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. Author manuscript; available in PMC: 2024 Nov 1.
Published in final edited form as: J Gastroenterol Hepatol. 2023 Aug 22;38(11):1998–2005. doi: 10.1111/jgh.16325

Abnormal bolus reflux on impedance-pH testing independently predicts 3-year pulmonary outcome and mortality in pulmonary fibrosis

Mariel E Bailey *,†, Lawrence F Borges *,†,‡, Hilary J Goldberg *,†,§, Kelly E Hathorn *,†,‡, Sravanya Gavini *,†,‡, Wai-Kit Lo *,†,‡, Walter W Chan *,†,‡
PMCID: PMC10761196  NIHMSID: NIHMS1954929  PMID: 37605548

Abstract

Background and Aim:

Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF), although the directionality of the relationship has been debated. Data on the value of objective reflux measures in predicting IPF disease progression and mortality remain limited. We aimed to evaluate the association between multichannel intraluminal impedance and pH testing (MII-pH) and 3-year pulmonary outcomes in IPF patients.

Methods:

This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant MII-pH off acid suppression at a tertiary center. Patients were followed for 3 years after MII-pH for poor pulmonary outcomes (hospitalization for respiratory exacerbation or death). A secondary analysis was performed using mortality as outcome of interest. Time-to-event analyses using Kaplan–Meier and Cox regression were performed to evaluate associations between MII-pH and poor outcomes.

Results:

One hundred twenty-four subjects (mean age = 61.7 ± 8 years, 62% male) were included. Increased bolus exposure time (BET) on MII-pH was associated with decreased time to poor pulmonary outcomes and death (log-ranked P-value = 0.017 and 0.031, respectively). On multivariable Cox regression analyses controlling for potential confounders including age, sex, smoking history, body mass index, proton pump inhibitor use, baseline pulmonary function, and anti-fibrotic therapy, increased BET was an independent predictor for poor pulmonary outcomes [hazard ratio 3.18 (95% confidence interval: 1.25–8.09), P = 0.015] and mortality [hazard ratio 11.3 (95% confidence interval: 1.37–63.9), P = 0.025] over 3 years.

Conclusions:

Increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients. These findings also support a role for gastroesophageal reflux in IPF disease progression and the potential impact of routine reflux testing and treatment.

Keywords: aspiration, extra-esophageal reflux, gastroesophageal reflux, lung disease, outcomes

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and a median life expectancy of 2–4 years at time of diagnosis.1 The estimated worldwide prevalence is ~13–20/100 000 people, with ~100 000 affected in the USA.2 While the inciting event is not clear, the current pathogenic model suggests dysregulated fibroproliferative repair secondary to non-specific alveolar epithelial injury.3 Gastro-esophageal reflux (GER) is common in IPF, with some studies suggesting abnormal GER in as many as 90% of IPF patients.4,5 Despite the association between GER and IPF found in prior cross-sectional studies, the directionality of the relationship remains debated. GER with proximal migration may lead to microaspiration of refluxate, resulting in onset of inflammatory cascade, causing recurrent injury and fibrosis of the lungs. On the other hand, changes in intrathoracic pressure and respiratory mechanics from pulmonary disease/injury may also worsen underlying GER.6

While prior studies found high prevalence of both acidic and weakly acidic/non-acidic reflux among IPF patients,7–9 data regarding the impact of GER on IPF disease progression remain limited. Our group previously showed that abnormal GER predicts higher likelihood of IPF-related hospitalization over 1 year.10,11 However, the follow-up time of 1 year may have been limited in assessing potential impact of GER on longer term outcomes, including mortality. Moreover, evidence to-date on the effect of anti-reflux treatment on IPF outcomes have been mixed, with some demonstrating benefits while others finding no improvement.12–14 On the other hand, data from the lung transplantation population found that GER burden among patients with restrictive lung diseases such as IPF may decrease with improvement of transdiaphragmatic pressure gradient post-transplant.15 Understanding the longitudinal relationship between GER and IPF outcomes may help establish GER as a potential modifiable risk factor for IPF and provide evidence for the role of reflux testing and antireflux therapy as important parts of IPF management.

