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The Effects of Pleural Plaques on Longitudinal Lung Function in Vermiculite Miners of Libby, Montana

Open AccessPublished:April 25, 2017DOI:https://doi.org/10.1016/j.amjms.2017.03.033

      Abstract

      Background

      This study was conducted to assess associations of pleural plaques (PP) and longitudinal lung function in vermiculite miners of Libby, Montana who are occupationally exposed to asbestos. High-resolution computed tomography (HRCT) was used to identify asbestos-related findings in former Libby vermiculite miners. We investigated annual lung function decline in miners with PP only and compared them to miners with normal HRCT findings.

      Materials and Methods

      HRCTs from 128 miners were categorized into the following 4 diagnostic groups: (1) normal computed tomography scan (n = 9); (2) PP only (n = 72); (3) PP and interstitial fibrosis (n = 26) and (4) additional HRCT abnormalities (n = 21) such as rounded atelectasis, diffuse pleural thickening, pleural effusions or pulmonary nodules or tumor >1 cm in diameter. Random intercept and slope linear mixed-effect regression models identified differences in lung function decline between miners with asbestos-associated outcomes and those with normal HRCT. Models were adjusted for follow-up time, body mass index, smoking status, latent exposure period and employment years. Interactions for smoking status with age and smoking status with pleural plaque severity were examined.

      Results

      Miners with PP only did not have an accelerated decline in lung function between 40 and 80 years. Miners with PP and additional HRCT abnormalities displayed significantly accelerated declines in forced expiratory volume in 1 second and diffusing capacity of the lungs for carbon monoxide (P = 0.05 and P < 0.01, respectively). Plaque severity did not affect lung function decline. However, smokers with extensive plaques displayed accelerated loss in diffusing capacity of the lungs for carbon monoxide and forced expiratory volume in 1 second when compared to nonsmoking miners with mild plaque formation.

      Conclusions

      PP alone did not significantly affect lung function decline in vermiculite miners of Libby, Montana.

      Key Indexing Terms

      Introduction

      Pleural plaques (PP) are the most common noncancerous finding in workers exposed to asbestos.
      American Thoracic Society.
      Diagnosis and initial management of nonmalignant diseases related to asbestos.
      PP are sharply circumscribed, rounded, smooth white nodules composed of bands of interwoven collagen. They normally occur along the posterior parietal pleura but can also be distributed along the surfaces of the diaphragm and pericardium.
      • Roggli V.L.
      • Greenberg S.D.
      • Pratt P.C.
      Pathology of Asbestos-Associated Diseases, 733.
      Single plaques may be present, but bilateral plaques are more common.
      American Thoracic Society.
      Diagnosis and initial management of nonmalignant diseases related to asbestos.
      • Gottschall E.B.
      • Newman L.S.
      • Musk A.W.
      • de Klerk N.H.
      PP may enlarge and become calcified over time. A 20-year latent period usually exists between the time of first asbestos exposure and PP development.
      American Thoracic Society.
      Diagnosis and initial management of nonmalignant diseases related to asbestos.
      However, a recent retrospective review observed that vermiculite miners from Libby, Montana displayed subtle pleural abnormalities within a shorter latency period (mean = 8.6 years; range: 1.4-14.7 years).
      • Larson T.C.
      • Meyer C.A.
      • Kapil V.
      • et al.
      Workers with Libby amphibole exposure: retrospective identification and progression of radiographic changes.
      PP are usually detected incidentally through chest radiography, conventional computed tomography (CT) or high-resolution computed tomography (HRCT).
      • Gottschall E.B.
      • Newman L.S.
      Chest radiographies may display high diagnostic sensitivity for the detection of PP (~96%), but positive predictive value is low (56-79%), as subpleural fat deposits are commonly misinterpreted as PP.
      • Friedman A.C.
      • Fiel S.B.
      • Fisher M.S.
      • et al.
      Asbestos-related pleural disease and asbestosis: a comparison of CT and chest radiography.
      HRCT provides both high sensitivity and positive predictive value (96% and 100%, respectively).
      • Friedman A.C.
      • Fiel S.B.
      • Fisher M.S.
      • et al.
      Asbestos-related pleural disease and asbestosis: a comparison of CT and chest radiography.
      Therefore, HRCT is most useful for eliminating false-positive diagnoses of PP, such as those caused by subpleural fat deposits.
      • Friedman A.C.
      • Fiel S.B.
      • Fisher M.S.
      • et al.
      Asbestos-related pleural disease and asbestosis: a comparison of CT and chest radiography.
      In 2004, an American Thoracic Society (ATS) document recognized PP as definitive markers of asbestos exposure, but concluded that they were not associated with significant loss in lung function.
      American Thoracic Society.
      Diagnosis and initial management of nonmalignant diseases related to asbestos.
      The document noted that some studies reported an approximately 5% reduction in forced vital capacity (FVC) or mildly diminished diffusion capacity among individuals with PP, but that most individuals maintained well preserved lung function. Furthermore, the document stated that recent longitudinal studies did not observe accelerated decline in those with PP only.
      American Thoracic Society.
      Diagnosis and initial management of nonmalignant diseases related to asbestos.
      Nevertheless, the effects of PP on lung function remain controversial. Two recently published systematic reviews arrived at opposite conclusions regarding the effects of PP on lung function.
      • Kerper L.E.
      • Lynch H.N.
      • Zu K.
      • et al.
      Systematic review of pleural plaques and lung function.
      • Kopylev L.
      • Christensen K.Y.
      • Brown J.S.
      • et al.
      A systematic review of the association between pleural plaques and changes in lung function.
      Both agreed that well-designed studies using longitudinal data were superior to cross-sectional studies. However, only 3 HRCT-based longitudinal studies were included in the systematic reviews.
      • Rui F.
      • De Zotti R.
      • Negro C.
      • et al.
      A follow-up study of lung function among ex-asbestos workers with and without pleural plaques.
      • Damian A.
      • Rui F.
      • De Zotti R.
      Respiratory function and smoking habit among shipyard and dock workers.
      • Schwartz D.A.
      • Galvin J.R.
      • Yagla S.J.
      • et al.
      Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach.
      Here, we perform a retrospective longitudinal analysis from serial pulmonary function test (PFT) records of miners who were occupationally exposed to Libby amphibole asbestos (LAA). The vermiculite mine was located 6 miles northeast of Libby, Montana. Libby is a town of approximately 2,600 people, located 40 miles south of the Canadian border and 20 miles east of the Idaho panhandle. In 1963, W.R. Grace & Company purchased the mine. The vermiculite was found to be contaminated with LAA, and in 1990 the mine was closed. LAA is composed of winchite (80%), richterite (12%), tremolite (6%) and other asbestiform minerals (2%).
      • Meeker G.P.
      • Bern A.M.
      • Brownfield I.K.
      • et al.
      The composition and morphology of amphiboles from the Rainy Creek complex, near Libby, Montana.
      In 2014, we published a cross-sectional analysis from this cohort. In it, we found no significant differences in mean lung function for miners with PP only when compared to miners with normal HRCT.
      • Clark K.A.
      • Jay Flynn III, J.
      • Goodman J.E.
      • et al.
      Pleural plaques and their effect on lung function in Libby vermiculite miners.
      For the current analysis, our primary goal is to investigate longitudinal lung function decline among LAA-exposed miners with PP only, when compared to miners with LAA exposure but normal HRCT scans. We also investigated longitudinal decline based on severity of plaque formation. Preliminary results of this study have been previously reported as a conference abstract.
      • Clark K.A.
      • Flynn J.J.
      • Karmaus W.J.
      • et al.
      The effect of pleural plaques on longitudinal lung function in Libby vermiculite miners.

