MII-pH monitoring. To thebest of our knowledge, this was the first study in which
24 h MII-pH monitoring was used in a large sample ofpediatric patients with chronic cough to study the relationship between chronic cough and gastroesophageal
reflux in children. In addition, the characteristics of 24 h
MII-pH for chronic cough in children are described.

Methods
The 24 h-MII-pH-monitoring results of 428 children
with chronic cough (cough persisting for > 4 weeks) who
underwent MII-pH monitoring for 24 h at Hubei Maternal and Child Health Hospital between 2017 and 2020
were analyzed in this study. Children were included ifthey were aged 0–14 years and had not received any acidsuppressive drugs or drugs that affect gastric motility inthe two weeks preceding their examination. Two patientswere excluded due to intolerance and short monitoring
duration. This study was approved by the Ethics Committee of Maternal and Child Health Hospital of Hubei
Province. The parents or guardians of all participants
provided written informed consent to take part in thepresent study.
The MII-pH monitoring device allowed for the simultaneous recording of esophageal multichannel intraluminal impedance and pH (Ohmega; Laborie, Enschede,
the Netherlands). Ideally, the pH probe tip should bepositioned in the lower esophagus at 87% of the total
esophageal length [7]. For infants, we applied the Strobel
formula (0.252*body length [cm] + 5) to localize the LES

Page 2 of 10[8]. For children, we combined pH gradients to localize
the LES, then confirmed by radiography. The patientsand their guardians were encouraged to maintain normal
activities, sleep schedules, meal types, and mealtimes.
Before the study, the guardians and older children were
instructed to press the “event” buttons on the device incase of specific symptoms. They were also asked to complete a written diary reporting any symptoms, meal andsleeping times, and position changes (supine/upright).
The chemical properties of reflux were detected by pH
probe, which were categorized into acidic (pH < 4.0),
weakly acidic (pH 4.0–7.0) and weakly alkaline reflux(pH > 7.0), with the latter two defined as non-acidic
reflux [9]. The physical properties of reflux were distinguished by MII monitoring(Liquid reflux: from theimpedance channel of the last end, there are at least twocontinuous impedance channels in the retrograde, andthe impedance value decreases by > 50%.;Pure gas reflux:
the impedance value increases rapidly > 5000 in at least
two continuous impedance channels.;Mixed reflux: Gas
reflux occurs immediately before or simultaneously withliquid reflux).
Symptom-association probability (SAP) correlated
symptoms to refluxes. The entire recording of MIIpH was divided into consecutive 2-min time windows
and assessed for the presence of reflux in each time
window. In combination with symptom time and thenumber of all the symptoms recorded in the journals,
each 2-min period of the recording was classified into
reflux alone (R + S −), reflux followed by symptom(R + S +), only symptom but no reflux (R − S +), andneither reflux nor symptom (R − S −). When a symptom occurred in the 2-min span after a reflux event,it was considered as “associated to reflux” [9]. A value
greater than 95% was considered statistically significant. Patients were divided into an acid GER and nonacid GER group based on reflux index (RI); RI indicatesthe percentage of the entire esophageal record having
a pH < 4.0. Patients with RI > 7% were included in theacid GER group, and those with RI ≤ 7% were includedin the non-acid GER group [10, 11]. A positive diagnosis based on the impedance data defined as total reflux
events > 100 in patients aged < 1 year or > 70 in patients
aged ≥ 1 years [12].Variables with values that were
not normally distributed are presented as the median(interquartile range [IQR]). Median values were compared using the Mann-Whitney U test. Pearson correlation was used for associations between sequential
parameters. All statistical analyses were performed
using SPSS software (Version26.0;SPSS,Inc.,Chicago,
IL,USA). P-values < 0.05 were considered statisticallysignificant.

