Abstract
Rationale
Some with interstitial lung abnormalities (ILA) are suspected to have interstitial lung disease (ILD), a subgroup with adverse outcomes. Rates of development and progression of suspected ILD and their effect on mortality are unknown.
Objectives
To determine rates of development, progression, and mortality in those with suspected ILD and assess effects of individual ILD and progression criteria.
Methods
Participants from COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) with ILA characterization and FVC at enrollment and 5-year follow-up were included. ILD was defined as ILA and fibrosis and/or FVC < 80% predicted. Prevalent ILD was assessed at enrollment and incident ILD and progression were assessed at 5-year follow-up. Computed tomography (CT) progression was assessed visually and FVC decline as relative change. Multivariable Cox regression tested associations between mortality and prevalent ILD, incident ILD, and progression groups.
Measurements and Main Results
Of 9,588 participants at enrollment, 268 (2.8%; 51% of ILA) had prevalent ILD. Those with prevalent ILD had 51% mortality after median 10.6 years, which was higher than those with ILA without prevalent ILD (henceforth ILA) (33%; hazard ratio [HR], 2.0; P < 0.001). The subgroup of prevalent ILD with only fibrosis criteria (FVC ≥ 80%) had worse mortality (58%) than ILA (HR, 2.2; P < 0.001). A total of 98 participants with prevalent ILD completed 5-year follow-up: 33% had stable CT and relative FVC decline <10%, 6% had FVC decline ≥10% only, 39% had CT progression only, and 22% had both CT progression and FVC decline ≥10%. Mortality rates were 31%, 50%, 45%, and 45%, respectively; those with only CT progression had worse mortality than those with ILA (HR, 2.6; P = 0.005). At 5-year follow-up, incident ILD occurred in 148/4,842 participants without prevalent ILD (5.5/1,000 person-years) and had worse mortality than ILA (HR, 2.4; P < 0.001).
Conclusion
Rates of mortality and progression are high among those with suspected ILD in COPDGene; fibrosis and radiologic progression are important predictors of mortality.
Keywords: idiopathic pulmonary fibrosis, ILD, interstitial lung abnormalities, pulmonary fibrosis
At a Glance Commentary
Scientific Knowledge on the Subject
In a large cohort of smokers, it has been shown that a group with interstitial lung abnormalities is suspected of having interstitial lung disease (ILD), and this group had worse outcomes, including mortality. It is not currently known what the incidence and rates of progression are for those with suspected ILD and what effect this has on mortality.
What This Study Adds to the Field
This study demonstrates that mortality is high among those with suspected ILD in a cohort of smokers; that imaging evidence for pulmonary fibrosis is a risk factor for imaging progression, FVC decline, and death; and that imaging progression in ILD is an important predictor of mortality. These findings have important implications for the clinical care of those who have smoked and for the evaluation and monitoring of all people found to have incidentally discovered interstitial abnormalities. Future studies are needed to validate these findings in other populations and to assess the effectiveness of monitoring and potentially targeted interventions in this high-risk group.
Numerous studies have demonstrated that interstitial lung abnormalities (ILA), incidental findings on chest computed tomography (CT) scans suggestive of an early or mild form of interstitial lung disease (ILD) or pulmonary fibrosis, are associated with an increased rate of mortality (1–4). Although much remains to be explained, the increased risk of mortality among those with ILA appears to be independent of some common exposures (e.g., smoking) (1) and comorbidities (e.g., cardiovascular disease) (1, 5). Importantly, those with ILA can be risk stratified into subgroups at an even greater risk for death. For example, compared with those with ILA without pulmonary fibrosis, those with evidence for pulmonary fibrosis (4, 6) are at an increased risk for mortality. Recently it was demonstrated that much of the excess mortality (and increased risk of respiratory-related comorbidities) among those with ILA was limited to the group with ILA believed to have suspected ILD, based on their combination of pulmonary fibrosis and/or reduced measures of lung function (7).
Although these studies provide evidence for methods to risk stratify those with ILA, what is less well understood is how commonly those without suspected ILD develop incident disease over time and experience progression and how these factors influence mortality. We sought to assess the rates of development and progression of suspected ILD, their effects on mortality, and the effects of baseline ILD features (fibrosis and abnormal FVC) and types of progression (radiologic progression and FVC decline). To address these questions, we assessed mortality rates of a large group of participants with serial chest CT image characterization and measures of pulmonary function in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. Some of the results of this study have been previously reported in the form of an abstract (8).
Methods
Study Population
This study included participants enrolled in COPDGene (9), a longitudinal multicenter cohort study designed to identify the epidemiologic and genetic risk factors of chronic obstructive pulmonary disease (COPD). Current and former smokers aged 45–80 years with at least a 10 pack-year smoking history were enrolled between January 2008 and June 2011 at 21 clinical centers. Those with a known history of lung diseases other than asthma (including ILD) were excluded. Participants completed a protocol at ∼5-year increments that included an assessment of medical history, questionnaires, pulmonary function tests (PFTs), and chest CT scan. The COPDGene study was approved by the institutional review boards of all participating centers.
