Abstract
Rationale
Occupational exposures to dust and fumes are associated with increased respiratory symptoms and worse lung function; however, their effect on future clinical outcomes has been incompletely explored.
Objectives
To examine the associations between self-reported occupational exposure to dust and fumes on future respiratory exacerbations, cardiovascular events, and other clinical outcomes in people with a history of smoking.
Methods
People with a current or former smoking status, aged 45 to 80 years, enrolled in COPDGene were assigned to 4 mutually exclusive occupational exposure groups (no exposure, dust-only exposure, fumes-only exposure, dust-and-fumes exposure) based on questionnaire responses at baseline. Clinical outcomes were assessed prospectively for up to 15 years. Respiratory exacerbations were defined as worsening respiratory symptoms requiring treatment with steroids and/or antibiotics; binary outcomes included atherosclerotic cardiovascular disease (ASCVD), cancer, pneumonia, and blood clots. Multivariable-adjusted models estimated the association between occupational exposure category and each clinical outcome.
Measurements and Main Results
Among 8991 participants (mean ± SD age, 60.1 ± 9.0 years; 51.7% male; 49.3% with a current smoking status), the prevalence of dust-only, fumes-only, and dust-and-fumes exposure was 12.0%, 12.4%, and 34.4%, respectively. Self-reported occupational exposure to both dust and fumes was associated with increased risk of future respiratory exacerbations (adjusted rate ratio, 1.38 [95% CI, 1.26-1.52]) relative to those reporting no exposures. Exposure to both dust and fumes was also associated with an increased risk (adjusted odds ratio [95% CI]) for future ASCVD (1.35 [1.17-1.56]) and pneumonia (1.39 [1.19-1.63]), but was not associated with future cancer or blood clots.
Conclusions
Self-reported occupational exposure to dust and fumes is associated with increased future risk for multiple clinically relevant outcomes among tobacco-exposed individuals.
ClinicalTrials.gov
NCT00608764 (COPDGene)
Keywords: occupational exposures, respiratory exacerbations, clinical outcomes, smokers
At a Glance Commentary.
Current Scientific Knowledge on the Subject: Occupational exposures (OEs) have been associated with the development of chronic respiratory and cardiovascular diseases, though the magnitude of the effects and outcomes examined have been highly variable. Among tobacco-exposed individuals, self-reported OEs to dust and fumes have been associated cross-sectionally with worse respiratory symptoms and spirometric lung function and increased radiographic emphysema; the association between self-reported OEs to dust and fumes with prospective outcomes, including respiratory exacerbations and cardiovascular outcomes, has been incompletely explored.
What This Study Adds to the Field: In a large cohort of tobacco-exposed individuals with a range of spirometric lung function and up to 15 years of prospective outcomes data, self-reported OE to dust and fumes was associated with an increased risk of future moderate-to-severe and severe respiratory exacerbations, pneumonia, and atherosclerotic cardiovascular disease.
Introduction
While tobacco smoking remains the most well-established risk factor for chronic obstructive pulmonary disease (COPD) and also has been associated with interstitial lung disease and asthma–COPD overlap,1-3 occupational exposures (OEs) to vapor, gases, dust, and fumes (VGDF) can also contribute to disease development, respiratory morbidity, and lung function decline.4-11 The pooled population attributable fraction for COPD due to occupational exposure to VGDF is estimated to be 14%.12 Prior studies have demonstrated that OE to dust or fumes is associated with increased risk of developing obstructive airway disease, including COPD and asthma, increased respiratory symptoms, and accelerated lung function decline.4,7-11 Within COPDGene, self-reported OE to both dust and fumes was associated with lower FEV1 to FVC ratio, increased emphysema on chest computed tomography (CT), and increased respiratory symptoms among tobacco-exposed individuals at baseline13; validation of these cross-sectional associations has been explored with job exposure matrices.14 OEs to VGDF may increase the risk of future respiratory exacerbations (REs) among those with established asthma or COPD15-18; however, the risk among tobacco-exposed individuals both with and without these respiratory diagnoses has been incompletely explored.
