Artificial Stone Silicosis Rapid Progression Following Exposure Cessation Antonio León-Jiménez, PhD; Antonio Hidalgo-Molina, MD; Miguel Ángel Conde-Sánchez, PhD; Aránzazu Pérez-Alonso, MD; José María Morales-Morales, MD; Eva María García-Gámez, MD; and Juan Antonio Córdoba-Doña, PhD BACKGROUND: Silicosis is rapidly emerging in high-income countries in relation to the replacement of natural stone with artificial stone, especially in the manufacturing and installation of kitchen and bathroom countertops. Progression of this form of silicosis following the cessation of exposure is unknown. RESEARCH QUESTION: The objective of this study was to determine the radiologic progression and lung function in individuals with artificial stone silicosis. STUDY DESIGN AND METHODS: Between 2009 and 2018, a total of 106 patients were diagnosed with artificial stone silicosis in the Bay of Cádiz area (southern Spain), 14.15% by using biopsy results and the remainder according to chest radiography and high-resolution CT imaging. Follow-up consisted of respiratory function tests and radiographic studies. All patients stopped working in the stone industry following diagnosis. RESULTS: All patients were men; their mean SD age at diagnosis was 36.2 7.0 years, and the mean duration of exposure was 12.0 4.3 years. At diagnosis, 99 patients were considered to have simple silicosis (93.4%) and seven to have progressive massive fibrosis (PMF) (6.6%). After a mean follow-up of 4.01 2.1 years, disease in 56% of patients had progressed two or more International Labour Office subcategories, and the number of pa- tients with PMF had increased to 40 (37.7%). Regarding lung function, there was a decrease in FVC and FEV 1 , with an average decrease of 86.8 and 83.4 mL per year, respectively; in 25% of patients, the annual decrease was > 157 mL in FVC and > 133 mL in FEV 1 . Multivariable analysis showed that lower FVC at diagnosis and longer duration of exposure to silica were associated with progression to PMF. INTERPRETATION: Artificial stone silicosis rapidly progresses to PMF even following exposure cessation, and a significant percentage of patients experience a very rapid decrease in lung function. CHEST 2020; 158(3):1060-1068 KEY WORDS: artificial stone; lung function; occupational disease; silicosis FOR EDITORIAL COMMENT, SEE PAGE 862 ABBREVIATIONS: AS = artificial stone; CXR = chest radiography; DLCO = diffusing capacity of the lung for carbon monoxide; ILO = International Labour Office; HRCT = high-resolution CT; PMF = progressive massive fibrosis AFFILIATIONS: From the Pulmonology, Allergy and Thoracic Surgery Department (Drs León-Jiménez and Hidalgo-Molina), Puerta del Mar University Hospital, Biomedical Research and Innovation Institute of Cádiz, Cádiz, Spain; Public Health Service (Dr Córdoba-Doña), Regional Directorate of the Department of Health and Families of Andalusia in Cádiz, Cádiz, Spain; Occupational and Public Health and Preventive Medicine Service (Dr Pérez-Alonso), Cádiz, Spain; and the Pulmonology Unit (Dr Morales-Morales) and Radiology Department (Drs Conde-Sánchez and García-Gámez), Puerto Real University Hospital, Puerto Real, Cádiz, Spain. Dr Córdoba-Doña is currently at the Preventive Medicine and Public Health Department, University Hospital, Jerez de la Frontera, Cádiz, Spain; Dr. Pérez-Alonso is currently at Occupational Safety and Health Services, Navantia, San Fernando, Cádiz, Spain; and Dr Morales- Morales is currently at Pulmonology Department, Lozano Blesa Uni- versity Hospital Clinic, Zaragoza, Spain. [ Diffuse Lung Disease Original Research ] 1060 Original Research [ 158#3 CHEST SEPTEMBER 2020 ]
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Artificial Stone SilicosisArtificial Stone Silicosis
Antonio León-Jiménez, PhD; Antonio Hidalgo-Molina, MD; Miguel Ángel Conde-Sánchez, PhD;
Aránzazu Pérez-Alonso, MD; José María Morales-Morales, MD; Eva María García-Gámez, MD;
and Juan Antonio Córdoba-Doña, PhD
ABBREVIATIONS: AS = artifi DLCO = diffusing capacity of International Labour Office; progressive massive fibrosis AFFILIATIONS: From the Pulm Department (Drs León-Jiméne University Hospital, Biomedic Cádiz, Cádiz, Spain; Public Regional Directorate of the D Andalusia in Cádiz, Cádiz, Spa
1060 Original Research
BACKGROUND: Silicosis is rapidly emerging in high-income countries in relation to the replacement of natural stone with artificial stone, especially in the manufacturing and installation of kitchen and bathroom countertops. Progression of this form of silicosis following the cessation of exposure is unknown.
RESEARCH QUESTION: The objective of this study was to determine the radiologic progression and lung function in individuals with artificial stone silicosis.
STUDY DESIGN AND METHODS: Between 2009 and 2018, a total of 106 patients were diagnosed with artificial stone silicosis in the Bay of Cádiz area (southern Spain), 14.15% by using biopsy results and the remainder according to chest radiography and high-resolution CT imaging. Follow-up consisted of respiratory function tests and radiographic studies. All patients stopped working in the stone industry following diagnosis.
