ASSOCIATION BETWEEN GASTROESOPHAGEAL REFLUX AND THE PROGRESSION OF IDIOPATHIC PULMONARY FIBROSIS: SYSTEMATIC REVIEW
Abstract
Background: Gastroesophageal reflux (GER) is one of the most prevalent comorbid conditions in idiopathic pulmonary fibrosis (IPF), detected in up to 87–94% of patients using objective ambulatory pH-impedance monitoring, yet frequently clinically occult. Chronic microaspiration of gastric refluxate—containing acid, pepsin, bile acids, and trypsin—has been proposed as a recurrent injurious stimulus to the vulnerable aged alveolar epithelium, potentially accelerating fibrogenesis and worsening disease trajectory. Methods: The study strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. Eligible primary studies included RCTs, cohort studies (prospective and retrospective), case-control studies, cross-sectional studies, and other observational designs. Systematic reviews and meta-analyses were excluded from the characteristic tables but considered in outcome analysis and discussion. Risk of bias was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies and Cochrane RoB 2.0 for RCTs. The review was conducted per PRISMA 2020 guidelines. Results: Twenty-five primary studies involving >45,000 patients across multiple countries were included. GER prevalence in IPF was 39–87% by objective testing and 45–56% in clinical registry populations. Mendelian randomization confirmed a unidirectional causal association (GORD→IPF: OR 1.6, 95% CI 1.04–2.49; p=0.032). BALF bile acid and pepsin levels correlated strongly with HRCT fibrosis scores (r²=0.567–0.63). Key clinical outcomes: (1) hiatal hernia independently predicted FVC decline and respiratory mortality (p<0.05); (2) novel impedance metrics (MNBI, PSPW index) independently predicted FVC and FEV₁ decline at 12 months (p<0.05); (3) GER medication use was associated with longer survival (adjusted HR 0.45, 95% CI 0.24–0.84 for IPF-related mortality; low-quality evidence); (4) the WRAP-IPF RCT showed a trend favoring laparoscopic antireflux surgery (LARS) but did not reach statistical significance; (5) large population-based propensity-matched cohort studies found PPI and H2RA use associated with increased adverse outcomes, challenging earlier observational optimism; (6) cough severity—closely linked to GER—was independently associated with disease progression and impaired quality of life. Conclusion: GER is a biologically plausible and causally supported contributor to IPF pathogenesis. However, the 2022 ATS/ERS/JRS/ALAT guidelines issued conditional recommendations against routine antacid medication and antireflux surgery for IPF, reflecting insufficient and conflicting prospective evidence. Well-powered RCTs with objective GER phenotyping are urgently needed. Non-acid reflux components remain incompletely addressed by current pharmacological strategies and warrant targeted investigation.Keywords
Idiopathic pulmonary fibrosis, gastroesophageal reflux disease, microaspiration, proton pump inhibitors, anti-reflux surgery, lung function decline, alveolar epithelial injury, WRAP-IPF, impedance-pH monitoring, hiatus hernia, systematic review