Position Paper
Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?

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Summary

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF.

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of unclear origin, associated with a median survival of 3–5 years from the time of diagnosis.1 At present, two IPF-specific pharmacological therapies are available that slow disease progression, but to date there is no known cure.2, 3 Patients with IPF have frequent comorbid conditions, including a high reported prevalence of gastro-oesophageal reflux (GER) and gastro-oesophageal reflux disease (GERD).4, 5, 6 The potential role of GER in the pathogenesis or progression of disease has been an important focus of research, in an effort to find effective therapeutic approaches to patient management. GER and consequent microaspirations have been proposed as pathogenic in IPF and there are data to suggest that treatment with antacid therapy might be of clinical benefit in terms of slowing chronic disease progression, and possibly even survival.7, 8, 9 Conversely, other reports10, 11 question the efficacy of antacid therapy in IPF and have suggested that possible harm cannot be excluded.

The most recent international guideline statement on the treatment of IPF12 attempted to address the role for antacid therapy in the management of IPF, with the non-conflicted voting members of the committee making a conditional recommendation for the use of antacid therapy in the treatment of patients with IPF. From the outset, this recommendation has been controversial in light of the absence of data generated from any placebo-controlled trial. We believe that there is equipoise regarding the pathogenic role of GER in IPF,13 and it is unclear whether the guideline recommendation should be interpreted to suggest that the majority of patients with IPF with no symptoms of GER might reasonably be offered regular antacid therapy, in the hope of slowing disease progression. In this perspective, we have summarised the evidence addressing the association between GER and IPF, and have sought to contextualise the current conditional guideline recommendation for practitioners caring for these patients.

In December, 2015, a working group of 48 international interstitial lung disease (ILD) experts assembled at the Ettore Majorana Foundation and Centre for Scientific Culture in Erice, Italy, to discuss priority clinical and research issues in ILD. Participants represented 17 countries from Europe and North America. Among the topics of discussion was the current conditional guideline recommendation for antacid therapy in IPF. In pro–con debates and round-table discussions, the evidence supporting this recommendation was presented for consideration. Given the current controversies, this Position Paper was prepared by the primary participants (authors) who discussed this issue while incorporating input from all other participants of the Erice ILD Working Group (appendix).

In recent literature on IPF, symptomatic GER has been termed GERD. However, in the current perspective, we discuss the hypothesis that asymptomatic reflux might be pathogenic in IPF and is, for that reason, a form of GERD. Therefore, to avoid confusion, we have adopted the following two concepts. First, when appropriate, GER (referring to acid or non-acid reflux) will be subdivided into asymptomatic and symptomatic GER, with symptoms categorised as oesophageal or non-oesophageal. Second, for reflux of gastric contents (acid or non-acid) into the airways (excluding aspiration pneumonia) causing pulmonary symptoms or complications we use the term microaspiration, which could be symptomatic or asymptomatic.

Key messages

  • Gastro-oesophageal reflux (GER) is proposed as pathogenic in the development or progression of idiopathic pulmonary fibrosis (IPF)

  • To date, international guidelines conditionally recommend the use of antacid therapy for patients with IPF

  • There is a paucity of high-quality data supporting a pathogenic role of GER in IPF, or a benefit of antacid therapy in patients with IPF

  • Given the clinical equipoise, we have aimed to contextualise the guideline recommendation for practitioners caring for patients with IPF

  • Moving forward, consistent terminology must be adopted and prospective randomised trials of antireflux therapy must be completed to meaningfully address the question of antacid therapy use for patients with IPF

Section snippets

What is GER?

GER is the reflux of gastric contents into the oesophagus with some degree of GER occurring physiologically. GER can be acidic or non-acidic with oesophageal pH below or above 4·0, respectively. GERD is termed as a condition that develops when the reflux of stomach contents causes symptoms or complications,14 a definition adopted in the field of gastroenterology. It is important to recognise that GERD is not synonymous with GER or simple heartburn, and that the GERD syndrome requires consequent

How is GER related to microaspiration?