Gan et al. BMC Pediatrics(2024) 24:538

Results
Basic characteristic of the study cohort

Four hundred and twenty-eight children were recruitedfor this study. The recording of impedance and pH
was well tolerated by the patients. After excluding twopatients due to intolerance and a short monitoring time,
426 patients were included within the final cohort. After
MII-pH monitoring was completed, a preliminary analysis was performed, and tracings were classified according
to their quality and the presence of technical artifacts.
None of the patients were treated for GERD before
examination.
The median patient age at the time of MII-pH monitoring was 12 months (IQR: 6–39.5 months). Of the 426
patients, 292 (68.5%) patients were male, and 134 (31.5%)
were female; 186 patients (43.7%) were infants whose ages
ranged from 0 to12 months. There were 40 cases of premature birth (9.4%), 23 cases of neonatal complications(5.4%), and 24 cases of congenital malformations (5.6%),
most of which were atrial septal. The number of recently
diagnosed infections within 2 weeks before examination was 259 (60.8%) (Table 1). There were 129 patients(30.3%) in the acid GER group and 297 patients (69.7%)
in the non-acid GER group. In acid GER group,97(67.4%)
patients were male, and the median age was 36 months(IQR:10–63 months) which is higher than non-acid GERgroup with the median age 8 months(IQR:4-18 months)(P < 0.01).
PH‑metry data

The total recording duration was 24.1 h (24–24.2 h).
Tracings were separately analyzed while the patientswere in the supine (11.5 h [9.1–13.5 h]) and upright positions (12.2 h [9.6–14.7 h]). There were total 50 (IQR:19–
140.25) acid reflux episodes occurring in 24 h and 1 (0–8)
reflux event with a acid reflux duration > 5 min. The
maximum reflux duration was 9.3 min (3.1–37.1 min).
The RI was 2.6% (0.8–9.2%), and 129 (30.3%) children had
RI > 7%.
Impedance data

Through the combined monitoring of impedance andpH, it was determined that the median number of reflux
events occurring in 24 h was 110 (IQR: 76–142); themedian percentages of total reflux events occurring inpatients that involved acid reflux, weakly acidic reflux,
and weakly alkaline reflux are 29.2% (IQR: 12.8%–57.1%),
57% (IQR: 31.8%–73.4%), and 5.6% (IQR: 0.8%–13.9%),
respectively. Liquid was present in 24.5% (12.5–38.9%)of all reflux events, and gas was present in 32.1% (20.1–
51.8%) of all reflux events. However, mixed gas–liquid
reflux events accounted for the greatest proportion ofPage 3 of 10

Table 1 Demographic and clinical data of the study population(N = 426)
Total cases

426

Clinic information
Sex (boy/girl)292/134

Age (months)

12 (6–39.5)

Prematurity

40(9.4%)

Neonatal complications

23(5.4%)

Congenital malformation

24(5.6%)

Neurological comorbidity15(3.5%)

Other chronic respiratory problems

95(22.3%)

Recent infections

259(60.8%)

Total recording time (hours)

24.1 (24–24.2)

Supine position time (hours)

11.5 (9.1–13.5)

Upright position time (hours)

12.2 (9.6–14.7)

pH metry
Total reflux episodes

50 (19–140.25)

Reflux time > 5 min events

1 (0–8)Maximum reflux time (minutes)

9.3 (3.1–37.1)

Reflux index

2.6 (0.8–9.2)

Impedance
Reflux events in 24 h

110 (76–142)

Acid (%)

29.2 (12.8–57.1)

Weakly acidic (%)

57 (31.8–73)

Weakly alkaline (%)

5.6(0.8–13.8)

Liquid reflux (%)

24.5(12.5–38.9)

Gas reflux (%)

32.1(20.1–51.6)

Mixed reflux (%)

36.2(24.5–45.4)

SAP > 95%

59 (13.8%)

SAP Symptom-association probability

total reflux events (36.4% [24.5–45.6%]). The correlationof reflux events and age in all patients was analyzed. We
found that there was no relationship between age and thetotal number of reflux events (r = 0.057, P = 0.234) but amild positive correlation was observed with acid reflux
events (r = 0.343, P < 0.05). On analyzing the SAP foreach patient, we found that for 59 children (13.8%), the
SAP was > 95%. According to total reflux events form theimpedance data, total 290 patients (68.1%) were MII positive and 136(31.9%) patients were MII negative. Patientswith SAP > 95% in MII positive group (47[16.2%]) is
higher than in MII negative group (P < 0.05) (Table 2).
Differences between upright and supine positions

