Acid gastroesophageal reflux (GER) is common both in children and adults with cystic fibrosis (CF) and has been associated with reduced pulmonary function (1). Whether increased GER in CF is a primary phenomenon or secondary to the disease is still debated. Furthermore, the impact of increased GER in the pathophysiology and evolution of CF lung disease is still unknown. In patients with CF, GER has been traditionally measured using esophageal pH monitoring. This technique detects acid GER. More recently, the development of esophageal impedance-pH monitoring has allowed a more sensitive detection of all types of reflux. Using this technique it has been shown that not only acid but also weakly acid (WA) reflux may be associated with respiratory symptoms (2–5).
It is a popular belief that in patients with CF, chest physiotherapy and frequent coughing may provoke GER because of the increased abdominal-thoracic pressure gradient (6). So far, the precise time relation between reflux and cough has not been fully assessed. Simultaneous measurement of reflux with impedance-pH-metry and objective detection of cough with gastroesophageal ambulatory manometry allows a precise assessment of the reflux-cough relation (2).
Aspiration of gastroduodenal contents into the lungs, during and/or after reflux, may be harmful for patients with CF (7,8). Recent studies have shown the presence of gastric markers (pepsin or bile acids [BA]) in bronchoalveolar lavage fluid of patients with CF after lung transplantation. In nontransplanted patients with CF, bronchoscopy with collection of bronchoalveolar lavage fluid is not routinely performed, so that aspiration is more difficult to prove. Detection of gastric markers in saliva has been proposed as a surrogate for identification of patients with a high risk of gastric aspiration (9).
We have recently studied GER and aspiration in adult patients with CF. Most patients had increased acid reflux, but a subgroup showed increased WA reflux and/or a significant association between WA reflux and cough. We demonstrated that GER is a primary phenomenon in CF and we found that 40% of the adult patients studied had measurable BA in saliva (10).
GER characteristics may change with age in patients with CF. There are clinical and functional differences between adult and pediatric patients with CF. Although pulmonary abnormalities are already present at a young age, pulmonary exacerbations and coughing become more frequent and severe with age. Accumulation of intraluminal secretions and chronic destruction of the airway wall together with bronchiolitis are associated with a progressive reduction of lung function in patients with CF (11). As a consequence, the need for antibiotics and bronchodilators increases and this may further affect the gastric and duodenal flora and may impair lower esophageal sphincter (LES) function, leading to the worsening of GER.
It is suggested that increased reflux and risk for aspiration is already present in young patients with CF (12). However, its prevalence, characteristics, and possible influence on progression of lung disease are still unknown.
The primary aim of this study was to assess the characteristics of GER (acid, WA, and weakly alkaline [WALK]) in children with CF and to investigate the relation between cough and reflux in this young age group. The secondary aim was to test the presence of gastric markers in saliva to identify those children with a high proximal extent of reflux and a potential risk for aspiration.
PATIENTS AND METHODS
GER monitoring was performed in 24 children with CF (12 boys, age 4 [range 0.3–13] years). Eleven children with CF at the pediatric CF center of the University Hospital Brussels, Belgium; 3 children at the pediatric CF center of the University Hospital Gasthuisberg, Leuven, Belgium; 6 children at Children's Hospital Virgen del Rocío, Seville, Spain and 4 children at the Division of Pediatrics, University Medical Center Ljubljana, Slovenia, were studied. Patients were selected for reflux monitoring based either on the presence of possible GER disease symptoms, such as epigastric pain, failure to thrive, presence of esophagitis, or an unexplained unfavorable respiratory evolution despite maximal therapy.
Nineteen children were stable at the time of the study, whereas the remaining 5 children were studied during an exacerbation period. Nine children demonstrated GER-related symptoms including abdominal pain, vomiting, belching, heartburn, or regurgitation.
