Lung Features in Individuals with Biomass Smoke Exposure Characterized by CT Scan and Changes in Pulmonary Function

Introduction

Chronic obstructive pulmonary disease (COPD) is associated with exposure to toxic particles or gases. Biomass smoke exposure (BSE) and cigarette smoke exposure (CSE) are the most important risk factors for development of COPD.^1,2 In recent decades, considerable progress has been made in the treatment of COPD, but its incidence and mortality remain high, which suggests that COPD-related environmental and occupational factors require further attention.^1–3 Among these factors, the absence of interventions for BSE is particularly obvious.⁴ Nearly 3 billion people worldwide use biomass as energy for heating and cooking, which results in substantial BSE exposure.¹ Individuals affected by BSE mainly women who use biomass for cooking in underdeveloped rural areas; these individuals have relatively lower socioeconomic status.^5–8

BSE has received insufficient attention.^9–11 For example, among users of Douyin (a popular social media service in China), there are currently 198 accounts that promote smoking cessation-related content; by contrast, only one professional account addresses the risks of biomass smoke pollution. BSE COPD patients have specific miRNA profile and pathological changes, such as more bronchiolitis, pulmonary fibrosis, and airway wall thickness. Moreover, few studies have reported clinical symptoms and the computed tomography (CT) findings of emphysema and/or small airway disease caused by BSE. They are presented with lower oxygen saturation and weaker activity tolerance compared with CSE COPD patients.^12–16 There is a lack of comprehensive studies regarding pulmonary lesions caused by BSE, how BSE affects the pulmonary small vessels, the respiratory muscles, the development of emphysema and airway remodeling.

Our study focused on populations with BSE in economically underdeveloped rural areas to comprehensively investigate CT findings in patients with and without COPD and exposures to cigarette smoke or biomass fuels. This study aimed to clarify the features of BSE-related lung injury compared to CSE induced injury that results in COPD vs those without COPD.

Methods

Study Design

The Ethics Committee of Guangzhou Institute of Respiratory Health approved the study protocol. This study was conducted in accordance with the Declaration of Helsinki. Participants were selected from among the rural population in an underdeveloped mountainous area of northern Guangdong, China, using an observatory research subgroup data from COPD community screening database (from 2014 to 2015).^13,17,18 No intervention was performed on participants and no medication was prescribed to patients with COPD. BSE exposure population and CSE population were followed for a year. Healthy control individuals were not followed up with pulmonary function. Written informed consent was obtained from all participants. Detailed information regarding recruitment, clinical management, and follow-up was described in previous studies.^13,17,18

Population

This study included individuals with BSE or CSE (including healthy individuals and patients with COPD) and healthy controls, who were >40 years of age, had complete clinical data, pulmonary function assessments, and lung HRCT data. The study excluded patients who had lung cancer, asthma, interstitial lung disease, pulmonary infarction, pneumonia, or pleural effusion, based on medical history or CT scan findings. The healthy control group included healthy individuals with normal lung function, without a history of CSE or BSE, without a history of pulmonary disease or respiratory symptoms, and without visible emphysema or low attenuation areas less than a threshold of −950 Hounsfield units (LAA-950%) <5% in CT scans.

Patient Groups

According to their history of CSE or BSE and whether they had been diagnosed with COPD, 98 eligible participants were allocated into five groups: BSE+COPD (n=19), BSE normal (n=16), CSE+COPD (n=25), CSE normal (n=13), and healthy control (n=25) (Figure 1). The BSE+COPD and CSE+COPD groups only included patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I and II (post-bronchodilator forced expiratory volume in 1 second [FEV₁]/forced vital capacity [FVC] < 0.7 and FEV₁ ≥ 50% predicted).

