Introduction
Progressive massive fibrosis (PMF) is defined radiographically by the formation of large (diameter ≥ one cm) opacities which is the well-known most severe form of silicosis and coal worker’s pneumoconiosis [
1]. Recent reports show that PMF is a significant and increasing problem throughout the world [
2]. In the United States, a resurgence of PMF and rapidly progressive pneumoconiosis (RPP ) have occurred over the last two decades [
3,
4]. In addition to traditional industries (such as mining and construction), many different studies have reported PMF in other new industries (such as denim sandblasting, artificial quartz stone exposure) [
4,
5]. Undoubtedly, removal from exposure is not enough and effective treatments are urgently needed. With great regret, no clinically validated effective treatment to prevent PMF is available by recent literature [
2,
6]. Tetrandrine (Tet) as a potent calcium channel blocker and in the treatment of different health issues has been referenced in
Chinese Pharmacopoeia for its use as an anti-silicosis agent [
7]. Previous studies have reported that silicotic nodules under X-ray have reduced and lung function have improved after Tet treatment [
8,
9]. However, the effect of Tet on PMF has not been reported. To explore the clinical effect of Tet on PMF, we collected patient data and conducted a retrospective cohort study.
Methods
Study design and participants
This study was a retrospective cohort study; we analyzed the clinical data of pneumoconiosis patients with PMF who were treated in Hunan Prevention and Treatment Institute for Occupational Diseases between January 2020 to January 2022. Patients who took Tet regularly (80 mg tid, for 6 days a week, with none on the 7th day) for ≥ 6 months were defined as the Tet treatment group, and those who took Tet for < 1 month/year were defined as the control group. Patients were enrolled to this study : (1) diagnosed as coal workers’ pneumoconisis or silicosis and combined with PMF; (2) willing to participate in the study and signed an informed consent form. Exclusion criteria: (1) Tet administration was not consistent with the Tet group or the control group; (2) lack of pre - and/or post-treatment imaging data; (3) comorbidites such as tuberculous mycobacterial infection, lung tumor, respiratory infection, pneumothorax, pleural effusion, and asthma, interstitial lung diseases and significant other organ dysfunction were also excluded. Pneumoconiosis according to a national criterion on the diagnosis of occupational pneumoconiosis (GBZ 70-2015) [
10], which is consistent with the criteria for pneumoconiosis of the International Labour Organization (ILO) classification [
1]. Small opacities and emphysema were assessed using the International Classification of HRCT of Occupational and Environmental Respiratory Diseases [
11]. PMF is defined radiographically by the formation of large (diameter ≥ 1 cm) opacities [
2]. PMF size was calculated as transverse diameter × long diameter (mm) according to the HRCT mediastinal window, and if there were 2 or more, the size was equal to the sum of the individual PMF sizes. PMF progression was defined as an increase in size of more than or equal to 10%, whereas an increase in size of less than 10% was defined as stable. All images were evaluated by two radiologists who had been engaged in the diagnosis of pneumoconiosis.
Data collection
The following data were collected: demographics, medical history (comorbidity, complication, regimen of Tet administration), detailed occupational history (including whether engaged in drilling, and the start and end dates of employment, exposure duration and so on), and smoking status, and pack-years smoked. Smoking intensity was analysed as both a categorical (0 pack-years, 1–19 pack-years and ≥ 20 pack-years). Rate of increase in PMF size was calculated as follows: post-treatment- pretreatment PMF size/baseline size *100%. We defined progression as an increase in PMF size of ≥ 10% from baseline, and stable as an increase of < 10% .
Pulmonary function tests
All the spirometry tests data based on criteria from the American Toracic Society and European Respiratory Society criteria [
12]. Trained technicians performed pulmonary function examinations using spirometry, whole body plethysmography, and single-breath diffusing capacity for carbon monoxide. We collected pulmonary function parameters including FVC, FEV
1, FEV
1/FVC, DLco% before and after treatment, and unreliable spirometric data were excluded.