      Methods

      Study Population

      All miner medical records were de-identified prior to investigation. The University of South Carolina Institutional Review Board approved the study protocol (ID#:Pro00020158) prior to medical record examination.
      Analysis was conducted from a convenience sample of former Libby vermiculite miners who applied or were enrolled in the Libby Medical Program (LMP) between April 2000 and September 2012. This program was established for W.R. Grace & Company employees, their household contacts, and residents of Libby, with identified asbestos-related abnormalities. We examined the medical records from miners who were occupationally exposed to LAA, and thus, had higher exposure than those with household or environmental exposures.
      • Peipins L.A.
      • Lewin M.
      • Campolucci S.
      • et al.
      Radiographic abnormalities and exposure to asbestos-contaminated vermiculite in the community of Libby, Montana, USA.
      • Larson T.C.
      • Ge M.
      • Antao V.C.
      Factors associated with the incidence of asbestos-related pleural abnormalities during nine years of screening in Libby, Montana.

      Inclusion Criteria

      To be included in this analysis, miners underwent 1 HRCT scan that had been peer reviewed by a board-certified university-based thoracic radiologist. At least 2 serial PFTs inclusive of spirometry, lung volumes via plethysmography, and carbon monoxide lung diffusion capacity (DLCO) were also needed. A minimal 3-year follow-up was required between each miners’ first and last PFT. Furthermore, at least 1 PFT needed to be performed within 3 years of the HRCT.

      HRCT Peer Review

      The LMP received 2 independent readings of the HRCTs that were done locally in Libby. When disagreement occurred between the readers, the HRCT scans were sent for independent peer review to resolve the differences.

      HRCT Classification

      HRCT results were used for miner group assignment. Miners were assigned to 1 of the following 4 groups: normal CT scan (NCTS), pleural plaques only (PPO), pleural plaques and interstitial fibrosis (PPIF) or other CT abnormalities (OCTA). The OCTA group contained miners with rounded atelectasis, diffuse pleural thickening, pleural effusions, or pulmonary nodules or tumors >1 cm in diameter. Diffuse pleural thickening was considered to be distinctly different from PP and defined as homogenous pleural thickening extending along the lateral chest wall over multiple rib interspaces and included “blunting” of the corresponding costophrenic angle.
      • Lockey J.E.
      • Dunning K.
      • Hilbert T.J.
      • et al.
      HRCT/CT and associated spirometric effects of low Libby amphibole asbestos exposure.
      For PPO miners, the severity of PP was divided into the following 3 categories: (1) mild (single, unilateral or sparsely distributed plaques), (2) moderate (bilateral plaques) and (3) extensive (bilateral, calcified and widely distributed plaques).

      Pulmonary Function

      PFTs were performed between January 1988 and September 2012, in accordance with the American Thoracic Society (ATS)/European Respiratory Society guidelines.
      ATS/ERS Task Force.
      Standardisation of spirometry.
      ATS/ERS Task Force.
      Standardization of the single-breath determination of carbon monoxide uptake in the lung.
      ATS/ERS Task Force.
      Standardization of the measurement of lung volumes.
      Outcome variables examined were as follows: FVC (FVC percent predicted), forced expiratory volume in 1 second (FEV1 percent predicted), total lung capacity (TLC percent predicted) and DLCO (DLCO percent predicted). Percent predicted values were determined using ATS suggested or validated reference equations.
      ATS Official Statement.
      Lung function testing: selection of reference values and interpretative strategies.
      • Hankinson J.L.
      • Odencrantz J.R.
      • Fedan K.B.
      Spirometric reference values from a sample of the general U.S. Population.
      • Crapo R.O.
      • Morris A.H.
      • Clayton P.D.
      • et al.
      Lung volumes in healthy nonsmoking adults.
      • Goldman H.I.
      • Becklake M.R.
      Respiratory function tests: normal values at median altitudes and the prediction of normal results.
      ATS/ERS Task Force.
      Interpretative strategies for lung function tests.

