Introduction
Gastroesophageal reflux disease (GERD) is a common comorbidity in chronic obstructive pulmonary disease (COPD). The prevalence of self-reported GERD in those with COPD is reported to be between 17% [
1] to 54% [
2] while studies using 24-h pH probe and manometry report prevalence as high as 78% [
3]. Pulmonary microaspiration and vagal-mediated reflex bronchoconstriction have been proposed as possible mechanisms by which GERD contributes to COPD outcomes [
4,
5]. Cross-sectional studies have consistently shown that, compared to COPD patients without GERD, those with GERD experience more frequent acute exacerbations [
6‐
9], more hospitalizations and emergency room visits [
2,
10‐
14], higher healthcare costs [
15], and worse quality-of-life [
12,
16]. However, it remains unclear whether GERD contributes to COPD pathogenesis and progression as measured by lung function or quantitative computed tomography (QCT) [
17].
Cross-sectional studies that evaluated the relationship between GERD and lung function have revealed conflicting results – some studies observed worse airflow obstruction [
2,
18,
19] in those with GERD, while other studies showed no significant relationship between GERD and lung function [
12,
20‐
22]. Due to the cross-sectional design of these studies, we cannot derive definitive conclusions about the causal associations between GERD and COPD disease progression. Therefore, to evaluate if GERD is associated with COPD disease progression as measured by lung function or quantitative chest imaging, we analyzed the data from a large, longitudinal, multicenter cohort study. To our knowledge, this is the first study to longitudinally assess both lung function and quantitative chest imaging over a five-year period to evaluate the association between GERD and COPD disease progression.
Results
Data were available for 5728/10,720 (53.4%) participants who were former or current smokers and completed both Phase I (baseline, 2008–2011) and Phase II (5-year follow-up, 2012–2016) study visits (Supplemental Fig.
1S). Physician-diagnosed GERD was reported in 2101/5728 (36.7%) participants at either Phase I and/or Phase II (Table
1). Those with GERD were more frequently female (55.6% vs. 45.9%), GOLD stages ≥2 (38.0% vs. 28.3%), and prescribed inhaled therapies (43.5% vs. 26.1%). In addition, participants with GERD were more likely to have experienced acute exacerbations of COPD (26.8% vs. 13.8%) and severe exacerbations of COPD (12.1% vs. 6.9%), worse SGRQ total score (median of 25 vs. 14), and more dyspnea as assessed by mMRC score ≥ 2 (45.3% vs. 30.0%). Cohort characteristics at Phase I comparing those with (
n = 4031) and without (
n = 1697) available QCT measurements at both visits are provided in the Supplemental Table
1S.
Table 1
Cohort characteristics at Phase I by gastroesophageal reflux (GERD) status. Data are presented as mean (standard deviation), median (first quartile, third quartile), or n (%)
Demographics |
Age, years | 59.0 (8.74) | 60.9 (8.38) |
Female | 1668 (46%) | 1168 (56%) |
African American | 1269 (35%) | 489 (23%) |
Current smoker | 1928 (53%) | 862 (41%) |
Pack-years | 40.9 (22.2) | 45.3 (25.4) |
BMI, kg/m2 | 28.6 (6.0) | 29.9 (6.3) |
Education beyond HS | 2348 (65%) | 1396 (66%) |
Spirometry |
FEV1% predicted | 82 (23) | 77 (23) |
FVC % predicted | 90 (17) | 87 (17) |
FEV1/FVC | 0.70 (0.14) | 0.67 (0.15) |
GOLD stage |
PRISm | 438 (12%) | 263 (13%) |
GOLD 0 | 1826 (51%) | 851 (41%) |