There were 93 (IQR: 59–128) reflux events that occurredin the upright position, of which the percentages of acidreflux events, weakly acidic reflux events, and weakly
alkaline reflux events were 33.1% (11.7–51.3%), 33.3%(13.5–52.5%), and 0% (0–4.3%), respectively. There were
18 (IQR: 8–34) reflux events that occurred in the supine

Gan et al. BMC Pediatrics(2024) 24:538

Page 4 of 10

Table 2 Comparison of 24 h impedance monitoring parameters between MII-positive group and MII-negative group
MII-positive groupn = 290(68.1%)

MII-negative groupn = 136(31.9%)

P valueage(month)13(6–46)

8(4–19.75)< 0.05Sex (boy/girl)

196/94

96/40

0.53

Total reflux episodes in pH-metry

58(20–152)

16(16–120.75)< 0.05

RI > 7%87(30%)

42(30.9%)

0.85

Total reflux events in MII

128(108–163)

64(47–79.25)< 0.01

Acid (%)

29.37(13.46–57.15)

26.97(11.98–56.28)

0.73

Weakly acidic (%)

55.79(31.11–72.24)

59.79(32.98–77.76)

0.48

Weakly alkaline (%)

6.42(1.25–14.62)

2.65(0–13.27)

0.61

Liquid reflux (%)

24.77(15–38.67)

21.52(9.38–40.83

0.25

Gas reflux (%)

37.7(28.11–46.38)

30.63(16.67–41.43)< 0.01

Mixed reflux (%)

30.12(19.21–47.76)

35.20(23.06–63.52)< 0.01

SAP > 95%

47 (16.2%)

12 (8.8%)< 0.05SAP Symptom-association probability, RI Reflux index, MII Multichannel intraluminal impedance

position, of which the percentage of acid reflux events
and weakly acidic reflux events were 4.4% (0.8–11.6%)
and 5.5% (0–15.2%), respectively. Upright periods tended
to be associated with the occurrence of a significantly
higher number of total reflux events than supine periods (P < 0.01). A high number of both acid (33.1% [11.7–
51.3%]) and weakly acidic reflux (33.3% [13.5–52.5%])
events occurred while the patients were in the uprightposition, whereas weakly acidic reflux (5.5% [0–15.2%]).
was the predominant reflux type that occurred in thesupine position. There was a significant difference inthe physical properties of reflux between reflux events
that occurred in the supine and upright positions: mixedreflux (29.7% [17.3–39.5%]) and gas reflux (25.3% [14.7–
42.6%]) were dominant in the upright position, while
liquid reflux (5.3% [1.7%-11.6%]) was dominant in thesupine position (Table 3).
Differences between the infant and children groups

Pediatric patients were divided based on age into theinfant (< 12 months; n = 186) and children (> 12 months;

n = 240) groups. The infant group had higher rates ofprematurity, chronic respiratory problems, and recent
infections than the children group (P < 0.01). There wasno significant difference in the proportion of neonatal
complications or congenital malformations between
the groups. Through pH monitoring, we found that,the infant group had significantly lower total reflux
episodes, reflux episodes in the upright position, andreflux episodes in the supine position than did the children group; they also had a lower number of acid reflux
events > 5 min and maximum reflux time (P < 0.01).
Through impedance monitoring, we found that there
was no difference between the two groups regarding
reflux events occurring in 24 h (P = 0.825). With respect
to the chemical properties of reflux, weakly acidic
reflux was predominant in the infant group (67.8%[52.1–81.4%]), while in the children group, acid reflux
was predominant (44.3% [20.7–63.2%]). The occurrenceof mixed reflux in the infant group 38.7 [28.8–49.5] wassignificantly higher than that in the children group 32.8

Table 3 Comparison of 24 h impedance monitoring parameters between upright and supine positions
Percentage Refluxof reflux
events intime in total impedancetime (%)