We hypothesized that abnormal GER on objective testing predicts more severe IPF disease course and worse long-term clinical outcome, including mortality. In particular, based on previous studies of IPF and lung transplant patients, we postulated that increased total bolus reflux is a risk factor for poorer outcomes. In this study, we aimed to evaluate the association between increased bolus reflux on 24-h multichannel intraluminal impedance-pH study (MII-pH) and poor pulmonary outcomes over 3 years, including hospitalizations and death, in IPF patients undergoing pre-transplant evaluation.

Methods

Subject selection and characteristics.

This was a retrospective cohort study of adults with IPF who underwent MII-pH for pre-lung transplant evaluation at a tertiary care center. All included subjects underwent MII-pH regardless of previous or current GER diagnosis or symptoms. Diagnosis of IPF was made if patients met at least one of three criteria based on American Thoracic Society guideline recommendations: (i) lung biopsy consistent with usual interstitial pneumonitis; (ii) lung biopsy consistent with possible usual interstitial pneumonitis or non-specific interstitial pneumonitis; and (iii) in the absence of biopsy data, diagnosis by the subject’s pulmonologist based on characteristic clinical and radiologic findings. Patients were excluded if they had a history of foregut surgery. Characteristics of the cohort were collected at the time of MII-pH and included age, sex, body mass index (BMI), history of smoking, and proton pump inhibitor (PPI) use. Consumption of PPI was estimated using the defined daily dose (DDD), which is a unit of measurement recommended by the World Health Organization and defined as the assumed average maintenance dose per day used for the medication’s main indication in adults.16 The overall PPI use was represented by the cumulative DDD (cDDD), calculated as the total DDD prescribed for all types of PPI during the follow-up period. Any use of anti-fibrotic therapy was also recorded, and pirfenidone was the standard agent utilized at our institution during the study period.

Baseline pulmonary function testing (PFT) and oxygen use data were collected within 3 months of MII-pH. Lung disease severity was assessed using several parameters, including the percent predicted diffusing capacity for carbon monoxide (DLCO) and percent predicted forced vital capacity (FVC) on PFT. The gender-age-physiology (GAP) index, a validated predictive score for IPF survival often used clinically for disease staging, was also calculated utilizing the patients’ age, sex, DLCO, and FVC.17 Staging based on GAP index was also derived, with GAP index 0–3 defined as stage 1 disease, GAP index 4–5 as stage 2, and GAP index 6–8 as stage 3.

Multichannel intraluminal impedance and pH testing.

GER was objectively measured on MII-pH. The MII-pH system (Diversatek Healthcare, Milwaukee, WI, USA) consists of a portable electronic datalogger and transnasal catheter equipped with two pH sensors (0 and 15 cm), and eight impedance electrodes (−3, −1, 1, 3, 5, 9, 11, and 13 cm). For each patient, the catheter was placed into the esophagus and positioned with the distal pH sensor at 5 cm above the lower esophageal sphincter (LES). Distal or “total” reflux was detected at the most caudal electrode 5 cm from the LES, while “proximal” reflux was defined by events reaching the most cranial electrode, 15 cm above the LES. All patients underwent MII-pH off acid suppressing medication for at least 7 days. MII-pH measurements were collected over a 24-h period during which patients were instructed to remain upright during the day and recumbent at night and to maintain their normal activities, including meals. All MII-pH tracings were manually analyzed by an expert reader, with the assistance of a dedicated software (Bioview Analysis, version 5.6.3.0; Diversatek Healthcare).

The primary variable of interest was total reflux bolus exposure time (BET), represented by the total percentage of time during which refluxate was present in the esophagus, regardless of pH. Other measures of reflux recorded on MII-pH included the number of bolus reflux episodes (total and proximal), acid exposure time (% time with reflux where pH < 4), non-acid reflux episodes (total and proximal episodes where pH > 4), acid reflux episodes (total and proximal episodes where pH < 4), and mean nocturnal baseline impedance (MNBI), which was calculated as the average baseline impedance at 5 cm above LES measured during three stable 10-min periods around midnight, 1 am, and 2 am. A reflux episode was defined as a 50% drop in impedance from baseline, progressing from distal to proximal impedance channels in a retrograde fashion. The duration of each reflux episode was defined by measuring the bolus contact time, which is the time between the initial drop below 50% of baseline impedance, signaling onset of reflux, and the return to 50% of baseline in the distal impedance channel, signaling completion of the reflux event. BET is a percentage calculated by dividing the total bolus contact time of all reflux episodes by the total analyzed study time (excluding meal times). Previously established 95th-percentile values, derived from normal volunteers, were used to determine normal cutoffs for reflux episodes and exposure times, in accordance with common clinical use.18 In particular, BET was considered abnormal if it was ≥1.4%.

