Occupational exposures are associated with worse morbidity in patients with COPD Laura M Paulin 1, Gregory B Diette 1,2, Paul D Blanc 3, Nirupama Putcha 1, Mark D Eisner 4, Richard E Kanner 5, Andrew J Belli 1, Stephanie Christenson 6, Donald P Tashkin 7, MeiLan Han 8, R Graham Barr 8, Nadia N Hansel 1,2 for the SPIROMICS Research Group Online Data Supplement
Full Methods: Study population SPIROMICS is a multicenter prospective cohort study aiming to identify new COPD subgroups and intermediate markers of disease progression that predict longterm clinical endpoints of morbidity. The SPIROMICS cohort included smokers with and without COPD. A smaller group of non-smoking controls was recruited into SPIROMICS, although this group was not included in this analysis of smokers. Participants in SPIROMICS with COPD were 40-80 years old with at least a 20 pack-year smoking history, and had a ratio of the post-bronchodilator forced expiratory volume in one second over the forced vital capacity (FEV 1 /FVC) of less than 0.70. Smokers without COPD were within the same age range and had at least a 20 pack year smoking history, a post-bronchodilator FEV 1 /FVC ratio of>0.70 and an FVC greater than the lower limit of normal (E1). Exclusion criteria included a diagnosis of other obstructive lung diseases besides asthma, BMI >40 kg/m 2, history of lung cancer, and diagnosis of unstable cardiovascular disease. The study and additional exclusion criteria have been previously described (E2). The current study is a cross-sectional analysis of baseline data from the first 1075 participants (n=354 smokers without COPD and 721 smokers with COPD) who had complete occupational exposure data available for analysis. At the baseline visit, trained staff collected extensive demographic and clinical data from participants. Smoking history was determined by current smoking status, defined as whether the participant reporting smoking within the last month, and lifetime cumulative pack years of smoking. COPD outcomes Validated questionnaires assessed participants health-related quality of life (HRQOL) using a respiratory-specific HRQOL measure (St. George s Respiratory Questionnaire [SGRQ] total score (E3)) and a generic HRQOL instrument (Short-Form Health Survey [SF-12] physical component scale) (E4)). We also assessed COPD health-related status using the COPD Assessment Test ([CAT] (E5)) and dyspnea using the Modified Medical Research Council Dyspnea Scale ([mmrc] (E6)). Participant- E2
reported COPD exacerbations over twelve months were defined by 1) worsening respiratory symptoms requiring additional antibiotics or steroids, or 2) those requiring health care utilization (HCU) (visit to doctor s office, urgent care facility, emergency room, or hospital); for analytic purposes, they were dichotomized to define yes as any exacerbation over the past 12 months. Each participant performed spirometry, including pre-and post-bronchodilator FEV 1 % predicted according to standard procedures (E1, E7). In addition, the Six Minute Walk Test (6MWT) was performed under supervision of trained clinical staff (E8). Occupational exposure Occupational history was obtained using an interviewer-administered semistructured questionnaire. The longest held job was documented using free text entry, assigned a 2000 Census code by a single reviewer, and if unclear, was reviewed by two separate authors and adjudicated by a third. Risk of occupational exposures based on the longest job census code was determined by a previously published Job Exposure Matrix (JEM) specific for COPD (jobs classified as not exposed, intermediate exposure, or high exposure likelihood) (E9). Self-reported exposure to vapors, gas, dust or fumes (VGDF) has also been used to assess occupational exposure, and has been shown to perform well in comparison to a JEM approach (E10). In SPIROMICS, self-reported occupational exposure was ascertained by the following question: Did this [longest held] job expose you to vapors, gas, dust or fumes? Statistical Analysis We used descriptive statistics to characterize the patient population. Summary statistics were compared using chi-squared tests for proportions, and t-tests or Wilcoxon-Mann-Whitney tests for continuous data, as appropriate. As there were no significant differences in health outcomes between those with intermediate risk of occupational exposures and those with high risk as determined by the JEM (data not shown), intermediate and high exposure groups were combined to create a dichotomous JEM variable (intermediate/high risk of exposure vs. low risk of exposure), as has been done in prior studies (E10). Secondary analyses used E3