GOLD 1 | 321 (8.9%) | 182 (8.7%) |
GOLD 2 | 626 (17%) | 483 (23%) |
GOLD 3 | 309 (8.6%) | 258 (12%) |
GOLD 4 | 86 (2.4%) | 55 (2.6%) |
Inhaled therapies |
SABA | 776 (22%) | 763 (37%) |
LABA | 57 (1.6%) | 85 (4.1%) |
ICS | 137 (3.9%) | 144 (7.0%) |
ICS/LABA | 438 (12%) | 460 (22%) |
LAMA | 362 (10%) | 389 (19%) |
Quantitative CT chest |
AWT-Pi10, mm | 2.2 (0.58) | 2.3 (0.58) |
Airway wall area, % | 50 (8.3) | 50 (8.2) |
Air trapping, % | 19 (17) | 22 (18) |
Emphysema, % | 5.1 (8) | 6.4 (9.1) |
Perc15 lung density, HU | 78 (22) | 76 (23) |
Clinical outcomes |
Acute exacerbation | 499 (14%) | 563 (27%) |
Severe exacerbation | 252 (6.9%) | 254 (12%) |
Cough | 1126 (31%) | 815 (39%) |
Phlegm | 1126 (31%) | 803 (38%) |
Wheeze | 1380 (38%) | 1093 (52%) |
SGRQ, total score | 14 (3.8, 32) | 25 (9.3, 45) |
mMRC ≥2 | 1086 (30%) | 949 (45%) |
6-MWD, feet | 1448 (368.8) | 1369 (370.4) |
Compared to participants without GERD, participants with GERD at Phase I and/or Phase II had faster decline in FEV
1 (difference of − 3.64 mL/year, 95% confidence interval (CI), − 6.56 to − 0.73) and FVC (difference of − 4.26 mL/year; 95% CI, − 8.52 to − 0.004), after adjustment for age, sex, race, smoking, BMI, clinic center, and FEV
1% predicted (Table
2). When additionally adjusted for acute exacerbations, the estimates were attenuated and no longer statistically significant, with 95% confidence interval bounds crossing zero. Participants with GERD showed faster progression of air trapping (difference of 0.159%/year; 95% CI, 0.054–0.264) on QCT. We observed no association between the rate of change of AWT-Pi10 (μm/year), airway wall area (%/year), emphysema (%/year), Perc15 lung density (HU/year), and GERD status.
Table 2
Linear regression models of the association between gastroesophageal reflux disease (GERD) and slopes of lung function and Quantitative CT measures of lung disease. ß coefficients reflect the mean differences in the row outcome of interest between those with GERD compared to those without GERD
Spirometry |
FEV1 (mL/year) | −0.01 (−2.92, 2.89) | −3.64 (−6.56, − 0.73) | −2.53 (−5.43, 0.37) |
FVC (mL/year) | −2.76 (− 6.93, 1.42) | −4.26 (−8.52, − 0.004) | −3.05 (− 7.29, 1.19) |
Quantitative CT chest |
AWT-Pi10 (μm/year) | 2.31 (−1.86, 6.48) | 1.28 (− 2.91, 5.48) | 0.64 (−3.57, 4.84) |
Airway wall area (%/year) | 0.037 (− 0.022, 0.097) | 0.013 (− 0.047, 0.073) | 0.003 (− 0.058, 0.063) |
Air trapping (%/year) | 0.117 (0.006, 0.227) | 0.167 (0.063, 0.271) | 0.159 (0.054, 0.264) |
Emphysema (%/year) | 0.035 (− 0.010, 0.081) | 0.015 (− 0.025, 0.055) | 0.012 (− 0.028, 0.052) |
Perc15 lung density (HU/year) | − 0.073 (− 0.207, 0.061) | − 0.024 (− 0.137, 0.089) | −0.023 (− 0.137, 0.090) |
In secondary analyses, ‘incident GERD’ (Phase I = ‘no’, Phase II = ‘yes’) was associated with faster decline in FEV
1 and FVC compared to ‘any GERD’ (Phase I = ‘yes’ and/or Phase II = ‘yes’), ‘persistent GERD’ (Phase I = ‘yes’
and Phase II = ‘yes’), and ‘resolved GERD’ (Phase I = ‘yes’ and Phase II = ‘no’) (Table
3). The odds of rapid FEV
1 decline (
n = 2572) was significantly increased for those reporting ‘any GERD’ (adjusted odds ratio [aOR]: 1.20; 95% CI, 1.07 to 1.35), ‘persistent GERD’ (aOR: 1.23; 95% CI, 1.06 to 1.43), and ‘incident GERD’ (aOR: 1.33; 95% CI, 1.11 to 1.60); the only participants that did not have an increased odds of rapid decline was the ‘resolved GERD’ (aOR: 1.01; 95% CI, 0.82 to 1.26) group (Table
4).