The refluxate content of GER is not only gastric acid but also bile salts; pepsin, trypsin, and other enzymes; food particles; and bacteria or their products; all of which can be potentially harmful.19 The reflux of gastric contents into the proximal oesophagus can lead to aspiration of these contents into the airways, leading to direct toxic injury. This microaspiration is proposed as a mechanism by which GER contributes to the development or exacerbation of pulmonary disease. Several reports

What is the recommended treatment for GER?

The recommended approach to managing a patient with symptomatic GER is multifaceted and should be based on disease severity according to symptoms and consequences. This approach applies to all individuals with symptomatic GER, including patients with IPF with documented symptoms or sequelae. Potential interventions range from lifestyle modification to surgical fundoplication, with the latter reserved for severe and refractory disease. Clinical practice guidelines from gastroenterological

How common is GER in IPF?

GER is generally considered to be common in IPF, and has been identified in up to 16 (94%) of 17 patients undergoing ambulatory oesophageal pH monitoring.26 The true frequency is unknown, with prevalence ranging from 0 to 94% across different cohorts.26, 27, 28 In several studies,28, 29 GER in patients with IPF has been more frequent than in the general population and other matched controls. The first prospective study to test for GER by use of invasive pH monitoring and oesophageal manometry

Does GER contribute to the development of IPF?

Based on the high prevalence of GER in IPF, it has been proposed that GER and consequent microaspiration play a pathogenic part in the development of disease. Gastric fluid can be retrogradely transported through a weakened lower oesophageal sphincter (eg, secondary to a hiatal hernia, traction from the diaphragm, medications, or smoking) up into the oesophagus.38 The gastric refluxate can travel as high up as the cricopharyngeal region and enter the airway. Normal host defences, such as cough,

Does GER contribute to disease progression, acute exacerbation or death in IPF?

There have been few randomised, placebo-controlled prospective studies that have examined interactions between GER and IPF outcomes including disease progression and mortality. There are few data addressing the possible role of GER in acute exacerbations of IPF. In a well characterised longitudinal cohort of patients with IPF, BALF pepsin levels were associated with an increased risk of acute exacerbations of IPF, largely driven by a subset of patients with markedly increased pepsin levels.47

Does treatment of GER or microaspiration improve clinical outcomes in IPF?

To date, there have been no prospective randomised clinical trials to address whether GER treatment improves clinical outcomes in IPF. A small case series (n=4) showed stability of lung function, as measured by pulmonary function testing, in patients with IPF solely receiving GER therapy in the form of PPI.48 A retrospective study of 14 patients with IPF awaiting lung transplantation found that those undergoing laparoscopic Nissen fundoplication surgery had stable oxygen requirements compared

Are there potential problems with treating all patients with IPF with PPI therapy?

The guideline recommendation was made in part by weighing the perceived potential benefit and relative low cost of PPI therapy against low perceived risks. Yet many questions remain as to the safety, tolerability, and drug interaction effects of PPI therapy, plus the academic implications of future research when such a therapy is broadly recommended. Importantly, the recommendation for widespread use of PPI therapy for IPF might remove the possibility of doing placebo-controlled trials to

How to interpret the international guideline recommendation

The 2015 ATS/ERS/JRS/ALAT international guideline committee on the treatment of IPF made a conditional recommendation for regular antacid treatment in patients with IPF.12 It should be noted that this recommendation is unchanged from the 2011 IPF guideline. Commendably, there was transparency on the fact that most of the expert conflicted non-voting IPF clinicians on the panel disagreed with the recommendation and would have preferred a non-recommendation because of insufficient definitive data.

What issues should be addressed in future studies?

It is important that terminology is standardised (figure). It remains unclear whether asymptomatic GER should be thought of as pathological in IPF and whether acid, non-acid, or all reflux should be targeted, and if so, by which therapy. Until consensus exists on terminology, it will be challenging to interpret the results of studies aimed at addressing these issues. Perhaps GER and GERD in this context should be replaced with the term microaspiration to indicate the mechanisms and consequences

Conclusion

The evidence as described above conveys the clinical and academic equipoise that exists around the association between GER and IPF. It is unclear whether the high prevalence of GER in patients with IPF is pathologically related to the development, progression, or exacerbation of disease over time. It is also unclear whether antacid treatment is an effective therapy for IPF, regardless of the presence of underlying GER. In the presence of abnormal GER, ongoing studies will attempt to address the

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