Beyond REs, the associations between OEs and other adverse clinical outcomes have been inconsistent. Several studies have identified positive associations between OE to dust and fumes and an increased risk of community-acquired pneumonia (CAP) and CAP-related hospitalizations.4,19,20 Multiple studies support the association between OE to fumes, particulate matter, and selected organic and inorganic dusts with an increased the risk of ischemic heart disease and stroke.21-26 Conflicting results have been reported regarding the association between OEs and the risk of respiratory tract and other cancers.27-37 Finally, limited data exist regarding the associations between OEs on fracture risk38-43 and venous thromboembolic events (VTEs).44
We hypothesize that OE to dust and fumes will be associated with increased risk for future REs and other clinical outcomes in tobacco-exposed individuals with a broad range of spirometric lung function. Given current knowledge gaps, we investigated the associations between self-reported OE to dust and fumes and (1) prospective respiratory exacerbations and (2) future adverse cardiovascular events, malignancies, pneumonia, VTEs, and fractures to provide a broad inquiry into the potential respiratory and systemic effects of OEs. Some of the results have been previously reported in abstract form.45
Methods
Study design
COPDGene is a multicenter, observational study that enrolled people with a current or former smoking status with ≥10 pack-years, aged 45 to 80 years. Institutional review board approval was obtained at each participating site; all participants provided written informed consent. Participants completed questionnaires, pre- and post-bronchodilator spirometry, and standardized volumetric chest CT scans at baseline. Full COPDGene study design and methods have been previously described.46
Lung function categories were defined as COPD (post-bronchodilator FEV1/FVC <0.70), Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 (FEV1/FVC ≥0.7 and FEV1 ≥80%), and preserved ratio impaired spirometry (PRISm; FEV1/FVC ≥0.7 and FEV1 <80%). Atherosclerotic cardiovascular disease (ASCVD) was defined by a self-reported diagnosis of myocardial infarction (MI), stroke, transient ischemic attack, coronary artery disease, or peripheral arterial disease, or history of cardiac angioplasty or coronary artery bypass graft (CABG). Subjects missing OE assessments and those who did not participate in longitudinal follow-up were excluded from analysis.
Occupational exposure history
OE history at baseline was assessed by the following structured questionnaire items:
Have you ever worked for a year or more in any dusty job? (Dust exposure)
Have you ever been exposed to gas, smoke, chemical vapors, or fumes in your work? (Fumes exposure)
Based on affirmative answers to one or both of the questions, participants were categorized into 4 mutually exclusive OE categories: (1) no exposure, (2) dust-only exposure, (3) fumes-only exposure, and (4) dust-and-fumes exposure.
Clinical outcomes
Participants were assessed prospectively every 6 months for up to 15 years.47 Respiratory exacerbations (REs) were defined as worsening respiratory symptoms requiring treatment with antibiotics or steroids (moderate), or unplanned emergency room (ER) visit or hospitalization (severe). Subjects were also asked (yes/no) if, since their most recent follow-up, they had been diagnosed with new conditions such as MI, stroke, CABG surgery, angioplasty/cardiac stenting, pneumonia, blood clots, hip fracture, lung cancer, or other cancers. The primary outcomes were the total number of moderate-to-severe and severe REs; secondary outcomes were binary ASCVD, lung cancer, other cancer, VTE/blood clot, pneumonia, and hip fracture during follow-up.
Statistical analyses
Bivariable comparisons by OE categories were performed using χ2 or 2-tailed t-test for categorical and continuous variables, respectively. Associations between OE categories and clinical outcomes were assessed using multivariable-adjusted (1) zero-inflated negative binomial models for the total number of RE episodes and (2) logistic regression models for binary or dichotomized clinical outcomes. Covariates for each model, subgroup and sensitivity analyses, mediation and interaction analyses, and quantitative bias analyses are outlined in the Supplementary Methods. The main analyses were performed in the full cohort for all primary and secondary outcomes; a Bonferroni-adjusted P value <.00208 (overall α = 0.05) was considered significant. For descriptive statistics and exploratory analyses (subgroup, sensitivity, mediation, etc.) an unadjusted P <.05 was considered significant. All analyses were performed using R software (version 4.4.1).
Results
Baseline characteristics
Among the 10,198 participants enrolled in COPDGene, 8991 participants were included in the final analysis (Figure 1). Excluded participants were younger and had lower educational attainment and a higher prevalence of African American ancestry, male sex, and current smoking (Table S1). Baseline characteristics of subjects, in aggregate and by OE exposure category, are summarized in Table 1. Participants with both dust and fumes exposure were more likely to be male (72.4%), had a higher prevalence of COPD, and had lower mean FEV1% predicted. Participants who reported no exposures were more likely to be female (65.1%). Participants who reported dust-only exposures had the highest prevalence of African American ancestry and current smoking. The prevalence of comorbid medical conditions at baseline is shown in Table S2; participants exposed to both dust and fumes had the highest prevalence of COPD and ASCVD at enrollment. Baseline respiratory symptoms, by lung function category, are summarized in Table S3.
Figure 1.
Consolidated Standards of Reporting Trials (CONSORT) diagram for COPDGene subjects included in the analysis.
