Discussion
As IPF is a progressive disease associated with high mortality, there is considerable interest in defining patient characteristics or markers of disease severity that associate with an increased risk of mortality or lung transplant. In a national US registry of patients diagnosed or confirmed with IPF at the enrolling centre within 6 months, we found that the probability of death or lung transplant over a follow-up period of 30 months, based on Kapan-Meier estimates, was approximately 50%. The variable that was most strongly associated with the risk of death or lung transplant was the use of supplemental oxygen at rest, reported in 20% of patients at enrolment. Interestingly, of the patients on oxygen at rest, only 41% had a diagnosis of IPF prior to being referred to the enrolling centre. Based on the limited arterial blood gas measurements (13% of this cohort) reported as part of clinical care in the registry, we cannot determine if there were more patients who may have qualified for oxygen at rest but were not reported as being on oxygen at rest. In a comparison of those reported to be or not to be on oxygen at rest, the patients on oxygen at rest had a higher CPI and more advanced GAP stage (Additional file
2: Table S10). Regardless, oxygen use at rest was an important predictor of death or lung transplant across univariable analyses, multivariable analyses, and analyses adjusted for other patient characteristics or markers of disease severity. While this finding is consistent with shorter studies [
8,
9,
19], confirmation in a large and diverse cohort of patients in the IPF-PRO Registry highlights the significance of this clinical characteristic as a predictor of mortality in patients with IPF in the real world. In addition, use of supplemental oxygen during activity was a predictor of death or lung transplant in the univariable, multivariable and adjusted models. This is consistent with previous observations that oxygen desaturation during exercise is a predictor of mortality in patients with IPF [
11,
20]. However, oxygen use during activity was not as strong a predictor of death or lung transplant as oxygen use at rest.
Decline in FVC is reflective of disease progression in patients with IPF and a predictor of mortality [
1]. Lower FVC % predicted at baseline has been associated with an increased risk of mortality in patients with IPF both in clinical trials [
12] and in registry studies [
11,
14,
21,
22]. In our analysis, the risk of death or lung transplant increased by 28% per 10% decrease in FVC % predicted at enrolment. Similarly, the risk of death or lung transplant increased by 25% per 10% decrease in DLco % predicted at enrolment. Importantly, these relationships persisted after adjusting for age and oxygen use.
We demonstrated a J-shaped relationship between age and death or lung transplant, with patients approximately 60 years of age being at the lowest risk, a gradual increase in risk with increasing age and a sharp increase in risk in younger patients. In our cohort, 91 patients (13.7%) were aged under 62 years and 18 patients (2.7%) were aged under 55 years. A greater proportion of patients aged under 55 years reported a family history of ILD than patients aged 62 years and older (35% versus 18%). We hypothesise that the youngest patients in the IPF-PRO Registry may represent a different disease cohort than the elderly patients, as familial pulmonary fibrosis has been associated with high mortality [
23‐
25]. However, in a recent single-centre study of 129 patients with IPF, there was no significant difference in mortality over 3 years in patients aged under 50 years (
n = 30) compared with older patients [
26].
Previous analyses of data from clinical trials [
12,
27] and retrospective studies [
28‐
30] have linked respiratory-related hospitalisation with increased mortality in patients with IPF. In our analysis, prior respiratory-related hospitalisation was associated with an increased risk of death or lung transplant in univariable but not multivariable analyses. Previous studies have suggested that patients with idiopathic interstitial pneumonia and definite UIP have a worse prognosis than those with possible UIP [
13,
31]. In our analyses, a site-confirmed diagnosis of definite IPF showed no association with the risk of death or lung transplant. This parallels data from the INPULSIS trials, which showed that patients with possible UIP and traction bronchiectasis on HRCT had the same rate of disease progression over 1 year as patients with honeycombing confirmed on HRCT or surgical lung biopsy [
32].
Recently, Torrisi et al. reported a TORVAN model and index that incorporates comorbidities into a survival model. Specifically, worse survival was associated with pulmonary hypertension, lung cancer, valvular heart disease and atrial arrhythmias. Gastro-oesophageal reflux disease (GERD; by history and medication use) was protective in survival models. Given this recent report, we reviewed the data from the IPF-PRO Registry for the comorbidities of interest. Of note, pulmonary hypertension was found not to be associated with death or lung transplant in our cohort, after adjusting for other patient characteristics. There were no patients with lung cancer. We did not collect any information on valvular heart disease so cannot provide those data. Regarding atrial arrhythmias, there were 68 patients (10.5%) with a reported atrial fibrillation or atrial flutter history. For GERD, there were 459 patients (73%) with GERD (by history, proton pump inhibitor use, or H2 antagonist use) at time of enrolment. Given the small number of atrial arrhythmias, we do not have enough data to evaluate the predictive value of this variable. As the GERD variable was more prevalent, we included that in both the univariable and multivariable analyses for all four endpoints studied and it was not significant in any analysis. Further, it was not selected for the adjustment model for any endpoint. Thus, in our registry, we are not able to validate the TORVAN model, though it is likely that comorbidities may impact outcomes in some cohorts.