Outcome measures.

The primary outcome of interest was poor pulmonary outcomes within 3 years of MII-pH, defined as hospitalization for IPF exacerbation or death. All hospitalization records for patients at participating institutions during the follow-up period were manually reviewed, and only those directly related to exacerbation of underlying respiratory disease were included. Reviewers of hospitalization records were blinded to MII-pH results. Elective admissions for procedures or completion of transplantation work-up, or those in which the admitting diagnoses were unrelated to lung disease, were excluded. Mortality data were collected through chart review.

Statistical analysis.

The association between BET and poor pulmonary outcomes was evaluated using time-to-event analysis with Cox proportional hazards models. Subjects not meeting this outcome were censored at the time of anti-reflux surgery, lung transplantation, or last clinic follow-up, whichever was earliest. A secondary analysis was performed using death as the outcome. The Kaplan–Meier method was used to construct time-to-event curves. For comparisons of baseline characteristics between groups, Fisher’s exact test (binary variables), and Student’s t-test (continuous variables) were performed. Multivariable analyses using Cox regression were also performed for the association between pulmonary outcomes and BET or other reflux parameters, controlling for potential confounders including age at time of MII-pH, sex, BMI, history of smoking, PPI use, lung disease severity, and anti-fibrotic medication use. Because several definitions of lung disease severity were available, separate models adjusting for different markers of baseline lung disease severity (DLCO, FVC, GAP index, and staging per GAP index) were constructed. For models including GAP index or staging based on GAP index, age and sex were not included as covariates as both were already part of formulating the GAP index. All statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, N.C.).

Results

Study population.

We identified 124 subjects with IPF who met inclusion criteria. The mean age at the time of MII-pH was 61.7 years (standard deviation, SD 8.0), and 76 (62%) patients were men. The mean percent predicted DLCO (%DLCO) and FVC (%FVC) on PFT were 30.7% (SD 13.5) and 55.9% (SD 20.7), respectively. The average GAP index was 4.79 (SD 1.25), with 24 (19.3%) patients with stage 1 disease, 73 (58.9%) stage 2, and 27 (21.8%) stage 3. During the 3-year follow-up period, 42 (33.9%) patients had respiratory-related hospitalization and there were 18 (14.5%) deaths. Overall, 7 (5.65%) subjects underwent anti-reflux surgery and 55 (44.4%) received a lung transplant over the study period, which were not statistically different between the normal versus abnormal BET groups.

Seventy-eight (62.9%) subjects had abnormal BET. Baseline characteristics at the time of MII-pH were assessed between subjects with and without abnormal BET to address possible confounding risk factors for hospitalization and death. Patients with abnormal BET were slightly younger (59.5 ± 7.88 vs 63.5 ± 7.29, P = 0.024) and were more likely to use PPI (71.8% vs 39.1%, P = 0.0007) compared with those with normal BET. Specifically, the average cDDD of PPI during the follow-up period was significantly higher in the abnormal BET group (1615.8 ± 857.1 vs 169.1 ± 116.4, P < 0.0001). On high-resolution esophageal manometry, patients with abnormal BET had more ineffective (8.90 ± 18.1% vs 47.9 ± 38.0%, P = 0.003) and failed (3.83 ± 7.97% vs 27.3 ± 35.8%, P = 0.027) swallows than those with normal BET, although the proportions of subjects meeting diagnostic criteria for ineffective esophageal motility per Chicago classification v4.019 were not significantly different (7.69% vs 0%, P = 0.115). Otherwise, there were no significant differences in other clinical characteristics, including sex, BMI, smoking history, anti-fibrotic agent use, or baseline lung disease severity between the two groups. (Table 1)

Table 1.