Measurements and Definitions
Participants underwent volumetric CT scans of the chest at full inspiration according to previously published protocols (9). Chest CT scans were assessed visually for ILA defined per Fleischner Society recommendations (10) using a sequential method by up to three blinded readers as previously described (11). As previously reported, chest CT scans demonstrating ILA were additionally categorized for fibrosis, defined by the presence of pulmonary parenchymal architectural distortion (i.e., traction bronchiectasis, honeycombing) (6), which would be characterized as fibrotic ILA in the Fleischner Society position paper (10). Those with ILA on either baseline or follow-up CT had images simultaneously compared to determine radiologic progression by consensus of up to three readers as previously described (6, 12). Post-bronchodilator FVC was performed with the EasyOne system in accordance with American Thoracic Society/European Respiratory Society recommendations (13). FVC% predicted values were calculated using both Global Lung Initiative global race-neutral reference equations (14) (primary analyses) and NHANES III (third National Health and Nutrition Examination Survey) reference values (15–17) (supplemental analyses). FVC decline was calculated as relative change compared with baseline over the 5-year interval. Suspected ILD (henceforth referred to as ILD) was defined as having ILA and either fibrosis (traction bronchiectasis and/or honeycombing) or FVC < 80% predicted (comparable to a prior publication with the exception that DlCO was not used to define ILD, as this was not available at baseline) (7). Given that recent data demonstrate increases in the extent of emphysema have minimal effect on FVC among those with ILA (18), and to be consistent with prior work (7), individual measures of FVC were not adjusted for emphysema (but COPD severity was adjusted for in multivariable analyses). Clinical data including demographic information, smoking history, and medical history were collected through standardized questionnaires (available at www.copdgene.org). Mortality was ascertained as of October 2022 using multiple approaches, including automated telecommunication and web-based survey instruments every 6 months for all available participants, direct verification of death, and searches of the Social Security Death Index conducted at regular intervals.
Study Design and Statistical Analysis
The study design is shown in Figure 1. Prevalent ILD was first assessed among all participants in COPDGene with CT characterization of ILA and FVC at baseline. Those with prevalent ILD at baseline who had 5-year follow-up with CT and PFTs had measures of ILD progression assessed; the primary analyses were radiologic progression and relative FVC decline ≥10%. Multivariable Cox proportional hazards regression was used for associations between mortality and types of ILD and progression compared with those with ILA who did not have evidence of ILD (ILA without ILD) and compared with the remaining cohort (without ILA [which includes those with no ILA and indeterminate ILA]). Those with ILA and ILD at baseline remained in these categories for the assessment at 5-year follow-up. Incident ILD was calculated at 5-year follow-up in participants not meeting ILD criteria at baseline. Models included the covariates of age, gender, race, body mass index (BMI), pack-years of smoking, current smoking status, and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Cox models were tested for violation of the proportional hazards assumption by including interaction terms of each predictor and survival time and using a global Wald test for proportionality. Analyses violating the proportional hazards assumption were adjusted as detailed in the results. All P values are two sided, and values less than 0.05 were considered statistically significant. All analyses were performed using Statistical Analysis Software version 9.4 (SAS Institute) and R (Version 4.0.3).
Figure 1.
Flow diagram of study design and the development, progression, and mortality for suspected ILD in COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease). 80%P = 80% predicted; CT = computed tomography; ILA = interstitial lung abnormalities; ILD = interstitial lung disease; prog = progression.
Results
Prevalence and Mortality of Baseline ILD
Of the 9,588 participants at baseline enrollment with CT and PFTs, 523 (6%) had ILA, of whom 268 (51% of ILA, 3% of cohort) met at least one criterion for prevalent ILD, including 138 with only FVC < 80% predicted, 89 with only fibrosis, and 41 meeting both criteria (51%, 33%, and 15% of those with ILD, respectively). Baseline characteristics for prevalent ILD compared with those with ILA without ILD (henceforth referred to as ILA when comparing to ILD) and compared with those without ILA are shown in Table 1. Compared with ILA, those with prevalent ILD had a higher percentage of self-identified Black or African American participants.
Table 1.