Chemical properties of reflux (%)

Physical properties of reflux (%)

Refluxepisodes inpH metry

Acid

WeaklyacidicWeaklyalkaline

LiquidGas

Mixed

Upright posi- 6.1 (1.7–28.7)
tion

93 (59–128)

38 (13–95)

33.1(11.7–51.3)

33.3(13.5–52.5)

0 (0–4.3)

15.3(6.7–26.3)

25.3(14.7–42.6)

29.7(17.3–39.5)

Supine position

2 (0.3–17.9)

18 (8–34)

7 (2–33)

4.4 (0.8–11.6)

5.5 (0–15.2)

0 (0–0)5.3 (1.7–11.6) 3.9 (1.2–8.9)

3.1 (0.9–7.3)

P-value< 0.01< 0.01< 0.01< 0.01< 0.01< 0.01< 0.01< 0.01< 0.01

Gan et al. BMC Pediatrics(2024) 24:538

Page 5 of 10

Table 4 Comparison of 24 h impedance monitoring parameters between infant and children groups
Infantn = 168

Childrenn = 258

p-valueAge (months)

5 (3–7)36 (17–64.5)< 0.01Sex (boy/girl)

135/33

157/101

0.06

Prematurity

29(17.3%)11(4.3%)< 0.01

Neonatal complications

15(9.0%)8(3.1%)

0.14

Congenital malformation

12(7.1%)12(4.7%)0.28

Neurological comorbidity10(6.0%)5(1.9%)

0.43

Other chronic respiratory problems

66(31.1%)

29(11.2%)< 0.01

Recent infections

170(80.2%)

89(34.5%)< 0.01

Total reflux episodes

31 (12–69)

96(30–191)< 0.01

Reflux episodes in upright position

21 (9–56)

68(23–137)< 0.01

Reflux episodes in supine position

5(1–18)14 (3–44)< 0.01

Reflux time > 5 min events

1(0–4)

3(0–16)< 0.01

Maximum reflux time (minutes)

6.55(2.8–19.5)

13.45(4.0–59.8)< 0.01

RI > 7%35(16.5%)

94(36.4%)< 0.01

Reflux events in 24 h

110(84–140.3)

110.5(72–146)

0.83

Acid (%)

19.9(8.1–37.6)

44.3(20.7–63.2)< 0.01

Weakly acidic (%)

67.8(52.1–81.4)

40.8(26.2–59.8)< 0.01

Weakly alkaline (%)

2.4(0–10.1)

8.1(2.6–18.1)< 0.01Liquid reflux (%)

22.6(12.2–38.3)

25.1(13.6–39.8)

0.3

Gas reflux (%)

30.7(20.7–47.8)

33.3(19.6–57.7)

0.38

Mixed reflux (%)

38.8(28.8–49.5)

32.8(21.4–42.6)< 0.01

Cough episodes

11 (5–21)

6(2–14)< 0.01

Reflux positive cough episodes

0 (0–2)1(0–2)

0.066

SAP > 95%

32(15.1%)

27(10.5%)

0.486

pH metry

Impedance

SAP Symptom-association probability, RI Reflux index[21.4–42.6] (P < 0.01). There was no difference in SAP
between the two groups (P = 0.486) (Table 4).
Differences between the acid GER and non‑ acid GERgroupsPatients were divided into an acid GER (RI > 7%;n = 129)and non-acid GER (RI ≤ 7%; n = 297) group which issolely based on based on pH monitoring. The proportion of recent infection in the non-acid GER group(66%) was significantly higher than that in the acid GERgroup (51.2%) (P < 0.01). There were no significant differences between the two groups in terms of prematurity, congenital malformation, and other chronic
respiratory problems. Furthermore, there was no difference in the total recording time between the twogroups (P = 0.762). Through pH monitoring, we foundthat the acid GER group had significantly higher total
reflux episodes (200[150–279]), reflux episodes in
the upright position (139[86–215]), and reflux episodes in the supine position (41[21–72]) than did the