Statistical analysis
Continuous data were expressed as the means ± SD or median (interquartile range) and were analyzed by the Student’s t test or Mann–Whitney U test. Paired data were analyzed with the use of a paired t test or a two-sample Wilcoxon test. Frequencies and percentages were used to describe categorical data; chi-square and Fishers exact tests were used to compare these data. P < 0.05 was considered statistically significant. SPSS 26.0 software (IBM Inc., Chicago, Illinois, USA); GraphPad Prism V8 (GraphPad Software, La Jolla, USA) were used for statistical analysis and to make plots. We did not impute missing data.
Discussion
Our study investigated the efficacy of Tet in the treatment of PMF. We found a rapid increase in PMF size in control group over a short period of time, with a 21.9% (median) increase from baseline in PMF size after 15 months of follow-up. And we also found a rapid decline in lung function, with FEV
1 falling by 120ml, FVC 85ml, FEV
1/FVC 1.75%, and DLco% 2.3%. Recently published literature including our previous study continues to indicate that presence of PMF is associated with worsening of pulmonary function [
13,
14], and indicate that development of PMF is associated with increased morbidity and mortality [
15]. Hence, effective antifibrotic drugs are urgently needed to slow the progression of fibrosis and reduce the decline in lung function.
In our study, we found that the PMF size decreased by 2.5% (median) after a median 13 months of Tet treatment, while the control group increased by 21.9% (Fig.
2A-E). And 70% of PMF achieved radiographic stability, in contrast, 67.2% of the patients in the control group showed progression. Similar favorable trends were observed in emphysema and small nodule profusion after treatment. From the results of this study, we found that Tet has great potential to slow the progression of PMF fibrosis as well as the aggravation of emphysema. Similar to the results of a recent study, which showed that after taking Tet for 3–12 months, 56.5 to 65.4% of silicosis patients had improved HRCT [
9].
We can also found improvement in lung function in parallel with radiographic improvement. FVC and FEV
1 improved by a median of 40ml in the Tet group, while they decreased by 85ml and 120ml in the control group (Fig.
3). However, beneficial effect on diffusion function was failed to found; with a statistically significant decrease in both groups.
Previous studies reported that Tet combined with other drugs such as quinolyl piperazine hydroxyl.
phosphate (QOHP) or poly-2-vinyl pyridine-nitrogen oxide (PVNO) or acetylcysteine, can improve imaging, pulmonary function, and pneumoconiosis symptoms in the treatment of pneumoconiosis [
16‐
19]. This retrospective cohort study further indicates that Tet has a potential therapeutic effect on PMF by delaying the progression of PMF and halting the rapid decline in lung function.
For decades, many studies have reported that Tet can inhibit the progression of pneumoconiosis fibrosis though different pathways. Early results showed that Tet exhibited cytoskeletal depolymerization activity by interrupting the process of collagen biosynthesis [
20,
21] and degrading the collagen in the silicic nodules formed and inhibiting the transcription of collagen genes [
22,
23]. Another report suggested that Tet could promote the activity of superoxide dismutase (SOD) in lung tissue [
7]. Recent findings showed that Tet down-regulated the silica-induced secretion of cytokines by NLRP3 inflammasome activation [
24,
25]. Song MY, et al. using multiple methods and multi-omics techniques, further confirmed that Tet can inhibit silicosis-associated inflammation and fibrosis by suppressing both the canonical and noncanonical NLRP3 inflammation pathways in lung macrophages [
14].
Our data provide new evidence of Tet in the treatment of PMF which may promote an acceptable individualized treatment regime of Tet. This study has some limitations. First, this study is a retrospective study, recall bias and selective bias cannot be excluded; second, it is a single center data and the follow-up period was short. Hence, multicenter randomized controlled trial (RCT) or prospective cohort studies are expected in the near future.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.