Figure 1 Flow chart of the study participants. Abbreviations: CT, computed tomography; CSE, cigarette smoke exposure; BSE, biomass smoke exposure; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Data Collected

Baseline records of participants were collected, including demographic information, lung function, history of BSE and/or CSE, and high-resolution CT findings; follow-up lung function data were also collected. The BSE and CSE indexes were calculated as previously described.¹³ The BSE index is defined as the cumulative exposure of biomass, calculated by multiplying the average number of hours per day in the kitchen with the number of years of cooking with biomass. Cigarette smoking index was expressed as pack-years.

Annual reductions in lung function (FEV₁ and FVC) were calculated. High-resolution CT findings were assessed to determine the severity of emphysema and airway remodeling, as well as damage to pulmonary small vessels, pectoralis major muscle, pectoralis minor muscle, and erector spinae muscle.

Imaging Methods

Quantitative CT Imaging Analysis

High-resolution CT was performed at suspended full inspiration using a multidetector row CT scanner (Aquilion 16, Toshiba, Tokyo, Japan).¹³ CT scan findings were analyzed with 3D slicer software, version 4.8.1 (https://www.slicer.org, Brigham and Women’s Hospital).

CT Measurement of Emphysema

Emphysema was detected using the chest imaging platform/parenchyma module of 3D slicer software, using a Hounsfield unit threshold of −950 (ie, %LAA-950). The (upper third)/(lower third) ratio of LAA-950 was used to assess the distribution of emphysema.^19,20

CT Measurement of Bronchial Inner Diameter and Bronchial Wall Thickness

Using the Airway Inspector module of 3D slicer software, the third, fourth, fifth, sixth generation of airway bronchi of the right upper lobe apical bronchus (ie, RB1) and right lower lobe posterior bronchus (ie, RB10) were identified.²¹ Then, the inner diameter, bronchial wall thickness, and bronchial wall area% were detected.

CT Measurement of Cross-Sectional Area (CSEA)% of Pulmonary Small Vessels

In accordance with the method described by Matsuoka et al, pulmonary small vessels were defined as “circular” blood vessels that were perpendicular to the cross-sectional plane and exhibited a cross-sectional area of <5 mm².^21,22 The upper, middle, and lower slices were captured 1 cm above the top of the aortic arch, 1 cm below the carina, and 1 cm below the right lower pulmonary vein, respectively. CSEA_<5% was calculated as the percentage of small vessel CSEA to lung CSEA in each slice. The total CSEA_<5% was calculated as the percentage of total small vessel CSEA to total lung CSEA of three slices.

CSEA% detection was performed as shown in Figure 2. First, the segmentation and modeling of the lungs were conducted using the Parenchyma Analysis and edit modules in the 3D slicer software. The segmented lung areas were filled with −200 to achieve a uniformly gray color. Second, chest vessels were segmented using the VTMK module in 3D slicer software. Pulmonary vessels were segmented by clipping chest vessels with the lung model. Third, in the above three slices, images of pulmonary vessels and gray lungs were saved separately. Image-Pro Plus 6.0 software (Media Cybernetics, Inc.) was used to measure the areas of gray lungs and small pulmonary vessels. Fourth, pulmonary vessels with “Rounders” of 0.9–1 (ie, circular blood vessels) and “Areas” of ≤5 mm² were segmented as pulmonary small vessels (CSEA_<5). Fifth, CSEAs of gray lungs and small vessels were measured using the count/size module in Image-Pro Plus software for each slice. Finally, CSEA_<5% in each slice and total CSEA_<5% were calculated using the formula described above.

Figure 2 Sample computed tomography (CT) scans used to determine pulmonary small vessels. (A) CT image in middle slice of lung. (B) Segmented lungs shaded in grey. (C) Pulmonary vessels shaded in green. (D) Pulmonary small vessels shaded in red.

CT Measurement of Pectoralis and Erector Spinae Muscles

The area and density of muscles were measured using the body composition module of 3D slicer software, as shown in Figure 3. The pectoralis major and minor muscles were measured at the first slice above the aorta, while the erector spinae muscle was measured at the lower slice of the T12 thoracic vertebra.^23,24

Figure 3 Sample computed tomography (CT) scans used to determine pectoralis muscle, erector spinae muscle. (A) Pectoralis major muscle shaded in red, pectoralis minor muscle shaded in brown. (B) Erector spinae muscle shaded in red.