Clinical characteristics between patients with normal reflux and abnormal reflux as defined by bolus exposure time (> 1.4%), including baseline demographics, lung disease severity, esophageal function testing measures, anti-fibrotic medication use, proton pump inhibitor (PPI) use, and lung transplantation or anti-reflux surgery during follow-up period

Normal bolus exposure time (n = 46) Abnormal bolus exposure time (n = 78) P-value
Mean age (years) 63.5 ± 7.29 59.5 ± 7.88 0.024
Male gender 30 (65.2%) 43 (55.1%) 0.361
BMI
 Normal (< 25) 7 (15.2%) 14 (17.9%) 0.897
 Overweight (≥ 25) 39 (84.8%) 64 (82.1%)
Smoking history 27 (58.7%) 52 (66.7%) 0.381
Baseline lung disease severity
 GAP index 4.84 ± 1.24 4..50 ± 1.24 0.229
  Stage 1 (GAP index 0–3) 7 (15.2%) 17 (21.8%)
  Stage 2 (GAP index 4–5) 27 (58.7%) 46 (59.0%) 0.529
  Stage 3 (Gap index 6–8) 12 (26.1%) 15 (19.2%)
 DLCO
  Mean DLCO (% predicted) 25.7 ± 15.6 31.6 ± 13.2 0.188
  Moderate disease (40–60% predicted) 4 (8.70%) 13 (12.8%) 0.330
  Severe disease (< 40% predicted) 42 (91.3%) 65 (83.3%)
 FVC
  Mean FVC (% predicted) 61.8 ± 25.2 53.0 ± 17.5 0.108
  Moderate disease (40–60% predicted) 15 (32.6%) 36 (46.2%) 0.284
  Severe disease (< 40% predicted) 12 (26.1%) 19 (24.4%)
 Oxygen requirement
  No oxygen 16 (34.8%) 25 (32.1%)
  Intermittent oxygen 7 (15.2%) 9 (11.5%) 0.745
  Continuous oxygen 23 (50%) 44 (56.4%)
High-resolution manometry parameters
 Normal swallows (%) 87.3 ± 19.5 82.1 ± 38.0 0.006
 Ineffective swallows (%) 8.90 ± 18.1 47.9 ± 38.0 0.003
  Failed swallows (%) 3.83 ± 7.97 27.3 ± 35.8 0.027
  Weak swallows (%) 5.06 ±11.3 20.7 ± 24.9 0.048
 Hypercontractile swallows (%) 4.17 ± 11.8 0.0 ± 0.0 0.351
 Integrated relaxation pressure (mmHg) 8.84 ± 5.40 7.16 ± 6.23 0.533
 Ineffective esophageal motility per Chicago classification v4.0 0 (0%) 6 (7.69%) 0.115
MII-pH parameters
 Total bolus reflux events 37.2 ± 20.1 78.2 ± 31.9 < 0.0001
 Acid exposure time (%) 1.91 ± 2.73 4.86 ± 5.47 0.002
  Normal (< 4%) 39 (84.8%) 45 (57.7%)
  Borderline (4–6%) 3 (6.52%) 12 (15.4%) 0.008
  Pathologic (> 6%) 4 (8.70%) 21 (26.9%)
 Mean nocturnal baseline impedance (MNBI) (Ω) 2278.3 ± 1167.3 1682.2 ± 1358.2 0.011
 Anti-fibrotic medication use 9 (19.6%) 14 (17.9%) 0.823
 PPI use
  Any PPI use 18 (39.1%) 56 (71.8%) 0.0007
  Cumulative defined daily dose 169.1 ± 116.4 1615.8 ± 857.1 < 0.0001
   < 30 30 (65.2%) 41 (52.6%)
   30–90 1 (2.17%) 2 (2.56%) 0.386
   > 90 15 (32.6%) 35 (44.9%)
 Surgery
  Anti-reflux surgery 1 (2.17%) 6 (7.69%) 0.384
  Lung transplantation 17 (37.0%) 38 (48.7%) 0.278
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DLCO, diffusing capacity of carbon monoxide; FVC, forced vital capacity; GAP index, Gender-Age-Physiology index; PPI, proton pump inhibitor.