Baseline Characteristics for Prevalent ILD, ILA without Prevalent ILD, and Without ILA
| Baseline (Enrollment) | Without ILA (n = 9,065) | ILA Without Prevalent ILD (n = 255) | Prevalent ILD (n = 268) |
|---|---|---|---|
| Age, yr, mean (SD) | 59.2 (9.0) | 63.4 (9.2) | 63.7 (9.3) |
| Female gender, n (%) | 4,217 (46.5) | 123 (48.2) | 123 (45.9) |
| Black or African American race, n (%) | 3,021 (33.3) | 57 (22.4) | 106 (39.6) |
| MUC5B variant, n (%)* | 1,194 (13.7) | 57 (23.0) | 64 (24.8) |
| BMI, kg/m2, mean (SD) | 28.8 (6.2) | 29.3 (5.7) | 30.6 (6.8) |
| Pack-years smoking, median (IQR)† | 39.0 (26.9–54.2) | 42.5 (33.0–59.6) | 43.5 (31.0–61.5) |
| Current smoking, n (%) | 4,798 (52.9) | 145 (56.9) | 130 (48.5) |
| COPD, n (%)‡ | 3,988 (44.0) | 111 (43.5) | 114 (42.5) |
| GOLD stage, n (%)§ | |||
| PRISm | 1,096 (12.1) | 26 (10.2) | 79 (29.5) |
| Stage 0 | 3,981 (43.9) | 118 (46.3) | 75 (28.0) |
| Stage 1 | 692 (7.6) | 41 (16.1) | 12 (4.5) |
| Stage 2 | 1,710 (18.9) | 54 (21.2) | 59 (22.0) |
| Stage 3–4 | 1,586 (17.5) | 16 (6.3) | 43 (16.1) |
| Emphysema, %, mean (SD)‖ | 6.4 (9.9) | 3.8 (6.2) | 5.7 (8.7) |
| FVC% predicted, mean (SD) | 89.4 (19.8) | 98.2 (13.2) | 77.8 (17.4) |
| TLC% predicted (by quantitative CT), mean (SD)‖ | 95.7 (16.8) | 92.6 (14.6) | 86.5 (16.2) |
Definition of abbreviations: BMI = body mass index; COPD = chronic obstructive pulmonary disease; CT = computed tomography; GOLD = Global Initiative for Obstructive Lung Disease; ILA = interstitial lung abnormalities; ILD = interstitial lung disease; IQR = interquartile range; PRISm = preserved ratio, impaired spirometry.
Missing muc5B data for 10 ILD participants, 7 ILA without-ILD participants, and 342 without-ILA participants.
Missing pack-year smoking history for 2 without-ILA participants.
COPD category includes participants with GOLD stage 1 or greater.
For the purposes of assessing differences in GOLD stage among groups, PRISm was included in GOLD stage 0.
Missing quantitative CT data for 9 ILD participants, 2 ILA without-ILD participants, and 322 without-ILA participants.
After a median follow-up of 10.6 years, 51% (138 of 268) with prevalent ILD had died, compared with 33% (85 of 255) of those with ILA and 25% (2,282 of the 9,065) without ILA (Figure 1). After adjusting for covariates (age, gender, race, BMI, pack-years of smoking, current smoking status, and GOLD stage), those with prevalent ILD had increased risk of death compared with those with ILA (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.5–2.7; P < 0.001). Mortality ratios and survival curves for these groups are shown in Figures 1 and 2, respectively, and adjusted mortality comparisons are shown in Table 2. Similar findings were noted when compared with the group without ILA (Figure 1 and Table 2 and see Figure E1 in the data supplement) and in sensitivity analyses when prevalent ILD was limited to those who had fibrosis or FVC < 80% predicted in those without COPD or obesity (BMI ≥ 30) (see data supplement). Differences in mortality when defining ILD by FVC% predicted using the NHANES race-specific reference equations are shown in the data supplement, Figure E2, and Tables E2 and E3.
Figure 2.
Kaplan-Meier survival curves for participants with (A) prevalent interstitial lung disease (ILD) (blue) versus interstitial lung abnormalities (ILA) without prevalent ILD (red); (B) incident ILD (blue) versus ILA without incident ILD (red); (C) prevalent ILD with 5-year computed tomography (CT) progression (dark blue), prevalent ILD without 5-year CT progression (light blue), ILA without prevalent ILD (red); (D) prevalent ILD with 5-year relative FVC decline ≥10% (royal blue), prevalent ILD without 5-year relative FVC decline ≥10% (blue-green), ILA without prevalent ILD (red).
Table 2.