Table 1.
Baseline characteristics of COPDGene participants.
| Exposure category | All subjects (N = 8991) | No exposure (n = 3704) | Dust only (n = 1079) | Fumes only (n = 1112) | Dust and fumes (n = 3096) |
|---|---|---|---|---|---|
| Age, y, mean ± SD | 60.1 ± 9.0 | 61.1 ± 9.3 | 58.2 ± 9.0* | 61.1 ± 8.9 | 59.3 ± 8.5* |
| Sex, No. (%) | |||||
| Male | 4646 (51.7) | 1293 (34.9) | 531 (49.2)* | 579 (52.1)* | 2243 (72.4)* |
| Female | 4345 (48.3) | 2411 (65.1) | 548 (50.8)* | 533 (47.9)* | 853 (27.6)* |
| Ancestry, No. (%) | |||||
| Non-Hispanic White | 6280 (69.8) | 2646 (71.4) | 602 (55.8)* | 882 (79.3)* | 2150 (69.4) |
| African American | 2711 (30.2) | 1058 (28.6) | 477 (44.2)* | 230 (20.7)* | 946 (30.6) |
| BMI, kg/m2, mean ± SD | 29.0 ± 6.3 | 28.8 ± 6.3 | 29.2 ± 6.4 | 29.1 ± 6.2 | 29.1 ± 6.3* |
| Smoking status, No. (%) | |||||
| Current | 4437 (49.3) | 1714 (46.3) | 661 (61.3)* | 441 (39.7)* | 1621 (52.4)* |
| Former | 4554 (50.7) | 1990 (53.7) | 418 (38.7)* | 671 (60.3)* | 1475 (47.6)* |
| Pack-years, mean ± SD | 44.3 ± 24.8 | 41.0 ± 23.3 | 44.6 ± 25.0* | 43.5 ± 23.6* | 48.4 ± 26.3* |
| FEV1% predicted, mean ± SD | 76.0 ± 25.4 | 78.9 ± 23.9 | 76.8 ± 24.8* | 76.7 ± 25.3* | 72.0 ± 27.0* |
| Lung function categorya, No. (%) | |||||
| GOLD 0 | 3816 (42.7) | 1729 (46.9) | 464 (43.5)* | 484 (43.8) | 1139 (37.0)* |
| PRISm | 1107 (12.4) | 455 (12.3) | 159 (14.9)* | 130 (11.8) | 363 (11.8)* |
| COPD | 4019 (44.9) | 1504 (40.8) | 444 (41.6)* | 492 (44.5) | 1579 (51.2)* |
| GOLD 1 | 694 (7.8) | 299 (8.1) | 71 (6.7) | 101 (9.1) | 223 (7.2) |
| GOLD 2 | 1741 (19.5) | 698 (18.9) | 208 (19.5) | 202 (18.3) | 633 (20.5) |
| GOLD 3 | 1063 (11.9) | 373 (10.1) | 113 (10.6) | 119 (10.8) | 458 (14.9) |
| GOLD 4 | 521 (5.8) | 134 (3.6) | 52 (4.9) | 70 (6.3) | 265 (8.6) |
| Education, No. (%) | |||||
| More than high school | 5641 (62.7) | 2587 (69.8) | 541 (50.1)* | 780 (70.1) | 1733 (56.0)* |
| High school or less | 3350 (37.3) | 1117 (30.2) | 538 (49.9)* | 332 (29.9) | 1363 (44.0)* |
| Baseline symptoms, No. (%) | |||||
| mMRC ≥2 | 3718 (41.4) | 1317 (35.6) | 474 (43.9)* | 416 (37.4) | 1511 (48.9)* |
| mMRC <2 | 5261 (58.6) | 2381 (64.4) | 605 (56.1)* | 695 (62.6) | 1580 (51.1)* |
| Duration of follow-up | 9.9 ± 4.0 | 10.1 ± 3.9 | 9.7 ± 4.1* | 10.4 ± 3.8 | 9.5 ± 4.2* |
Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mMRC, modified Medical Research Council dyspnea scale; PRISm, preserved ratio impaired spirometry; SD, standard deviation.
Lung function categories: GOLD 0 = post-bronchodilator FEV1/FVC ≥0.7 with FEV1 %predicted ≥80; PRISm = post-bronchodilator FEV1/FVC ≥0.7 and FEV1 %predicted <80; COPD = post-bronchodilator FEV1/FVC <0.7.
Denotes P <.05 when compared to participants with no exposure.
Prospective clinical outcomes
The number and proportion of participants reporting each clinical outcome during longitudinal follow-up, as well as the number of moderate-to-severe and severe RE episodes, is summarized in Table S4.