Statistical Analysis

Data are presented as mean ± standard deviation, median (quartile), or numbers. Comparisons of continuous variables among groups or between multiple groups were evaluated by one-way analysis of variance with a post hoc test (least significant difference method), Kruskal–Wallis test or Mann–Whitney U-test. Comparisons of categorical variables among groups were performed using Fisher’s exact test. Pearson’s correlation coefficients were used to assess associations between lung function decline and CT index. Statistical analyses were conducted using IBM SPSS Statistics, version 23.0 (IBM Corp., Armonk, NY, USA). Two-tailed P-values <0.05 were considered statistically significant.

Results

Baseline Characteristics

Table 1 describes the baseline characteristics of participants in each group. This study focused on economically underdeveloped mountainous rural areas, where individuals with BSE were mainly women who cook with biofuel, while smokers were mainly men. The BIOFUEL-index for BSE COPD and the smoking index for CSE COPD were not significantly different compared to the BSE and CSE normal groups (P>0.05). There were no significant differences in baseline lung function (FEV₁% and FEV₁/FVC) and GOLD stage between the BSE+COPD and CSE+COPD groups (both P>0.05).

Table 1 Baseline Characteristics Among BSE, CSE Groups and Healthy Control Groups

This study discovered that lung function decline (FEV₁ and FEV₁/FVC) was slower in the BSE+COPD group than in the CSE+COPD group (both P<0.05), suggesting that patients with BSE and COPD may exhibit slower progression of disease and may have greater benefit from early active intervention.

CT Features of Individuals with BSE

Emphysema Distribution in Patients with BSE and COPD

Like patients in the CSE+COPD group, those in the BSE+COPD group had greater extent of emphysema than BSE normal group; however, there was no significant difference in the total percentage of emphysema between the two groups (P>0.05). Lower lung emphysema was more in the BSE+COPD group than in the CSE+COPD group (P<0.05). See Table 2.

Table 2 Comparison of CT Characteristics on Emphysema, Pulmonary Small Vessel and Airway Remodeling Among BSE, CSE Groups and Healthy Groups

Pulmonary Small Vessel Area in Healthy Individuals with BSE

Compared with the healthy control group, both the BSE normal and CSE normal groups showed reduced pulmonary small vessel areas (P<0.05); this was consistent among the upper, middle, and lower regions of the lung (P<0.05). Compared with the BSE normal and CSE normal groups, the pulmonary small vessel areas in BSE+COPD and CSE+COPD groups were further reduced, but these differences were not statistically significant (all P>0.05). Finally, there was no significant difference in the reduction of pulmonary small blood vessel areas between the BSE+COPD and CSE+COPD groups (P>0.05). See Table 2 and Supplementary Table 1.

Airway Remodeling in Medium and Small Airways (Grades III–VI Bronchi)

Small airway remodeling was present in otherwise healthy individuals with BSE, while patients with BSE and COPD exhibited serious medium and small airway remodeling. Compared with the CSE normal group, small airway remodeling (ie, narrow airway and thickened airway wall) was obvious in grades IV–VI bronchi in the BSE normal group (all P<0.05). Compared with the CSE+COPD group, more serious airway remodeling in medium and small airways (grades III–VI bronchi) was observed in the BSE+COPD group (all P<0.05). See Table 2 and Supplementary Table 1.

Left Pectoralis Major Muscle Areas in Patients with BSE and COPD

The left and right pectoralis major muscle area and density were considerably greater in the BSE normal group than in the healthy control group (all P<0.05); similar findings were present in the CSE normal group (all P<0.05). Compared with the BSE normal group, the left pectoralis major muscle area significantly decreased in the BSE+COPD group (P<0.05). See Table 3.