Treatment with antisecretory medication (proton pump inhibitor or H2 blockers) was interrupted for at least 7 days before the study. Enzymatic pancreatic supplements were continued. Patient characteristics are displayed in Table 1.
A separate group of children with CF was evaluated for presence of BA in saliva (risk for gastric aspiration). In 65 consecutive children attending the outpatient clinic of the pediatric CF center of the University Hospital Gasthuisberg, K.U.Leuven, saliva samples were collected and analyzed for the presence of BA (Fig. 1). Fifteen children were receiving supplemental oral BA (ursochol/Ursofalk, Axcan Pharma, Birmingham, AL). Lung function (forced expiratory volume in 1 second [FEV1%] predicted) and body mass index (BMI) standard deviation score were assessed on the day of the sample collection. Saliva was collected in 23 healthy children as a pediatric control group (12 boys, age 8 [range 4.5–12] years). Impedance-pH recording was performed as an investigation for standard good practice.
Reflux Detection (Impedance-pH Recording)
GER was monitored using ambulatory impedance-pH-metry (Sleuth, Sandhill Scientific Inc; Highlands Ranch, CO). Esophageal impedance-pH was recorded with a 2.1-mm diameter catheter that comprised 6 electrode pairs to measure intraluminal impedance and 2 antimony pH sensors. The proximal pH sensor was positioned approximately 3 cm above the LES, the distal pH sensor in the stomach (Fig. 2).
The impedance-pH recording was analyzed using criteria described in a recent consensus report on detection and definitions of acid, nonacid, and gas reflux (13). GER was defined as a sequential orally progressing drop in impedance to <50% of the baseline values starting distally and propagating retrograde to at least the next 2 more proximal measuring segments. According to the corresponding pH change, impedance-detected reflux was classified as acid if pH fell below 4 for at least 4 seconds or, if pH was already below 4, as a decrease of at least 1 pH unit sustained for more than 4 seconds. Weakly acidic reflux was defined as a pH drop of at least 1 pH unit sustained for more than 4 seconds with the basal pH remaining between 7 and 4. Reflux was judged to be WALK when there was impedance evidence of reflux but the pH did not drop below 7. pH-only events were defined as a drop of the esophageal pH below 4 for less than or equal to 5 seconds, without a typical impedance pattern.
For each patient, the total number of reflux events (acid, WA, and WALK), the number of episodes with a high proximal extent (number of episodes reaching impedance channel 1), and the exposure of the esophageal body to acid and volume were calculated. Total 24-hour acid exposure was calculated, independent from impedance, as the percentage of time that the esophageal pH was below 4. The total esophageal acid exposure was considered increased >6% in children older than 1 year and >12% in children <1 year (14). Total volume exposure per 24 hours was obtained from the impedance tracing by addition of the volume exposures during reflux measured at 5 cm above LES. Parents were asked to carefully record meal times and posture changes.
Cough Detection (Manometry)
An objective cough detection system could be used in 11 of the 24 children with CF who underwent reflux monitoring in the Academic Hospital of Brussels. Cough was detected by adding to the ambulatory reflux monitoring a separate thin manometric catheter with 2 solid-state pressure sensors (15 cm apart) (Unisensor AG, Attikon, Switzerland) that was positioned so that 1 pressure sensor was located in the esophageal body and the other in the stomach. The impedance-pH and manometric catheters were connected to a single ambulatory device containing the respective amplifiers (Sleuth, Sandhill Scientific Inc). All signals (impedance, pH, and manometry) were digitized at 50 Hz and stored in the data logger.
The manometric tracing was independently analyzed for cough episodes. A “cough burst” was defined as 2 or more rapid simultaneous pressure peaks within 3 seconds that occurred in both manometric channels with the same configuration (15).
As we did in our previous studies on GER-related cough, only cough bursts were considered in the reflux-cough association analysis (2,4).