non-acid GER group. The acid GER group also had ahigher acid reflux events > 5 min episodes (17 [7–25])
and maximum reflux time (62.5[30.9–146.3]) (P < 0.01).
However, through impedance monitoring, we foundthat there was no difference between the two groups
regarding reflux events occurring in 24 h (P = 0.85).
With respect to the chemical properties of reflux,
most reflux events in the acid GER group involved acidreflux (64.7% [51.5–76.4%]). The proportion of total
reflux events in the non-acid GER group that involved
weakly acidic reflux (65.7%[52.2–79.7%]) and alkaline
reflux (6.8%[1.1–19.7%]) was significantly greater thanthat in the acid GER group (P < 0.01). With respect
to the physical properties of reflux, the percentage of
reflux events that involved gas reflux was higher in the
non-acid GER group (33.8%[23.7–54.8%]) than in theacid GER group (24.7%[14.6–42.7%]) (P < 0.01). The
reflux-positive cough episodes were higher in the acid
GER (1[0–4]) group than in the non-acid GER group(0[0–1]) (P < 0.01). With respect to SAPs, there was no

Gan et al. BMC Pediatrics(2024) 24:538

Page 6 of 10

Table 5 Comparison of 24 h impedance monitoring parameters between acid GER and non-acid GER groupsGroup

Acid GER

Non-acid GER

P-valueSex (boy/girl)

87/42

205/920.74

Age (months)

36(10–63)

8(4–18)< 0.01Prematurity

9(7%)

31(10.4%)

0.28

Neonatal complications8(6.2%)

15(5.1%)

0.64

Congenital malformation

5(3.9%)

19(6.4%)0.5

Neurological comorbidity

4(3.1%)

11(3.7%)

0.21

Other chronic respiratory problems

23(17.8%)

72(24.2%)

0.16

Recent infections

66(51.2%)

196(66%)< 0.05

Total reflux episodes

200(150–279)

30(13–62)< 0.01

Reflux episodes in upright position

139(86–215)

21(10–49)< 0.01

Reflux episodes in supine position

41(21–72)

3(1–10)< 0.01

Reflux time > 5 min episodes17(7–25)0(0–2)< 0.01

Maximum reflux time (minutes)

62.5(30.9–146.3)

4.7(2.3–10.3)< 0.01

Reflux events in 24 h

110(69–149)

110(80–140)

0.85

Acid (%)

64.7(51.5–76.4)

19.3(8.0–33.1)< 0.01

Weakly acidic (%)

28.2(18.6–38.4)

65.7(52.2–79.7)< 0.01

Weakly alkaline (%)

4.0(0–8.3)

6.8(1.1–19.7)< 0.01Liquid reflux (%)

32.1(20.1–45.8)

21.6(10.8–35.8)< 0.01

Gas reflux (%)

24.7(14.6–42.7)

33.8(23.7–54.8)< 0.01

Mixed reflux (%)

37.1(25.3–46.0)

35.3(23.9–44.6)

0.5

Cough episodes

6(3–15)9(5–19)0.013

Reflux positive cough episodes

1(0–4)

0(0–1)< 0.01

SAP > 95%

17(13.2%)

42(14.1%)

0.88

pH metry

Impedance

GERD Gastro-esophageal reflux disease, SAP Symptom-association probability

significant difference between the two groups (P = 0.88)(Table 5).