      Statistical Analysis

      Repeated measures regression analysis was performed to determine intercept and slope differences between HRCT groups using random intercept and slope linear mixed models (LMM).
      • Vonesh E.F.
      Generalized Linear and Nonlinear Models for Correlated Data: Theory and Applications Using SAS.
      • Hopper J.L.
      • Hibbert M.E.
      • Macaskill G.T.
      • et al.
      Longitudinal analysis of lung function growth in healthy children and adolescents.
      PPO, PPIF and OCTA miner groups were compared to NCTS miners. Age was nested within each miner group for slope analyses and centered at 40 years. Inferences were made based on the estimated slope between 40 and 80 years. Fixed effects considered were smoking status at the time of initial follow-up (heavy ≥15 pack-years; mild <15 pack-years and never smoker), body mass index (BMI), time since first occupational asbestos exposure to HRCT (years) and years of employment. For the PPO group, we also performed a random coefficients analysis to identify plaque severity association with decline in lung function. We considered statistical significance to be at α ≤ 0.05 for fixed effects and α ≤ 0.10 for interaction terms. Manuscript statistical procedures and results were also independently, professionally reviewed before submission (Analysis Factor, Ithaca, NY). SAS 9.3 was used for all analyses (SAS Institute, Cary, NC).
      Pearson correlations were determined for the predictor variables before their inclusion into regression models (data not shown). Additionally, for each outcome parameter, an alternative random resampling with replacement was performed to increase the size of the NCTS reference group. We sought to artificially increase each models’ ability to detect potential miner group differences by increasing the sample size of the NCTS control group. Results from the original random coefficient models were then compared to their respective bootstrap models.

