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Combined multi-channel intraluminal impedance measurement and pHmetry in the detection of gastroesophageal reflux disease in children with cystic fibrosis

Abstract

Objective

To assess the prevalence of GERD exclusively by means of multichannel intraluminal impedanciometry associated with pH monitoring (MIIpH) and compare it with respiratory symptoms in children with CF. To compare MIIpH with pHmetry alone to perform GERD diagnosis.

Methods

An analytical cross-sectional study was conducted with children diagnosed with CF who underwent MIIpH. Clinical and laboratory markers, including respiratory and digestive symptoms, were used for comparative analyses. High-resolution chest computed tomography was performed on patients with symptoms of chronic lung disease. Severity was classified according to the Bhalla score.

Results

A total of 29 children < 10 yo (18 girls) were evaluated; 19 of whom with physiological GER and 10 with GERD. Of the children with GERD, seven had predominantly acid GER, two acid+non-acid GER, and one non-acid GER. Three patients had GERD diagnosed only by MIIpH. Bhalla scores ranged from seven to 17.75 with no significant relationship with GERD. The number of pulmonary exacerbations was associated with a decrease in esophageal clearance regardless of the position in pHmetry and MIIpH.

Conclusions

The prevalence of GERD was 34% in children with CF. There was no association between respiratory disease severity and GER types. MIIpH detected 30% more patients with GERD than pHmetry.

Keywords
Children; Cystic fibrosis; Gastroesophageal reflux; Multi-channel intraluminal impedance-pHmetry

Introduction

Gastroesophageal reflux disease (GERD) mainly affects children and adults with cystic fibrosis (CF) compared to healthy individuals and contributes to the worsening of lung disease (LD).11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.,22 Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Grupo de Trabalho das Diretrizes Brasileiras de Diagnóstico e Tratamento da Fibrose Cística. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43:219-45. The prevalence of acid gastroesophageal reflux (AGER) in CF ranges from 35-81%.33 Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8. To date, it has not been defined whether GERD in CF is a primary or secondary phenomenon to LD.44 Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastroesophageal reflux in adult cystic fibrosis patients. J R Soc Med. 1998;91:7-9.

Gastroesophageal reflux (GER) is physiological; if the reflux episodes cause symptoms or complications, they evolve into GERD.55 Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, 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;66:516-54. Currently, multi-channel intraluminal impedance associated with pHmetry (MIIpH) and pHmetry has been widely used to perform GERD diagnosis55 Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, 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;66:516-54. with high specificity66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39. and sensitivity.66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39.

7 Gonçalves ES, Assumpção MS, Servidoni MF, Lomazi EA, Ribeiro JD. Multi-channel intraluminal impedance-pH and psychometric properties in gastroesophageal reflux: a systematic review. J Pediatr (Rio J). 2020;96:673-85.

8 Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400.
-99 Roman S, Gyawali CP, Savarino E, Yadlapati R, Zerbib F, Wu J, et al. Ambulatory reflux monitoring for diagnosis of gastroesophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29:1-15.

Many CF children show early LD symptoms. Most studies evaluating the prevalence and association of GERD and CF provide heterogeneous information about age, and tools used to diagnose GERD and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) genotype.1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6.

11 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.

12 Woodley FW, Machado RS, Hayes D Jr, Di Lorenzo C, Kaul A, Skaggs B, et al. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis. Dig Dis Sci. 2014;59:623-30.

13 Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, et al. Gastroesophageal reflux disease in children with cystic fibrosis. Adv Exp Med Biol. 2015;873:1-7.
-1414 Hauser B, De Schepper J, Malfroot A, De Wachter E, De Schutter I, Keymolen K, et al. Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros. 2016;15:540-7.

This study investigated GERD exclusively by means of MIIpH and aimed: (i) to assess the prevalence of GERD in CF children with and without typical GERD manifestations; (ii) to compare MIIpH and pH monitoring values during 24 hours for GERD diagnosis; and (iii) to analyze the association between episodes of GER and MIIpH and clinical symptoms.

Methods

An analytical cross-sectional study was conducted in CF children <10 yo, who received follow-up care at the CF Referral Center of a tertiary hospital for two years. Patients with CF detected through newborn screening were included,22 Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Grupo de Trabalho das Diretrizes Brasileiras de Diagnóstico e Tratamento da Fibrose Cística. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43:219-45.,33 Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8. namely with two sweat chloride specimens ≥60 mEq/L and/or two pathogenic variants in the CFTR gene.22 Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Grupo de Trabalho das Diretrizes Brasileiras de Diagnóstico e Tratamento da Fibrose Cística. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43:219-45. After the Ethics Committee's approval, the study was conducted in agreement with the Declaration of Helsinki (CAAE: 60629616.2.0000.5404).