participant-reported exposure to VGDF as the metric of occupational exposure. We used multiple logistic regression analysis to determine the association between occupational exposures and the odds of COPD among all smokers. We re-tested this association in analyses stratified by current vs. former smoking status and by cumulative smoking above and below the median value of 45 pack years. In the subset of participants with established COPD, we used multiple linear and logistic regression analyses, as appropriate, to estimate the association between occupational exposure and COPD outcomes. All multivariate models included adjustment for age, race, sex, current smoking within the last month (yes/no), and total pack years as a continuous variable. Consistent with studies assessing occupational exposure on health outcomes (E9, E11, E12, E10, E13), we did not adjust for markers of socio-economic status (SES) in our main model, because this is a marker for, but not the cause of, occupational status and associated exposures, similar to the potential relationship of SES to cigarette smoking (E9). A mediation analysis, including post-bronchodilator FEV 1 % predicted as a covariate in multivariate models, was used to determine whether the effect of occupational exposure on health outcomes was independent of lung function. Similar analyses included the addition of income to the model. Secondary analysis included adjustment for medication use (long-acting inhaled bronchodilators within the last three months, inhaled corticosteroids within in the last three months, or current use of oral corticosteroids). Similarly, the role of comorbidities was assessed using the comorbidity score (a count of the number of comorbidities), a validated tool used to quantify comorbidity burden (E14). Additional analyses were also conducted that defined COPD as FEV 1 /FVC ratio<lower limit of normal (LLN) (E1). Interaction terms were tested to determine whether sex or smoking status (current smoking and pack years) modified the effect of occupational exposures on health outcomes. We further stratified analyses by sex and smoking status (current smoker vs. former smoker and, in a separate stratification, above vs. below median number of smoking pack years) for each of the linear and logistic regression models. All analyses were performed with StataMP statistical software, version 12.1 (StataCorp, College Station, TX). Statistical E4
significance was defined as a p-value of <0.05 for main effects as well as interaction terms. E5
Table E1: Multivariate analyses of effect of occupational exposure (JEM) on COPD health outcomes: Addition of Comorbidity Index Multivariate model * Addition of Comorbidity index to model β 95% CI p β 95% CI p Severity 6MWT distance (m) -26.0-44.4,-7.7 0.006-24.7-42.7, -6.7 0.007 Post bronchodilator FEV 1 % predicted -2.6-6.5, 1.4 0.20-2.8-6.7, 1.1 0.16 mmrc 0.23 0.07, 0.38 0.004 0.22 0.07,0.38 0.005 CAT 1.8 0.6, 3.0 0.003 1.8 0.57, 2.9 0.004 HRQOL SGRQ 4.5 1.5, 7.4 0.003 4.3 1.4, 7.2 0.003 SF-12 Physical -3.3-4.9, -1.6 <0.0001-3.2-4.8, -1.5 <0.0001 Exacerbations OR 95% CI p Requiring HCU 1.53 1.04, 2.25 0.03 1.51 1.02, 2.21 0.04 Requiring Meds 1.24 0.83, 1.84 0.29 1.22 0.82, 1.81 0.33 Definition of abbreviations: JEM=Job Exposure Matrix; SD=Standard deviation; IQR=Interquartile range; 6MWT=Six Minute Walk Test; m=meters; FEV 1 =forced expiratory volume in 1 second; mmrc= Modified Medical Research Council Dyspnea Scale; CAT=COPD Assessment Test; HRQOL=Health related quality of life; SGRQ= St. George s Respiratory Questionnaire; SF-12 Physical= Short-Form Health Survey physical component scale; HCU=health care utilization. * Model adjusted for age, sex, race, current smoking status, pack years smoking Model adjusted for age, sex, race, current smoking status, pack years smoking and Comorbidity Index Table E2: Multivariate analyses of effect of occupational exposure (JEM) on COPD health outcomes: Fixed ratio vs. LLN definition of COPD Multivariate model using FEV/FVC < 0.7 to define COPD * n=721 Multivariate model using FEV/FVC LLN to define COPD * n=595 β 95% CI p β 95% CI p Severity 6MWT distance (m) -26.0-44.4,-7.7 0.006-29.0-49.0, -9.0 0.005 Post bronchodilator FEV 1 % predicted -2.6-6.5, 1.4 0.20 0.16-3.7, 4.0 0.93 mmrc 0.23 0.07, 0.38 0.004 0.16-0.01, 0.33 0.07 CAT 1.8 0.6, 3.0 0.003 1.3 0.2, 2.6 0.05 HRQOL SGRQ 4.5 1.5, 7.4 0.003 3.4 0.3, 6.6 0.03 SF-12 Physical -3.3-4.9, -1.6 <0.0001-2.5-4.4, -0.6 0.008 Exacerbations OR 95% CI P OR 95% CI P Requiring HCU 1.53 1.04, 2.25 0.03 1.34 0.88, 2.05 0.18 Requiring Meds 1.24 0.83, 1.84 0.29 1.03 0.66, 1.59 0.91 Definition of abbreviations: JEM=Job Exposure Matrix; SD=Standard deviation; IQR=Interquartile range; 6MWT=Six Minute Walk Test; m=meters; FEV 1 =forced E6