RESULTS: All patients were men; their mean SD age at diagnosis was 36.2 7.0 years, and the mean duration of exposure was 12.0 4.3 years. At diagnosis, 99 patients were considered to have simple silicosis (93.4%) and seven to have progressive massive fibrosis (PMF) (6.6%). After a mean follow-up of 4.01 2.1 years, disease in 56% of patients had progressed two or more International Labour Office subcategories, and the number of pa- tients with PMF had increased to 40 (37.7%). Regarding lung function, there was a decrease in FVC and FEV1, with an average decrease of 86.8 and 83.4 mL per year, respectively; in 25% of patients, the annual decrease was > 157 mL in FVC and > 133 mL in FEV1. Multivariable analysis showed that lower FVC at diagnosis and longer duration of exposure to silica were associated with progression to PMF.
INTERPRETATION: Artificial stone silicosis rapidly progresses to PMF even following exposure cessation, and a significant percentage of patients experience a very rapid decrease in lung function.
CHEST 2020; 158(3):1060-1068
FOR EDITORIAL COMMENT, SEE PAGE 862
cial stone; CXR = chest radiography; the lung for carbon monoxide; ILO = HRCT = high-resolution CT; PMF =
onology, Allergy and Thoracic Surgery z and Hidalgo-Molina), Puerta del Mar al Research and Innovation Institute of Health Service (Dr Córdoba-Doña), epartment of Health and Families of in; Occupational and Public Health and
Preventive Medicine Service (Dr Pérez-Alonso), Cádiz, Spain; and the Pulmonology Unit (Dr Morales-Morales) and Radiology Department (Drs Conde-Sánchez and García-Gámez), Puerto Real University Hospital, Puerto Real, Cádiz, Spain. Dr Córdoba-Doña is currently at the Preventive Medicine and Public Health Department, University Hospital, Jerez de la Frontera, Cádiz, Spain; Dr. Pérez-Alonso is currently at Occupational Safety and Health Services, Navantia, San Fernando, Cádiz, Spain; and Dr Morales- Morales is currently at Pulmonology Department, Lozano Blesa Uni- versity Hospital Clinic, Zaragoza, Spain.
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Silica inhalation is the main cause of occupational respiratory disease worldwide.1 Exposure to respirable crystalline silica can cause silicosis, eventually leading to progressive massive fibrosis (PMF), respiratory failure, and death. It is estimated that the number of workers in Europe who have been exposed to silica is between 3 and 5 million2 and that this exposure is responsible for > 10,000 deaths per year worldwide,3 mainly in developing countries, although there is significant underreporting.4
In high-income countries, the incidence of silicosis has decreased progressively over the last decades, primarily due to the implementation of more effective occupational health surveillance and prevention systems. In the United Kingdom, 216 cases of silicosis were reported from 1996 to 2017.5 Most cases of silicosis occur among workers engaged in industrial activities such as mining, quarrying, rock drilling, and sandblasting, among others.6 However, in recent years, an increase in the incidence of silicosis has been detected in relation to new occupational exposures.
In 2010, three cases of silicosis related to a new construction material used in kitchen and bathroom
Preliminary data were presented in abstract form at the 2017 European Respiratory Society International Congress (León-Jiménez A, Morales- Morales J, Córdoba-Doña JA, et al. Euro Respir J. 2017;50:OA483). FUNDING/SUPPORT: The authors received a grant from the Associa- tion of Pneumology and Thoracic Surgery of the South [Neumosur Grant 7/2016]. CORRESPONDENCE TO: Antonio León-Jiménez, PhD, Pulmonology, Allergy and Thoracic Surgery Department, Puerta del Mar University Hospital, Avda Ana de Viya 21, 11009 Cádiz, Spain; e-mail: antonio. [email protected] Copyright 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2020.03.026
chestjournal.org
countertops and in flooring were reported in young subjects. This material, called artificial quartz agglomerate or conglomerate or artificial stone (AS), is composed of finely crushed rock mixed with synthetic resins, has a high silica content (approximately 90%), and also contains other components such as pigments.7
Since 2010, some isolated cases of silicosis have been reported in other Spanish cities.8,9 In 2012, Kramer et al10 reported 25 cases of AS silicosis in patients who were evaluated for lung transplantation in Israel. In 2014, we reported 47 new cases in our area,11 and since then, isolated cases have continued to appear in countries throughout the world, including Italy,12 the United States,13 Australia,14 and Belgium.15
Some of these cases have progressed rapidly, suggesting that AS silicosis is more aggressive than classic silicosis. However, despite the growing body of knowledge about AS silicosis,most studies are cross-sectional and donot provide information on disease progression or possible associated factors. The aim of the current study was to evaluate the radiologic and lung function progression of a large group of patients with AS silicosis following exposure cessation and to assess the possible risk factors affecting progression.
Patients and Methods Study Population
From January 2009 to June 2018, a total of 106 native Spanish male workers were diagnosed with silicosis in the area of Bay of Cádiz (province of Cádiz, southern Spain), which has a population of 514,512 (2018 data). Since the 1980s, many small companies in this area have been involved in the manufacturing and installation of countertops, primarily kitchen countertops. The peak number of exposed AS workers in the area was estimated to be around 220 in 2008.11 All cases in the current study were workers in these small factories (from three to seven workers per factory), and none of them had other jobs or hobbies that could be the origin of their silicosis. Most of the cases were diagnosed between 2010 and 2013 (Fig 1).
