Anti-acid Therapies in Idiopathic Pulmonary Fibrosis: Premature to Dismiss?

To the Editor:

We read with great interest the latest “Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults” official American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Asociación Latinoamericana de Tórax clinical practice guideline published in the May 2022 issue of the Journal (1). The committee addressed antacid medication and antireflux surgery in patients with idiopathic pulmonary fibrosis (IPF). We were surprised to see that, in contrast to prior versions (2), the updated edition recommends against commencing antacid medication or antireflux surgery for the purpose of improving respiratory outcomes in IPF (1). We consider the formulation of this opinion as premature at this stage, the reason for which will be described, particularly as we await the completion of the TIPAL (Treating People with Idiopathic Pulmonary Fibrosis with the Addition of Lansoprazole) trial (3).

The results of the systematic review by Khor and colleagues published in the May 2022 issue of the Annals of the American Thoracic Society informed the latest committee recommendations and highlighted the poor evidence available in this subject area (4). A total of 19 studies assessing antacid medication or antireflux surgery in IPF were included, only two of which were randomized controlled trials (RCTs) (5, 6), the remaining being case series or observational studies. The quality of evidence for all outcomes (disease progression, mortality, exacerbations, hospitalizations, and respiratory symptoms) was judged as “very low” (4). Thereby, the authors concluded that there was insufficient evidence that these therapies improve respiratory outcomes in IPF, thus informing the latest recommendation against their use (1, 4).

We are concerned that the numerous poor-quality observational studies drown out the two RCTs that have been performed. One of these trials, a feasibility pilot, demonstrated that omeprazole may reduce cough and is well tolerated in patients with IPF (5). The second RCT showed promising effects of laparoscopic antireflux surgery on IPF respiratory-related outcomes (6). Although both studies were underpowered to demonstrate statistical significance, in our opinion, they support the feasibility and importance of undertaking larger, more informative trials to answer this clinical question. Stratification/minimization of patients with IPF who may most benefit from anti-acid therapies needs to be strongly considered on devising these trials. A clear definition of how to identify clinically significant gastroesophageal reflux in IPF also needs to be devised.

The phase III, randomized, multicenter clinical trial, TIPAL, hopes to answer the question whether proton pump therapy slows lung fibrosis progression, as measured by FVC at 12 months after randomization (3). The TIPAL trial also explores important secondary outcomes that include quality of life and cough indices. Recruitment to the TIPAL trial is underway, with expected completion in 2025 (3).

In summary, we wanted to highlight the difficulty of making decisions for our patients with IPF in this area, given the lack of high-quality evidence. With such a devastating and perplexing condition as IPF, perhaps it is beneficial to lean toward neutrality when publishing guidelines until sufficient evidence is generated to prevent premature dismissal of potential beneficial therapies.