Rachel K Putman1, Hiroto Hatabu2, Tetsuro Araki3, Gunnar Gudmundsson4, Wei Gao5, Mizuki Nishino2, Yuka Okajima6, Josée Dupuis7, Jeanne C Latourelle8, Michael H Cho9, Souheil El-Chemaly1, Harvey O Coxson10, Bartolome R Celli1, Isis E Fernandez11, Oscar E Zazueta1, James C Ross12, Rola Harmouche13, Raúl San José Estépar14, Alejandro A Diaz1, Sigurdur Sigurdsson15, Elías F Gudmundsson15, Gudny Eiríksdottír15, Thor Aspelund16, Matthew J Budoff17, Gregory L Kinney18, John E Hokanson18, Michelle C Williams19, John T Murchison20, William MacNee21, Udo Hoffmann22, Christopher J O'Donnell23, Lenore J Launer24, Tamara B Harrris24, Vilmundur Gudnason16, Edwin K Silverman9, George T O'Connor25, George R Washko26, Ivan O Rosas1, Gary M Hunninghake26. 1. Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 2. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts3Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 3. Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 4. Department of Respiratory Medicine and Sleep, Landspital University Hospital, University of Iceland, Reykjavik, Iceland. 5. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts. 6. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts6Department of Radiology, St. Luke's International Hospital, Tokyo, Japan. 7. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts7National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts. 8. Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts9Department of Neurology, Boston University, Boston, Massachusetts. 9. Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts10Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 10. Department of Radiology, University of British Columbia, Vancouver, BC, Canada. 11. Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts12Comprehensive Pneumology Center, Ludwig-Maximilians-University, University Hospital Grosshadern, Munich, Germany13Helmholtz Zentrum München. 12. Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts14Surgical Planning Laboratory, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. 13. Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts14Surgical Planning Laboratory, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. 14. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts14Surgical Planning Laboratory, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts. 15. Icelandic Heart Association, Kopavogur, Iceland. 16. Icelandic Heart Association, Kopavogur, Iceland16University of Iceland, Reykjavik, Iceland. 17. Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California. 18. Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Denver, Colorado. 19. University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Edinburgh, Scotland. 20. Royal Infirmary of Edinburgh, University of Edinburgh, Edinburgh, Scotland. 21. Centre for Inflammation Research, University of Edinburgh, Edinburgh, Scotland. 22. Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. 23. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts23Cardiovascular Epidemiology and Human Genomics Branch, NHLBI Division of Intramural Research, Bethesda, Maryland. 24. Intramural Research Program, National Institute of Aging, NIH, Bethesda, Maryland. 25. National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts8Pulmonary Center, Department of Medicine, Boston University, Boston, Massachusetts. 26. Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts3Center for Pulmonary Functional Imaging, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
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.
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.
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