Cough Inducing Reflux
A reflux event was considered “induced by” cough if cough occurred in the 30 seconds preceding reflux (15). The total esophageal acid and volume exposures because of cough were calculated by adding the acid and volume exposures (second) at 5 cm above the LES from the individual reflux events “induced by” cough, divided by the total recording time.
Reflux Inducing Cough
A 2-minute time interval following the start of a reflux episode was used to delimit the time window for reflux-cough association. A 2-minute period was chosen based on previous analysis of acid reflux-chest pain association (16). Thus, if a cough episode occurred in the 2-minute time period after the start of a reflux event, cough was considered “induced by reflux.” The statistical significance of the association between reflux and cough was assessed using the symptom association probability (SAP) analysis. The SAP was calculated as previously described; SAP values >95% were considered statistically significant (17).
Detection of Bile Acids in Saliva
Standard samples of 1 to 2 mL were obtained using a commercially available method (Salivette, Sarstedt, Germany). As control, bile acid was measured in saliva from 23 healthy children (11 boys, age 7 [range 3.5–13] years).
Bile Acids Assay
Saliva samples were analyzed for the presence of total BA using a commercially available enzymatic assay (Bioquant, San Diego, CA). The lowest level of accurate detection for this assay was 0.2 μmol/L.
The respiratory status was evaluated by clinical information (number of exacerbations in the previous year and presence or absence of a respiratory exacerbation at time of impedance-pH measurement with an exacerbation defined as symptoms necessitating the start of additional antibiotics therapy); by objective cough measurement during reflux monitoring and by lung function assessment (FEV1% predicted) in children older than 5 years (n = 10). The number of exacerbation periods in the year before the study was assessed by identifying the number of times the treating physician initiated treatment with antibiotics.
Statistical analysis was performed using GraphPad software (Prism 4 GraphPad Software Inc, San Diego, CA). Data are presented as median (25th–75th percentile) unless otherwise stated. Comparison between groups was done with unpaired t test or 1-way ANOVA. If data were not normally distributed, then nonparametric analysis was performed (Mann-Whitney rank U test or Kruskal-Wallis test). Correlation between GER and other parameters was performed using a Pearson/Spearman correlation index. Fisher exact test was used to calculate SAP. Statistical significance was accepted if P < 0.05.
Impedance monitoring detected 1051 reflux events, 40 (range 33–59) per patient. From the total number of reflux episodes detected by impedance, 62.7% were acid, 37% were WA, and 0.3% were WALK. One third (32%) of reflux events contained gas. Thirty-one percent of reflux events reached the proximal esophagus. In addition to the reflux events detected by impedance, esophageal pH recording identified 325 acid-only events, 7 (range 2–14) per patient.
An increased total esophageal acid exposure was found in 16 of the 24 children with CF. In 1 child the acid exposure was increased exclusively during the day, in 10 children exclusively during the night, and in 5 children both during the night and day. Seven of the 16 patients with increased GER did not have symptoms that could be associated with GER.
Age, sex, and pancreatic function were similar in patients with and without increased GER. There was no difference in reflux parameters between patients with genotype DF508 homozygote, DF508 heterozygote, and patients with other genotypes. Reflux parameters are displayed in Table 2.
Bile Acids Detection in Saliva
Twenty-three of the 65 children had BA in the saliva (4.9 [range 3.0–6.0] μmol/L), compared with none of the healthy controls. Age (9.5 [range 7–14.5] years vs 10.8 [range 8–14.3] years) and sex (9/14 vs 21/25, male/female) were similar in children with and without BA in the saliva. Only 2 of the 15 patients receiving oral BA had BA in the saliva.
Gastroesophageal Reflux and Respiratory Symptoms/Function
Cough was recorded simultaneously with GER in 11 children with CF. All of the children were studied outside an exacerbation period. The median number of cough burst events was 15 (range 9–21) per 24 hours. The number of cough bursts per 24 hours was slightly higher in those children with increased GER compared with those children with normal GER (20 ± 13 vs 13 ± 10); however, this did not reach statistical significance.
