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Original research
The relationship between interstitial lung abnormalities, mortality, and multimorbidity: a cohort study
  1. Jason Leigh Sanders1,
  2. Gisli Axelsson2,3,
  3. Rachel Putman4,
  4. Aravind Menon4,
  5. Josée Dupuis5,
  6. Hanfei Xu5,
  7. Shuai Wang6,
  8. Joanne Murabito7,8,
  9. Ramachandran Vasan7,8,
  10. Tetsuro Araki9,
  11. Mizuki Nishino10,
  12. George R Washko4,
  13. Hiroto Hatabu10,11,
  14. George O'Connor8,12,
  15. Gunnar Gudmundsson2,13,
  16. Vilmundur Gudnason2,3,
  17. Gary M Hunninghake4
  1. 1 Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA
  2. 2 Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  3. 3 Icelandic Heart Association, Kopavogur, Iceland
  4. 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  5. 5 Biostatistics Department, Boston University School of Public Health, Boston, Massachusetts, USA
  6. 6 Pfizer Inc, New York, New York, USA
  7. 7 Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA
  8. 8 Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
  9. 9 Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  10. 10 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  11. 11 Center for Pulmonary Functional Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
  12. 12 Boston University Medical Center, Boston, Massachusetts, USA
  13. 13 Department of Respiratory Medicine and Sleep, Landspitali University Hospital, Reykjavik, Iceland
  1. Correspondence to Dr Gary M Hunninghake, Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; ghunninghake{at}


Background Interstitial lung abnormalities (ILAs) are associated with increased mortality. It is unclear whether multimorbidity accounts for the mortality association or how strongly ILA is associated with mortality relative to other common age-associated diseases. We determined the association of ILA with all-cause mortality adjusted for multimorbidity, compared mortality associated with ILA and prevalent cardiovascular disease (CVD), diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease and cancer and also determined the association between ILA and these diseases.

Methods We measured ILA (none, indeterminant, definite) using blinded reads of CT images, prevalent chronic diseases and potential confounders in two observational cohorts, the Framingham Heart Study (FHS) (n=2449) and Age, Gene/Environment Susceptibility - Reykjavik Study (AGES-Reykjavik) (n=5180). We determined associations with mortality using Cox proportional hazards models and between ILA and diseases with multinomial logistic regression.

Results Over a median (IQR) follow-up of 8.8 (1.4) years in FHS and 12.0 (7.7) years in AGES-Reykjavik, in adjusted models, ILAs were significantly associated with increased mortality (HR, 95% CI 1.95, 1.23 to 3.08, p=0.0042, in FHS; HR 1.60, 1.41 to 1.82, p<0.0001, in AGES-Reykjavik) adjusted for multimorbidity. In both cohorts, the association of ILA with mortality was of similar magnitude to the association of most other diseases. In adjusted models, ILAs were associated only with prevalent kidney disease (OR, 95% CI 1.90, 1.01 to 3.57, p=0.0452) in FHS and with prevalent CVD (OR 1.42, 1.12 to 1.81, p=0.0040) in AGES-Reykjavik.

Conclusions ILAs were associated with mortality adjusted for multimorbidity and were similarly associated with increased mortality compared with several common chronic diseases. ILAs were not consistently associated with the prevalence of these diseases themselves.

  • clinical epidemiology
  • idiopathic pulmonary fibrosis
  • imaging/CT MRI etc

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • JLS and GA contributed equally.

  • Correction notice This article has been corrected since it was published Online First. A typo has been corrected in the results section from 'female' to 'male'.

  • Contributors Conception and design: JLS, JD, GMH; acquisition, analysis, and interpretation of data: JLS, GA, RP, AM, JD, HX, SW, JM, RV, TA, MN, GRW, HH, GO', GG, VG, GMH; drafting of the work and critical revisions: JLS, GA, RP, AM, JD, HX, SW, JM, RV, TA, MN, GRW, HH, GO', GG, VG, GMH; accountability for the work: JLS, GA, JD, GG, VG, GMH; guarantor, GMH.

  • Funding JLS is supported by the National Institutes of Health (NIH) grant T32 HL007633. RP is supported by NIH grant K08 HL140087. MN is supported by NIH grant R01 CA203636. GRW is supported by NIH grants U01 HL146408 and R01 HL122464. GO’ is supported by NIH grant OT2 OD026553. GG is supported by the Landspitali Scientific Fund A-2019-029 and 030, A-2020-017 and 018, University of Iceland Research Fund, and the Icelandic Research Fund project grant 141513-051 (to GG, VG, GMH). GA is supported by the Eimskip University Fund. VG is supported by National Institute on Aging grant 27120120022C. GMH and this work are supported by NIH grants R01 HL111024, R01135142, and R01130974. The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract Numbers N01-HC25195, HHSN268201500001 and 75N92019D00031. Additional support from 1R01 HL64753; R01 HL076784; 1R01 AG028321; 2R01 HL092577; 2U54HL120163; R01 AG031287 and R01 HL077477. The Age, Gene/Environment Susceptibility-Reykjavik Study was supported by NIH contracts N01-AG-1-2100 and HHSN27120120022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). RV is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine.

  • Competing interests JLS reports personal fees for consultancy from Apneo Therapeutics and, outside the submitted work. At the time of publication, JLS was employed by Vertex Pharmaceuticals. MN reports personal fees for consultancy from Daiichi Sankyo and AstraZeneca; honoraria from Roche; and grants from Merck, AstraZeneca, Canon Medical Systems and NIH (R01CA203636, U01CA209414, R01HL111024), outside the submitted work. HH reports grants from Canon Medical System Inc. and Konica-Minolta Inc., personal fees for consultancy from Mitsubishi Chemical Inc. and personal fees for advisory board work from Canon Medical System Inc., outside the submitted work. JM reports fees to her institution on her behalf for guest lecture/consultant outside the submitted work from Merck. GMH reports personal fees from Genentech, Boehringer Ingelheim, The Gerson Lehrman Group and Mitsubishi Chemical, outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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