The initial cases in 2009 were evaluated because they presented with symptoms; after that, an active surveillance program was performed.
This program included epidemiologic, clinical, radiologic, and spirometry assessments of workers. High-resolution CT (HRCT) scanning was performed in cases of symptoms or radiologic or lung function changes as well as in cases of high-risk workers (employed in a factory with at least one worker diagnosed with the disease and with an exposure period equal to or longer than that of the index case). Following 2012, most of the cases were diagnosed through follow-up visits in workers exposed years earlier.
The patients were treated at the two public hospitals in the area (Puerta del Mar and Puerto Real university hospitals). The diagnosis was made by using video-assisted thoracoscopic, transbronchial, or mediastinoscopic biopsy in 15 patients, especially in the first cases and in those with unusual presentation. In the remaining patients, the diagnosis was made by using a radiologic procedure that included, in all cases, chest radiography (CXR) and HRCT imaging. In addition, each patient underwent respiratory function tests (spirometry, lung volumes, and diffusion capacity), blood analyses, and tuberculin skin tests as part of the clinical protocol designed following diagnosis of the initial cases. All patients stopped working at diagnosis or earlier.
Study Procedures
Once diagnosed with silicosis, patients were followed up regularly in hospital consultations with respiratory function tests (at least one forced spirometry) and annual CXR. All patients had one HRCT scan at diagnosis and at least one HRCT scan in the follow-up, except for cases diagnosed in 2017 and 2018. The average number of HRCT scans per patient was 2.16, and the average interval between them was 3.59 years.
Respiratory function tests were performed by trained personnel using a MasterScreen PFT/Body System (Jaeger, Viasys, CareFusion) according to international recommendations.16,17 The diffusing capacity of the
2009 0
2010 2011 2012 2013 2014 2015 2016 2017 2018
lung for carbon monoxide (DLCO) was measured by the single-breath procedure. Spirometry reference values for the Mediterranean population were taken from Roca et al,18 and diffusion values were taken from Cotes et al.19 The severity of spirometric abnormalities was classified according to the recommendations of scientific societies.20
Chest radiographs were classified according to International Labour Office (ILO) criteria21 by three trained readers, and any disagreement was resolved by consensus. Silicosis was defined as ILO category 1/0 or greater with a history of occupational exposure or by biopsy results and/or HRCT scans with a history of exposure, after excluding other diagnoses. We defined CXR progression in cases of increased profusion of small opacities in two or more subcategories, the presence of large opacities (A, B, or C), or an increase in the large opacities category.
CT scans were read by using the criteria of the International Classification of HRCT for Occupational and Environmental Respiratory Diseases. Large opacities were defined as those in which the mean of two perpendicular diameters exceeded 1 cm.22
Data were retrieved prospectively and retrospectively. Prospective data included standard clinical and epidemiologic history, radiographic studies, and the respiratory function tests mentioned earlier. For
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retrospective data (between 2009 and 2016), hospital clinical records were reviewed.
The study was approved by the Research Ethics Committee of Cádiz on December 20, 2016 (registration no. 157/16-SIL-2016-01). All data were anonymized to preclude patient identification and were included in a database to which only the researchers had access. All participants prospectively included in the study signed an informed consent form. For retrospective data, the committee waived informed consent.
Statistical Analysis
First, a descriptive analysis of the main clinical and epidemiologic variables was performed. Progression was assessed in patients with at least 2 years of follow-up (N ¼ 100). For comparisons between groups or between the first and last examination, the paired Student t test and the c2 test were used, as applicable. To assess the rate of decline in lung function parameters over time, a fixed effects linear regression model was performed, as patients had dissimilar number of observations and time points for data collection. For the multivariable study of associated factors, Cox proportional hazards models were used to estimate the hazard ratios for progressing to PMF according to HRCT imaging, using years since last exposure to event as the time variable.
Results All 106 workers diagnosed with silicosis were male, with a mean SD age at diagnosis of 36.2 7.0 years. Most diagnoses (73.6%) were made between 2010 and 2013 (Fig 1), and the duration of exposure to AS was 12.0 4.3 years. The latency period from onset of exposure to diagnosis was 13.7 4.1 years. In 28 cases (26.4%), silicosis developed in an accelerated form between 5 and 10 years following the initial exposure, but there were no cases with an exposure period < 5 years. All of the patients worked cutting and polishing slabs of AS in small factories and were also involved during in-home installation performing dry operations (on many
occasions without effective personal protective equipment). Thirty-two patients (30.2%) were diagnosed after they had left their jobs.
At diagnosis, 17.9% were smokers, 37.7% were ex- smokers, and 44.3% were nonsmokers. Cumulative tobacco consumption in pack-years was 10.6 7.6 for both smokers and ex-smokers. Four patients had been previously diagnosed with bronchial asthma, and one had been previously diagnosed with pulmonary TB. Symptoms were predominantly mild, and the most common were cough and dyspnea (81% patients with modified Medical Research Council dyspnea scale grade
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TABLE 1 ] Chest Radiography at Baseline and at Final Follow-up (ILO Classification)
Baseline Value No.