Adjusted Mortality Rates for ILD and Types of Progression Compared to ILA without ILD and Without ILA
| n | Mortality (%) | Compared to ILA Without ILD |
Compared to Without ILA |
|||
|---|---|---|---|---|---|---|
| HR (95% CI) | P Value | HR (95% CI) | P Value | |||
| Enrollment (median, 10.6 yr) | ||||||
| Prevalent ILD | 268 | 51.5 | 2.0 (1.5–2.7) | <0.001 | 2.1 (1.6–2.8)* | <0.001* |
| Fibrosis only | 89 | 58.4 | 2.2 (1.5–3.1) | <0.001 | 3.3 (1.8–6.2)* | <0.001* |
| FVC < 80% predicted only | 138 | 44.2 | 1.5 (1.0–2.3) | 0.05 | 1.5 (1.0–2.2)* | 0.03* |
| Fibrosis + FVC < 80% predicted | 41 | 61.0 | 2.2 (1.3–3.7) | 0.002 | 5.5 (3.0–10.1)* | <0.001* |
| 5-yr follow-up (median, 6.4 yr) | ||||||
| Incident ILD | 148 | 31.8 | 2.4 (1.6–3.7) | <0.001 | 2.2 (1.6–3.0) | <0.001 |
| Prevalent ILD | 98 | 40.8 | 2.4 (1.4–4.0) | 0.001 | 2.5 (1.8–3.5) | <0.001 |
| Types of ILD progression | ||||||
| Stable CT and FVC | 32 | 31.3 | 1.6 (0.7–3.8) | 0.3 | 2.0 (1.1–3.8) | 0.03 |
| ≥10% FVC decline only† | 6 | 50.0 | 6.1 (1.3–28.7)† | 0.02† | 3.7 (1.2–11.6)† | 0.03† |
| CT progression only | 38 | 44.7 | 2.6 (1.3–5.1) | 0.005 | 2.8 (1.7–4.6) | <0.001 |
| CT progression + ≥10% FVC decline | 22 | 45.5 | 3.4 (1.4–7.8) | 0.005 | 3.1 (1.6–5.8) | <0.001 |
Definition of abbreviations: CI = confidence interval; CT = computed tomography scan of the chest; HR = hazard ratio; ILA = interstitial lung abnormalities; ILD = interstitial lung disease.
Multivariable Cox proportional hazards regression models were used with the covariates of age, gender, body mass index, pack-years smoking, current smoking status, and Global Initiative for Obstructive Lung Disease stage.
Analyses with the base model above violated the proportional hazard assumption; to meet the assumption, analyses were done in a subset of participants with age within the interquartile range. Mortality by age quartile is shown in Table E1.
Sample sizes are small and confidence intervals are wide for these analyses; recommend interpreting with caution.
Effects of Baseline ILD Criteria on Mortality
Participants with prevalent ILD who only met fibrosis criteria (fibrosis only; i.e., FVC > 80%) had worse mortality than those with ILA after adjusting for covariates (58%; HR, 2.2; 95% CI, 1.5–3.1; P < 0.001). Participants with prevalent ILD who had FVC < 80% only (without fibrosis) did not have worse mortality than those with ILA (44%; HR, 1.5; 95% CI, 1.0–2.3; P = 0.05) (Table 2). For additional assessment of the effect of ILD criteria on mortality, CT fibrosis and FVC < 80% were assessed individually: those with prevalent ILD based on the presence of fibrosis (regardless of FVC) had a mortality rate of 59% (77 of 130) compared with 44% (61 of 138) for those without fibrosis, whereas those with FVC < 80% (regardless of fibrosis) had 48% mortality (86 of 179) compared with 58% (52 of 89) with FVC ≥ 80% (adjusted comparisons to ILA and without ILA in Table E4).
Progression of Prevalent ILD
There were 98 participants with prevalent ILD at baseline who had complete 5-year follow-up. Of the remaining 170 participants with prevalent ILD who did not complete 5-year follow-up, 62 (36%) had died by the median 5-year follow-up time of 5.4 years. Differences between those with prevalent ILD who had 5-year follow-up and those who did not are included in Table E5. Of the participants with prevalent ILD, 61% had radiologic progression at 5-year follow-up; the percentages of those with ≥5% and ≥10% FVC relative decline among those with ILD were 46% and 29%. Applying the primary criteria of CT progression and relative FVC decline ≥ 10%, 32 participants (33%) had stable CT and FVC, 6 (6%) had ≥10% FVC decline only, 38 (39%) had CT progression only, and 22 (22%) had CT progression and ≥10% FVC decline. Examples of each group are shown in Figure 3. Those with prevalent ILD who had fibrosis at baseline had more radiologic progression and FVC decline than those without fibrosis, whereas there was not more radiologic progression or FVC decline in those with baseline FVC < 80% compared with those ≥80% (see data supplement).
Figure 3.
Serial chest computed tomography (CT) scans from four participants with prevalent ILD at enrollment and 5-year follow-up. The participant in the upper left had no CT progression, did not have relative FVC decline ≥10% at 5-year follow-up, and is alive. The participant in the upper right had a relative FVC decline ≥10% without CT progression at 5-year follow-up and is alive. The participant in the lower left had CT progression without relative FVC decline ≥10% at 5-year follow up and died 5.8 years later. The participant in the lower right had both CT progression and a relative FVC decline ≥10% at 5-year follow up and died 3.9 years later. ILD = interstitial lung disease.
Effects of Progression Criteria on Mortality
Over a median follow-up time of 6.4 years, the mortality rates for the four individual ILD progression groups were: 31% (10 of 32) for those with stable CT and FVC, 50% (3 of 6) for ≥10% FVC decline only, 45% (17 of 38) for CT progression only, and 45% (10 of 22) for both CT progression and ≥10% FVC decline (Figure 1). For comparison, of those with 5-year follow-up, mortality rates were 22% (30 of 139) for those with ILA and 16% (743 of 4,703) for those without ILA. Compared with ILA, mortality was worse for the ILD groups who had ≥10% FVC decline only (HR, 6.1; 95% CI, 1.3–28.7; P = 0.02), CT progression only (HR, 2.6; 95% CI, 1.3–5.1; P = 0.005), and CT progression and ≥10% FVC decline (HR, 3.4; 95% CI, 1.4–7.8; P = 0.005); there was no difference for the group with stable CT and FVC (Table 2). Overall, similar trends were seen for progression groups based on a ≥5% relative FVC decline (Table E6).