Discussion
To the best of our knowledge, this was the largest study
involving MII-pH monitoring for evaluating the association between chronic cough and gastroesophageal
reflux in children. Using this technique, we can detect
previously overlooked gastroesophageal reflux eventsin infants and young children with chronic cough. Our
results showed that more than 30.3% of the enrolled children with chronic cough were associated with acid reflux,and impedance monitoring also detected significant
amounts of weakly acidic reflux events in the remaining
children, highlighting the importance of 24 h MII-PH
monitoring in evaluating these children. Using an accurate diagnostic tool, children with gastroesophagealreflux-related chronic cough can be accurately identified,
and their treatment can be improved.
Cough is one of the most common symptoms of respiratory diseases in children, and chronic cough has several
causes. Reflux-related cough is caused by direct irritationof the tracheobronchial tree after aspirating gastric contents into the airway; it may also be caused by stimulation of the esophageal-bronchial neural cough reflex [13].
Changes in the pressure gradient between the abdominal
and thoracic cavities that occur during cough events may
also lead to a cycle of cough and reflux [14]. Accurately
diagnosing an individual with chronic cough caused by
gastroesophageal reflux is a major challenge [15], and tothe best of our knowledge, only a few studies involving
MII-pH monitoring in patients with chronic cough havebeen performed previously [15].
A study by Rosen and Nurko showed that in children
with various respiratory symptoms (including chronic
cough), cough events in 37.6% of children were related
to gastroesophageal reflux [16]. The findings of a study
by Ghezzi et al. suggested a 78.3% correlation between
cough and gastroesophageal reflux [17]. However, in ourstudy, we found that more than 30.3% of the included
children with chronic cough related to acid reflux. Discrepancies among study findings might have occurred
due to differences in sample sizes and recording methodologies. The American College of Gastroenterology

Gan et al. BMC Pediatrics(2024) 24:538

guidelines for the diagnosis and treatment of GERD
define GERD as “chronic symptoms or mucosal damage produced by the abnormal reflux of gastric contents
into the esophagus” [18]. The diagnosis of cough causedby reflux may be challenging because many children do
not exhibit typical symptoms of reflux. Symptoms suchas heartburn, acid regurgitation, dysphagia in older children, or agitation and food refusal in toddlers and infants
are not specific to GERD and are, therefore, a diagnostic
challenge. In cases involving patients with atypical GERD
symptoms, respiratory manifestations have been found tobe either the only significant manifestation or the mostsignificant manifestation of GERD [19]. In one of thelargest pediatric studies regarding chronic cough in children, the “big three” causes of chronic cough in adults(asthma, upper airway cough syndrome, and GERD)
were found in a small proportion of children (≤ 10% of
the study cohort) [20]. This might have been due to thelack of diagnostic tools for GERD in children and the lackof awareness regarding gastroesophageal reflux cough.
The most commonly used method to confirm the presence of GERD is ambulatory 24-h esophageal pH monitoring, which can only be used to evaluate acid reflux
events [19]. The development of MII-pH monitoring is
an addition to pH monitoring. MII-pH monitoring allows
for a more comprehensive evaluation of different aspects
of GERD than pH monitoring; this technique is based on
a combination of pH-metry and the evaluation of esophageal contents using multiple channels, which allows
for the description and evaluation of acid and non-acidreflux events, the physical and chemical properties ofreflux, and the association between symptoms [21, 22].
The role of MII-pH has gradually increased in the past
few years, especially for the evaluation of children. Children receiving enteral nutrition through continuous orbolus regimens can only be accurately evaluated throughMII-pH monitoring because in these children, the majority of gastroesophageal reflux events involve non-acidreflux due to the buffering effect of feedings [7]. MII-pH
monitoring currently represents the gold standard diagnostic technique for measuring acid and non-acid GERD
and symptom association [23]. However, as MII-pH
monitoring is expensive, the technique is only available
in a limited number of centers [5]. Pavić et al. demonstrated that pH-metry alone did not show an association between acid reflux and cough in children; however,a relationship between weakly acidic reflux and coughwas described [24]. Their results suggest that the use of
pH-metry alone may be insufficient to identify refluxrelated cough in children, especially young children. Thisis consistent with our results, acid reflux events detectedby pH-metry in infants group was less than that in older
group, whereas the infant group had more weakly acid