Final Follow-Up Category
Lost to Follow-upCategory 0 Category 1 Category 2 Category 3 PMF
Category 0 19a 3 8 4 0 1 3
Category 1 56 ... 31 11 0 12 2
Category 2 19 ... ... 9 1 9 0
Category 3 7 ... ... ... 2 4 1
PMF 5 ... ... ... ... 5 0
ILO ¼ International Labour Office; PMF ¼ progressive massive fibrosis. aDiagnosis by high-resolution CT scan.
0, 14% with grade 1, and 5% with grade 2). Results of the tuberculin test were positive in 5.7% of the cases.
The mean follow-up time from diagnosis of silicosis to the last visit was 4.01 2.1 years. During follow-up, four patients died, two following lung transplantation and two for reasons unrelated to silicosis. In six patients, only the initial diagnostic consultation was recorded; thus, no follow-up data are available (four diagnosed in 2018 and two in 2017). In another four patients, retrospective data were incomplete because they were lost to follow-up.
Table 1 presents the CXR findings according to the ILO classification at diagnosis and at the time of the last CXR.
TABLE 2 ] Progression of Respiratory Function
Variable
Overall Follow Annual Decre
FVC, mL 4,324 879 4,068 868 86.8 62. 11
FVC, % 86.0 15.1 80.2 15.09 1.13 0.6 1.
FEV1 , mL 3,429 579 3139 752 83.4 61. 10
FEV1, % 86.6 16.1 78.9 16.9 1.5 1.0 1.
FEV1/FVC 79.1 5.9 76.6 7.0 0.65 0.4 0.
DLCO, mmoL/ min/kPa
DLCO, % 76.8 15.7 76.1 15.5 0.12 –0.6 0.
Values are expressed as mean SD. Respiratory function data are at diagn monoxide. aPatients with only one test (diagnosed in 2017 and 2018) or lost to follow-up bFixed effects linear regression models. cP value for mean reduction for the lung function parameter in the overall per dStatistically significant (P < .05) when comparing first and second periods.
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At baseline, 19 cases were classified in category 0, and five cases were assessed as PMF. After the follow-up period, 51 more cases showed radiologic progression (then 56% of patients that finished the follow-up were considered progressors), and 31 cases were classified as PMF. Only three patients remained in ILO category 0. Initial HRCT imaging showed two additional patients with PMF. Therefore, seven patients were diagnosed as having PMF, and 99 were considered to have simple silicosis at baseline. At the end of the follow-up, 40 of 106 (37.7%) patients were classified as PMF according to HRCT imaging. Thus, at baseline, HRCT scans exhibited a micronodular pattern in 19 patients (17.9%) who had a CXR that was negative for silicosis. In addition, at the end
-up, aseb
P c
CI Mean 95% CI Mean 95% CI
7 to 0.9
0.04 –0.19 to 0.27
–0.85 –3.02 to 1.30
osis and last follow-up. DLCO ¼ diffusing capacity of the lung for carbon
were excluded.
TABLE 3 ] Cox Proportional Hazards Model for Factors Associated With the Development of Progressive Massive Fibrosis (n ¼ 100)
Variable HR SE 95% CI P
Baseline FVC 0.96 0.01 0.94-0.99 <.01
Duration of exposure to AS (y) 1.09 0,05 1.00-1.19 .06
Age at onset of exposure 0.98 0.03 0.92-1.04 .55
Smoking index by smoking status
Never smoker Ref
Ex-smoker 1,04 0.03 0.98-1.11 .14
AS ¼ artificial stone; HR ¼ hazard ratio; Ref ¼ reference category.
of the follow-up period, nine of 40 cases classified as PMF according to HRCT imaging remained as simple silicosis according to the CXR results.
Table 2 presents the spirometry and DLCO values at diagnosis and at the last follow-up visit. Fixed effect linear regression showed a significant decrease in FVC and FEV1, with average annual decreases of 86.8 and 83.4 mL, respectively. It should be noted that 25% of the patients had an even more accelerated decline in lung function ($ 157 mL in FVC and $ 133 mL in FEV1 per year). The average annual decline rate of FVC was 111.2 mL (95% CI, 77.2 to 145.3) in the first 4 years of follow-up, whereas it was 54.2 mL (95% CI, –12.2 to 120.5) between 5 and 8 years of follow-up. These results show a higher rate of decline in the first years of disease, although it was not statistically significant.
A different pattern was observed both in FEV1, which remained stable in the two periods, and FEV1/FVC, which showed a significantly steeper decrease in the second period. The decrease in DLCO was minimal during the follow-up, although 25% of patients experienced a decrease of$ 0.2 mmol/min/kPa per year. According to the severity of spirometric abnormality, the percentage of patients with FVC within normal limits was 74.5% at diagnosis, which decreased to 57.8% at the end of follow-up. We found no correlation between changes in FVC and radiologic progression in the bivariate analyses. Regarding the degree of bronchial obstruction, which was determined based on the FEV1/ FVC ratio, a significant risk for airflow obstruction was observed (6.6% of patients with FEV1/FVC < 70% at baseline and 16.7% after follow-up; P ¼ .025).