Primary outcome: respiratory exacerbations
An increased risk for future moderate-to-severe and severe REs was observed among participants who reported OE to both dust and fumes relative to those with no exposures (Table 2). This association was consistent in subgroup analyses by sex and lung function category (Table 2) as well as by current smoking status, educational attainment category, and baseline dyspnea category (Table S5). Results were similar in sensitivity analyses with additional adjustment for asthma (Tables S6 and S7).
Table 2.
Associations between occupational exposure categories and total number of prospective moderate-to-severe and severe respiratory exacerbation episodes.
| Exacerbation | No exposure | Dust only | Fumes only | Dust and fumes |
|---|---|---|---|---|
| All subjects (N = 8991)a | ||||
| Moderate-to-severe exacerbations | Ref | 1.06 [0.94-1.20] | 1.09 [0.97-1.23] | 1.38 [1.26-1.52] |
| P = .352 | P = .148 | P <.001 * | ||
| Severe exacerbations | Ref | 1.03 [0.88-1.21] | 1.07 [0.91-1.26] | 1.34 [1.18-1.51] |
| P = .692 | P = .389 | P <.001 * | ||
| Subgroup analyses by sexb | ||||
| Male subjects (n = 4646) | ||||
| Moderate-to-severe exacerbations | Ref | 0.97 [0.79-1.19] | 1.06 [0.88-1.28] | 1.43 [1.24-1.64] |
| P = .760 | P = .540 | P <.001 | ||
| Severe exacerbations | Ref | 0.92 [0.71-1.19] | 1.03 [0.81-1.31] | 1.32 [1.10-1.57] |
| P = .527 | P = .811 | P = .002 | ||
| Female subjects (n = 4345) | ||||
| Moderate-to-severe exacerbations | Ref | 1.12 [0.96-1.32] | 1.12 [0.96-1.31] | 1.29 [1.13-1.46] |
| P = .150 | P = .144 | P <.001 | ||
| Severe exacerbations | Ref | 1.10 [0.89-1.35] | 1.11 [0.90-1.37] | 1.28 [1.08-1.52] |
| P = .391 | P = .345 | P = .005 | ||
| Subgroup analyses by lung function categoryc , d | ||||
| GOLD 0 subjects (n = 3816) | ||||
| Moderate-to-severe exacerbations | Ref | 1.17 [0.91-1.50] | 1.04 [0.81-1.33] | 1.43 [1.18-1.74] |
| P = .221 | P = .762 | P <.001 | ||
| Severe exacerbations | Ref | 1.19 [0.85-1.67] | 0.94 [0.66-1.33] | 1.42 [1.09-1.86] |
| P = .302 | P = .729 | P = .010 | ||
| PRISm subjects (n = 1107) | ||||
| Moderate-to-severe exacerbations | Ref | 1.37 [0.94-2.00] | 1.12 [0.75-1.67] | 2.12 [1.57-2.86] |
| P = .098 | P = .568 | P <.001 | ||
| Severe exacerbations | Ref | 1.19 [0.74-1.91] | 0.92 [0.55-1.53] | 1.77 [1.21-2.59] |
| P = .479 | P = .752 | P = .003 | ||
| COPD subjects (n = 4019) | ||||
| Moderate-to-severe exacerbations | Ref | 0.97 [0.83-1.15] | 1.15 [0.99-1.35] | 1.37 [1.22-1.54] |
| P = .741 | P = .069 | P <.001 | ||
| Severe exacerbations | Ref | 0.98 [0.79-1.20] | 1.15 [0.95-1.40] | 1.36 [1.17-1.58] |
| P = .813 | P = .161 | P <.001 | ||
Data are shown as adjusted relative risk [95% confidence interval]. Analyses were performed by multivariable adjusted zero-inflated negative binomial (ZINB) regression model.
Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; PRISm, preserved ratio impaired spirometry.
ZINB models for all subjects were adjusted for age at enrollment, sex, ancestry, body mass index, current smoking status, pack-years, FEV1% predicted at enrollment, and education.
ZINB models for sex subgroups were adjusted for age at enrollment, ancestry, body mass index, current smoking status, pack-years, FEV1% predicted at enrollment, and education.
ZINB models for lung function subgroups were adjusted for age at enrollment, sex, ancestry, body mass index, current smoking status, pack-years, and education.
Lung function categories: GOLD 0 = post-bronchodilator FEV1/FVC ≥0.7 and % FEV1 predicted ≥80; PRISm = post-bronchodilator FEV1/FVC ≥0.7 and FEV1 %predicted <80; COPD = post-bronchodilator FEV1/FVC <0.7.