Our analyses of data from the IPF-PRO Registry have several strengths that distinguish them from other analyses of survival in patients with IPF. Firstly, the use of a large cohort of patients with IPF (n = 662) from many centres, recruited using broad inclusion criteria, emphasises the generalisability of our study in the real world. Secondly, the registry systematically collected data on a large number of covariates with high rates of follow-up, and was of longer duration than most clinical trials. There are also several limitations to note. Given the small number of lung transplants, we could not assess predictors of lung transplant as a stand-alone endpoint. Furthermore, we cannot confirm if older age in this cohort limited the number of lung transplants. We were limited in the analysis of associations between 6MWD at enrolment and death or lung transplant because many patients did not perform a 6-min walk test at enrolment. Due to the timing of the registry inception and the approval of nintedanib and pirfenidone in the US, we were not able to evaluate associations between the use of antifibrotic therapy at enrolment and death or lung transplant. Finally, our analyses were limited to patient characteristics at enrolment. In future, as the IPF-PRO Registry matures, it will provide an opportunity to assess novel measures of disease severity, such as quantitative lung fibrosis scores, and genetic, proteomic and metabolomic biomarkers of disease progression.
Acknowledgments
The authors acknowledge the IPF-PRO™ Registry principal investigators: Wael Asi, Renovatio Clinical, The Woodlands, TX; Albert Baker, Lynchburg Pulmonary Associates, Lynchburg, VA; Scott Beegle, Albany Medical Center, Albany, NY; John A. Belperio, University of California Los Angeles, Los Angeles, CA; Rany Condos, NYU Medical Center, New York, NY; Francis Cordova, Temple University, Philadelphia, PA; Daniel A. Culver, Cleveland Clinic, Cleveland, OH; Joao A.M. de Andrade, University of Alabama at Birmingham, Birmingham, AL; Daniel Dilling, Loyola University Health System, Maywood, IL; Kevin Flaherty, University of Michigan, Ann Arbor, MI; Marilyn Glassberg, University of Miami, Miami, FL; Mridu Gulati, Yale School of Medicine, New Haven, CT; Kalpalatha Guntupalli, Baylor College of Medicine, Houston, TX; Nishant Gupta, University of Cincinnati Medical Center, Cincinnati, OH; Amy Hajari Case, Piedmont Healthcare, Austell, GA; David Hotchkin, The Oregon Clinic, Portland, OR; Tristan Huie, National Jewish Hospital, Denver, CO; Robert Kaner, Weill Cornell Medical College, New York, NY; Hyun Kim, University of Minnesota, Minneapolis, MN; Maryl Kreider, University of Pennsylvania, Philadelphia, PA; Lisa Lancaster, Vanderbilt University, Nashville, TN; Joseph Lasky, Tulane University, New Orleans, LA; David Lederer, Columbia University Medical Center/New York Presbyterian Hospital, New York, NY; Doug Lee, Wilmington Health and PMG Research, Wilmington, NC; Timothy Liesching, Lahey Clinic, Burlington, MA; Randolph Lipchik, Froedtert & The Medical College of Wisconsin Community Physicians, Milwaukee, WI; Jason Lobo, UNC Chapel Hill, Chapel Hill, NC; Yolanda Mageto, Baylor University Medical Center at Dallas, Dallas, TX; Prema Menon, Vermont Lung Center, Colchester, VT; Lake Morrison, Duke University Medical Center, Durham, NC; Andrew Namen, Wake Forest University, Winston Salem, NC; Justin Oldham, University of California, Davis, Sacramento, CA; Rishi Raj, Stanford University, Stanford, CA; Murali Ramaswamy, PulmonIx LLC, Greensboro, NC; Tonya Russell, Washington University, St. Louis, MO; Paul Sachs, Pulmonary Associates of Stamford, Stamford, CT; Zeenat Safdar, Houston Methodist Lung Center, Houston, TX; Barry Sigal, Salem Chest and Southeastern Clinical Research Center, Winston Salem, NC; Leann Silhan, UT Southwestern Medical Center, Dallas, TX; Mary Strek, University of Chicago, Chicago, IL; Sally Suliman, University of Louisville, Louisville, KY; Jeremy Tabak, South Miami Hospital, South Miami, FL; Rajat Walia, St. Joseph’s Hospital, Phoenix, AZ; Timothy P. Whelan, Medical University of South Carolina, Charleston, SC. Writing support was provided by Julie Fleming, BSc and Wendy Morris, MSc of FleishmanHillard Fishburn, London, UK which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. The authors were fully responsible for all content and editorial decisions, had access to all data, were involved in all stages of development and have approved the final version.