When performing multivariable analysis (Table 3) with the most relevant variables considered in the literature, it was observed that lower FVC at diagnosis was closely associated with progression to PMF, whereas for each
1064 Original Research
additional year of exposure to AS, there was a 9% increase in the hazard of PMF (hazard ratio, 1.09; 95% CI, 1.00-1.19). Estimations were adjusted by age at onset of exposure to AS and cigarette consumption at diagnosis.
Discussion Several studies have reported a high percentage of patients with AS silicosis who present with PMF at diagnosis. For example, 8.7% of the cases in our previous series11 and 15% of the cases described by Edwards23 had PMF. Although some studies24,25 have described the clinical and radiologic features of PMF, the progression of this form of silicosis is unknown. To the best of our knowledge, the cohort we present here is the first and largest group of artificial stone workers in which the progression of the patients has been described once diagnosed as well as following cessation of exposure to silica.
One of the main findings of our study is that, despite the cessation of exposure, there was an accelerated decline in lung function and a rapid progression to PMF in these patients over a short period of time. At diagnosis, 6.6% of patients were classified as having PMF, but after an average follow-up of 4 years, the percentage of patients who progressed to PMF rose to 37.7%. Comparing the progression of AS silicosis with that of silicosis caused by natural stone, Carneiro et al26 studied gold mine workers and found that after exposure cessation and a mean follow-up of 17.9 years, only three of 39 patients with silicosis progressed to PMF (7.6%). Lee et al27 described a series of 141 patients with silicosis due to exposure in granite quarries. In these cases, the duration of exposure was 23.5 years, and 17.7% of patients had large opacities in the baseline radiograph; after a 7.5-year follow-up, 52 (36.9%) had developed large opacities. In a follow-up study of sandblasting
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workers conducted 4 years following diagnosis and cessation of exposure to silica, Akgun et al28 found that 82% of the…
Antonio León-Jiménez, PhD; Antonio Hidalgo-Molina, MD; Miguel Ángel Conde-Sánchez, PhD;
Aránzazu Pérez-Alonso, MD; José María Morales-Morales, MD; Eva María García-Gámez, MD;
and Juan Antonio Córdoba-Doña, PhD
ABBREVIATIONS: AS = artifi DLCO = diffusing capacity of International Labour Office; progressive massive fibrosis AFFILIATIONS: From the Pulm Department (Drs León-Jiméne University Hospital, Biomedic Cádiz, Cádiz, Spain; Public Regional Directorate of the D Andalusia in Cádiz, Cádiz, Spa
1060 Original Research
BACKGROUND: Silicosis is rapidly emerging in high-income countries in relation to the replacement of natural stone with artificial stone, especially in the manufacturing and installation of kitchen and bathroom countertops. Progression of this form of silicosis following the cessation of exposure is unknown.
RESEARCH QUESTION: The objective of this study was to determine the radiologic progression and lung function in individuals with artificial stone silicosis.
STUDY DESIGN AND METHODS: Between 2009 and 2018, a total of 106 patients were diagnosed with artificial stone silicosis in the Bay of Cádiz area (southern Spain), 14.15% by using biopsy results and the remainder according to chest radiography and high-resolution CT imaging. Follow-up consisted of respiratory function tests and radiographic studies. All patients stopped working in the stone industry following diagnosis.
RESULTS: All patients were men; their mean SD age at diagnosis was 36.2 7.0 years, and the mean duration of exposure was 12.0 4.3 years. At diagnosis, 99 patients were considered to have simple silicosis (93.4%) and seven to have progressive massive fibrosis (PMF) (6.6%). After a mean follow-up of 4.01 2.1 years, disease in 56% of patients had progressed two or more International Labour Office subcategories, and the number of pa- tients with PMF had increased to 40 (37.7%). Regarding lung function, there was a decrease in FVC and FEV1, with an average decrease of 86.8 and 83.4 mL per year, respectively; in 25% of patients, the annual decrease was > 157 mL in FVC and > 133 mL in FEV1. Multivariable analysis showed that lower FVC at diagnosis and longer duration of exposure to silica were associated with progression to PMF.
INTERPRETATION: Artificial stone silicosis rapidly progresses to PMF even following exposure cessation, and a significant percentage of patients experience a very rapid decrease in lung function.
CHEST 2020; 158(3):1060-1068
FOR EDITORIAL COMMENT, SEE PAGE 862
cial stone; CXR = chest radiography; the lung for carbon monoxide; ILO = HRCT = high-resolution CT; PMF =
onology, Allergy and Thoracic Surgery z and Hidalgo-Molina), Puerta del Mar al Research and Innovation Institute of Health Service (Dr Córdoba-Doña), epartment of Health and Families of in; Occupational and Public Health and
Preventive Medicine Service (Dr Pérez-Alonso), Cádiz, Spain; and the Pulmonology Unit (Dr Morales-Morales) and Radiology Department (Drs Conde-Sánchez and García-Gámez), Puerto Real University Hospital, Puerto Real, Cádiz, Spain. Dr Córdoba-Doña is currently at the Preventive Medicine and Public Health Department, University Hospital, Jerez de la Frontera, Cádiz, Spain; Dr. Pérez-Alonso is currently at Occupational Safety and Health Services, Navantia, San Fernando, Cádiz, Spain; and Dr Morales- Morales is currently at Pulmonology Department, Lozano Blesa Uni- versity Hospital Clinic, Zaragoza, Spain.