Clinical data were collected using medical records and interviews with parents/guardians. All patients were clinically stable and showed no pulmonary exacerbation at the examination. The following markers were assessed: (i) Clinical markers: sex, age, reported race, family history of CF, chronic cough, recurrent wheezing, number of previous cases of pneumonia, number of episodes of unexplained LD (Apparent life-threatening events/Brief resolved unexplained events), laryngitis, dysphonia, otitis media, number of pulmonary CF exacerbations, regurgitation, vomiting, abdominal pain, diarrhea, low weight gain, anemia, dental erosion, Sandifer syndrome, pancreatic sufficiency or insufficiency, medications used, weight, height, body mass index; and (ii) Laboratory markers: immunoreactive trypsinogen levels (IRT), sweat test, CFTR genotype, sputum culture, high-resolution chest computed tomography (HRCCT) using the Bhalla's scoring system,1515 Folescu TW, Marques EA, Boechat MC, Daltro P, Higa LY, Cohen RW. High-resolution computed tomography scores in cystic fibrosis patients colonized with Pseudomonas aeruginosa or Staphylococcus aureus. J Bras Pneumol. 2012;38:41-9. and esophageal monitoring with MIIpH.

Two pediatric pulmonologists and a radiologist analyzed the HRCCT images without knowing the patient's clinical evolution. The modified Bhalla score, the Fleischner Society guidelines, and the Brazilian consensus on HRCCT were utilized for analysis. Discordant screening readings were consensually reviewed by the evaluators to obtain the final score. The scores ranged from zero (no abnormality) to 37 points (severe changes).1515 Folescu TW, Marques EA, Boechat MC, Daltro P, Higa LY, Cohen RW. High-resolution computed tomography scores in cystic fibrosis patients colonized with Pseudomonas aeruginosa or Staphylococcus aureus. J Bras Pneumol. 2012;38:41-9. HRCCT was performed in children with a clinical indication from the referral center team.

MIIpH was monitored during 20-24 hours. A software-based analysis was made and two MIIpH probes (ZIN: ≤2 yo and ZPN: >2 yo) from Sandhill Scientific-ComforTec Z/pH, Inc., Highlands Ranch, CO, USA were used. After calibration, the probes were placed transnasally according to the modified Strobel formula: [(height×0.252)+5]×0.8718.66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39. The probe position was checked using radiographic scanning.66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39.

All parents/guardians were instructed to follow their children's daily routine and report symptoms, times of meals, and position (orthostatic: sitting or standing; supine: lying; overall: orthostatic+supine). Data were analyzed with BioVIEW Analysis version 5.6 (Sandhill Scientific). A software-based analysis was conducted, followed by a manual review of each test in pairs, i.e., by the leading author and another author - a pediatric gastroenterologist. A reflux episode was considered GER when the impedance wave was retrograde in at least two distal channels, with a drop of 50% or more from baseline, and duration ≥5 seconds;66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39. AGER and non-acid GER (NAGER) episodes, if the distal pH electrode remained below or above 4.0, respectively.66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39. The refluxate was considered to be proximal if it reached either or both of the proximal channels (channels 1 and/or 2).66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39.,1616 Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJ, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351-62. In pHmetry alone, the reflux index (RI) was used to define GERD, representing pH <4.0. When RI ≥10% in children <1 year or ≥5% in children >1 year, the episode was considered GERD.55 Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, 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;66:516-54.

The parameters evaluated were: (i) pHmetry: RI, GER episodes, mean acid clearance time, GER >5 minutes, duration and position of the longest episode of GER, and patient's final score according to age (Boix-Ochoa <2 years and Johnson/DeMeester 2-10 years); (ii) MIIpH: monitoring period in hours and minutes; proximal and distal episodes of GER, AGER, and NAGER; percentage of reflux exposure time; and bolus contact time. The parameters were evaluated in total number, and in the orthostatic and supine positions and correlation with symptoms.66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39.,88 Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400.

The relationship between GER episodes and symptoms was considered positive in the presence of two or more of the following indexes: symptom index (SI) >50% and/or symptom sensitivity index (SSI) ≥10% and symptom association probability index (SAP) >95%.66 Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39.,88 Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400.,1616 Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJ, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351-62. SAP values >95% for all symptoms, including cough, were considered altered.

For MIIpH, the normality values by Mousa et al. (2014)88 Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400. were considered for both pediatric age groups: ≤12 months and 1-17 yo (Supplementary material 1).

The authors considered the presence of GERD in MIIpH when altered parameters occurred in pHmetry and/or MIIpH correlated with symptoms.55 Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, 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;66:516-54.,88 Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400.