      Results

      Between January 1988 and September 2012, 179 Libby vermiculite miners underwent HRCT (Figure 1). Most of them (n = 152) performed at least 2 complete PFTs. However, only 128 (71.5%) performed their first and last PFT at least 3 years apart. On average, miners performed 6 PFTs (total = 767 PFTs) during an average 7.1 year follow-up period (Table 1). More than 92% of miners (n = 118) performed at least 3 PFTs (data not shown).
      FIGURE 1
      FIGURE 1Flow diagram for Libby Medical Program miner selection into analytical dataset. HRCT, high-resolution computed tomography; PFT, pulmonary function test.
      TABLE 1Characteristics of Libby vermiculite miners based on HRCT groups (n = 128).
      TotalPPOPPIFOCTANCTS
      Mean (std)Mean (std)Mean (std)Mean (std)Mean (std)
      n = 128n = 72n = 26n = 21n = 9
      Number of PFTs6.1 (2.2)6.0 (2.1)5.4 (1.8)6.1 (3.1)
      Follow-up (years)7.1 (2.5)7.2 (2.2)7.5 (3.2)6.3 (2.4)6.7 (2.3)
      Latent period (years)37.1 (7.8)35.4 (7.1)40.1 (7.4)41.5 (8.5)31.6 (4.7)
      Employment (years)6.7 (7.9)5.6 (6.7)7.1 (8.8)10.5 (10.2)5.5 (7.2)
      Age (years)
       At entry56.7 (9.7)54.6 (9.1)59.3 (9.7)60.7 (8.9)57.1 (20.4)
       At follow-up66.4 (8.3)64.5 (8.1)69.4 (7.5)69.3 (7.8)66.4 (10.8)
      Height (cm)
       At entry175.5 (6.8)175.3 (6.9)174.7 (5.9)176.0 (7.3)178.2 (7.5)
       At follow-up174.6 (6.6)174.4 (6.8)173.5 (6.0)174.8 (6.5)178.4 (6.2)
      Weight (kg)
       At entry91.0 (16.6)90.2 (16.8)94.1 (16.7)85.4 (12.6)100.8 (18.7)
       At follow-up91.6 (19.1)91.4 (17.1)94.3 (26.7)86.5 (12.7)97.3 (21.4)
      BMI (kg/m2)
       At entry29.7 (5.0)29.5 (5.1)31.0 (5.6)27.8 (3.5)31.6 (4.0)
       Follow-up30.3 (5.4)30.1 (5.1)32.7 (7.0)28.2 (3.0)30.3 (5.0)
      Smoker (pack-years)
       At entry30.5 (18.8)28.2 (16.7)31.3 (20.0)33.9 (22.6)36.8 (20.4)
      n (%)n (%)n (%)n (%)n (%)
      Smokers86 (67.1)45 (62.5)19 (73.1)18 (85.7)4 (44.4)
      Smoking groups
       ≥15 (ppm-years)64 (50.0)34 (47.2)15 (57.7)12 (57.1)3 (33.3)
       <15 (ppm-years)22 (17.2)11 (15.3)4 (15.4)6 (28.6)1 (11.1)
       None42 (32.9)27 (37.5)7 (26.9)3 (14.3)5 (55.6)
      PPO, pleural plaques only; PPIF, pleural plaques and interstitial fibrosis; OCTA, other computed tomography abnormalities; NCTS, normal computed tomography scan; PFT, pulmonary function test.
      All miners were adult, white, males, whose average age at first PFT was 56.7 years (Table 1). Mean latency period between first LAA occupational exposure and HRCT was 37.1 years (range: 19.6-62.2 years). Mean employment tenure was 6.7 years (range: 3 days-32.3 years) (Table 1). More than 67% (n = 86) were either current or former smokers with an average pack-year history of 30.5 years at first PFT (Table 1). Average BMI was 29.7 kg/m2, with 47% (n = 60) being obese (i.e., ≥ 30 kg/m2) at the start of the follow-up (Table 1).
      HRCT group classification yielded 72 PPO (56.2%), 26 PPIF (20.3%), 21 OCTA (16.4%) and 9 NCTS miners (7.0%) (Table 1). Statistically significant group differences were seen for mean age (P < 0.001) and latency period (P = 0.05) at first PFT (data not shown). On average, PPO group miners were the youngest, and OCTA group miners the oldest (P = 0.001). OCTA miners also had the longest latency period since first LAA exposure and were employed longer than other groups (Table 1).
      LMM identified both intercept and slope differences when evaluating PFTs for the various miner groups compared to the NCTS group. At intercept, PPO group percent predicted estimates were slightly lower than the NCTS miner group, but these differences were not statistically significant (Table 2). In addition, at 60 and 80 years, PPIF miners exhibited mean DLCO percent predicted levels statistically lower than NCTS miners (Table 2). OCTA miner FEV1, FVC and DLCO percent predicted estimates were significantly lower at 60 and 80 years when compared to the NCTS miner group (Table 2). Overall, OCTA miners had the greatest reduction in unadjusted mean FEV1, FVC and TLC percent predicted from 40-80 years of age (Table 2).
      TABLE 2Adjusted FEV1, FVC, TLC and DLCO percent predicted means at 40, 60 and 80 years with comparison to NCTS miner group. Tukey adjustment was made for multiple comparisons (significant at 0.05) within each model. Predictor variables included: age at first PFT, years of follow-up, smoking (≥15 ppm-years, <15 ppm-years and none). BMI, years of employment and years since last occupational exposure to LAA. NHANESIII percent predicted prediction equations adjusted for age, sex and height. Least square means (LS mean) were estimated from an age-adjusted regression models.
      PPOPPIFOCTANCTSNCTS vs.
      LS mean (SE)LS mean (SE)LS mean (SE)LS mean (SE)PPOPPIFOCTA
      n = 72n = 26n = 21n = 9P valueP valueP value
      FEV1
       At 40 years95.6 (3.5)94.4 (6.0)98.9 (7.2)99.3 (9.90.720.670.97
       At 60 years87.1 (2.1)83.6 (3.5)76.0 (4.0)93.1 (5.9)0.330.170.02
      Indicates statistical significance at alpha = 0.05.
       At 80 years78.6 (3.6)72.7 (5.6)53.2 (6.6)87.0 (9.8)0.420.210.004
      Indicates statistical significance at alpha = 0.05.
       % change−17.0−21.7−45.7−12.3
      FVC
       At 40 years98.5 (2.9)98.2 (4.9)97.8 (6.0)103.6 (7.9)0.530.560.55
       At 60 years87.9 (1.8)86.4 (3.0)81.7 (3.5)94.0 (5.1)0.250.200.05
      Indicates statistical significance at alpha = 0.05.
       At 80 years77.3 (3.2)74.5 (4.9)65.6 (5.8)84.4 (8.6)0.430.310.07
       % change−21.2−23.7−32.2−19.2
      DLCO
       At 40 years108.1 (3.4)101.4 (5.7)110.7 (7.0)106.6 (8.0)0.850.580.69
       At 60 years91.7 (1.9)83.0 (3.1)79.5 (3.6)98.9 (5.2)0.180.008
      Indicates statistical significance at alpha = 0.05.
      0.002
      Indicates statistical significance at alpha = 0.05.
       At 80 years75.3 (4.2)64.6 (6.3)48.3 (7.3)91.3 (10.9)0.170.03
      Indicates statistical significance at alpha = 0.05.
      0.001
      Indicates statistical significance at alpha = 0.05.