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Silica inhalation is the main cause of occupational respiratory disease worldwide.1 Exposure to respirable crystalline silica can cause silicosis, eventually leading to progressive massive fibrosis (PMF), respiratory failure, and death. It is estimated that the number of workers in Europe who have been exposed to silica is between 3 and 5 million2 and that this exposure is responsible for > 10,000 deaths per year worldwide,3 mainly in developing countries, although there is significant underreporting.4
In high-income countries, the incidence of silicosis has decreased progressively over the last decades, primarily due to the implementation of more effective occupational health surveillance and prevention systems. In the United Kingdom, 216 cases of silicosis were reported from 1996 to 2017.5 Most cases of silicosis occur among workers engaged in industrial activities such as mining, quarrying, rock drilling, and sandblasting, among others.6 However, in recent years, an increase in the incidence of silicosis has been detected in relation to new occupational exposures.
In 2010, three cases of silicosis related to a new construction material used in kitchen and bathroom
Preliminary data were presented in abstract form at the 2017 European Respiratory Society International Congress (León-Jiménez A, Morales- Morales J, Córdoba-Doña JA, et al. Euro Respir J. 2017;50:OA483). FUNDING/SUPPORT: The authors received a grant from the Associa- tion of Pneumology and Thoracic Surgery of the South [Neumosur Grant 7/2016]. CORRESPONDENCE TO: Antonio León-Jiménez, PhD, Pulmonology, Allergy and Thoracic Surgery Department, Puerta del Mar University Hospital, Avda Ana de Viya 21, 11009 Cádiz, Spain; e-mail: antonio. [email protected] Copyright 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2020.03.026
chestjournal.org
countertops and in flooring were reported in young subjects. This material, called artificial quartz agglomerate or conglomerate or artificial stone (AS), is composed of finely crushed rock mixed with synthetic resins, has a high silica content (approximately 90%), and also contains other components such as pigments.7
Since 2010, some isolated cases of silicosis have been reported in other Spanish cities.8,9 In 2012, Kramer et al10 reported 25 cases of AS silicosis in patients who were evaluated for lung transplantation in Israel. In 2014, we reported 47 new cases in our area,11 and since then, isolated cases have continued to appear in countries throughout the world, including Italy,12 the United States,13 Australia,14 and Belgium.15
Some of these cases have progressed rapidly, suggesting that AS silicosis is more aggressive than classic silicosis. However, despite the growing body of knowledge about AS silicosis,most studies are cross-sectional and donot provide information on disease progression or possible associated factors. The aim of the current study was to evaluate the radiologic and lung function progression of a large group of patients with AS silicosis following exposure cessation and to assess the possible risk factors affecting progression.
Patients and Methods Study Population
From January 2009 to June 2018, a total of 106 native Spanish male workers were diagnosed with silicosis in the area of Bay of Cádiz (province of Cádiz, southern Spain), which has a population of 514,512 (2018 data). Since the 1980s, many small companies in this area have been involved in the manufacturing and installation of countertops, primarily kitchen countertops. The peak number of exposed AS workers in the area was estimated to be around 220 in 2008.11 All cases in the current study were workers in these small factories (from three to seven workers per factory), and none of them had other jobs or hobbies that could be the origin of their silicosis. Most of the cases were diagnosed between 2010 and 2013 (Fig 1).
The initial cases in 2009 were evaluated because they presented with symptoms; after that, an active surveillance program was performed.
This program included epidemiologic, clinical, radiologic, and spirometry assessments of workers. High-resolution CT (HRCT) scanning was performed in cases of symptoms or radiologic or lung function changes as well as in cases of high-risk workers (employed in a factory with at least one worker diagnosed with the disease and with an exposure period equal to or longer than that of the index case). Following 2012, most of the cases were diagnosed through follow-up visits in workers exposed years earlier.
The patients were treated at the two public hospitals in the area (Puerta del Mar and Puerto Real university hospitals). The diagnosis was made by using video-assisted thoracoscopic, transbronchial, or mediastinoscopic biopsy in 15 patients, especially in the first cases and in those with unusual presentation. In the remaining patients, the diagnosis was made by using a radiologic procedure that included, in all cases, chest radiography (CXR) and HRCT imaging. In addition, each patient underwent respiratory function tests (spirometry, lung volumes, and diffusion capacity), blood analyses, and tuberculin skin tests as part of the clinical protocol designed following diagnosis of the initial cases. All patients stopped working at diagnosis or earlier.
Study Procedures
Once diagnosed with silicosis, patients were followed up regularly in hospital consultations with respiratory function tests (at least one forced spirometry) and annual CXR. All patients had one HRCT scan at diagnosis and at least one HRCT scan in the follow-up, except for cases diagnosed in 2017 and 2018. The average number of HRCT scans per patient was 2.16, and the average interval between them was 3.59 years.