Regarding other measures of reflux collected during the study, the mean total number of bolus reflux episodes was 59.6 (SD 35.3), including a mean of 27 (SD 23.9) acid and 31.0 (SD 22.8) non-acid reflux episodes, and the average MNBI was 1887.7 (SD 1310.2) Ω. Acid reflux burden was classified by acid exposure time (AET) on pH-monitoring, with a mean AET of 3.86% (SD 5.13) for the cohort. When AET was classified per Lyon consensus,20 84 (67.8%) patients were normal (AET: < 4%), 15 (12.1%) had borderline acid reflux (AET: 4–6%), and 25 (20.2%) had pathologic acid reflux (AET: > 6%). The mean total bolus reflux episodes, mean AET, MNBI, and proportion of patients with borderline or pathologic acid reflux per Lyon consensus were higher in the abnormal BET group compared with the normal BET cohort (Table 1).

Multichannel intraluminal impedance and pH testing measurement and 3-year poor pulmonary outcome.

On time-to-event univariate analyses, abnormal BET on MII-pH was associated with decreased time to poor pulmonary outcomes, defined as pulmonary hospitalization or death [Hazard ratio (HR) 2.79 (95% confidence interval, CI: 1.15–6.75), P = 0.023]. Kaplan–Meier analysis confirmed the relationship between abnormal BET and poor outcomes in 3 years (log rank P-value 0.017) (Fig. 1a). On multivariable Cox regression analysis controlling for potential confounders including GAP index for lung disease severity, abnormal BET remained an independent predictor for decreased time to poor pulmonary outcome within 3 years [HR 3.18 (95% CI: 1.25–8.09), P = 0.015]. Neither borderline acid reflux [HR 0.94 (95% CI: 0.34–2.59), P = 0.90] nor pathologic acid reflux [HR 0.55 (95% CI: 0.21–1.43), P = 0.22] as defined by AET alone per Lyon consensus significantly correlated with pulmonary outcomes. Multivariable models utilizing other lung disease severity parameters (%DLCO, %FVC, and staging per GAP index) demonstrated similar independent association between abnormal BET and poor pulmonary outcome (Table 2).

FIGURE 1.

FIGURE 1

FIGURE 1

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Kaplan–Meier curves comparing patients with increased and normal bolus exposure time (BET) on pre-transplant MII-pH study. Increased BET was associated with significantly shorter time to (a) poor pulmonary outcome (hospitalization or death) (log-rank P-value 0.017) and (b) death (log-rank P-value 0.031) in 3 years. (a, b) +, Censored. BET: Inline graphic, Abnormal BET; Inline graphic, Normal BET.

Table 2.

Multivariable time-to-event Cox regression models adjusting for age, sex, and body-mass index (BMI), smoking history, proton pump inhibitor (PPI) use [cumulative defined daily dose (cDDD)], baseline pulmonary function [gender-age-physiology (GAP) index, staging per GAP index, percent predicted diffusing capacity for carbon monoxide (%DLCO), or percent predicted forced vital capacity (%FVC)], and use of anti-fibrotic therapy (pirfenidone) to compare normal and increased bolus exposure time (BET) for poor pulmonary outcome and death in 3 years

Outcome: poor pulmonary outcome Outcome: 3-year mortality
Hazard ratio [95% CI] P-value Hazard ratio [95% CI] P-value
Model 1: Adjusting for GAP index, BMI, smoking history, PPI cDDD, pirfenidone use
Abnormal BET 3.18 [1.25–8.09] 0.015 11.3 [1.37–63.9] 0.025
Model 2: Adjusting for GAP staging, BMI, smoking history, PPI cDDD, pirfenidone use
Abnormal BET 3.06 [1.20–7.81] 0.019 11.9 [1.82–66.7] 0.013
Model 3: Adjusting for %DLCO, age, sex, BMI, smoking history, PPI cDDD, pirfenidone use
Abnormal BET 3.35 [1.27–8.85] 0.015 11.6 [1.40–65.5] 0.023
Model 4: Adjusting for %FVC, age, sex, BMI, smoking history, PPI cDDD, pirfenidone use
Abnormal BET 2.84 [1.09–7.42] 0.033 8.01 [1.14–50.2] 0.048
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CI, confidence interval.

Multichannel intraluminal impedance and pH testing measurement and 3-year mortality.