expiratory volume in 1 second; mmrc= Modified Medical Research Council Dyspnea Scale; CAT=COPD Assessment Test; HRQOL=Health related quality of life; SGRQ= St. George s Respiratory Questionnaire; SF-12 Physical= Short-Form Health Survey physical component scale; HCU=health care utilization. * Model adjusted for age, sex, race, current smoking status, pack years smoking Table E3: Multivariate analyses of effect of occupational exposure (VGDF) on COPD health outcomes Multivariate model * Addition of post-bronchodilator FEV 1 % predicted to model n=721 n=721 β 95% CI p β 95% CI p Severity 6MWT distance (m) -28.0-45.7, -10.2 0.002-20.5-37.2, -3.8 0.02 Post bronchodilator FEV 1 % predicted -5.4-9.2, -1.7 0.005-5.4-9.2, -1.7 0.005 mmrc 0.12-0.03, -0.28 0.12 0.07-0.08, 0.21 0.36 CAT 1.2 0.1, 2.4 0.04 0.6-0.5, 1.8 0.27 HRQOL SGRQ 2.7-0.2, 5.6 0.06 1.7-0.9, 4.3 0.20 SF-12 Physical -2.0-3.7, -0.4 0.02-1.5-3.0, 0.1 0.07 Exacerbations OR 95% CI p OR 95% CI p Requiring HCU 1.37 0.94, 1.99 0.10 1.31 0.88, 1.96 0.19 Requiring Meds 1.47 1.00, 2.16 0.05 1.34 0.89, 2.03 0.16 Definition of abbreviations: VGDF=self-report exposure to vapors, gas, dust and fumes; 6MWT=Six Minute Walk Test; m=meters; FEV 1 =forced expiratory volume in 1 second; mmrc= Modified Medical Research Council Dyspnea Scale; CAT=COPD Assessment Test; HRQOL=Health related quality of life; SGRQ= St. George s Respiratory Questionnaire; SF-12 Physical= Short-Form Health Survey physical component scale; HCU=health care utilization. * Model adjusted for age, sex, race, current smoking status, pack years smoking history Model adjusted for age, sex, race, current smoking status, pack years smoking and post bronchodilator FEV 1 % predicted. Post-bronchodilator FEV 1 % predicted not included in model predicting lung function. E7
Online Data Supplement References E1. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999; 159: 179-187. E2. Couper D, Lavange LM, Han M, Barr RG, Bleecker E, Hoffman EA, Kanner R, Kleerup E, Martinez FJ, Woodruff PG, Rennard S, for the SRG. Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax 2014; 69: 491-4. E3. Barr JT, Schumacher GE, Freeman S, LeMoine M, Bakst AW, Jones PW. American translation, modification, and validation of the St. George's Respiratory Questionnaire. Clin Ther 2000; 22: 1121-1145. E4. Ware J, Jr., Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Medical care 1996; 34: 220-233. E5. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J 2009; 34: 648. E6. Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 581-586. E7. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005; 26: 319-338. E8. ATS Statement: Guidelines for the Six-Minute Walk Test. Am J Respir Crit Care Med 2002; 166: 111-117. E9. Trupin L, Earnest G, San Pedro M, Balmes JR, Eisner MD, Yelin E, Katz PP, Blanc PD. The occupational burden of chronic obstructive pulmonary disease. Eur Respir J 2003; 22: 462-9. E10. Blanc PD, Eisner MD, Balmes JR, Trupin L, Yelin EH, Katz PP. Exposure to vapors, gas, dust, or fumes: assessment by a single survey item compared to a detailed exposure battery and a job exposure matrix. Am J Ind Med 2005; 48: 110. E11. Harber P, Tashkin DP, Simmons M, Crawford L, Hnizdo E, Connett J, Lung Health Study G. Effect of occupational exposures on decline of lung function in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 176: 994-1000. E8
E12. Rodriguez E, Ferrer J, Marti S, Zock JP, Plana E, Morell F. Impact of occupational exposure on severity of COPD. Chest 2008; 134: 1237-43. E13. Blanc PD, Eisner MD, Earnest G, Trupin L, Balmes JR, Yelin EH, Gregorich SE, Katz PP. Further exploration of the links between occupational exposure and chronic obstructive pulmonary disease. J Occup Env Med 2009; 51: 804. E14. Putcha N PM, Drummond MB, Han MK, Regan EA, Hanania NA, Martinez C, Bhatt SP, Make B, Ramsdell J, Demeo D, Foreman M, Barr RG, Rennard SI, Martinez F, Silverman EK, Crapo J, Wise RA, Hansel NN. A simplified score to quantify comorbidity in COPD. PloS one 2014; In press. E9