Respiratory function tests were performed by trained personnel using a MasterScreen PFT/Body System (Jaeger, Viasys, CareFusion) according to international recommendations.16,17 The diffusing capacity of the
2009 0
2010 2011 2012 2013 2014 2015 2016 2017 2018
lung for carbon monoxide (DLCO) was measured by the single-breath procedure. Spirometry reference values for the Mediterranean population were taken from Roca et al,18 and diffusion values were taken from Cotes et al.19 The severity of spirometric abnormalities was classified according to the recommendations of scientific societies.20
Chest radiographs were classified according to International Labour Office (ILO) criteria21 by three trained readers, and any disagreement was resolved by consensus. Silicosis was defined as ILO category 1/0 or greater with a history of occupational exposure or by biopsy results and/or HRCT scans with a history of exposure, after excluding other diagnoses. We defined CXR progression in cases of increased profusion of small opacities in two or more subcategories, the presence of large opacities (A, B, or C), or an increase in the large opacities category.
CT scans were read by using the criteria of the International Classification of HRCT for Occupational and Environmental Respiratory Diseases. Large opacities were defined as those in which the mean of two perpendicular diameters exceeded 1 cm.22
Data were retrieved prospectively and retrospectively. Prospective data included standard clinical and epidemiologic history, radiographic studies, and the respiratory function tests mentioned earlier. For
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retrospective data (between 2009 and 2016), hospital clinical records were reviewed.
The study was approved by the Research Ethics Committee of Cádiz on December 20, 2016 (registration no. 157/16-SIL-2016-01). All data were anonymized to preclude patient identification and were included in a database to which only the researchers had access. All participants prospectively included in the study signed an informed consent form. For retrospective data, the committee waived informed consent.
Statistical Analysis
First, a descriptive analysis of the main clinical and epidemiologic variables was performed. Progression was assessed in patients with at least 2 years of follow-up (N ¼ 100). For comparisons between groups or between the first and last examination, the paired Student t test and the c2 test were used, as applicable. To assess the rate of decline in lung function parameters over time, a fixed effects linear regression model was performed, as patients had dissimilar number of observations and time points for data collection. For the multivariable study of associated factors, Cox proportional hazards models were used to estimate the hazard ratios for progressing to PMF according to HRCT imaging, using years since last exposure to event as the time variable.
Results All 106 workers diagnosed with silicosis were male, with a mean SD age at diagnosis of 36.2 7.0 years. Most diagnoses (73.6%) were made between 2010 and 2013 (Fig 1), and the duration of exposure to AS was 12.0 4.3 years. The latency period from onset of exposure to diagnosis was 13.7 4.1 years. In 28 cases (26.4%), silicosis developed in an accelerated form between 5 and 10 years following the initial exposure, but there were no cases with an exposure period < 5 years. All of the patients worked cutting and polishing slabs of AS in small factories and were also involved during in-home installation performing dry operations (on many
occasions without effective personal protective equipment). Thirty-two patients (30.2%) were diagnosed after they had left their jobs.
At diagnosis, 17.9% were smokers, 37.7% were ex- smokers, and 44.3% were nonsmokers. Cumulative tobacco consumption in pack-years was 10.6 7.6 for both smokers and ex-smokers. Four patients had been previously diagnosed with bronchial asthma, and one had been previously diagnosed with pulmonary TB. Symptoms were predominantly mild, and the most common were cough and dyspnea (81% patients with modified Medical Research Council dyspnea scale grade
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TABLE 1 ] Chest Radiography at Baseline and at Final Follow-up (ILO Classification)
Baseline Value No.
Final Follow-Up Category
Lost to Follow-upCategory 0 Category 1 Category 2 Category 3 PMF
Category 0 19a 3 8 4 0 1 3
Category 1 56 ... 31 11 0 12 2
Category 2 19 ... ... 9 1 9 0
Category 3 7 ... ... ... 2 4 1
PMF 5 ... ... ... ... 5 0
ILO ¼ International Labour Office; PMF ¼ progressive massive fibrosis. aDiagnosis by high-resolution CT scan.
0, 14% with grade 1, and 5% with grade 2). Results of the tuberculin test were positive in 5.7% of the cases.
The mean follow-up time from diagnosis of silicosis to the last visit was 4.01 2.1 years. During follow-up, four patients died, two following lung transplantation and two for reasons unrelated to silicosis. In six patients, only the initial diagnostic consultation was recorded; thus, no follow-up data are available (four diagnosed in 2018 and two in 2017). In another four patients, retrospective data were incomplete because they were lost to follow-up.
Table 1 presents the CXR findings according to the ILO classification at diagnosis and at the time of the last CXR.
TABLE 2 ] Progression of Respiratory Function
Variable
Overall Follow Annual Decre
FVC, mL 4,324 879 4,068 868 86.8 62. 11
FVC, % 86.0 15.1 80.2 15.09 1.13 0.6 1.
FEV1 , mL 3,429 579 3139 752 83.4 61. 10
FEV1, % 86.6 16.1 78.9 16.9 1.5 1.0 1.
FEV1/FVC 79.1 5.9 76.6 7.0 0.65 0.4 0.
DLCO, mmoL/ min/kPa
DLCO, % 76.8 15.7 76.1 15.5 0.12 –0.6 0.