On secondary analysis of 3-year mortality as outcome, abnormal BET was also significantly associated with decreased time to death [HR 6.89 (95% CI: 1.9–52.7), P = 0.029]. This relationship was also demonstrated on Kaplan–Meier analysis (log-rank P-value 0.031) (Fig. 1b). After controlling for potential confounders on multivariable Cox regression analysis including GAP index for lung disease severity, abnormal BET remained an independent predictor for 3-year mortality [HR 11.3 (95% CI: 1.37–63.9), P = 0.025]. AET was again found to not be a significant predictor of decreased time to death, for both borderline acid reflux [HR 0.89 (95% CI: 0.17–4.64), P = 0.89] and pathologic acid reflux [HR 1.76 (95% CI: 0.48–6.47), P = 0.39] per Lyon classifications. Multivariable models utilizing other lung disease severity parameters (%DLCO, %FVC, and staging per GAP index) demonstrated similar independent association between abnormal BET and increased 3-year mortality (Table 2).

Discussion

While GERD has long been associated with chronic pulmonary disorders including IPF, the nature and directionality of the relationship remain debated due to the cross-sectional nature of most prior studies. Our study sought to determine the correlation between objective measures of GER and longitudinal clinical course of IPF over a 3-year follow-up period. Our findings demonstrated that abnormal GER as measured through increased BET on MII-pH was associated with increased risk of hospitalizations and death over 3 years in our population. This association remained significant even after adjusting for potential confounders including baseline lung disease severity, age, BMI, smoking history, and use of PPI and anti-fibrotic therapy. Importantly, no increase in risk was found associated with borderline or pathologic acid reflux alone. This suggests that the presence of increased bolus reflux may play a role in the progression of IPF or serve as a marker for more rapid decline. These findings support the consideration of objective reflux assessment in the care of IPF patients to potentially help guide management and improve outcomes.

Our study adds to growing literature highlighting the association of GER with IPF. GER may promote or worsen IPF by acting as a source of alveolar epithelial injury in the pathogenesis of IPF progression. This presumes that refluxed contents of the upper gastrointestinal tract may be aspirated into the lungs and trigger an inflammatory response resulting in fibrotic changes.21–23 In this pathway, GER may be a modifiable risk factor in the pathogenesis of IPF, where anti-reflux therapy may improve clinical course of the disease. However, evidence to-date on the impact of medical and surgical anti-reflux therapy on IPF outcomes remain inconsistent,13,24–30 although many of these prior studies may be limited by the retrospective design, duration of follow-up, outcome measures utilized, and possible residual confounding. In the only randomized control trial on the role of anti-reflux surgery in IPF, no statistically significant benefits in PFT outcomes were found, although the study did not reach intended enrollment target and the duration of follow-up may not be adequate to capture significant clinical improvements.13 Nevertheless, a trend of improved PFT findings was noted in the anti-reflux surgery arm that may still suggest potential benefits. On the other hand, changes in respiratory mechanics and transdiaphragmatic pressure gradient associated with IPF may also promote the development of GER. Indeed, in a prior study of patients undergoing pre-lung transplant esophageal function testing, patients with restrictive lung disease were found to have higher thoraco-abdominal pressure gradient, which also positively correlated with increased reflux burden.6 Moreover, lung transplantation, with the resultant correction of the altered respiratory physiology, was associated with improvement of the thoraco-abdominal pressure gradient and GER in restrictive lung disease patients.31

Given the potential bi-directionality of the association between GER and IPF, understanding the impact of GER on longitudinal clinical course of IPF is important. In a previous study by our group, increased BET was predictive of increased pulmonary hospitalizations at 1 year follow-up.10 In our current extended analysis with a larger sample size and incorporating data over a 3-year follow-up period, we found that objectively measured GER independently correlated with both earlier hospitalizations and mortality, even after controlling for important confounders such as smoking history.32 Our findings have several critical clinical implications. In particular, they add to the existing literature suggesting that objectively measured reflux in patients with IPF may be a marker of more rapid progression of disease and higher risk of poor outcomes, including mortality. Early identification of reflux in individuals with IPF through routine use of objective reflux assessment may, therefore, offer a potential target for treatment to improve pulmonary outcomes and empower clinicians to provide more intensive management. With the association with increased mortality, our findings would, hopefully, stimulate further well-designed, prospective clinical trials on the potential role of reflux prevention or therapy in modifying IPF progression.