Statistical analysis

The descriptive analysis was performed according to data distribution using a number of individuals (N) and percentage for categorical data; means (standard deviation) or medians (interquartile range) for parametric and non-parametric data, respectively. Normality was assessed using descriptive measures for central tendency, graphical method (Normal Q-Q plot, Q-Q plot without trend and Boxplot), and statistical tests (Kolmorov-Smirnov and Shapiro-Wilk tests).

Intergroup comparisons of numerical data were performed with the Mann-Whitney test; the Chi-square and Fisher's Exact tests, for categorical data. Additionally, the Spearman correlation was applied for clinical and laboratory markers and MIIpH parameters. Alpha was set at 0.05, and no techniques were employed to impute missing data values. All statistical analyses were performed with Statistical Package for the Social Sciences version 24.0 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp).

Results

Of the 43 children invited to participate in the study, 30 accepted and underwent MIIpH. One patient was excluded due to an artifact caused by monitoring probe problems. Eighteen of 29 (62%) patients were females; 19/29 (65.5%) were 2 years or older, and 28/29 (96.6%) had pancreatic insufficiency (Table 1). The descriptive analysis of the demographic data of the CF children is described in Table 1.

Table 1
Descriptive analysis of demographic data, peripheral oxygen saturation (SpO2) and Bhalla score, and family history of patients with cystic fibrosis.

A total of 25/29 (86.20%) patients were identified with the p.Phe508del (F508del) variant of the CFTR [19/29 (65.61%) heterozygotes and 6/29 (20.68%) homozygotes]; 3/29 (10.3%) patients did not have the CFTR genotype, and 1/29 (3.44%) patient had p.Gly542X/p.Gln1100Pro (G542X/Q1100P) genotype.

Analyses of clinical and laboratory markers showed that 28/29 (96.5%) patients had one or more pulmonary exacerbations; 25/29 (86.2%) had chronic colonization by Staphylococcus aureus or non-mucosal Pseudomonas aeruginosa; 7/29 (24.13%) by Burkholderia cepacia and 6/29 (20.08%) by mucoid Pseudomonas aeruginosa.

The authors found 10/29 (34%) children with GERD further classified into AGER (7/10; 70%), AGER+NAGER (2/10; 20%), and NAGER (1/10; 10%). Four patients, all with AGER, showed a correlation with symptoms. Regarding the extension to the proximal channels, 5/10 (50%) had proximal reflux 2/5 (40%) AGER, 2/5 (40%) AGER+NAGER, and 1/5 (20%) NAGER (Figure 1).

Figure 1
Flow chart with the results of impedanciopHmetry, physiological GER (gastroesophageal reflux) and GERD (Gastroesophageal reflux disease), correlation with symptoms, extension to the position of the proximal channel associated with reflux of the patients with cystic fibrosis included in the study. Comb, combined; corr, correlation; ortho, orthostatic; sup, supine.

Table 2 summarizes the reported symptoms and the correlation with GER episodes based on two or more altered SI or SSI and SAP values, including tests, such as physiological GER and GERD at MIIpH. The authors observed that 9/29 (31.03%) children showed a correlation between GER episodes and symptoms. Among the children with physiological GER, the authors found a 5-month-old infant with cough in 8/15 (53%) records; eructation in 8/12 (67%) and regurgitation in 3/4 (75%); three children between two and four year olds with correlation only with cough, in 27/83 (33%), 74/145 (51%) and 17/43 (39.5%) records, respectively; and a 4-yo child with a correlation of GER with eructation+hiccups in 8/16 (50%) records.

Table 2
Symptoms recorded during monitoring and correlation with GER episodes, based on two or more altered SI or SSI, and SAP score values, including tests analyzed as physiological GER and GERD by MIIpH.

The description of the respiratory and digestive symptoms correlated with GER episodes in the patients with physiological GER and GERD does not show any association between these variables (Supplementary material 2).

The markers for identification, quantification, and localization of GER episodes in pHmetry and MIIpH are outlined in (Supplementary material 3). In pHmetry, there was a positive association between the number of episodes ≥5 minutes (p = 0.05) and the duration of the longest episode (p = 0.002) with GERD. In impedanciometry, GERD was positively associated with the total number of AGERs (orthostasis, p = 0.002) and acidic episodes in the proximal channels (overall and orthostasis, p = 0.021).

Table 3 displays the relationship of MIIpH markers with clinical and laboratory features in patients with CF. In pHmetry, the mean acid clearance time positively correlated with the number of exacerbations (P=0.014). In impedanciometry, there was an inverse correlation between total NAGER and the episodes reaching the proximal channels with exacerbations. An inverse relationship was observed between peripheral oxygen saturation (SpO2) and NAGER episodes in the supine position (total and proximal channels) (Table 3).