Table 3
Multivariable linear regression models of the association between gastroesophageal reflux disease (GERD) and slopes of lung function. ß coefficients reflect the mean differences in the row outcome of interest between those with GERD compared to those without GERD
Spirometry |
FEV1 (mL/yr) | −2.53 (− 5.43, 0.37) | − 2.07 (− 5.75, 1.61) | −5.47 (− 9.87, − 1.07) | −0.24 (− 5.87, 5.39) |
FVC (mL/yr) | −3.05 (− 7.29, 1.19) | − 1.69 (− 7.01, 3.63) | −6.29 (− 13.0, 0.42) | −1.62 (− 9.38, 6.15) |
Table 4
Multivariable logistic regression models of the association between gastroesophageal reflux disease (GERD) and rapid FEV1 decline (FEV1 decline of ≥40 mL/year, n = 2572). Adjusted odds ratios reflect the relative odds of rapid FEV1 decline between those with GERD, compared to those without GERD
Any GERD (n = 2101) | 1.20 (1.07, 1.35) |
Persistent GERD (n = 1080) | 1.23 (1.06, 1.43) |
Incident GERD (n = 604) | 1.33 (1.11, 1.60) |
Resolved GERD (n = 417) | 1.01 (0.82, 1.26) |
Among our 5728 study participants, pharmacologic treatment with PPIs was reported by 990 (24%) and H
2 blockers by 260 (6.5%), of whom most (81%) reported GERD at either visit, though 19% did not report GERD at either visit. Among those with GERD, treatment with PPI and/or H
2 blocker at either Phase I and/or Phase II was associated with faster decline in lung function (Table
5). Among participants with GERD, the decline in both FEV
1 (difference of − 6.61; 95% CI, − 11.9 to − 1.36) and FVC (difference of − 9.26; 95% CI, − 17.2 to − 1.28) were faster in those receiving PPI and/or H2 blocker compared to those who are not receiving either medication. Among those without GERD, PPI and/or H
2 blocker treatment was not associated with lung function decline, though these estimates had less precision than in those with GERD due to the smaller sample.
Table 5
Multivariable linear regression models of the association between treatment with proton-pump inhibitor (PPI) and/or H2 blocker and slopes of lung function, in those with and without gastroesophageal reflux disease (GERD). ß coefficients reflect the mean differences in the row outcome of interest between those with treatment with PPI and/or H2 blocker, compared to those not receiving treatment
GERD (n = 960) |
FEV1 (mL/year) | −6.61 (−11.9, − 1.36) |
FVC (mL/year) | −9.26 (− 17.2, − 1.28) |
No GERD (n = 221) |
FEV1 (mL/year) | 6.38 (−3.04, 15.8) |
FVC (mL/year) | 3.97 (−7.66, 15.6) |
No significant differences in the slopes of change of the QCT chest measures was found in those taking PPI and/or H
2 blockers compared to those who were not taking medications (Supplemental Table
2S).
Discussion
Data from our large, multicenter, longitudinal cohort suggest that GERD may contribute to progressive loss of lung function and increases in air trapping over time. Although other studies have found cross-sectional associations between GERD and lung health, to our knowledge, our study is the first to use a longitudinal study design over a five-year period and assess both lung function and quantitative imaging measurements.
Despite several statistically significant associations between GERD and longitudinal changes in spirometry and QCT measures, we note that the magnitude of the effect sizes were clinically small, with point estimates of 2–5 mL/year faster FEV
1 decline among those with GERD. Although this degree of faster lung function decline might not be expected to lead to significant clinical problems, we note that the effect size of cigarette smoking has been estimated at 4–27 mL/year faster decline, so an additional 2–5 mL/year might still contribute to disease progression, in combination with other factors that might contribute to lung function decline such as non-cigarette smoke exposures, respiratory infections, and abnormal inflammatory responses [
27,
28]. Although we have little data to guide us in categorizing more significant rates of QCT changes over time, for spirometry, we applied a common definition of rapid FEV
1 decline of ≥40 mL/year [
29]. In this categorical logistic regression analysis, we saw that GERD was associated with a 20–33% increased odds of rapid decline. Although we must advise caution in interpreting this secondary analysis, these results suggest there might be a subgroup of persons more susceptible to pulmonary effects of GERD, but further research is needed to explore this hypothesis.
We included acute exacerbations as a covariate in our models as episodes of acute exacerbations have been known to accelerate lung function decline [
30]. We found that rapid FEV
1 decline and progression in QCT-measured air trapping were associated with GERD, but the estimates of slopes of FEV
1 and FVC were attenuated compared to the model that did not include acute exacerbations as a covariate.