For additional assessment of the effect of progression criteria on mortality, CT progression and ≥10% relative FVC decline were assessed individually. Those ILD participants with CT progression (regardless of FVC decline) had a mortality rate of 45% (27 of 60) compared with 34% (13 of 38) for those without CT progression, whereas those with FVC decline ≥10% (regardless of CT progression) had 46% mortality (13 of 28) compared with 39% (27 of 70) without FVC decline (Figure 2; adjusted comparisons to ILA and without ILA in Table E4).
Development and Mortality of Incident ILD
Of the 4,842 participants at 5-year follow-up who did not have prevalent ILD at enrollment (139 with ILA and 4,703 without ILA), 148 met criteria for incident ILD (5.5 per 1,000 person-years). For comparison, of the 4,703 participants at 5-year follow-up without ILA at enrollment, 359 had incident ILA (13.6 per 1,000 person-years). Baseline characteristics for incident ILD compared with those with ILA and compared with those without ILA are shown in Table E7. At 5-year follow-up, 19% of those with ILA at baseline developed incident ILD compared with 3% of those without ILA at baseline, whereas 6% of those with FVC < 80% at baseline developed incident ILD compared with 2% of those with FVC ≥ 80% (Table E8).
Of the 148 participants with incident ILD at 5-year follow-up, 32% (47) died after a median follow-up of 6.4 years, which was worse than 17% (52 of 309) with ILA (HR, 2.4; 95% CI, 1.6–3.7; P < 0.001) and 15% (674 of 4,385) without ILA (HR, 2.2; 95% CI, 1.6–3.0; P < 0.001) (Figures 1 and 2 and Table 2). Similar findings were noted in sensitivity analyses when incident ILD was limited to those who had fibrosis or FVC < 80% predicted in those without COPD or obesity (BMI ≥ 30) (see data supplement). Effects of ILD criteria on mortality were similar to those seen in prevalent ILD (Table E9).
Discussion
This study, in a population of smokers where known ILD was excluded, affirms previous findings about the prevalence and outcomes associated with suspected ILD, demonstrates that it is not uncommon, and reveals concerning rates of mortality and progression among those with ILD identified over a 10-year interval. In addition, these findings provide important insight into the fact that evidence for pulmonary fibrosis on chest CT imaging and its progression among those with suspected ILD are associated with increased mortality rates. This work provides additional evidence that the development of fibrosis on CT and radiologic progression, in addition to changes in pulmonary function, may be critical to the prognosis of ILD in general.
Although this work adds to the consistent and growing list of studies showing that ILA is associated with an increased rate of mortality (1–7), it also adds to data supporting methods of risk stratification (4, 6, 7). In addition to confirming the utility of using imaging characteristics and pulmonary function to identify a subset with increased mortality (7), the current study highlights the importance of radiologic characterization of imaging abnormalities, as many with ILD had lung volumes within the normal range. We also demonstrated that the presence of pulmonary fibrosis (more so than reduced measures of FVC) was associated with increased rates of radiologic progression and FVC decline. This confirms prior work in ILA showing the association of the fibrotic subtype with progression and mortality in the general population (6) and is consistent with prior work in progressive pulmonary fibrosis showing that those with definite/probable usual interstitial pneumonia (UIP) experienced more annual FVC decline than those with non-UIP patterns (19). Linking the presence of imaging features that were discovered incidentally with the longitudinal outcomes of FVC decline, radiologic progression, and mortality highlights the importance of qualitative assessments of radiologic severity at baseline in ILA to predict adverse outcomes and suggests an opportunity for further research into quantitative assessments of imaging severity.
This study also provides compelling evidence that longitudinal data in those with imaging abnormalities have important prognostic implications. This study demonstrates that even among research participants with undiagnosed ILD, declines in FVC and imaging progression occur frequently over time, and these changes are correlated with considerable changes in the rates of mortality, similar to what would be expected in patients with IPF, albeit not over the same time scale (20, 21). This work also adds further support to studies of those with clinically diagnosed forms of ILD where imaging progression has an independent effect on mortality (22). Although assessments of mortality rates alone have limitations, the fact that those with prevalent ILD in our study had >50% mortality after a median of 10.6 years should require us to consider prioritizing future interventional efforts targeted to this group. As a comparison, although overall survival of these groups is more favorable than IPF (23) and other progressive forms of pulmonary fibrosis (22), these mortality rates are worse than most other incidentally discovered diseases, including lung cancer (24).