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and weakly alkaline reflux detected by MII; however, nodifference in reflux events was detected between the twogroups by impedance. This may be because a significant
number of gastroesophageal reflux events occurringin infants involve non-acid reflux (pH > 4). However, itappears that extraesophageal symptoms, such as laryngitis, pharyngitis, asthma, cough, and dental erosion,
may be caused by both acid (pH < 4) and non-acid reflux(pH > 4) [25, 26]. In our study, the acid GER and non-acid
GER groups showed significant differences with respect
to the occurrence of acid reflux; however, there was nodifference with respect to impedance events. Similar
results have been reported in other studies; in a past
study involving eight children for whom the results of pH
monitoring were normal, abnormal impedance events
could still be detected, and the impedance events mainly
involved gas and mixed gas–liquid reflux [27]. In anotherstudy, pH and impedance were monitored in 27 children with asthma, and non-acid reflux events accounted
for half of the reflux events detected through MII-pH
monitoring [28]. This indicates that with respect to thediagnosis of GERD, the diagnostic sensitivity of MII-pH
monitoring is significantly higher than that of pH monitoring [29]. Another study showed that age is positively
correlated with acid reflux and negatively correlated withweakly acidic reflux. This is consistent with our researchwith the result that the infants with weak acidic reflux are
significantly higher than the children [30]. A large proportion of reflux events in children, especially those ininfants, involve gas reflux and weakly alkaline reflux, andthe evaluation of such patients through only pH monitoring may lead to misdiagnoses. The significant effect of
non-acid reflux on the development of respiratory symptoms in children was previously reported by Wenzel et al.
in their study involving 22 infants who underwent MIIpH monitoring [31].
Similarly, the findings of the present study regarding
relatively younger children included in the non-acid GERgroup suggest that children who have chronic cough at a
young age tend to have non-acid reflux, which can only
be detected through impedance monitoring. Therefore,
physicians should be aware of the limitations of pH monitoring in pediatric populations [26].
Blondeau et al. found that there was a significant correlation between gastroesophageal reflux and cough in
26 children, which was mainly caused by weakly acidic
reflux [32]. In a previous study involving 45 children withchronic cough, 158 cough episodes were related to reflux
events; of these, 53 involved non-acid reflux, which might
not have been identified if only pH monitoring had beenused [33]; these results are consistent with the results ofour study demonstrating that the proportion of reflux
events that involve weakly acidic reflux was significantly

Gan et al. BMC Pediatrics(2024) 24:538

greater than the proportion of reflux events that involve
acid reflux. In addition, Pavić et al. confirmed that weakly
acidic reflux is more significantly associated with coughthan acid reflux and that children < 2 years of age have asignificantly higher number of cough episodes associatedwith acid and weakly acidic reflux. [24] This is consistent with our findings. Weakly acidic reflux occurs mostcommonly in younger children due to physiological reasons; during infancy, gastric contents are buffered by frequent feeding, and the composition and volume of eachfeed differ [34]. One hypothesis is that small amounts ofproximal weakly acidic reflux cannot stimulate acid- andvolume-sensitive esophageal receptors, which play a significant role in providing protection against aspiration[35].
The occurrence of reflux is more common when babies
are in the upright position than in the supine position,and the findings of our study are consistent with this fact;
the increased occurrence of reflux in the upright position
may be caused by increased intra-abdominal pressure
in babies [36]. Our study suggested that both acid andnon-acid reflux events mainly occur in children when
they were in the upright position; this may also havebeen caused by eating, which is often carried out in the
upright position. With respect to the physical properties of reflux, our study showed that reflux events mainly
involved gas and mixed gas–liquid reflux, which is difficult to detect through pH monitoring. In children, thepresence of these types of reflux may render anti-reflux
treatment ineffective.
SAP is commonly used to analyze the relationshipbetween symptoms and gastroesophageal reflux [37]. The
findings of our study indicate that 13.8% of all included
patients and 17% of patients in the acid GER group were
SAP positive. These values represent a relatively small
proportion of the total number of patients. Borrelli et al.
reported that only 17 of 45 children with unexplained
chronic cough had a positive SAP and that asymptomaticand non-acid gastroesophageal reflux may be important[33]. The findings of another study showed that there
is a low correlation between cough and reflux events inchildren [38]. The relationship between gastroesophageal reflux and cough is very complicated, which makes
it difficult to analyze and interpret associated results.
The SAP only reflects the cough episodes and symptoms that occur after 2 min of the occurrence of a reflux
event [37]. It has been reported that cough episodes that
occur in individuals within 2 min of the occurrence of a
reflux event only account for 56–81% of the total coughepisodes that occur in them [19]. Patients often omit therecording of the occurrence of cough episodes or mislabel the same cough event; therefore, SAP calculations areoften not very accurate. As under-reporting of symptoms