Table 3
Correlation of pHmetry (pH) and multi-channel intraluminal impedance (MII) imaging markers with clinical and laboratory features in patients with cystic fibrosis.

The MIIpH results did not have any statistically significant association with demographic, clinical, and laboratory markers (Supplementary materials 4 and 5). The values of IRT and chloride in the ST of the first and second specimens showed no statistically significant relationship with the evaluated parameters of MIIpH and pHmetry (Supplementary material 5).

Discussion

To the best of our knowledge, this is the first study to assess the characteristics of physiological GER and GERD in CF children <10 yo in a single center using MIIpH. Previous research on MIIpH included children, adolescents, and adults, and, in some cases, it was performed in multiple centers.1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6.

11 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.

12 Woodley FW, Machado RS, Hayes D Jr, Di Lorenzo C, Kaul A, Skaggs B, et al. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis. Dig Dis Sci. 2014;59:623-30.

13 Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, et al. Gastroesophageal reflux disease in children with cystic fibrosis. Adv Exp Med Biol. 2015;873:1-7.
-1414 Hauser B, De Schepper J, Malfroot A, De Wachter E, De Schutter I, Keymolen K, et al. Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros. 2016;15:540-7.,1717 Lee AL, Varjavandi V, Lemberg DA, Ooi CY, Gupta N, Krishnan U. Does combined multi-channel intraluminal impedance and pH (MII-pH) testing improve clinical outcomes in children with gastroesophageal reflux disease? J Pediatr Gastroenterol Nutr. 2020;71:596-603.,1818 Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics. 2010;125:e925-30.

The pathophysiological relationship between esophagus reflux and the worsening of LD in CF is still poorly understood, in comparison with other LD, such as asthma,1818 Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics. 2010;125:e925-30.

19 Kilic M, Ozturk F, Kirmemis O, Atmaca S, Guner SN, Caltepe G, et al. Impact of laryngopharyngeal and gastroesophageal reflux on asthma control in children. Int J Pediatr Otorhinolaryngol. 2013;77:341-5.

20 Ozcan C, Erkocoglu M, Civelek E, Demirkan H, Kırsaçlıoğlu CT, Tiryaki HT, et al. The relationship between gastro-oesophageal reflux disease and asthma during childhood. Allergol Immunopathol (Madr). 2014;42:109-14.
-2121 Huang C, Liu Y, Shi G. A systematic review with meta-analysis of gastroesophageal reflux disease and exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med. 2020;20:2. bronchopulmonary dysplasia,2222 Cunha GS, Mezzacappa Filho F, Ribeiro JD. Maternal and neonatal factors affecting the incidence of bronchopulmonary dysplasia in very low birth weight newborns. J Pediatr (Rio J). 2003;79:550-6.,2323 Gonçalves Eda S, Mezzacappa-Filho F, Severino SD, Ribeiro MÂ, Marson FAL, Morcilo AM, et al. Association between clinical variables related to asthma in schoolchildren born with very low birth weight with and without bronchopulmonary dysplasia. Rev Paul Pediatr. 2016;34:271-80. and chronic obstructive LD in adults.2121 Huang C, Liu Y, Shi G. A systematic review with meta-analysis of gastroesophageal reflux disease and exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med. 2020;20:2.

GER episodes are more common in CF patients, regardless of age, compared with their respective healthy counterparts. Moreover, GER is present in almost all end-stage LD CF patients.11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.

The present study showed a prevalence of GERD of 34% in CF children. This prevalence is high when compared with the prevalence of GERD in patients without CF, i.e., 3.5-6.2% in children and adolescents2424 Poddar U. Gastroesophageal reflux disease (GERD) in children. Paediatr Int Child Health. 2019;39:7-12. and 9-28% in adults.2525 El-Serag H B, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63:871-80. On the other hand, the 34% prevalence of GERD here is lower than that of most studies about GERD in CF, with values ranging from 35-81%.22 Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Grupo de Trabalho das Diretrizes Brasileiras de Diagnóstico e Tratamento da Fibrose Cística. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43:219-45.,2626 Cystic Fibrosis Foundation [homepage on the Internet]. Complications. Cystic fibrosis foundation patient registry 2018 annual data report. Maryland (USA): Cystic Fibrosis Foundation. 2018: 62. [Cited 2022 Jul 17]. Available from: https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf.
https://www.cff.org/Research/Researcher-...
Furthermore, the authors have not found studies in the literature that included the age range to allow for a comparison of the prevalence of GERD in CF patients. One hypothesis suggested for the lower prevalence of GERD in the patients is the younger age.11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69. In addition, in CF, lung function (LF) decreases considerably with age and worsens the esophagogastric function.11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.