These findings demonstrate high rates of mortality in those with CT imaging progression even in the absence of FVC decline, although comparisons are limited by small sample size. There is no straightforward way to meaningfully compare these two measurements of progression, and it is likely that follow-up time for these comparisons matters. These data provide evidence that imaging progression has important prognostic implications in addition to FVC decline. There is considerable debate about the best way to define and monitor progression for the purposes of both clinical management and pharmaceutical trials (25, 26). Bolstered by its cost, reproducibility of measurement, and the U.S. Food and Drug Administration acceptance of this criterion for drug approval (27), FVC has been the primary outcome for clinical trials in IPF (28, 29) and progressive pulmonary fibrosis (30). The hazard ratio for mortality associated with imaging progression alone in this study (HR, 2.6) is comparable to that obtained in a study of progressive pulmonary fibrosis in which imaging progression was noted in ∼50% of patients who did not have a relative FVC decline of ≥10% (HR, 2.0) (22). The fact that imaging progression is associated with increases in mortality, even among those without substantial declines in lung function, adds weight to efforts to consider imaging progression as an additional important trial outcome in those with pulmonary fibrosis.
Finally, this study helps to characterize the development of ILD. Given the heterogeneity of ILD and subjectivity with respect to diagnosis, it has historically been challenging to establish accurate rates of incidence. We estimated the incidence of ILD to be 5.5/1,000 person-years in this population of smokers, which is more than 10 times higher than another U.S.-based study from 3 decades ago (31). Part of this difference is likely a result of incidental and, in many cases, asymptomatic people with ILD identified in this study compared with the registry, where participants had to seek medical attention and obtain a clinical diagnosis to be included. In addition, it is worth noting that our study includes those with substantial tobacco smoke exposure, a known risk factor for ILA and ILD (11, 32). Compared with a recent population-based study, our study demonstrated a three-times-lower incidence of ILD meeting the criteria of ILA and fibrosis (1/1,000 person-years vs. 3.8/1,000 person-years), although the rates of ILA incidence in this study and ours were nearly the same (13/1,000 person-years) (33). Of note, the elevated incidence (and prevalence) of ILD among self-identified Black or African American subjects warrants further exploration and demonstrates the importance of including this group in research and clinical trials.
Our study has several potential limitations. First, there is no consensus definition of ILD in this setting of research cohorts in which participants were not suspected of having ILD, and thus multidisciplinary evaluation was not completed. We used a definition of ILD consistent with prior literature (7, 34), with the exception that DlCO was not included, as this measurement was not available at enrollment in COPDGene. Given the importance of DlCO in ILD assessment (7), it is possible that our estimates of prevalence, incidence, and mortality could be biased by this exclusion. This work supports the importance of further clinical evaluations to establish a specific ILD diagnosis when patients meeting these criteria are identified in clinical practice. Second, the study used a large cohort of smokers, many of whom have COPD. We attempted to account for this by adjusting for COPD diagnosis and GOLD stage in multivariable analyses. However, we cannot rule out the possibility that some of our findings could be limited to populations of smokers. Furthermore, we are unable to assess how mortality estimates differ from those of the general population, which is estimated to be 20–30% 10-year mortality for individuals over the age of 60 years (35). Third, the exact cause of increased mortality cannot be ascertained using the data available. Given the associated lung function loss and radiologic progression, it would be expected that a large number are due to respiratory failure, but future studies should attempt to obtain detailed accounts of the cause of death. Fourth, because of small sample sizes among those with ILD and complete 5-year follow-up, we urge caution when interpreting comparisons between groups. Fifth, analyses on subjects at 5-year follow-up are subject to bias from nonindependent censoring. Sixth, to comply with the proportional hazards assumption, some of the mortality analyses were completed in a limited age range. Seventh, PFT measures were only available at two time points, so we were unable to analyze trajectories of PFT changes. Future studies would benefit from including serial measurements of pulmonary function and other longitudinal outcomes.
In conclusion, our study demonstrates that mortality is high among smokers with suspected ILD and that imaging evidence for pulmonary fibrosis is a risk factor for imaging progression, FVC decline, and death. Our study also suggests that CT imaging progression in suspected ILD is an important predictor of mortality, irrespective of FVC decline. These findings highlight the importance of assessing radiologic subsets of ILA and radiologic progression longitudinally, as these findings have important implications for clinical management and potentially for clinical trial design.
Supplemental Materials
Footnotes
Supported by NIH grants T32 HL007633 (C.C.), K08 HL173562 (J.A.R.) NIH NHLBI grants R01 HL152728, U01 HL089856, R01 HL147148, R01 HL137927, and R01 HL133135 (E.K.S.); NIH grants R01 HL153248, R01 HL135142, R01 HL149861, R01 HL137927, and R01 HL137148 (M.H.C.); NIH grants R01 CA203636, U01CA209414, R01 HL111024, R01 HL135142, and R01 HL130974 (H.H.); NIH grant K08 HL140087 (R.K.P.); and NIH grants R01 HL111024, R01 HL130974, and R01 HL135142 (G.M.H. and this work). COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) is supported by NIH grant numbers U01 HL089897 and U01 HL089856. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.