       % change−32.8−36.8−62.4−15.3
      TLC
       At 40 years105.1 (2.6)102.0 (4.5)109.9 (5.6)108.8 (7.0)0.620.420.90
       At 60 years96.5 (1.7)89.2 (2.8)90.0 (3.2)97.5 (4.7)0.830.130.20
       At 80 years87.8 (2.9)76.5 (4.5)70.1 (5.3)86.2 (7.9)0.850.280.09
       % change−17.3−25.5−39.8−22.6
      FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; DLCO, carbon monoxide lung diffusion capacity; NCTS, normal computed tomography scan; PFT, pulmonary function test; BMI, body mass index; LAA, Libby amphibole asbestos; NHANESIII, The Third National Health and Nutrition Examination Survey; PPO, pleural plaques only; PPIF, pleural plaques and interstitial fibrosis; OCTA, other computed tomography abnormalities; LS, least square; SE, standard error of mean.
      low asterisk Indicates statistical significance at alpha = 0.05.
      No significant differences were observed in the annual rate of decline for FEV1, FVC, DLCO or TLC between PPO miners and NCTS miners between 40 and 80 years (Table 3 and Figure 2). Nor were there any significant outcome differences between the original and bootstrapped models for each outcome measure (data not shown). We did observe a significant accelerated rate of annual decline in OCTA miners when compared to NCTS miners (Figure 2 and Table 3) for both DLCO and FEV1. On average, the OCTA group experienced over a 1% per year greater reduction in FEV1 percent predicted when compared to NCTS miners (P = 0.05, Table 3). Accelerated annual declines were also seen in DLCO for the OCTA group when compared to NCTS miners (−2.1% versus −0.7% per year, P < 0.01) (Table 3 and Figure 2).
      TABLE 3Results for mixed effects analysis for FEV1, FVC, DLCO and TLC (percent predicted) longitudinal decline. PPO, PPIF, and OCTA miner groups are each compared to Libby miners with normal HRCT (NCTS) (n = 128).
      FEV1 percent predicted fixed effects (%)DLCO percent predicted fixed effects (%)FVC percent predicted fixed effects (%)TLC percent predicted fixed effects (%)
      EstimateSEP valueEstimateSEP valueEstimateSEP valueEstimateSEP value
      Intercept112.218.1<0.0173.812.6<0.01116.8.315.5<0.01102.010.9<0.01
      Smoker
       Mild <15 (ppm-years)−3.64.60.445.73.80.130.73.90.851.93.60.60
       Heavy >15 (ppm-years)−10.13.5<0.01
      Fixed effect: statistically significant at α ≤ 0.05.
      −12.82.9<0.01
      Fixed effect: statistically significant at α ≤ 0.05.
      −2.83.00.343.62.70.20
       NoneRefRefRefRefRefRefRefRefRefRefRefRef
      BMI (kg/m2)−0.80.2<0.01
      Fixed effect: statistically significant at α ≤ 0.05.
      0.20.20.32−0.80.1<0.01
      Fixed effect: statistically significant at α ≤ 0.05.
      −0.20.10.09
      Latent years−0.00.20.110.40.20.04
      Fixed effect: statistically significant at α ≤ 0.05.
      0.30.20.0940.40.20.04
      Fixed effect: statistically significant at α ≤ 0.05.
      Years exposure−0.10.20.630.20.20.360.00.20.89−0.00.20.78
      Follow-up (years)0.20.60.751.00.5<0.06−0.40.60.52−0.40.50.36
      ARPD group
      PPO, pleural plaques only (n = 72); PPIF, pleural plaques with interstitial fibrosis (n = 26); OCTA, other CT abnormalities (n = 21); NCTS, normal CT scan (n = 9).
       PPO−4.110.30.683.37.80.67−5.08.20.54−3.57.30.62
       PPIF−3.911.50.73−2.79.20.77−4.49.10.63−5.78.30.49
       OCTA0.2412.20.985.710.00.57−5.39.80.581.69.00.85
       NCTSRefRefRefRefRefRefRefRefRefRefRefRef
      Yearly decline (%/years)
       PPO−0.40.40.65−0.70.40.16−0.40.30.730.10.30.82
       PPIF−0.50.50.47−0.80.50.13−0.50.40.60−0.20.30.64
       OCTA−1.10.50.05
      Interaction: Statistically significant at α ≤ 0.10.
      −1.40.5<0.01
      Interaction: Statistically significant at α ≤ 0.10.
      −0.70.40.32−0.50.40.16
       NCTS−0.20.4Ref−0.10.41Ref−0.30.3Ref−0.40.3Ref
      Residual (SSEModel)4414543521
      Intercept SSE354490266224
      R20.870.710.840.77
      Bold text indicates significant values.FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; DLCO, carbon monoxide lung diffusion capacity; NCTS, normal computed tomography scan; PFT, pulmonary function test; BMI, body mass index; LAA, Libby amphibole asbestos; NHANESIII, The Third National Health and Nutrition Examination Survey; PPO, pleural plaques only; PPIF, pleural plaques and interstitial fibrosis; OCTA, other computed tomography abnormalities; LS, least square; SE, standard error of the mean; ARPD, asbestos related pleural disease; SSE, sum of squares errors of prediction.
      low asterisk Fixed effect: statistically significant at α ≤ 0.05.
      low asterisklow asterisk Interaction: Statistically significant at α ≤ 0.10.
      a PPO, pleural plaques only (n = 72); PPIF, pleural plaques with interstitial fibrosis (n = 26); OCTA, other CT abnormalities (n = 21); NCTS, normal CT scan (n = 9).
      FIGURE 2
      FIGURE 2Longitudinal declines in FEV1, FVC, DLCO and TLC percent predicted values based on HRCT group classifications. Shading represents PPO and NCTS miner group with 90% confidence bands. PPO, pleural plaques only (n = 72); PPIF, pleural plaques with interstitial fibrosis (n = 26); OCTA, other CT abnormality (n = 21); NCTS, normal CT findings (n = 9).
      Other factors also independently contributed to changes in lung function within the miner groups. Smoking status affected both FEV1 and DLCO percent predicted values. Heavy smokers had, on average, FEV1 percent predicted value 10% lower than nonsmokers. Heavy smokers also had an average DLCO percent predicted value 12% lower than nonsmokers (Table 3, P < 0.001). BMI significantly contributed to average reductions in FEV1 and FVC (P < 0.01 and P < 0.01, respectively). On average, the longer the time between first occupational asbestos exposure and first PFT, the greater their DLCO and TLC percent predicted values (Table 3). For each model, much of the variance was explained by the predictor variables as R2 = 0.87, 0.71, 0.84 and 0.77 for FEV1, DLCO, FVC and TLC, respectively (Table 3).