The population included children <10 yo, caucasians, eutrophic, and without other CF-related comorbidities, such as diabetes mellitus and liver disease. All children showed positive neonatal screening and molecular CF diagnosis, with CFTR class I and II mutations with at least one allele of the p.Phe508del variant in 86.2% of patients. These features have not been described in previous studies.1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6.

11 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.

12 Woodley FW, Machado RS, Hayes D Jr, Di Lorenzo C, Kaul A, Skaggs B, et al. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis. Dig Dis Sci. 2014;59:623-30.

13 Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, et al. Gastroesophageal reflux disease in children with cystic fibrosis. Adv Exp Med Biol. 2015;873:1-7.
-1414 Hauser B, De Schepper J, Malfroot A, De Wachter E, De Schutter I, Keymolen K, et al. Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros. 2016;15:540-7.

Blondeau et al. (2010)1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6. performed a multi-center study using MIIpH to screen GERD in 24 CF children/adolescents of 0.3-13 yo. The authors confirmed a 67% prevalence of GERD; all cases were AGER, and 16 cases had no association with symptoms.

Dziekiewicz et al. (2015) analyzed GERD by MIIpH in a multi-center study of 44 children/adolescents aged 3-17 yo. The prevalence of GERD was 54%, with AGER predominance (77%), and 44% of reflux episodes reached the proximal channels.1313 Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, et al. Gastroesophageal reflux disease in children with cystic fibrosis. Adv Exp Med Biol. 2015;873:1-7.

In a prospective study, Hauser et al. (2016) investigated the relationship between GER and gastric emptying in 56 CF children/adolescents, aged 1-17 yo, divided into two groups. Group 1 included 28 patients with GERD symptoms who performed a gastric emptying test and MIIpH; Group 2 had 28 patients with and without GERD symptoms who performed a gastric emptying test. The authors found a 46% prevalence of AGER, with 21.4% delayed gastric emptying, and no relationship between GER and gastric emptying.1414 Hauser B, De Schepper J, Malfroot A, De Wachter E, De Schutter I, Keymolen K, et al. Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros. 2016;15:540-7.

The analysis of laboratory markers of chronic infection in the patients is similar to that described in the literature about GERD in CF. Palm et al. (2012) investigated a group of 7-19 yo patients and found that reflux was common in CF children/adolescents, and AGER and NAGER were related to greater reductions in forced expiratory volume in the first second.1111 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.

The high prevalence of GERD is described in all international CF registries. It correlates directly with the deterioration of LF; and both increase with age,11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.,33 Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8.,1111 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.,2626 Cystic Fibrosis Foundation [homepage on the Internet]. Complications. Cystic fibrosis foundation patient registry 2018 annual data report. Maryland (USA): Cystic Fibrosis Foundation. 2018: 62. [Cited 2022 Jul 17]. Available from: https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf.
https://www.cff.org/Research/Researcher-...
probably due to the vicious cycle between GERD and chronic LD.33 Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8.,1111 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.,2121 Huang C, Liu Y, Shi G. A systematic review with meta-analysis of gastroesophageal reflux disease and exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med. 2020;20:2. There is no consensus on whether GERD is a primary or secondary phenomenon to LD in CF.44 Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastroesophageal reflux in adult cystic fibrosis patients. J R Soc Med. 1998;91:7-9.

The relationships between GERD and LD are complex, and controversies about their interaction abound in the literature. A classic example of this controversy is asthma: some studies show a positive relationship between GERD and asthma;1818 Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics. 2010;125:e925-30. others yield diverging results for this association.1919 Kilic M, Ozturk F, Kirmemis O, Atmaca S, Guner SN, Caltepe G, et al. Impact of laryngopharyngeal and gastroesophageal reflux on asthma control in children. Int J Pediatr Otorhinolaryngol. 2013;77:341-5.,2020 Ozcan C, Erkocoglu M, Civelek E, Demirkan H, Kırsaçlıoğlu CT, Tiryaki HT, et al. The relationship between gastro-oesophageal reflux disease and asthma during childhood. Allergol Immunopathol (Madr). 2014;42:109-14. Here, this relationship shows a clear positive association between acid clearance and pulmonary exacerbations.

In the present study, of the 19 patients classified with physiological GER, five (26%) showed a significant relationship with symptoms; however, they did not meet other criteria for GERD diagnosis by pHmetry and/or MIIpH and were not considered GERD. Some questions need to be answered: Is the relationship between reflux episodes and the symptoms real? Can the high cough frequency alone define GERD? Is it a coincidence that children who already cough a lot due to chronic LD in CF had a simultaneous cough and GER episodes, suggesting a relationship between them? These data should be thoroughly investigated, preferably with longitudinal studies, to provide a better understanding of the relationship between LD symptoms in CF patients and the presence or absence of GERD.

