The idea that idiopathic pulmonary fibrosis (IPF) could be mechanistically and pathogenetically attributed to repeated, often silent events of gastric fluid microaspiration (so-called lungburns) was first introduced almost 40 years ago.1 Since then, an increasing body of evidence has provided useful insights about a potential link between diffuse lung fibrosis and gastro-oesophageal reflux. A high prevalence of abnormal acid gastro-oesophageal reflux (identified by 24-h pH monitoring) in patients with IPF—almost 90%—was first reported in two different cohorts.2, 3 However, a much smaller proportion of patients complain of heartburn-related symptoms,4 rendering the diagnosis of abnormal acid gastro-oesophageal reflux clinically occult and thus insidious.
Several reports have associated anti-reflux treatment with improved survival and substantial functional and radiological benefits in patients with IPF.5 Additionally, increased amounts of microaspiration biomarkers, such as pepsin, in bronchoalveolar lavage fluid of patients with IPF experiencing an acute exacerbation6 directly implicates clinically silent microaspiration of gastric fluid as a triggering factor of fibrogenesis.5
In The Lancet Respiratory Medicine, Joyce Lee and colleagues present results of an analysis of the potential usefulness of anti-acid treatment (proton-pump inhibitors [PPIs] and histamine-receptor-2 [H2] blockers) in patients with IPF.7 Their method was well designed: they used prospectively obtained data from the placebo groups of the three randomised clinical trials from the Idiopathic Pulmonary Fibrosis Clinical Research Network (PANTHER, ACE, and STEP). They assessed the effect of anti-acid treatment on functional deterioration in a 30-week period for 242 patients.
The most important finding of their study was that patients taking anti-acid treatment (n=124) had a significantly smaller decrease in forced vital capacity (—0·06 L, 95% CI −0·11 to −0·01) than did those who were not taking anti-acid treatment (n=118; −0·12 L, −0·17 to −0·08; difference 0·07 L, 0—0·14; p=0·05). Moreover, patients taking anti-acid treatment had significantly fewer acute exacerbations (no events) than did those who were not (nine events; p=0·0017). Although the results suggested improved survival with anti-acid treatment, the difference was not significant (p=0·12).
Nevertheless, several mechanistic issues and safety concerns should be addressed before anti-acid treatment in patients with IPF can be widely implemented. So far, no rigid pathogenetic link between gastro-oesophageal reflux and IPF has been identified, and anti-acid treatment has inconsistent effects on survival, because it does not inhibit reflux.5 Patients included in Lee and colleagues’ analysis,7 and those in previous retrospective analyses,8 were heterogeneous in terms of disease severity and presence of comorbidities, such as sleep apnoea, that can significantly affect survival and cause further deterioration of abnormal gastro-oesophageal reflux. Finally, assessment of abnormal acid gastro-oesophageal reflux and gastro-oesophageal reflux disease was superficially based solely on heartburn symptoms in most patients; endoscopy was used in a small proportion of patients.
But do physicians really need to treat symptoms of gastro-oesophageal reflux? Or should the primary outcome be to prevent further lung injuries by intervening directly in the fibrogenic cascade? A study by Ho and colleagues8 extended the beneficial contribution of PPIs beyond neutralisation of highly acidic gastric juice. The investigators concluded that PPI inhibition of dimethylarginine dimethylaminohydrolase and inducible nitric oxide synthase, which are known to be increased within lung epithelium and fibroblastic foci,9, 10 eliminated aberrant signalling in the TGF-β pathway, ultimately leading to decreased collagen production in an experimental model of lung fibrosis. These findings suggest a novel antifibrotic mechanism for PPIs in patients with IPF.
Another crucial issue is to clarify whether anti-acid treatments will be used as adjunctive or primary therapeutic regimens. Many questions about which patients, the length of treatment, and what doses to use remain unanswered. The idea that all patients with IPF could receive anti-acid treatment as prophylaxis could be risky in view of the potentially harmful side-effects, such as infections, electrolyte disturbances, and, importantly, drug interactions. H2 blockers and PPIs are potent inducers of P450 enzymes, particularly CYP1A2, and therefore might limit the plasma concentrations of several antifibrotic agents, including pirfenidone, which has been approved for IPF treatment.11
Overall, a randomised placebo-controlled trial of patients with IPF, with and without symptoms of gastro-oesophageal reflux, is needed. Assessment of agent-specific and dose-dependent therapeutic outcomes will be necessary to better define individuals who could benefit from such interventions.