We evaluated loss of lung function both as continuous variables (mL/year) and as a categorical variable (FEV
1 decline ≥40 mL, yes vs. no), then stratified GERD into ‘persistent’, ‘incident’, and ‘resolved.’ Rapid decline in FEV
1 is a strong predictor of mortality and COPD-related hospitalization [
31]. This current study suggests that GERD is an independent predictor of rapid FEV
1 decline, using a multivariate logistic regression model controlling for age, sex, race, smoking status, BMI, FEV
1% predicted at baseline, and acute exacerbations. Participants with ‘resolved GERD’ do not appear to have increased odds of rapid FEV
1 decline raising the question about the potential role of GERD treatment in slowing lung function decline, which will need to be addressed in future clinical trials.
Smaller cross-sectional studies that have evaluated the relationship between lung function severity and GERD have shown mixed results. Mokhlesi et al. [
32] found that symptomatic GERD was more prevalent in COPD patients with FEV
1 ≤ 50% compared to those with FEV
1 > 50% (23% vs. 9%, respectively;
p = 0.08), while Rogha et al. [
2] showed that patients with GERD have more severe COPD compared to those without GERD (GOLD stage ≥2 or higher: 88% vs. 67%, respectively;
p = 0.005) supporting our findings. In contrast, several other studies found no association between lung function and GERD, possibly due to relatively small sample sizes [
12,
33‐
35]. Our present study expands the literature on the relationship between lung function and GERD by adding temporal dimension and a larger sample size.
In addition to adding a temporal dimension in the assessment of the impact of GERD in lung function, we also evaluated whether GERD contributes to the progression of small airway disease and emphysema over time using QCT. Small airway obstruction and emphysematous lung destruction reflect abnormalities in lung function [
36]. Airway changes using QCT in the context of aspiration have been evaluated previously [
37‐
42], but these studies are also limited to small cross-sectional studies. Hiller et al. found that patients with recurrent aspiration of gastric contents had QCT evidence of bronchial wall thickening (95%) and air trapping (44%) [
42]. Similarly, Cardasis et al. found increased airway wall thickening on QCT of patients with pathologically-confirmed chronic occult aspiration of whom 96% had diagnosis of GERD [
41]. We found that the rate of air trapping progression over 5 years was faster in those with GERD compared to those without GERD. This could represent the development of distal small airway disease as a result of ongoing pulmonary micro-aspiration of refluxed gastric material and/or vagally-mediated reflex bronchoconstriction in GERD [
4,
5]. However, the slopes of the other QCT measurements of small airway disease (AWT-Pi10 and airway wall area) and emphysema (% emphysema and Perc15 lung density) were not different between those with and without GERD. We hypothesize that air trapping in the setting of GERD is a possible early measurable imaging manifestation of small airway disease, possibly an imaging finding that can be seen prior to the other QCT measurements of small airway disease and emphysema. This hypothesis will need to be addressed in future longitudinal studies.
The association between GERD and lung health bring into question the role of anti-reflux treatment in management of COPD. We observed that pharmacologic treatment with PPI and/or H
2 blocker among participants with GERD was associated with an accelerated decline in FEV
1 and FVC. Using the same COPDGene cohort, Martinez et al. showed that the use of PPI was associated with improved SGRQ total score, but also increased exacerbations highlighting the possibility of confounding-by-indication [
16]. The significant decline in lung function with PPI and/or H
2 blocker use in this cohort is also likely due to confounding-by-indication. Xiong et al. suggested that treatment of GERD with PPI in patients with COPD is associated with delayed deterioration of FEV
1 after 1-year follow-up [
43]. However, several other studies evaluating the efficacy of anti-reflux medications in COPD did not report on the impact of these pharmacologic therapies on lung function [
12,
32,
44‐
46]. A limitation to the pharmacologic treatment of GERD is that anti-reflux medications do not target nonacid reflux and weakly acidic reflux. Surgical intervention with fundoplication, on the contrary, impacts both acid and non-acid reflux. Most of the literature on anti-reflux surgery focuses on lung transplant. Although the evidence is conflicting, a systematic review by Robertson et al. suggested that anti-reflux surgery provided benefit in lung function among lung transplant patients [
47]. We did not find studies specifically addressing anti-reflux surgery in COPD and lung function. The effects of anti-reflux therapies in COPD outcomes, specifically lung function, are unclear highlighting the need for carefully-designed clinical trials.
Our study has limitations. GERD was based on self-report of a physician diagnosis, not on validated reflux questionnaires, pH monitoring, or esophageal manometry. Therefore, GERD misclassification might have affected our results. Because this is an observational study, we cannot establish causal inferences.
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