Denotes P <.00208 (Bonferroni-adjusted threshold) for a primary or secondary outcome analysis.
When prospective REs outcomes were dichotomized (any/none), consistently increased risk was observed in the participants exposed to dust and fumes within the full cohort (adjusted odds ratio [aOR], 1.48 [95% CI, 1.32-1.65]) and in subgroup analyses by sex and lung function category (Figure 2A). Results were consistent with additional adjustment for a history of asthma (Figure 2B). OE to dust and fumes was also associated with prospective RE requiring hospitalizations (Figure 2C) and ER visits (Figure 2D) in the full cohort; in subgroup analyses by lung function category, the association in the GOLD 0 group was attenuated. Associations between OE to dust and fumes and REs was also consistent in subgroup analyses by current smoking status, educational attainment, and baseline dyspnea (Figure S1).
Figure 2.
Forest plots of risk for dichotomized prospective REs by occupational exposure category. (A) Any moderate-to-severe RE vs none. (B) Any moderate-to-severe RE vs none with additional adjustment for history of asthma. (C) Any RE requiring hospitalization vs none. (D) Any RE requiring ER visit vs none. Results of logistic regression models for dichotomized RE-related prospective outcomes. Unless otherwise specified, logistic regression models were adjusted for age, sex (except for subgroup analyses by sex), ancestry, smoking status, pack-years, body mass index, FEV1% predicted (except for subgroup analyses by lung function category), and education. Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease (post-bronchodilator FEV1/FVC <0.70); ER, emergency room; GOLD 0, Global Initiative for Chronic Obstructive Lung Disease stage 0 (FEV1/FVC ≥0.7 and FEV1 ≥80%); OR, odds ratio; PRISm, preserved ratio impaired spirometry (FEV1/FVC ≥0.7 and FEV1 <80%).
Secondary clinical outcomes
Cardiovascular outcomes
OE to dust and fumes was associated with an increased risk of prospective ASCVD (aOR, 1.35 [95% CI, 1.17-1.56]) (Table 3). Subgroup analyses by sex (Table S8), lung function category (Table S9), current smoking status (Table S10), educational attainment (Table S11), and baseline dyspnea (Table S12) were largely consistent with the exception of the PRISm subgroup, where the association between OE to dust and fumes no longer met nominal significance. When we examined the individual components of ASCVD (eg, MI, stroke, CABG, angioplasty/stent placement), OE to dust and fumes was associated with an increased risk of MI and stroke in the full cohort (Table S13); these associations were robust in subgroup analyses by sex. Similar associations were observed in the GOLD 0 and COPD subgroups, however, the PRISm subgroup demonstrated a distinct association pattern with increased risk for CABG, but no increased risk of MI, stroke, or angioplasty/stent in the dust-and-fumes exposure group. Sensitivity analyses excluding participants with a prior history of ASCVD demonstrated similar findings for ASCVD and its subcomponents relative to analyses performed in the full cohort (Table S14).
Table 3.
Associations between secondary prospective clinical outcomes and occupational exposure categories (N = 8991).
| Clinical outcome | No exposure | Dust only | Fumes only | Dust and fumes |
|---|---|---|---|---|
| ASCVDa | Ref | 1.24 [1.02-1.51] | 1.07 [0.88-1.30] | 1.35 [1.17-1.56] |
| P = .033 | P = .488 | P <.001* | ||
| Lung cancerb | Ref | 0.96 [0.72-1.27] | 1.02 [0.78-1.33] | 1.02 [0.83-1.26] |
| P = .801 | P = .875 | P = .826 | ||
| Other cancerb | Ref | 1.02 [0.84-1.24] | 1.06 [0.89-1.26] | 0.94 [0.82-1.08] |
| P = .812 | P = .485 | P = .403 | ||
| VTE/blood clotc | Ref | 1.06 [0.83-1.35] | 1.01 [0.79-1.28] | 1.20 [1.01-1.44] |
| P = .623 | P = .949 | P = .038 | ||
| Pneumonia | Ref | 0.96 [0.77-1.20] | 1.19 [0.97-1.45] | 1.39 [1.19-1.63] |
| P = .737 | P = .093 | P <.001* | ||
| Hip fractured | Ref | 1.06 [0.77-1.43] | 1.07 [0.79-1.43] | 1.24 [0.99-1.56] |
| P = .722 | P = .658 | P = .057 |
Data are shown as odds ratio [95% confidence interval]. All logistic regression models were adjusted for age at enrollment, sex, ancestry, body mass index, current smoking status, pack-years, FEV1% predicted at enrollment, and education with additional covariates noted as follows.