      PPO Group Plaque Severity

      Within the PPO miner group (n = 72), LMM analysis revealed that plaque severity alone did not significantly contribute to lung function changes over time (Table 4). Here, 11 miners had extensive (15%), 44 had moderate (61%) and 17 had minimal (24%) PP as determined by 1 of 3 board-certified thoracic radiologists (Table 4).
      TABLE 4PPO
      Pleural plaques only (n = 72).
      miner group mixed effects results for lung function parameters based on plaque severity (n = 72).
      FEV1 percent predicted fixed effects (%)DLCO percent predicted fixed effects (%)FVC percent predicted fixed effects (%)TLC percent predicted fixed effects (%)
      EstimateSEP valueEstimateSEP valueEstimateSEP valueEstimateSEP value
      Intercept93.717.2<0.0167.213.9<0.01106.914.2<0.01109.013.1<0.01
      Years of follow-up0.21.00.801.50.70.04
      Fixed effect: statistically significant at α ≤ 0.05.
      0.30.80.720.10.70.0.90
      Latent years0.40.30.170.20.30.540.10.20.70
      Smoker (n = 42)7.310.5.00.4813.18.60.132.18.60.81−1.28.00.88
      BMI−0.70.2<0.01
      Fixed effect: statistically significant at α ≤ 0.05.
      0.40.20.12−0.80.2<0.01
      Fixed effect: statistically significant at α ≤ 0.05.
      −0.40.20.03
      Fixed effect: statistically significant at α ≤ 0.05.
      Plaque severity
       Extensive (n = 11)13.512.40.285.09.50.606.78.10.412.77.60.72
       Moderate (n = 44)14.110.40.164.47.80.586.29.90.532.59.30.72
       Minimal (n = 17)RefRefRefRef
      Severity × annual decline
       Extensive−0.10.40.73−0.10.50.98−0.30.30.72−0.10.20.55
       Moderate0.21.00.22−0.10.40.84−0.10.30.840.10.30.67
       Minimal−0.10.3Ref−0.40.4Ref−0.10.3Ref−0.30.2Ref
      Smoking × plaque severity
       Smoker
      Fixed effect: statistically significant at α ≤ 0.05.
      extensive plaques
      −25.714.10.07
      Interaction: statistically significant at α ≤ 0.10.
      −21.010.80.05
      Interaction: statistically significant at α ≤ 0.10.
      −17.111.70.14−6.910.80.52
       Smoker
      Fixed effect: statistically significant at α ≤ 0.05.
      moderate plaques
      −9.910.70.35−16.48.20.05
      Interaction: statistically significant at α ≤ 0.10.
      −2.68.80.77−0.68.20.94
       Smoker
      Fixed effect: statistically significant at α ≤ 0.05.
      minimal plaques
      RefRefRefRef
      Smoking × annual decline
       Smoker−0.40.30.14−0.60.30.06
      Interaction: statistically significant at α ≤ 0.10.
      −0.20.20.350.10.20.47
       NonsmokerRefRefRefRef
      FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; TLC, total lung capacity; DLCO, carbon monoxide lung diffusion capacity; BMI, body mass index; PPO, pleural plaques only; SE, standard error of the mean.
      low asterisk Fixed effect: statistically significant at α ≤ 0.05.
      low asterisklow asterisk Interaction: statistically significant at α ≤ 0.10.
      a Pleural plaques only (n = 72).
      At baseline, 58% of PPO miners reported being current or former smokers (Table 4). PPO miners with a history of smoking showed steeper annual DLCO percent predicted declines when compared to nonsmoking PPO miners (−0.6% per year greater, P = 0.06, Table 4). In addition, extensive plaque severity further reduced FEV1 percent predicted and DLCO percent predicted levels when miners were smokers (P = 0.07 and P = 0.05, respectively). On average, PPO smokers with extensive plaques had mean DLCO percent predicted values 21% lower (P = 0.04) and FEV1 percent predicted values 26% lower than nonsmoking PPO miners with minimal plaque formation (P = 0.07, Table 4). Smokers with moderate plaque formation had mean DLCO percent predicted values 16% lower than nonsmoking PPO miners with minimal plaque formation (P = 0.05, Table 4). BMI also independently contributed to reductions in FEV1, FVC and TLC percent predicted outcomes within the PPO group (Table 4).

