Silicosis

We identified 74,040 workers from 20 metal mines and nine pottery factories in central and southern China. All individuals were unrelated ethnic Han Chinese. We selected workplaces with systematically collected data on silica dust exposure and workers' health condition. The study included ten tungsten mines in Jiangxi and Hunan provinces, six iron and copper mines in Hubei province, four tin mines in Guangxi province, and nine pottery factories in Jiangxi, Hunan, and Henan provinces (Figure S1). The cohort included all 74,040 workers who were registered in company employment records—which included personnel files, individual medical records, occupational records, and wage rosters—for at least 1 y between January 1, 1960, and December 31, 1974. We collected retrospective data on vital status, work history, and newly diagnosed pneumoconiosis (silicosis) until 1986, with mortality follow-up until the end of 2003.
Trained investigators used a questionnaire to collect data on demographic information, cigarette use, and drinking habits since 1986. In 2004, occupational history and other updates were collected from survivors or those still employed. We defined positive silica dust exposure status as employment in a silica-dust-exposed job for 6 mo or more. Work histories for silica-dust-exposed workers were taken from company occupational records. Data included job titles, work start and end dates, and reasons for leaving (e.g., retirement or workplace change).
All individuals were tracked for their vital status by local hygienists (or occupational health doctors) from January 1, 1960, through December 31, 2003. We classified cause of death evidence by levels of confidence in the data: Level 1—medical record from a hospital or a personal doctor at a local hospital (60.5%); Level 2—cause of death recorded in an employment register, accident record, or death certificate (35.2%); and Level 3—oral reports from relatives (4.3%). Results did not change materially after excluding Level 3 deaths. We used the 10th International Classification of Diseases (ICD-10) to code causes of death.
All workers exposed to silica dust received chest radiographs every 2 to 4 y, even after cessation of dust exposure. National diagnostic criteria for pneumoconiosis were standardized as stage I, II, or III. These categories have been previously described [16] (link). The study was approved by the Tongji Medical College Institutional Review Board and the US National Institute for Occupational Safety and Health Institutional Review Board.

We applied base-case assumptions used in the published mathematical model of the Thibela study data to calculate a crude estimate of the average incidence rate of TB disease attributable to reinfection in the first year after IPT [22 (link)]. We did this overall and by cluster to allow for the varying annual risk of infection per cluster. We thereby assumed an annual risk of infection (averaged across clusters) before the intervention of 20 % per year and, based on outputs from the original model [22 (link)], a reduction in the annual risk of infection ranging between 11–20 % after IPT was introduced. For all clusters we assumed an HIV prevalence of 30 % of whom 25 % had a CD4 count below 200 cells/μL (and all of whom were eligible for and on ART), an initial pre-treatment loss to follow-up of 40 % and an average time to detection of 1 year. The age distribution and prevalence of silicosis depended on the cluster and were based on data collected as part of the study. The origin of these assumptions are explained in detail elsewhere [22 (link)]. Furthermore, also based on the original model, we assumed that reinfection, but no progression, could take place during IPT. We then calculated the observed TB incidence rate in the first 12 months after IPT (ITT), overall and per cluster, and compared these rates to the modelled estimates of TB incidence.

Healthy human lung tissue was obtained from Donor Alliance, and IPF tissue was obtained from lung biopsies or explanted lungs from confirmed cases of IPF (IRB 11-1664) as described previously (74 (link)). Tissue from patients with silicosis was obtained after lung transplant as described previously (75 (link)). For the generation of PCLS, freshly explanted healthy or IPF lungs were kept on ice and processed within 24 hours. Peripheral sections of lungs were inflated with low–melting point agarose (MilliporeSigma) by cannulation of a visible bronchus; then 6 × 6 × 6 mm cubes were cut from the lung, embedded in low–melting point agarose, and sectioned using a vibratome (Leica). We cultured 300 μm slices in Eagle minimal essential medium (EMEM, Lonza) with 10% heat-inactivated fetal bovine serum (FBS, Atlanta Biologicals) and 1% penicillin/streptomycin/l-glutamine with or without ABT-263 (5 μM, Medchemexpress) for 24 hours.