Values are expressed as mean SD. Respiratory function data are at diagn monoxide. aPatients with only one test (diagnosed in 2017 and 2018) or lost to follow-up bFixed effects linear regression models. cP value for mean reduction for the lung function parameter in the overall per dStatistically significant (P < .05) when comparing first and second periods.
chestjournal.org
At baseline, 19 cases were classified in category 0, and five cases were assessed as PMF. After the follow-up period, 51 more cases showed radiologic progression (then 56% of patients that finished the follow-up were considered progressors), and 31 cases were classified as PMF. Only three patients remained in ILO category 0. Initial HRCT imaging showed two additional patients with PMF. Therefore, seven patients were diagnosed as having PMF, and 99 were considered to have simple silicosis at baseline. At the end of the follow-up, 40 of 106 (37.7%) patients were classified as PMF according to HRCT imaging. Thus, at baseline, HRCT scans exhibited a micronodular pattern in 19 patients (17.9%) who had a CXR that was negative for silicosis. In addition, at the end
-up, aseb
P c
CI Mean 95% CI Mean 95% CI
7 to 0.9
0.04 –0.19 to 0.27
–0.85 –3.02 to 1.30
osis and last follow-up. DLCO ¼ diffusing capacity of the lung for carbon
were excluded.
TABLE 3 ] Cox Proportional Hazards Model for Factors Associated With the Development of Progressive Massive Fibrosis (n ¼ 100)
Variable HR SE 95% CI P
Baseline FVC 0.96 0.01 0.94-0.99 <.01
Duration of exposure to AS (y) 1.09 0,05 1.00-1.19 .06
Age at onset of exposure 0.98 0.03 0.92-1.04 .55
Smoking index by smoking status
Never smoker Ref
Ex-smoker 1,04 0.03 0.98-1.11 .14
AS ¼ artificial stone; HR ¼ hazard ratio; Ref ¼ reference category.
of the follow-up period, nine of 40 cases classified as PMF according to HRCT imaging remained as simple silicosis according to the CXR results.
Table 2 presents the spirometry and DLCO values at diagnosis and at the last follow-up visit. Fixed effect linear regression showed a significant decrease in FVC and FEV1, with average annual decreases of 86.8 and 83.4 mL, respectively. It should be noted that 25% of the patients had an even more accelerated decline in lung function ($ 157 mL in FVC and $ 133 mL in FEV1 per year). The average annual decline rate of FVC was 111.2 mL (95% CI, 77.2 to 145.3) in the first 4 years of follow-up, whereas it was 54.2 mL (95% CI, –12.2 to 120.5) between 5 and 8 years of follow-up. These results show a higher rate of decline in the first years of disease, although it was not statistically significant.
A different pattern was observed both in FEV1, which remained stable in the two periods, and FEV1/FVC, which showed a significantly steeper decrease in the second period. The decrease in DLCO was minimal during the follow-up, although 25% of patients experienced a decrease of$ 0.2 mmol/min/kPa per year. According to the severity of spirometric abnormality, the percentage of patients with FVC within normal limits was 74.5% at diagnosis, which decreased to 57.8% at the end of follow-up. We found no correlation between changes in FVC and radiologic progression in the bivariate analyses. Regarding the degree of bronchial obstruction, which was determined based on the FEV1/ FVC ratio, a significant risk for airflow obstruction was observed (6.6% of patients with FEV1/FVC < 70% at baseline and 16.7% after follow-up; P ¼ .025).
When performing multivariable analysis (Table 3) with the most relevant variables considered in the literature, it was observed that lower FVC at diagnosis was closely associated with progression to PMF, whereas for each
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additional year of exposure to AS, there was a 9% increase in the hazard of PMF (hazard ratio, 1.09; 95% CI, 1.00-1.19). Estimations were adjusted by age at onset of exposure to AS and cigarette consumption at diagnosis.
Discussion Several studies have reported a high percentage of patients with AS silicosis who present with PMF at diagnosis. For example, 8.7% of the cases in our previous series11 and 15% of the cases described by Edwards23 had PMF. Although some studies24,25 have described the clinical and radiologic features of PMF, the progression of this form of silicosis is unknown. To the best of our knowledge, the cohort we present here is the first and largest group of artificial stone workers in which the progression of the patients has been described once diagnosed as well as following cessation of exposure to silica.
One of the main findings of our study is that, despite the cessation of exposure, there was an accelerated decline in lung function and a rapid progression to PMF in these patients over a short period of time. At diagnosis, 6.6% of patients were classified as having PMF, but after an average follow-up of 4 years, the percentage of patients who progressed to PMF rose to 37.7%. Comparing the progression of AS silicosis with that of silicosis caused by natural stone, Carneiro et al26 studied gold mine workers and found that after exposure cessation and a mean follow-up of 17.9 years, only three of 39 patients with silicosis progressed to PMF (7.6%). Lee et al27 described a series of 141 patients with silicosis due to exposure in granite quarries. In these cases, the duration of exposure was 23.5 years, and 17.7% of patients had large opacities in the baseline radiograph; after a 7.5-year follow-up, 52 (36.9%) had developed large opacities. In a follow-up study of sandblasting
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workers conducted 4 years following diagnosis and cessation of exposure to silica, Akgun et al28 found that 82% of the…
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