      Discussion

      Our analysis suggested that PP alone did not significantly affect lung function decline in the Libby vermiculite miner cohort. Specifically, mean FEV1, FVC, DLCO and TLC percent predicted estimates and rates of decline were not statistically different between PPO and NCTS miner groups. Yet, the OCTA group did show significantly steeper annual decline for FEV1 and DLCO percent predicted values when compared to NCTS miners (Table 3 and Figure 1). Confidence intervals were also much wider for the OCTA group than were PPO group confidence intervals (Table 3). Thus, we believe that our analyses had the ability to detect statistically significant differences in lung function between PPO and NCTS miner groups.
      Recent systematic reviews suggest that longitudinal rather than cross-sectional studies are preferred when assessing the effect of PP on lung function.
      • Kerper L.E.
      • Lynch H.N.
      • Zu K.
      • et al.
      Systematic review of pleural plaques and lung function.
      • Kopylev L.
      • Christensen K.Y.
      • Brown J.S.
      • et al.
      A systematic review of the association between pleural plaques and changes in lung function.
      Here, we performed a repeated measures analysis using LMM procedures. LMM is a powerful tool for modeling dependent data. It employs the use of a cohort-specific covariance structure to help reduce standard error and test statistic bias.
      • Vonesh E.F.
      Generalized Linear and Nonlinear Models for Correlated Data: Theory and Applications Using SAS.
      • Hopper J.L.
      • Hibbert M.E.
      • Macaskill G.T.
      • et al.
      Longitudinal analysis of lung function growth in healthy children and adolescents.
      In LMM, missing or unbalanced data do not necessitate case deletion the way conventional, general linear regression (GLM) analysis does.
      • Vonesh E.F.
      Generalized Linear and Nonlinear Models for Correlated Data: Theory and Applications Using SAS.
      Also, the restricted maximum likelihood estimation procedure performed in LMM helps to eliminate the effects of nuisance parameters. Thus, LMM generally produces less biased variance and covariance parameters when compared to conventional GLM procedures that use maximal likelihood estimates.
      • Vonesh E.F.
      Generalized Linear and Nonlinear Models for Correlated Data: Theory and Applications Using SAS.
      In another recent study, Ohio factory workers exposed to asbestos via a fertilizer expanding process were evaluated in an effort to determine associations between the presence of PP and reduction in lung function.
      • Lockey J.E.
      • Dunning K.
      • Hilbert T.J.
      • et al.
      HRCT/CT and associated spirometric effects of low Libby amphibole asbestos exposure.
      Lockey et al
      • Lockey J.E.
      • Dunning K.
      • Hilbert T.J.
      • et al.
      HRCT/CT and associated spirometric effects of low Libby amphibole asbestos exposure.
      used HRCT or CT imaging and simple spirometry to clinically evaluate these workers. They compared workers with PP only to workers with normal HRCT using conventional GLM statistical procedures. Of the 191 factory workers with known commercial asbestos exposure, 61 had PP only and 65 had normal HRCT or CT (n = 126). Furthermore, 103 of these participants reported exposure to only the LAA contained within the fertilizer expanding process (n = 46 with PP only; and n = 57 with normal HRCT). Here, mean FEV1 and FVC percent predicted estimates were slightly reduced when compared to workers with normal HRCT (−3.3 and −5.4, respectively), but these findings were not statistically significant (P > 0.05). Only when they included workers with “other” known commercial asbestos exposure (n = 23), did factory workers exhibit a statistically significant reduction in mean FVC percent predicted (−6.1%, P < 0.05) spirometry.
      • Lockey J.E.
      • Dunning K.
      • Hilbert T.J.
      • et al.
      HRCT/CT and associated spirometric effects of low Libby amphibole asbestos exposure.
      Zu et al
      • Zu Ke
      • Tai Ge
      • Goodman Julie E.
      Pleural plaques and lung function in the Marysville worker cohort: a re-analysis.
      recently analyzed this same data using multivariate and logistical regression analysis. They did not detect statistical differences in lung function between workers with normal HRCT and those with only PP.
      In our study, participants underwent complete PFT to assess both FVC and TLC percent predicted measures in “actual” Libby vermiculite miners. Our absolute percent predicted value differences were similar to those found in the Ohio factory worker cohort.
      • Lockey J.E.
      • Dunning K.
      • Hilbert T.J.
      • et al.
      HRCT/CT and associated spirometric effects of low Libby amphibole asbestos exposure.
      However, unlike the Ohio worker study, we did not find statistically significant differences in lung function for miners with PP only when compared to LAA miners with normal HRCT. Owing to the fact that we used full PFTs inclusive of DLCO, and advanced statistical methodology, we believe our conclusions are more robust.
      Few longitudinal studies have been performed that specifically investigate the effect of PP on lung function in asbestos-exposed cohorts. To our knowledge, only 4 longitudinal studies have been performed using chest X-rays to identify PP with PFT data.
      • Ohlson C.G.
      • Bodin L.
      • Rydman T.
      • et al.
      Ventilatory decrements in former asbestos cement workers: a four year follow up.
      • Ostiguy G.
      • Vaillancourt C.
      • Begin R.
      Respiratory health of workers exposed to metal dusts and foundry fumes in a copper refinery.
      • Glencross P.M.
      • Weinberg J.M.
      • Ibrahim J.G.
      • et al.
      Loss of lung function among sheet metal workers: ten-year study.
      • Sichletidis L.
      • Chloros D.
      • Chatzidimitriou N.
      • et al.
      Diachronic study of pleural plaques in rural population with environmental exposure to asbestos.
      In a Swedish study of asbestos cement workers (n = 75), years of fiber exposure, age and smoking led to a statistically significant loss in lung function. However, PPs alone were not associated with lung function deficits.
      • Ohlson C.G.
      • Bodin L.
      • Rydman T.
      • et al.
      Ventilatory decrements in former asbestos cement workers: a four year follow up.
      In a Canadian study of copper refinery workers (n = 494), smoking and BMI significantly affected lung function but PP did not.
      • Ostiguy G.
      • Vaillancourt C.
      • Begin R.
      Respiratory health of workers exposed to metal dusts and foundry fumes in a copper refinery.
      In a study involving New England sheet metal workers (n = 122), smoking, years of asbestos exposure and past shipyard work contributed to loss of lung function but PP alone did not.
      • Glencross P.M.
      • Weinberg J.M.
      • Ibrahim J.G.
      • et al.
      Loss of lung function among sheet metal workers: ten-year study.
      Only a Greek study that investigated a population who were environmentally exposed to asbestos found increasing PP surface area to be significantly correlated with loss in TLC over a 15-year follow-up.
      • Sichletidis L.
      • Chloros D.
      • Chatzidimitriou N.
      • et al.
      Diachronic study of pleural plaques in rural population with environmental exposure to asbestos.
      In that study, sample sizes were small (n = 18), and no adjustment was made for smoking or BMI within the regression models.
      • Sichletidis L.
      • Chloros D.
      • Chatzidimitriou N.
      • et al.
      Diachronic study of pleural plaques in rural population with environmental exposure to asbestos.
      We are aware of 4 additional studies that used HRCT scanning with longitudinal PFT data to evaluate lung function in asbestos-exposed populations.
      • Rui F.
      • De Zotti R.
      • Negro C.
      • et al.
      A follow-up study of lung function among ex-asbestos workers with and without pleural plaques.
      • Damian A.
      • Rui F.
      • De Zotti R.
      Respiratory function and smoking habit among shipyard and dock workers.
      • Schwartz D.A.
      • Galvin J.R.
      • Yagla S.J.
      • et al.
      Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach.
      • Algranti E.
      • Coeli Mendonca E.M.
      • Hnizdo E.
      • et al.
      Longitudinal decline in lung function of former asbestos exposed workers.
      In 2 of these studies (n = 117 and n = 502, respectively), the only pleural finding reported was “pleural fibrosis;” PP were not specifically reported or included in the analyses.
      • Schwartz D.A.
      • Galvin J.R.
      • Yagla S.J.
      • et al.
      Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach.
      • Algranti E.
      • Coeli Mendonca E.M.
      • Hnizdo E.
      • et al.