Author Contributions: Study design: J.A.R, R.K.P, and G.M.H. Acquisition, analysis, or interpretation of the data: J.A.R., C.C., A.-M.C.T., N.W., M.N., M.M., S.K., B.C., D.A.L., B.A.R., I.O.R., R.S.J.E., G.R.W., E.K.S., M.H.C., H.H., R.K.P., and G.M.H. Critical revision of the manuscript for important intellectual content: J.A.R., C.C., A.-M.C.T., N.W., M.N., M.M., S.K., B.C., D.A.L., B.A.R., I.O.R, G.R.W., E.K.S., M.H.C., H.H., R.K.P., and G.M.H. Statistical analysis: J.A.R, R.K.P, and G.M.H. Obtained funding: G.R.W., E.K.S., M.H.C., and G.M.H.
This paper is subject to the NIH public access policy: https://sharing.nih.gov/public-access-policy.
A data supplement for this article is available via the Supplements tab at the top of the online article.
Originally Published in Press as DOI: 10.1164/rccm.202402-0313OC on August 12, 2024
Author disclosures are available with the text of this article at www.atsjournals.org.
References
- 1. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators; COPDGene Investigators Association between interstitial lung abnormalities and all-cause mortality. JAMA . 2016;315:672–681. doi: 10.1001/jama.2016.0518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Pompe E, de Jong PA, Lynch DA, Lessmann N, Isgum I, van Ginneken B, et al. Computed tomographic findings in subjects who died from respiratory disease in the National Lung Screening Trial. Eur Respir J . 2017;49:1601814. doi: 10.1183/13993003.01814-2016. [DOI] [PubMed] [Google Scholar]
- 3. Grant-Orser A, Min B, Elmrayed S, Podolanczuk AJ, Johannson KA. Prevalence, risk factors, and outcomes of adult interstitial lung abnormalities: a systematic review and meta-analysis. Am J Respir Crit Care Med . 2023;208:695–708. doi: 10.1164/rccm.202302-0271OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Park S, Choe J, Hwang HJ, Noh HN, Jung YJ, Lee JB, et al. Long-term follow-up of interstitial lung abnormality: implication in follow-up strategy and risk thresholds. Am J Respir Crit Care Med . 2023;208:858–867. doi: 10.1164/rccm.202303-0410OC. [DOI] [PubMed] [Google Scholar]
- 5. Sanders JL, Axelsson G, Putman R, Menon A, Dupuis J, Xu H, et al. The relationship between interstitial lung abnormalities, mortality, and multimorbidity: a cohort study. Thorax . 2023;78:559–565. doi: 10.1136/thoraxjnl-2021-218315. [DOI] [PubMed] [Google Scholar]
- 6. Putman RK, Gudmundsson G, Axelsson GT, Hida T, Honda O, Araki T, et al. Imaging patterns are associated with interstitial lung abnormality progression and mortality. Am J Respir Crit Care Med . 2019;200:175–183. doi: 10.1164/rccm.201809-1652OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Rose JA, Menon AA, Hino T, Hata A, Nishino M, Lynch DA, et al. Suspected interstitial lung disease in COPDGene study. Am J Respir Crit Care Med . 2023;207:60–68. doi: 10.1164/rccm.202203-0550OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rose JA, Cutting CC, Tukpah A-MC, Wada N, Nishino M, Lynch DA, Kalra S, Moll M, Choi B, Washko GR, Silverman EK, Cho M, Hatabu H, Putman RK, Hunninghake GM. American Thoracic Society International Conference. San Diego, CA: 2024. Development and Progression of Interstitial Lung Disease in COPDGene. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, et al. Genetic Epidemiology of COPD (COPDGene) study design. COPD . 2010;7:32–43. doi: 10.3109/15412550903499522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Hatabu H, Hunninghake GM, Richeldi L, Brown KK, Wells AU, Remy-Jardin M, et al. Interstitial lung abnormalities detected incidentally on CT: a position paper from the Fleischner Society. Lancet Respir Med . 2020;8:726–737. doi: 10.1016/S2213-2600(20)30168-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y, Yamashiro T, et al. COPDGene Investigators Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med . 2011;364:897–906. doi: 10.1056/NEJMoa1007285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Araki T, Putman RK, Hatabu H, Gao W, Dupuis J, Latourelle JC, et al. Development and progression of interstitial lung abnormalities in the Framingham Heart Study. Am J Respir Crit Care Med . 2016;194:1514–1522. doi: 10.1164/rccm.201512-2523OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Standardization of spirometry, 1994 update. American Thoracic Society. Am J Respir Crit Care Med . 1995;152:1107–1136. doi: 10.1164/ajrccm.152.3.7663792. [DOI] [PubMed] [Google Scholar]
- 14. Bowerman C, Bhakta NR, Brazzale D, Cooper BR, Cooper J, Gochicoa-Rangel L, et al. A race-neutral approach to the interpretation of lung function measurements. Am J Respir Crit Care Med . 2023;207:768–774. doi: 10.1164/rccm.202205-0963OC. [DOI] [PubMed] [Google Scholar]
