Association Between Interstitial Lung Abnormalities and All-Cause Mortality

Abstract

Importance: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an association with mortality has not been previously investigated.

Objective: To investigate whether interstitial lung abnormalities are associated with increased mortality.

Design, setting, and population: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic [CT] scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006).

Exposures: Interstitial lung abnormality status as determined by chest CT evaluation.

Main outcomes and measures: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort.

Results: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference [95% CI, 2% to 10%]), 56% vs 33% in AGES-Reykjavik (23% difference [95% CI, 18% to 28%]), and 11% vs 5% in ECLIPSE (6% difference [95% CI, 1% to 11%]). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio [HR], 2.7 [95% CI, 1.1 to 6.5]; P = .03), AGES-Reykjavik (HR, 1.3 [95% CI, 1.2 to 1.4]; P < .001), COPDGene (HR, 1.8 [95% CI, 1.1 to 2.8]; P = .01), and ECLIPSE (HR, 1.4 [95% CI, 1.1 to 2.0]; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis.

Conclusions and relevance: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.

Trial registration: ClinicalTrials.gov NCT00292552.

Figure 1

Chest computed tomographic (CT) images of four participants, one from each cohort with interstitial lung abnormalities with Definite Fibrosis. Definite Fibrosis is defined as pulmonary parenchymal architectural distortion diagnostic of fibrotic lung disease. Each letter represents a different participant (A from FHS, B from AGES-Reykjavik, C from COPDGene, and D from ECLIPSE), in all panels images 1–3 are axial images, image 1 is at the level of the carina, image 2 is at the level of the right inferior pulmonary vein and image 3 is at the base of the lungs.

Figure 2

The top panel of the figure is participants included in the analysis by cohort and interstitial lung abnormality status. CT stands for computed tomography, FHS-MDCT2 stands for the Framingham Heart Study Multidetector Computed Tomography 2, and ILA stands for interstitial lung abnormalities. Respiratory deaths included the following: ICD9 codes 460–519, ICD 10 codes J00-J99. Cardiovascular deaths included the following: ICD9 codes 390–459 and ICD 10 codes I00-I99. Cancer deaths included the following: ICD9 codes 140–239 and ICD 10 codes C00-D48. All causes of death not contained in these ICD9 and ICD10 codes were included in “other”. *percentages were all rounded to the nearest whole number, at times the percentages may sum to greater than 100%

Figure 3

Curves showing percent mortality, comparing participants with and without interstitial lung abnormalities (ILA). P-values included in each panel are those associated with the hazard ratios from the adjusted Cox proportional hazards model, including adjustments for age, gender, race, body-mass index, pack-years of smoking, current or former smoking status and GOLD stage of COPD (except in AGES-Reykjavik where GOLD stage was not available). The results are for the comparison between participants with interstitial lung abnormalities to participants without interstitial lung abnormalities.