Another important finding of our study is the association of bolus reflux as measured on impedance, rather than acid reflux on pH monitoring alone, with IPF clinical outcomes. Prior studies have implicated a role of both acid and non-acid GER in the disease progression of IPF.7–9,33 Moreover, both pepsin and bile acids have been identified in the bronchoalveolar lavage and saliva samples of patients with IPF,7,34 suggesting that the potential alveolar injury, inflammation, and fibrotic changes may be due to more than the acidity of refluxate alone. We also previously demonstrated that impedance measures of bolus reflux on objective testing correlate with pulmonary outcomes more strongly than pH-based measures of acid reflux alone in both IPF patients and lung transplant recipients.8,35 Prior study of patients with extra-esophageal symptoms undergoing combined impedance and dual-pH sensor testing also found that the majority of reflux events classified as acidic by the distal pH sensor became non-/weakly acidic upon reaching the proximal pH sensor, possibly due to neutralizing effects by oral secretions.36 While the relative importance of acid versus other components of refluxate in pulmonary diseases is still not fully known, these prior evidence and our current findings would support at least a potential role for the non-acidic components of refluxate in inducing pulmonary injury. Moreover, this may also explain the mixed previous results on the effects of acid suppression therapy on IPF outcomes.25–27 Treatments aiming to improve the anti-reflux barrier and reduce proximal migration of liquid bolus may provide more benefits over acid suppression alone to improve clinical outcomes and reduce disease progression in this population. While further prospective studies are needed to assess these therapeutic implications, our results would at least support a role for objective reflux testing with MII-pH, rather than pH-only modalities, in IPF patients. In addition, given that many chronic lung disease patients with GER do not report typical esophageal symptoms of reflux,37 routine objective reflux testing may be considered in the management algorithm in IPF to allow early intervention on a potential modifiable risk factor to reduce disease progression.

Our study is primarily limited by its retrospective design, although our center had a standardized approach to lung transplant evaluation that required objective GER evaluation with MII-pH on all candidates regardless of presence of esophageal symptoms, thereby limiting the potential for selection bias. The inclusion of patients undergoing lung transplant evaluation may potentially reduce the generalizability of our results for patients with milder disease severity. In addition, about half of the cohort received lung transplantation or underwent anti-reflux surgery during the study period, although the proportions were not statistically different between the two groups. Our time-to-event design allowed censoring at the time of these surgical interventions, thereby removing the person-time follow-up post-surgery from the analyses. Another potential limitation is that longitudinal monitoring of changes in MII-pH findings was not available, as few patients underwent repeat studies before lung transplantation. Our study size (n = 124) was also moderate, although this is, to our knowledge, one of the larger IPF cohorts to-date analyzing objective reflux findings on MII-pH and lung disease outcomes. Finally, as IPF may also contribute to increase GER, there is a possibility of reverse causation, which we sought to minimize by controlling for baseline lung disease severity in our multivariable models. Similarly, the exact pathogenic role of GER in the IPF disease course could not be ascertained in this clinical study, despite the 3-year longitudinal follow-up. While we believe that GER may directly contribute to worse clinical course in IPF, it is also possible that it was merely a prognostic marker for poor outcome. Nevertheless, this would still support the role of objective reflux testing to help identify patients at higher risk for more rapid disease progression.

In conclusion, we found that increased BET on MII-pH is an independent predictor of poor pulmonary outcomes and mortality over 3 years in IPF patients, even after controlling for potential confounders including baseline pulmonary function. This supports the concept that GER may play a role in and serve as a potential modifiable risk factor for IPF pathogenesis and disease progression. Future prospective studies are needed to further assess the causal relationship between GER and IPF, including the effects of different components of refluxate on lung injury, and to further explore the therapeutic benefits of anti-reflux therapy. Given the devastating prognosis associated with IPF and the limited effective treatments available, we believe that routine objective reflux assessment with MII-pH may have clinical value in the management of IPF patients and determining the need for more intensive therapies.

Financial support:

Kelly E. Hathorn was supported by the NIH grant T32 DK007533-35.

Footnotes

Declaration of conflict of interest: MEB, LFB, HJG, KEH, SG, and WKL declare no conflict of interest. WWC is under Scientific Advisory Board (Phathom Pharmaceuticals, Sanofi Pharmaceuticals, Regeneron Pharmaceuticals).

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