      Longitudinal decline in lung function of former asbestos exposed workers.
      However, both studies commented on the deleterious effects of smoking on lung function.
      • Schwartz D.A.
      • Galvin J.R.
      • Yagla S.J.
      • et al.
      Restrictive lung function and asbestos-induced pleural fibrosis. A quantitative approach.
      • Algranti E.
      • Coeli Mendonca E.M.
      • Hnizdo E.
      • et al.
      Longitudinal decline in lung function of former asbestos exposed workers.
      The other 2 studies (n = 103 and n = 196, respectively) investigated shipbuilding or repairing workers in Italy.
      • Rui F.
      • De Zotti R.
      • Negro C.
      • et al.
      A follow-up study of lung function among ex-asbestos workers with and without pleural plaques.
      • Damian A.
      • Rui F.
      • De Zotti R.
      Respiratory function and smoking habit among shipyard and dock workers.
      In the first study, smoking and previous asbestos exposure contributed to a statistically significant loss of lung function, but PP alone were not related to a decline in lung function.
      • Rui F.
      • De Zotti R.
      • Negro C.
      • et al.
      A follow-up study of lung function among ex-asbestos workers with and without pleural plaques.
      The second study also concluded that PP alone did not affect lung function decline.
      • Damian A.
      • Rui F.
      • De Zotti R.
      Respiratory function and smoking habit among shipyard and dock workers.
      To further explore if varying levels of PP severity independently contributed to reductions or accelerated losses in lung function, we subdivided the PPO miners into 3 severity groups (minimal, moderate and extensive). Plaque severity did not independently affect lung function (Table 4). However, smoking PPO miners with extensive or moderate PP did have significantly accelerated annual decline in DLCO and FEV1 percent predicted when compared to nonsmoking PPO miners with mild PP. Our results indicate that the interaction between the severity of plaques and smoking contributed to accelerated loss. That is, smoking acted as an effect modifier for the observed accelerated annual decline in PPO miners with severe and moderate plaque formation. This finding has also been observed by other investigators.
      • Ohlson C.G.
      • Bodin L.
      • Rydman T.
      • et al.
      Ventilatory decrements in former asbestos cement workers: a four year follow up.
      • Ostiguy G.
      • Vaillancourt C.
      • Begin R.
      Respiratory health of workers exposed to metal dusts and foundry fumes in a copper refinery.
      There was much inherent strength in our study. First, there was a long follow-up period of 24 years, and multiple PFT studies were performed for each miner. On average, miners were followed for nearly 7 years after their first PFT. Additionally, LMM (random coefficients analysis) enabled us to determine rates of lung function decline between miner HRCT groups.
      • Vonesh E.F.
      Generalized Linear and Nonlinear Models for Correlated Data: Theory and Applications Using SAS.
      We also considered independent factors that are known to affect lung function such as BMI, smoking history and disease comorbidities.
      • Jones R.L.
      • Nzekwu M.-M.
      The effects of body mass index on lung volumes.
      • Pistelli F.
      • Bottai M.
      • Carrozzi L.
      • et al.
      Changes in obesity status and lung function decline in a general population sample.
      • Miller A.
      • Thornton J.C.
      • Warshaw R.
      • et al.
      Single breath diffusing capacity in a representative sample of population of Michigan, a large industrial stat. Predictive values, lower limits of normal, and frequencies of abnormality by smoking history.
      • Alfonso H.S.
      • Fritschi L.
      • de Klerk N.H.
      • et al.
      Effects of asbestos and smoking on the levels and rates of change of lung function in a crocidolite exposed cohort in Western Australia.
      • Lee P.N.
      • Fry J.S.
      Systematic review of the evidence relating FEV1 decline to giving up smoking.
      • Mannino D.M.
      • Reichert M.M.
      • Davis K.J.
      Lung function decline and outcomes in an adult population.
      Next, we investigated the effects of plaque severity on lung function among PPO miners with a long average latency period between first occupational asbestos exposure and first PFT (mean = 37 years).
      • Larson T.C.
      • Meyer C.A.
      • Kapil V.
      • et al.
      Workers with Libby amphibole exposure: retrospective identification and progression of radiographic changes.
      • de Klerk N.H.
      • Cookson W.O.
      • Musk A.W.
      • et al.
      Natural history of pleural thickening after exposure to crocidolite.
      All miners were exposed at the same location, to the same type of asbestos (i.e., LAA), and our asbestos-exposed reference group came from the same internal occupational cohort.
      Our greatest limitation was the small sample size of our NCTS reference group. Our study population came from the health records of 291 Libby vermiculate miners with confirmed occupational LAA exposure. Before applying to the LMP, the HRCTs on-record were ordered by local primary care providers and interpreted at community-based hospitals (n = 179). During the application process, Libby miner radiographic records were reviewed by board-certified academic thoracic radiologists for confirmation of asbestos-related changes. Once asbestos-related findings were identified, miners were enrolled into the LMP for further health surveillance until September 2012. If no asbestos-related findings could be established, miners were ineligible for LMP enrollment. Furthermore, 5 of 9 NCTS miners applied but were not enrolled into the LMP. The other 4 miners were enrolled “early on” into the LMP though no asbestos-related HRCT changes were observed by peer review. This illustrates that selection bias was present, however, toward the follow-up of miners with confirmed asbestos-related findings. This overall effect resulted in a reduced number of miners within the reference NCTS group. Nonetheless, we believed that a control group of nonminers would have less exposure or no exposure to LAA, which in turn, may affect longitudinal rates of lung function decline. We felt our control group should come from the miner cohort with similar LAA exposure to accurately evaluate the effect of PP on lung function. When we artificially increased the NCTS cohort size (n = 200) and we compared those regression analyses to the original analyses, no differences in outcomes were observed. Also, the Akaike Information Criteria values in the original models revealed a significantly better fit than did the alternative models with a greater NCTS group sample size (data not shown).
      We also incorporated a number of techniques that enhanced the ability to identify statistically significant changes in lung function decline over time. First, the inherent characteristics of mixed effects analyses provide more power given the same sample size compared to GLM.
      • Vonesh E.F.
      Generalized Linear and Nonlinear Models for Correlated Data: Theory and Applications Using SAS.
      Additionally, we relaxed the alpha level for interaction terms (α ≤ 0.10) instead of using the conventional α ≤ 0.05. This enhanced our ability to identify potentially significant miner group differences and reduced the potential for type II error. We adjusted for multiple predictors within each model but did not adjust for multiple testing across the various models. We were also able to identify significantly higher rates of FEV1 and DLCO annual decline in the OCTA miners. In view of the fact that the PPO miner group had a much larger sample size and narrower confidence intervals than all other miner groups, we believed the potential for type 2 error to be minimized during the comparative analyses between the PPO and the NCTS miner groups.

      Conclusions

      Our analysis suggested that PP alone had no statistically significant effect on longitudinal lung function in Libby vermiculite miners. However, smoking, BMI and latent period from first occupational asbestos exposure did independently contribute to lung function decline in Libby miners with only PP.

      Acknowledgments

      The authors acknowledge and thank the following academic chest radiologists who peer reviewed the high-resolution chest CT scans used in our study: Daniel A. Henry, MD, Virginia Commonwealth University and Medical Center; Paul L. Molina, MD, University of North Carolina School of Medicine; and Ralph T. Shipley, MD, University of Cincinnati College of Medicine. The authors also acknowledge and thank the biostatisticians at The Analysis Factor, Ithaca, New York, who independently reviewed and validated the statistical analyses performed in this study.

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