Reflux-cough sequences were found in 8 of the 11 children (2 [1–3]/patient) and 1 child showed a statistical significant association between WA reflux and cough (positive SAP). Cough-reflux was observed in only 3 children. In these children only a small fraction of the esophageal acid exposure (0.01%) and volume exposure (0.005%) was secondary to cough. The esophageal acid exposure was similar in stable patients (n = 19) and patients studied during exacerbation (n = 5) (3.4% [1.6%–12.3%] vs 2.9% [2.4%–16.5%]).
The age (4 [2.3–5.3] vs 4.8 [2.3–9.3] years), lung function (FEV1% predicted) (94% [65%–112%] vs 91% [60%–101%]), BMI (15 [15.5–16] vs 16.5 [15–21]), pseudomonas colonization (2/8 vs 2/16), and number of exacerbations during the last year (3 [2–5] vs 3 [2–4]) were similar in patients with increased GER compared with patients with normal GER. There was no correlation between clinical parameters (lung function, BMI, and number of exacerbations) and any of the reflux parameters.
In 23 patients with detectable BA in saliva, there was a negative correlation between the concentration of BA in saliva and lung function (FEV1% predicted), r2 = 0.32, P = 0008.
It is known that acid GER is increased in patients with CF. Recently, we have demonstrated that in adult patients with CF not only acid but also WA-GER may be increased. The prevalence and characteristics of GER and respiratory symptoms may change with age. In the present study, we investigated the prevalence of acid, WA, and WALK reflux in children with CF and the relation between GER and respiratory disease. In addition, we studied the presence of bile acid in saliva, a possible surrogate marker for duodenogastroesophageal reflux and aspiration.
The main findings of the study were 16 of the 24 (67%) children with CF have increased acid GER, GER in CF is not secondary to cough, and one third of children with CF have BA in saliva suggesting duodenogastroesophageal reflux and possibly a high risk of aspiration.
In children, GER has been associated with respiratory symptoms such as chronic cough and wheezing (18,19). In 1975, GER was first reported in patients with CF (20). Since then several studies described a high prevalence of acid GER in both adults and children with CF. The prevalence of increased acid GER in children with CF has been estimated to be between 58% and 86% of the patients (12,21–24). The present study confirmed the high prevalence of acid GER that was found in 16 of the 24 (66.7%) children with CF and was associated with increased esophageal acid exposure. Not only the number of reflux events but also the volume of the refluxate and impaired esophageal clearance could contribute to the high esophageal acid exposure in patients with CF. Saliva is critical for esophageal acid clearance and saliva volume; composition or buffering capacity can be altered in CF (25).
Patient selection may have an impact on the prevalence of GER in patients with CF. We studied a heterogeneous group including both subjects with and without typical GER symptoms. Different patient selection criteria, such as based on specific genotype, may result in a different GER profile.
A limitation of the present study is that in contrast to previous studies, we used an impedance catheter crossing the LES that may lead to slightly higher levels of GER (14).
Previous studies looking at GER in patients with CF have used 24 hours of esophageal pH-metry. This technique allows detection of acid GER. Combined esophageal impedance-pH-metry has demonstrated that not only acid but also WA-GER may be associated with respiratory symptoms (2,4,26). We have recently demonstrated, using combined impedance-pH recordings, that a group of adults with CF may have exclusively increased WA-GER. This is the first study on GER in children with CF using combined impedance-pH measurements. Normal values for impedance recording in children are lacking and therefore it is impossible to determine whether WA-GER was increased in children with CF. Previous studies using this technique in children with respiratory symptoms demonstrated that 56% of the reflux episodes were WA (27). In the present study, in children with CF we found that from the total amount of reflux detected by impedance monitoring, only 37% was WA and only 0.3% WALK. It may be that gastric composition in children with CF differs from that observed in other GER-related respiratory disorders. It has been demonstrated that patients with CF have increased gastric acidity (6,28,29) and perhaps increased duodenogastric reflux (30). Symptom anamnesis is insufficient for the diagnosis of increased GER, because only half of the patients with increased GER presented typical symptoms such as heartburn, regurgitation, or abdominal pain. Most reflux episodes in children with CF were acid. These findings do support the usefulness of pH-metry for evaluation of GER in children with CF in centers where impedance is not available.