- 15. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med . 1999;159:179–187. doi: 10.1164/ajrccm.159.1.9712108. [DOI] [PubMed] [Google Scholar]
- 16. Bhakta NR, Bime C, Kaminsky DA, McCormack MC, Thakur N, Stanojevic S, et al. Race and ethnicity in pulmonary function test interpretation: an official American Thoracic Society statement. Am J Respir Crit Care Med . 2023;207:978–995. doi: 10.1164/rccm.202302-0310ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of spirometry 2019 update: an official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med . 2019;200:e70–e88. doi: 10.1164/rccm.201908-1590ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Menon AA, Putman RK, Sanders JL, Hino T, Hata A, Nishino M, et al. Interstitial lung abnormalities, emphysema and spirometry in smokers. Chest . 2021;161:999–1010. doi: 10.1016/j.chest.2021.10.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Oldham JM, Lee CT, Wu Z, Bowman WS, Pugashetti JV, Dao N, et al. Lung function trajectory in progressive fibrosing interstitial lung disease. Eur Respir J . 2022;59:2101396. doi: 10.1183/13993003.01396-2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH, Colby TV, et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med . 2003;168:543–548. doi: 10.1164/rccm.200209-1112OC. [DOI] [PubMed] [Google Scholar]
- 21. Hwang JH, Misumi S, Curran-Everett D, Brown KK, Sahin H, Lynch DA. Longitudinal follow-up of fibrosing interstitial pneumonia: relationship between physiologic testing, computed tomography changes, and survival rate. J Thorac Imaging . 2011;26:209–217. doi: 10.1097/RTI.0b013e3181e35823. [DOI] [PubMed] [Google Scholar]
- 22. Pugashetti JV, Adegunsoye A, Wu Z, Lee CT, Srikrishnan A, Ghodrati S, et al. Validation of proposed criteria for progressive pulmonary fibrosis. Am J Respir Crit Care Med . 2023;207:69–76. doi: 10.1164/rccm.202201-0124OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Ley B, Collard HR, King TE., Jr Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med . 2011;183:431–440. doi: 10.1164/rccm.201006-0894CI. [DOI] [PubMed] [Google Scholar]
- 24. Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS, International Early Lung Cancer Action Program Investigators Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med . 2006;355:1763–1771. doi: 10.1056/NEJMoa060476. [DOI] [PubMed] [Google Scholar]
- 25. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an Official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med . 2022;205:e18–e47. doi: 10.1164/rccm.202202-0399ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. George PM, Spagnolo P, Kreuter M, Altinisik G, Bonifazi M, Martinez FJ, et al. Erice ILD working group Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities. Lancet Respir Med . 2020;8:925–934. doi: 10.1016/S2213-2600(20)30355-6. [DOI] [PubMed] [Google Scholar]
- 27. Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis: FDA review of pirfenidone and nintedanib. N Engl J Med . 2015;372:1189–1191. doi: 10.1056/NEJMp1500526. [DOI] [PubMed] [Google Scholar]
- 28. King TE, Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al. ASCEND Study Group A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2083–2092. doi: 10.1056/NEJMoa1402582. [DOI] [PubMed] [Google Scholar]
- 29. Richeldi L, Du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. INPULSIS Trial Investigators Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med . 2014;370:2071–2082. doi: 10.1056/NEJMoa1402584. [DOI] [PubMed] [Google Scholar]
- 30. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. INBUILD Trial Investigators Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med . 2019;381:1718–1727. doi: 10.1056/NEJMoa1908681. [DOI] [PubMed] [Google Scholar]
- 31. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med . 1994;150:967–972. doi: 10.1164/ajrccm.150.4.7921471. [DOI] [PubMed] [Google Scholar]
- 32. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med . 1997;155:242–248. doi: 10.1164/ajrccm.155.1.9001319. [DOI] [PubMed] [Google Scholar]
- 33. McGroder CF, Hansen S, Hinckley Stukovsky K, Zhang D, Nath PH, Salvatore MM, et al. Incidence of interstitial lung abnormalities: the MESA Lung Study. Eur Respir J . 2023;61:2201950. doi: 10.1183/13993003.01950-2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Hunninghake GM, Quesada-Arias LD, Carmichael NE, Martinez Manzano JM, De Frias P, Baumgartner S, et al. Interstitial lung disease in relatives of patients with pulmonary fibrosis. Am J Respir Crit Care Med . 2020;201:1240–1248. doi: 10.1164/rccm.201908-1571OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Xu J, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2021. NCHS Data Brief . 2022;456:1–8. [PubMed] [Google Scholar]
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