Development and Progression of Interstitial Lung Abnormalities in the Framingham Heart Study

Abstract

Rationale: The relationship between the development and/or progression of interstitial lung abnormalities (ILA) and clinical outcomes has not been previously investigated.

Objectives: To determine the risk factors for, and the clinical consequences of, having ILA progression in participants from the Framingham Heart Study.

Methods: ILA were assessed in 1,867 participants who had serial chest computed tomography (CT) scans approximately 6 years apart. Mixed effect regression (and Cox) models were used to assess the association between ILA progression and pulmonary function decline (and mortality).

Measurements and main results: During the follow-up period 660 (35%) participants did not have ILA on either CT scan, 37 (2%) had stable to improving ILA, and 118 (6%) had ILA with progression (the remaining participants without ILA were noted to be indeterminate on at least one CT scan). Increasing age and increasing copies of the MUC5B promoter polymorphism were associated with ILA progression. After adjustment for covariates, ILA progression was associated with a greater FVC decline when compared with participants without ILA (20 ml; SE, ±6 ml; P = 0.0005) and with those with ILA without progression (25 ml; SE, ±11 ml; P = 0.03). Over a median follow-up time of approximately 4 years, after adjustment, ILA progression was associated with an increase in the risk of death (hazard ratio, 3.9; 95% confidence interval, 1.3-10.9; P = 0.01) when compared with those without ILA.

Conclusions: These findings demonstrate that ILA progression in the Framingham Heart Study is associated with an increased rate of pulmonary function decline and increased risk of death.

Keywords: MUC5B; idiopathic pulmonary fibrosis; interstitial lung abnormalities; interstitial lung disease; progression.

Figure 1.

Workflow and results of computed tomography (CT) scan reading by CT scan timing and ILA status. The top row shows the results of FHS-MDCT1 by ILA status. Directly below is a depiction of what percentage from each ILA category remained the same or changed between FHS-MDCT1 and FHS-MDCT2, and if the ILA status changed what change occurred. Next, the results of FHS-MDCT2 are shown by ILA status. Finally, the results of the sequential comparison are shown, divided into improving/stable ILA and developing/progressive ILA. FHS-MDCT1 = Framingham Heart Study Multidetector Computed Tomography 1 Study; FHS-MDCT-2 = Framingham Heart Study Multidetector Computed Tomography 2 Study; ILA = interstitial lung abnormalities.

Figure 2.

Sequential chest computed tomography (CT) images of three participants; each panel (A– C) represents a different participant. In each panel, images 1–3 are representative axial cuts from MDCT1 and images 4–6 are representative axial cuts from MDCT2. In all panels, images 1 and 4 are at the level of the carina, images 2 and 5 are at the level of the right inferior pulmonary vein, and images 3 and 6 are at the base of the lungs. (A) Interstitial lung abnormalities (ILA) in MDCT1 (images 1–3) that progressed over a period of 7 years to ILA with definite fibrosis in MDCT2 (images 4–6), for which definite fibrosis is defined as pulmonary parenchymal architectural distortion diagnostic of fibrotic lung disease. (B) ILA in MDCT1 (images 1–3) that progressed over approximately 6 years to a usual interstitial pneumonia pattern of fibrosis in MDCT2 (images 4–6). (C) Indeterminate ILA status in MDCT1 (images 1–3) that progressed over 5 years to a usual interstitial pneumonia pattern of fibrosis in MDCT2 (images 4–6). MDCT1 = Framingham Heart Study Multidetector Computed Tomography 1 Study; MDCT-2 = Framingham Heart Study Multidetector Computed Tomography 2 Study.

Figure 3.

Kaplan-Meier survival curves comparing participants without ILA, participants with ILA without progressive imaging, and participants with ILA with progressive imaging. Follow-up for the mortality analyses (time zero) begins at MDCT-2, the second computed tomography scan used for sequential comparisons. ILA = interstitial lung abnormalities; MDCT-2 = Framingham Heart Study Multidetector Computed Tomography 2 Study.