Abbreviations: ASCVD, atherosclerotic cardiovascular disease (defined as any history of myocardial infarction, stroke, coronary artery bypass grafting, angioplasty/stent during prospective follow-up); VTE, venous thromboembolism.
Models additionally adjusted for prior history of ASCVD, diabetes, hypertension, and hyperlipidemia.
Models additionally adjusted for prior history of cancer.
Models additionally adjusted for prior history of cancer and blood clot.
Models additionally adjusted for prior history of osteoporosis.
Denotes P <.00208 (Bonferroni-adjusted threshold) for a primary or secondary outcome analysis.
Pneumonia
OE to dust and fumes was consistently associated with an increased risk of pneumonia in the full cohort (Table 3) and in subgroup analyses by sex, lung function category, smoking status, and educational attainment (Tables S8-S11). OE to dust and fumes was associated with increased pneumonia risk only in the subgroup with less dyspnea (modified Medical Research Council dyspnea scale <2) (Table S12).
Other outcomes
OE to dust and fumes was nominally associated with an increased risk of VTE in the full cohort (Table 3); in subgroup analyses, the association was stronger in females, COPD, people with a current smoking status, and those with lower educational attainment (Tables S8-S11). In post hoc analyses, the association between dust-and-fumes OE and VTE was attenuated after additional adjustment for prospective hip fracture (aOR, 1.16 [95% CI, 0.96-1.39], P = .11); there were no associations between dust-only and fume-only OEs with VTE. There were no significant associations between any OE category and lung cancers or hip fractures. For the outcome of “other cancers,” dust-only exposure was associated with an increased risk in people with a current smoking status and decreased risk in people who formerly smoked (Table S10); the opposite directions of effect likely contributed to the lack of significance in the analysis of the full cohort for this outcome and exposure category. A qualitative representation of the associations between OE categories and all clinical outcomes is shown in Table 4.
Table 4.
Summary of association between occupational exposure categories and clinical outcomes.
| Clinical outcomes | Dust only | Fumes only | Dust and fumes |
|---|---|---|---|
| Moderate-to-severe REs | ⬌ | ⬌ | ⬆ |
| Severe REs | ⬌ | ⬌ | ⬆ |
| Lung cancer | ⬌ | ⬌ | ⬌ |
| Other cancer | ⬌ | ⬌ | ⬌ |
| ASCVD | ⬆ | ⬌ | ⬆ |
| Blood clot | ⬌ | ⬌ | ⬌ |
| Pneumonia | ⬌ | ⬌ | ⬆ |
| Hip fracture | ⬌ | ⬌ | ⬌ |
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; REs, respiratory exacerbations.
Symbols; ⬆ = positive association in main analysis with P <0.05; ⬌ = no association in main analysis.
Interaction and mediation analyses
There was no significant interaction between sex and OE category when a multiplicative interaction term was included in our models (results not shown). To examine the potential role of FEV1 in mediating the effects of OEs on significantly associated respiratory and cardiovascular outcomes examined in our analyses, we performed exploratory mediation analyses using the construct illustrated in the directed acyclic graph in Figure S2B. The associations between OE to dust and fumes and respiratory outcomes, including REs, hospitalization, ER visits, and pneumonia were partially mediated through abnormal FEV1, with evidence of both direct and indirect effects (Table S15). Notably, no evidence of mediation by FEV1 was observed for cardiovascular outcomes. These analyses support that OE to dust and fumes may impact distinct pathways or mechanisms for different clinical outcomes.
Additional exploratory analyses
Additional sensitivity analyses exploring the potential role of FEV1 as a collider in conjunction with other exposures (eg, history of REs prior to enrollment) are shown in Figure S2C and D. Similar associations were observed in respiratory and cardiovascular outcomes when FEV1% predicted was removed from the main model and when a history of exacerbations prior to enrollment was added to the models (Tables S16-S19). To explore the role of longitudinal change in FEV1 on the association between OEs and clinical outcomes, an exploratory analysis was performed on the subset of participants with spirometry data at baseline and 5 years after enrollment. OE to dust and fumes remained robustly associated with prospective respiratory and cardiovascular outcomes with additional adjustment for absolute change in FEV1 between enrollment and 5-year follow-up (Table S20).
Quantitative bias analysis
Quantitative bias analysis of the dichotomized RE phenotype comparing the OE to dust and fumes group with individuals without dual exposure demonstrated a similar direction of effect with a generally increased effect size estimate relative to the unadjusted estimate for a wide range of sensitivities and specificities for both cases and controls (Table S21). All confidence intervals excluded 1.0.