In CF, it is also not well established whether GERD worsens LD or vice versa.44 Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastroesophageal reflux in adult cystic fibrosis patients. J R Soc Med. 1998;91:7-9.,1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6.,1111 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.,1414 Hauser B, De Schepper J, Malfroot A, De Wachter E, De Schutter I, Keymolen K, et al. Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros. 2016;15:540-7. However, GERD may be further exacerbated in CF patients due to chronic cough. Cough increases the gastroesophageal pressure gradient, causes alteration in the diaphragm with impaired lower esophageal sphincter (LES) function, increases the frequency of transient LES relaxations, and prolongs gastric emptying time.33 Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8. Both cough and regurgitation are frequent symptoms in CF patients' first years of life. One should be careful about using a single parameter for the GERD diagnosis in the pediatric age group where physiological GER is more frequent than in the adult population.2424 Poddar U. Gastroesophageal reflux disease (GERD) in children. Paediatr Int Child Health. 2019;39:7-12.,2525 El-Serag H B, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63:871-80.

Blondeau et al. (2010) evaluated 24 CF children/adolescents between 0.3 and 13 yo and found that AGER was prevalent in comparison with NAGER and previous to the onset of respiratory symptoms.1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6. Van der Doef et al. (2009) showed that treatment of AGER did not change bacterial acquisition, but it might improve LF. The authors associated reduced LF and earlier P. aeruginosa and S. aureus infection with GERD diagnosis; this provided evidence that diagnosis and treatment of GERD should be performed as early as possible in CF.2727 Van der Doef HP, Arets HG, Froeling SP, Westers P, Houwen RH. Gastric acid inhibition for fat malabsorption or gastroesophageal reflux disease in cystic fibrosis: longitudinal effect on bacterial colonization and pulmonary function. J Pediatr. 2009;155:629-33. Palm et al. (2012) evaluated CF children/adolescents and GERD and found MIIpH tracings showed a positive association between GERD and a higher number of pulmonary exacerbations, worsening LF, and earlier infection by P. aeruginosa.1111 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.

Characteristics of chronic LD in CF, such as cough, increased gastroesophageal pressure gradient, impaired LES function, increased frequency of transient LES relaxations, and prolonged gastric emptying time result in upper digestive tract physiology changes, which are most likely to be aggravated with age.11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.,33 Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8. Woodley et al. (2019) demonstrated that aging is associated with increased acid exposure in a cohort study with CF patients.11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.

Most of the patients with GERD (70%) had AGER, which is in line with the literature.99 Roman S, Gyawali CP, Savarino E, Yadlapati R, Zerbib F, Wu J, et al. Ambulatory reflux monitoring for diagnosis of gastroesophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29:1-15.,1616 Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJ, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351-62. The presence of 30% NAGER here is noteworthy. Studies with larger sample sizes would provide a better understanding of the harmful effects of reflux in the airways and esophagus in CF. Palm et al. (2012) found that AGER and NAGER are common in CF children and related to the worsening of LF.1111 Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.

Importantly, most studies on GERD evidence that GER episodes occur more frequently in the orthostatic position.99 Roman S, Gyawali CP, Savarino E, Yadlapati R, Zerbib F, Wu J, et al. Ambulatory reflux monitoring for diagnosis of gastroesophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29:1-15.,1616 Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJ, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351-62. The authors found various GER prevalence rates in different decubitus positions: 5/10 (50%) overall, 4/10 (40%) orthostatic, and 1/10 (10%) supine.

Some studies used pHmetry to evaluate GERD in CF children and adolescents, demonstrating an AGER prevalence of 55-76%.2828 Brodzicki J, Trawińska M, Korzon M. Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis. Med Sci Monit. 2002;8:CR529-537.,2929 Vic P, Tassin E, Turck D, Gottrand F, Launay V, Farriaux JP. [Frequency of gastroesophageal reflux in infants and in young children with cystic fibrosis]. Arch Pediatr. 1995;2:742-6. Most studies show higher specificity and sensitivity outcomes for MIIpH than for pHmetry alone.77 Gonçalves ES, Assumpção MS, Servidoni MF, Lomazi EA, Ribeiro JD. Multi-channel intraluminal impedance-pH and psychometric properties in gastroesophageal reflux: a systematic review. J Pediatr (Rio J). 2020;96:673-85.,1010 Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6.,1616 Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJ, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351-62.,1717 Lee AL, Varjavandi V, Lemberg DA, Ooi CY, Gupta N, Krishnan U. Does combined multi-channel intraluminal impedance and pH (MII-pH) testing improve clinical outcomes in children with gastroesophageal reflux disease? J Pediatr Gastroenterol Nutr. 2020;71:596-603. In the present study, among the 10 patients with GERD, three patients were diagnosed by combined MII and pHmetry: 2/10 AGER+NAGER and 1/10 NAGER. The prevalence of 30% of patients with GERD confirmed by MIIpH and not pHmetry reiterates the importance of evaluating the esophageal content with MIIpH.