The relation between GER, aspiration, and respiratory symptoms in children with CF has never been fully clarified. Whether GER is a primary phenomenon or secondary to cough or physiotherapy has been a matter of debate (24,31,32). Reduced LES pressure, increased number of transient LES relaxations, and delayed gastric emptying are primary mechanisms associated with increased GER in CF. Chest physiotherapy and frequent coughing, however, have been suggested to provoke reflux as a secondary phenomenon in children with CF.
An increase in intraabdominal pressure during coughing may be responsible for increased reflux in CF (cough-reflux) (6). We recently demonstrated that cough does not provoke reflux in adults with CF. However, in children cough and reflux characteristics may be different compared with adults. In the present study, we investigated the time relation between GER and cough in children with CF using objective techniques for both reflux and cough detection (2,4,15). We observed that the cough-reflux sequence is rare in children with CF. Cough was responsible for a small portion of the esophageal acid (0.01%) and volume exposures (0.005%).
Although chest physiotherapy has been associated with increased GER in CF, evidence has conflicted. Button et al showed an increase of GER during postural drainage with head-down tilt (33); however, others failed to show such an increase. In the present study, we did not specifically evaluate the effect of chest physiotherapy on GER. Chest physiotherapy with a head-down position was not performed in the children with CF during the study period.
Patients with CF and increased GER may have a poorer lung function compared with patients having CF without GER, and antireflux treatment has been associated with an improvement in the evolution of the FEV1 (1,34). Other studies, however, failed to show such a relation (35). Impairment of lung function in CF is multifactorial, therefore a possible causal link between GER and lung disease may be difficult to document. In the present study, we could not identify a direct relation between GER and clinical parameters, such as lung function or BMI. This may be partially due to small patient numbers.
Proximal reflux followed by aspiration of gastric contents into the lungs is one of the mechanisms associated with GER-related pulmonary damage. In adults with CF, aspiration has been demonstrated, based on the presence of tracheal acidification during GER episodes (36). We have recently demonstrated that 40% of the adults with CF have BA in the saliva, suggesting duodenogastroesophageal reflux with a high proximal extent and possibly a risk for aspiration (10). In this study, BA in saliva were measured in 35% of the children with CF compared with none of the healthy controls. The presence of BA in the saliva seemed not related to the intake of oral BA, because saliva sampling was preformed away from drug administration and only 2 of the 15 patients receiving oral BA had BA in the saliva. BA in saliva can be detected in adults after subtotal Billroth II resection and correlated to duodenogastric reflux and laryngeal damage (37). Whether in patients with CF the presence of gastric components in saliva may indicate a high degree of duodenogastric reflux and a risk of aspiration will need to be confirmed.
In conclusion, acid GER is prevalent and merely a primary phenomenon in children with CF. GER is predominantly acid in children with CF. One third of children with CF have BA in the saliva. The relevance of this finding in light of the risk for aspiration needs further study. The impact of GER on the pulmonary disease in children with CF is still unclear. In clinical practice treatment is merely offered for documented GER in case of gastric symptoms (heartburn and regurgitation) and/or in case of unfavorable pulmonary evolution despite maximal therapy. Whether GER must be treated in asymptomatic and pulmonary stable children with CF to prevent later lung damage should be studied by randomized intervention studies. Because both children and adults with CF have predominantly increased acid reflux, intense antiacid treatment may be recommended. However, proton pump inhibitor treatment cannot prevent aspiration in case of WA reflux and bile reflux in patients with CF.
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