Discussion
Our work supports that self-reported OE to dust and fumes is associated with an increased risk of future respiratory and nonrespiratory clinical outcomes among tobacco-exposed individuals. Our findings extend the previously reported cross-sectional associations between self-reported OE to dust and fumes and increased respiratory symptoms, worse spirometric lung function, and higher prevalence of structural lung disease on chest CT.13 Importantly, the associations with prospective clinical outcomes were robust following adjustment for baseline active smoking status and cumulative cigarette smoke exposure, as well as baseline lung function and relevant comorbid conditions within each analysis (eg, asthma, preexisting ASCVD). Our results remained robust in multiple sensitivity analyses, including exploratory analyses, which suggest that the effect of OE to dust and fumes on respiratory exacerbations may be partially mediated via FEV1 reduction while cardiovascular outcomes were not. These data support that self-reported OEs to dust and fumes are independent risk factors that contribute unique information regarding important clinical outcomes.
Prior studies, including pooled data from multiple investigations, support the association between OEs and a higher prevalence of both airway4,6,8 and parenchymal lung disease.4 Furthermore, an increased risk associated with OE for REs among individuals with established lung disease, such as asthma15,18 and COPD,16 has been reported. Our work is consistent with prior observations and supports that the increased risk for moderate-to-severe and severe REs due to OE to dust and fumes is also relevant in nonobstructed populations such as PRISm and GOLD 0. Similarly, OE to dust and fumes was consistently associated with an increased risk for pneumonia, both in the overall cohort and in all subgroup analyses. These data are consistent with previous reports of increased rates of pneumonia among individuals with OEs.19 Given the significant burden of REs and infectious pneumonia for individuals as well as for healthcare systems, evaluation of OE to dust and fumes may have utility in risk assessments and disease prevention.
An increased risk of cardiovascular disease has also been reported with OEs, though the specific agents (eg, asbestos, silica) and outcomes investigated have been highly variable between studies.21-26 Within the current work, OE to dust and fumes increased the risk of future stroke and MI, as well as the combined endpoint of ASCVD (defined as MI, stroke, angioplasty/stenting, or CABG), but did not increase the risk of reporting a cardiac intervention (angioplasty/stenting and/or CABG). The lack of associations between cardiac interventions and OEs in the full cohort may be attributable to the lower prevalence of these procedures (ranging from 3.1% to 4.7%) given that a substantial proportion of ASCVD may be medically managed. A notable exception was the increased risk for CABG among participants with PRISm who reported OE to dust and fumes. Within the PRISm subgroup, there was paradoxically no increased risk for stroke or MI in any OE category; this may be due to inadequate power due to smaller sample size (relative to the GOLD 0 and COPD subgroups) or the high baseline rate of cardiovascular disease in this subgroup, which may contribute to the inability to detect the incremental effects of OEs.48 The positive association with CABG may be attributable in part to the higher prevalence of diabetes in the PRISm subgroup, since diabetes is both a risk factor for complex coronary artery disease and an indication for CABG. Given the uniqueness of PRISm subgroup, dedicated studies are warranted to further investigate associations between OE and adverse cardiovascular outcomes.
There were no consistent associations between OEs and lung or other cancers within our cohort despite a high prevalence (24.8%) of malignancies reported during follow-up. This is in contrast to previous reports that have linked certain types of VGDF, including asbestos, silica, polycyclic aromatic hydrocarbons, and other substances, to an increased risk of lung and other types of cancer.27-30,33-36 It is notable, however, that certain subtypes of dust, such as wood and cotton dust, are not associated with an increased risk of cancer.31,32,36,37 We acknowledge that the lack of detail regarding the specific type of dust or fume exposure within our self-reported exposure assessment may have limited our ability to detect associations with malignancies.
In our cohort, OEs were not associated with prospective hip fractures. There are several studies demonstrating that exposure to cadmium and air pollution may increase risk of osteoporosis38-40 and a limited number of studies examining the risk of fracture related to cadmium or perfluoroalkyl exposures.41-43 The lack of association is likely due to heterogeneity of exposure agents captured in our self-reported responses. Notably, the increased risk of prospective blood clots within the group with OE to dust and fumes was obviated after adjustment for prospective hip fractures. These data, and prior data demonstrating an association between OE to sedentary behavior and prolonged work hours,49 support that self-reported OE to dust and fumes is not an independent predictor of blood clots. However, we acknowledge that our statistical models may be at risk for collider bias and dedicated studies on OE and venous thromboembolism are warranted.
