There is equipoise among pulmonologists as to how aggressively to diagnose and treat GER in patients with IPF. There are no convincing data demonstrating a clinical benefit to treatment of GER in this setting and there are risks to medical and surgical treatment (4
). In this study, approximately half of patients with IPF reported taking GER medications at the time of initial diagnosis. The use of GER medications was associated with lower HRCT fibrosis score and was an independent predictor of longer survival time. Although preliminary, these findings support the hypothesis that GER and chronic microaspiration may play important roles in the pathobiology of IPF.
Although the indication for GER medication use in this cohort is unknown, GER symptoms and diagnosis were more common in patients reporting GER medication use, suggesting the indication was likely for the treatment of GER. It is possible that GER medications were prescribed for gastro-protection in patients also receiving prednisone. However, there was no difference in prednisone use among those reporting and not reporting GER medication use, making this explanation unlikely.
Our results are consistent with two previous reports suggesting stabilization of IPF with medical or surgical therapy for GER (5
). In a study of four patients with IPF, aggressive medical management of GER resulted in apparent physiological stabilization (5
). One of the cases demonstrated physiologic stabilization with GER medications, then worsening with cessation of therapy, followed by restabilization after resuming therapy once again. A second study demonstrated stabilization of oxygen requirements in pretransplant patients with IPF who underwent Nissen fundoplication for GER, although no change in pulmonary function was observed (9
). Our study adds substantially to these results by linking GER-related variables to the extent of HRCT fibrosis and survival time in a large, two-center cohort of well-characterized patients with IPF.
There are several possible explanations for the results of our study. The most straightforward is also the most controversial: that the treatment of GER is beneficial to survival in IPF. It is hypothesized that GER may impact progression in IPF through microaspiration of gastric droplets either causing slowly progressive lung injury and fibrosis or by triggering acute exacerbation of IPF (4
). Suppressing the acidity of gastric contents may reduce the injury caused by microaspiration. However, acid suppression alone does not prevent microaspiration of weakly acidic reflux, and this may also contribute to lung fibrosis (16
). Nissen fundoplication is a surgical intervention that reduces both acid and weakly acidic GER. An additional survival benefit to Nissen fundoplication is suggested by our data, which would support a role for both acid and weakly acidic GER. Our small sample size limits any firm conclusions that can be made from this data.
Our results could also be due to confounding by unmeasured associated variables. For example, patients receiving GER therapy might also be more likely to receive other medical interventions (e.g., pulmonary rehabilitation, influenza vaccination, or simply more comprehensive care) that could impact survival. Arguing against this somewhat is that any confounder would have to exist at both centers involved in the study. Another possible explanation for our findings is lead-time bias. GER could cause patients to seek medical attention sooner than those who do not have GER, leading to the diagnosis of IPF earlier in the course of disease. Although most measures of disease severity (e.g., pulmonary function values) were similar between groups, the association between lower percent of radiologic fibrosis on HRCT and GER medication use could suggest lead-time bias. However, after adjustment for the degree of radiologic fibrosis, the relationship between GER medication use and survival time remained significant.
Finally, it is possible that the association between GER and survival time in IPF is real, but that GER may develop as a consequence of progressive fibrotic lung disease, rather than vice versa. Architectural distortion and increased traction on mediastinal structures may lead to weakening of the lower esophageal sphincter and increased GER (4
). The association of GER medication use with less radiologic fibrosis and the lack of an association with standard measures of thoracic restriction (e.g., pulmonary function tests) argue against this hypothesis.
The results of our study need validation to confirm the association between reported GER medication use and survival time. Although large and well-defined, our cohort had limited information on GER diagnosis and responsiveness to treatment. Information on 24-hour pH and/or esophageal impedance testing, dosing, duration, and compliance with GER therapy, and effectiveness of acid suppression with therapy should be collected in future studies. A prospective longitudinal cohort of patients with carefully recorded GER-related variables would address these issues more rigorously. If our results are validated, future studies should look beyond association and address how the treatment of GER might affect survival in IPF.