An intriguing aspect of pediatrics is the physiological differences between infants, preschoolers, and schoolchildren, whose body systems show rapid and progressive development at different paces and stages of maturation, including the digestive and respiratory tracts.3030 Montgomery RK, Mulberg AE, Grand RJ. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology. 1999;116:702-31.

Therefore, unlike the classification for adults, these parameters should be stratified by age for the pediatric population, as it is well established that GERD increases with age in CF.11 Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.

The authors applied the reference values proposed by Mousa et al. (2014),88 Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400. who assessed two age groups (<12 months and 1.3-17 yo) to define the normality parameters for MII values. In contrast to MII, pHmetry has specific parameters for infants, preschoolers, schoolchildren, and adults, being able to characterize acid refluxes and define GERD.55 Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, 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;66:516-54.

Several suggestions for future research can be proposed: to evaluate the interactions between GERD and CF; to carry out multi-center studies; to design studies according to the specific age range for pediatrics; to correlate CF severity determined by genotypic and phenotypic characteristics with GERD; to evaluate bronchial hyperreactivity by acid stimulation of the esophagus; to correlate GERD determined by MIIpH with anatomical pathological markers obtained by esophageal biopsy; to conduct studies to identify which children would benefit from surgical treatments for GERD and devices that increase contraction and muscle competence of the LES;, and standardizes type and timing of treatment in CF children and GERD.

In conclusion, the prevalence of GERD was 34% in CF children ̶ which is high compared to children without CF in the same age group, and yet at the lower limit of the prevalence described for CF adults. There was no association between LD severity and type of GER acid or non-acid. Most episodes of GERD occurred in the overall position. MIIpH detected 30% more patients with GERD than pHmetry.

  • Funding
    JDR: FAEPEX (Fundo de Apoio ao Ensino, à Pesquisa e à Extensão) Unicamp: #519.294; CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico): #407364407364/2016-1.

Supplementary materials

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.jped.2022.11.007.