Page 8 of 10

may lead to false negative results, a past study of 20 children found that while only 48% of all cough episodes
were reported by children and/or their parents, 94% of all
cough episodes were detected by recording intra-esophageal pressure [39]. Further, the accuracy of symptom
records is limited, which affects the relevance of eventsand reflux [40]. As chronic cough itself can also cause
gastroesophageal reflux, this increases the difficulty ofdetermining the causal relationship between cough andreflux [41]. And our study shows that 14.1% of children
in non-acid GER group were SAP positive, which means
non-acid reflux is also associated with chronic cough.
These factors indicate that anti-acid therapy may not
be effective for the treatment of cough associated withgastroesophageal reflux, which is consistent with thefindings of other studies. A meta-analysis showed that
proton pump inhibitors were not efficacious for coughassociated with gastroesophageal reflux symptoms inyoung children [13]. Medical treatment with acid-suppression therapy and dietary and lifestyle modifications
are recommended in clinical guidelines for children withchronic cough and typical symptoms of GERD. Based on
our results, we suggest that proton pump inhibitors areadministered to children in whom a significant proportion of reflux events involve acid reflux; however, forinfants who do not have acid reflux, treatment should bebased on the introduction of appropriate dietary and lifestyle changes.
This study has some limitations worth noting. First,
symptoms were recorded by the family members of the
included patients, which might have resulted in inaccuracies. Second, children were not followed up to evaluate treatment outcomes and prognosis. In the future, wewill do a better job of following up with the children andimprove the clinical data.

Conclusions
In conclusion, the use of 24 h MII-pH monitoring inthis study improved our understanding of children
with reflux-related chronic cough. It can identify weakacidic reflux, weak alkaline reflux and reflux eventswith different physical properties, which can explain
the relationship between GER and chronic cough morecomprehensively. The high proportion of non-acid reflux
events in children identified in this study highlights theneed for increased awareness among healthcare providers and the importance of being cautious about thetreatment of reflux and reflux-related cough with antacid medications. It provides new approach for exploring the etiology, diagnosis and treatment of children withchronic cough.

Gan et al. BMC Pediatrics(2024) 24:538

Acknowledgements
We appreciate the participation of the children and their families. We would
like to thank Editage (www.​edita​ge.​com) for English language editing.
Authors’ contributions
Junhua Shu and Danna Tu is acting as the submission’s guarantor. Zhaoxuan
Huang, Shan Gao and Junhua Shu performed the research. Shan Gao, Li Gu,
Di Zhang, Lingzhi Yan, Shanshan Shang and Guirong Wang collected thedata. Yi Gan analysed the data. Yi Gan, Xiaoqin Zhou, Danna Tu and Junhua
Shu designed the research study, Yi Gan and Junhua Shu wrote the paper. All
authors approved the final version of the article, including the authorship list.
Funding
This research was supported by the Hubei Provincial Natural Science Foundation of China (Grant Number: 2022CFB401 and Grant Number:2021CFB558).
Availability of data and materials
The datasets generated during and/or analyzed during the current study areavailable from the corresponding author on reasonable request.

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9.
10.

11.
12.
13.
14.
15.

Declarations

16.

Ethics approval and consent to participate
This study was approved by the Ethics Committee of Maternal and Child
Health Hospital of Hubei Province (2022IEC105). All methods were performedin accordance with the relevant guidelines and regulations. The parents or
guardians of all participants provided written informed consent to take part in
the present study.

17.

Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.

18.
19.
20.
21.

Author details
1
Department of Pediatric, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology,
Wuhan City, Hubei Province, P.R. China.

22.

Received: 21 April 2023 Accepted: 26 July 2024

24.

23.

25.
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