Within our cohort, OE to both dust and fumes was consistently associated with respiratory and cardiovascular outcomes, while OE to dust only or fumes only demonstrated limited associations. While the lower prevalence of dust-only and fumes-only exposure relative to dust-and-fumes exposure may have resulted in reduced power to detect associations, additional reasons may include greater-than-additive or synergistic risks associated with dual exposure. Additional considerations include the possibility that dual exposure to dust and fumes may be inherent to some occupations or that the intensity of exposures may differ between OE groups.
In summary, we have demonstrated that self-reported OE to both dust and fumes is associated with an increased risk for multiple clinical adverse outcomes, including REs, pneumonia, and cardiovascular disease. Strengths of our study include a large cohort with highly detailed physiological and functional characterization at baseline, an extended duration of follow-up, systematically assessed prospective outcomes, and analyses that included adjustment for multiple confounding variables, including age, sex, current smoking status, and cumulative smoking exposure. Our exploratory and sensitivity analyses support that our findings are robust to additional concerns, such as potential collider bias and model misspecification. Despite these strengths, we acknowledge certain limitations. First, our self-reported OEs did not allow for characterization of specific agents, or the duration, intensity, or timing of the exposures. Second, our clinical outcomes were based on self-reported responses; thus, both the exposure and outcome assessments may be subject to recall, solicitation, and misclassification bias. We assert, however, that this is mitigated by systematic collection of prospective outcomes data and the use of structured questions; our exploratory quantitative bias analyses also support that our results are likely robust. Third, we acknowledge nonrandom missingness in that subjects excluded due to missing OE or outcomes data were younger, more likely to be male, have a current smoking status, and of African American ancestry; survival bias and drop-out bias may exist within our cohort and additional studies in independent cohorts are warranted. Fourth, we acknowledged that we used the GOLD criteria (FEV1/FVC <0.70) to define COPD participants, which might be prone to age and sex bias; age and sex were included as covariates in all models (except sex-stratified analyses) to reduce this potential bias. Finally, our study did not include people who have never smoked or participants with <10 pack-years of exposure and thus generalizability to these populations may be limited. Despite these limitations, we assert that self-reported OEs to dust and fumes through the use of simple, structured questions provides unique and independent information on the future risk for multiple clinically relevant respiratory and cardiovascular outcomes. Future studies with detailed OE data to clarify the nature of the exposures and identify pathological processes underlying the reported associations, as well as studies to explore the utility of these self-reported measures in clinical settings, are warranted.
Supplementary Material
Acknowledgments
The authors would like to thank Dr. Michael H Cho, MD, MPH, for facilitating the statistical coding review. We also would like to thank the COPDGene investigators and participants for their contributions to the project.
Contributor Information
Nutchapon Xanthavanij, Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States.
Riddhi Deshpande, Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, United States.
Junsun Yu, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States.
Nathaniel Marchetti, Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, PA, United States.
Eric Garshick, Pulmonary, Allergy, Sleep and Critical Care Section, VA Boston Healthcare System, West Roxbury, MA, United States; Department of Medicine, Harvard Medical School, Boston, MA, United States.
Paul D Blanc, Division of Occupational, Environmental and Climate Medicine, University of California, San Francisco, San Francisco, CA, United States.
Elizabeth A Regan, Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, National Jewish Health, Denver, CO, United States.
James D Crapo, Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, National Jewish Health, Denver, CO, United States.
Edwin K Silverman, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States.
Emily S Wan, Email: Emily.wan@va.gov, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, United States; Pulmonary, Allergy, Critical Care, & Sleep Section, Minneapolis VA Health Care System, Minneapolis, MN, United States.
Author contributions
N.X. and E.S.W. contributed to the conceptualization, analysis, and primary drafting of the manuscript. R.D., N.M., E.G., P.D.B., E.A.R., J.D.C., and E.K.S. contributed to data acquisition and critical interpretation of the work. E.S.W., E.G., P.D.B., and J.Y. provided statistical and technical support. All authors contributed to critical review and revision of the work and have approved of the current version submitted. N.X. and E.S.W. had full access to the data and assume responsibility for the analyses and results presented.
Supplementary material
Supplementary material is available at American Journal of Respiratory and Critical Care Medicine online.
Conflicts of interest
Please see the ICMJE disclosure forms, which have been provided as supplementary material.
Funding
This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011. The COPDGene study (NCT00608764) has also been supported by the COPD Foundation through contributions made to an industry advisory committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. E.S.W. is supported by funding from the US Department of Veterans Affairs (Merit Awards CX002193 and BX005957). E.K.S. is supported by NIH grants R01 HL152728, P01 HL114501, and R01 HL133135. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sponsors.
Data availability
This article has an online data supplement, which is accessible from the Supplements tab.
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Data Availability Statement
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