References

  • 1
    Woodley FW, Hayes D Jr, Kopp BT, Moore-Clingenpeel M, Machado RS, Nemastil CJ, et al. Gastroesophageal reflux in cystic fibrosis across the age spectrum. Transl Gastroenterol Hepatol. 2019;16:69.
  • 2
    Athanazio RA, Silva Filho LVRF, Vergara AA, Ribeiro AF, Riedi CA, Procianoy EDFA, et al. Grupo de Trabalho das Diretrizes Brasileiras de Diagnóstico e Tratamento da Fibrose Cística. Brazilian guidelines for the diagnosis and treatment of cystic fibrosis. J Bras Pneumol. 2017;43:219-45.
  • 3
    Robinson NB, DiMango E. Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease. Ann Am Thorac Soc. 2014;11:964-8.
  • 4
    Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastroesophageal reflux in adult cystic fibrosis patients. J R Soc Med. 1998;91:7-9.
  • 5
    Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, 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;66:516-54.
  • 6
    Mousa HM, Rosen R, Woodley FW, Orsi M, Armas D, Faure C, et al. Esophageal impedance monitoring for gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 2011;52:129-39.
  • 7
    Gonçalves ES, Assumpção MS, Servidoni MF, Lomazi EA, Ribeiro JD. Multi-channel intraluminal impedance-pH and psychometric properties in gastroesophageal reflux: a systematic review. J Pediatr (Rio J). 2020;96:673-85.
  • 8
    Mousa HM, Machado R, Orsi M, Chao CS, Alhajj T, Alhajj M, et al. Combined multi-channel intraluminal impedance-pH (MII-pH): multi-center report of normal values from 117 children. Curr Gastroenterol Rep. 2014;16:400.
  • 9
    Roman S, Gyawali CP, Savarino E, Yadlapati R, Zerbib F, Wu J, et al. Ambulatory reflux monitoring for diagnosis of gastroesophageal reflux disease: update of the Porto consensus and recommendations from an international consensus group. Neurogastroenterol Motil. 2017;29:1-15.
  • 10
    Blondeau K, Pauwels A, Dupont Lj, Mertens V, Proesmans M, Orel R, et al. Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis. J Pediatr Gastroenterol Nutr. 2010;50:161-6.
  • 11
    Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with cystic fibrosis. Pediatr Pulmonol. 2012;47:582-7.
  • 12
    Woodley FW, Machado RS, Hayes D Jr, Di Lorenzo C, Kaul A, Skaggs B, et al. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis. Dig Dis Sci. 2014;59:623-30.
  • 13
    Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, et al. Gastroesophageal reflux disease in children with cystic fibrosis. Adv Exp Med Biol. 2015;873:1-7.
  • 14
    Hauser B, De Schepper J, Malfroot A, De Wachter E, De Schutter I, Keymolen K, et al. Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros. 2016;15:540-7.
  • 15
    Folescu TW, Marques EA, Boechat MC, Daltro P, Higa LY, Cohen RW. High-resolution computed tomography scores in cystic fibrosis patients colonized with Pseudomonas aeruginosa or Staphylococcus aureus. J Bras Pneumol. 2012;38:41-9.
  • 16
    Gyawali CP, Kahrilas PJ, Savarino E, Zerbib F, Mion F, Smout AJ, et al. Modern diagnosis of GERD: the Lyon Consensus. Gut. 2018;67:1351-62.
  • 17
    Lee AL, Varjavandi V, Lemberg DA, Ooi CY, Gupta N, Krishnan U. Does combined multi-channel intraluminal impedance and pH (MII-pH) testing improve clinical outcomes in children with gastroesophageal reflux disease? J Pediatr Gastroenterol Nutr. 2020;71:596-603.
  • 18
    Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics. 2010;125:e925-30.
  • 19
    Kilic M, Ozturk F, Kirmemis O, Atmaca S, Guner SN, Caltepe G, et al. Impact of laryngopharyngeal and gastroesophageal reflux on asthma control in children. Int J Pediatr Otorhinolaryngol. 2013;77:341-5.
  • 20
    Ozcan C, Erkocoglu M, Civelek E, Demirkan H, Kırsaçlıoğlu CT, Tiryaki HT, et al. The relationship between gastro-oesophageal reflux disease and asthma during childhood. Allergol Immunopathol (Madr). 2014;42:109-14.
  • 21
    Huang C, Liu Y, Shi G. A systematic review with meta-analysis of gastroesophageal reflux disease and exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med. 2020;20:2.
  • 22
    Cunha GS, Mezzacappa Filho F, Ribeiro JD. Maternal and neonatal factors affecting the incidence of bronchopulmonary dysplasia in very low birth weight newborns. J Pediatr (Rio J). 2003;79:550-6.
  • 23
    Gonçalves Eda S, Mezzacappa-Filho F, Severino SD, Ribeiro MÂ, Marson FAL, Morcilo AM, et al. Association between clinical variables related to asthma in schoolchildren born with very low birth weight with and without bronchopulmonary dysplasia. Rev Paul Pediatr. 2016;34:271-80.
  • 24
    Poddar U. Gastroesophageal reflux disease (GERD) in children. Paediatr Int Child Health. 2019;39:7-12.
  • 25
    El-Serag H B, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63:871-80.
  • 26
    Cystic Fibrosis Foundation [homepage on the Internet]. Complications. Cystic fibrosis foundation patient registry 2018 annual data report. Maryland (USA): Cystic Fibrosis Foundation. 2018: 62. [Cited 2022 Jul 17]. Available from: https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf
    » https://www.cff.org/Research/Researcher-Resources/Patient-Registry/2018-Patient-Registry-Annual-Data-Report.pdf
  • 27
    Van der Doef HP, Arets HG, Froeling SP, Westers P, Houwen RH. Gastric acid inhibition for fat malabsorption or gastroesophageal reflux disease in cystic fibrosis: longitudinal effect on bacterial colonization and pulmonary function. J Pediatr. 2009;155:629-33.
  • 28
    Brodzicki J, Trawińska M, Korzon M. Frequency, consequences and pharmacological treatment of gastroesophageal reflux in children with cystic fibrosis. Med Sci Monit. 2002;8:CR529-537.
  • 29
    Vic P, Tassin E, Turck D, Gottrand F, Launay V, Farriaux JP. [Frequency of gastroesophageal reflux in infants and in young children with cystic fibrosis]. Arch Pediatr. 1995;2:742-6.
  • 30
    Montgomery RK, Mulberg AE, Grand RJ. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology. 1999;116:702-31.

Publication Dates

  • Publication in this collection
    16 June 2023
  • Date of issue
    2023

History

  • Received
    17 July 2022
  • Accepted
    7 Nov 2022
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