Table 3 Comparison of CT Characteristics on Pectoralis Muscle and Erector Spinae Muscle Among BSE, CSE Groups and Healthy Groups

CT Presentation and Lung Function Changes

Lung function decline was relatively slow in the BSE+COPD group; there were no correlations between CT indexes and annual reduction of FEV₁ (all P>0.05). However, FEV₁ reduction was relatively rapid in the CSE+COPD group; this reduction negatively correlated with right pectoralis minor muscle area (r=−0.68, P<0.01; See Supplementary Table 2).

Discussion

The harmfulness of smoking is well known because of social media and smoking cessation clinics.^10,11,25,26 In contrast, the risks of BSE are not well known among the public and health-related efforts are insufficient.

This study was conducted in an underdeveloped mountainous area of rural China. The composition of the study population was representative of the local region. The study specifically focused on describing the lung damage caused by BSE, with CSE used as a reference exposure.

The limited evidence regarding lung damage caused by BSE has mainly emphasized emphysema and air trapping, which does not provide sufficient insights to guide BSE intervention.^12–14 In this study, we used 3D slicer software to make an overall assessment of lung damage, including airway remodeling in medium and small airways, emphysema, pulmonary small vessels, and respiratory muscles. Qualitative and quantitative determinations of lung damage caused by BSE were performed following three-dimensional and two-dimensional imaging of the lung.

Different from previous reports, we discovered that airway damage was more serious in the BSE+COPD group than in the CSE+COPD group, such that it involved substantial remodeling of small and medium airways.^12,13 Furthermore, pectoralis major muscle area decreased in the BSE+COPD group, compared with the BSE normal group; a corresponding difference was not observed between CSE+COPD and CSE normal groups. The impacts of BSE on skeletal muscle changes compared with CSE require further investigation.

An interesting finding was that both the BSE+COPD and BSE normal groups had significant reductions in pulmonary small vessel area. To the best of our knowledge, this is the first study to show changes in pulmonary small vessel area with BSE. The reduction of pulmonary small vessel area is associated with acute exacerbation of COPD and serves as an independent risk factor for mortality.^27,28 Additionally, BSE is associated with elevated risks of hypertension, coronary heart disease, and stroke.²⁹

The present study showed that lung function decline was slightly slower in the BSE+COPD group, which was consistent with the results reported by Salvi et al.³⁰ Since efforts to improve cooking fuels and kitchen ventilation will reduce indoor PM_2.5 concentrations, delay lung function decline, and lower the risk of respiratory disease, early intervention for BSE patients may provide greater clinical improvements.^18,31

Phenotyping studies regarding COPD have found that specific lung CT features are closely related to the progression of COPD. Specific types of emphysema, airway remodeling, and changes in pulmonary small vessel and chest muscle areas, all of which can be reversed by active intervention, are associated with the progression of COPD.^{19,21,23,27,28,32–34} Therefore, we examined correlations between these pathological changes and the annual reduction of FEV₁, with the aim of identifying a target to delay lung function decline in patients with BSE and COPD. However, we did not find an association between any CT index and reduction of FEV₁ in the BSE+COPD group. This may have been influenced by the small number of participants in the BSE+COPD group, therefore producing no statistically significant findings.

Age is an important risk factor for COPD. In normal people, alveolar sacs increase in size with age. However, the pathological changes of COPD and aging lung are different.³⁵ In this study, BSE+COPD patients have significant airway remodeling changes in the middle and small airways, and relatively mild emphysema, suggesting that this change is mainly caused by biomass exposure rather than aging.

This study had some limitations. First, the number of participants was relatively small, and there were no follow-up lung CT data for any participants. Second, this study did not specifically recruit women in the CSE+COPD group or men in the BSE+COPD group. Data from COPDGene show that gender differences have an impact on the clinical phenotype and acute exacerbation of COPD.³⁶ In current study, the differences in gender proportions exist may also have biased the results. Therefore, future studies should focus on sex differences between BSE+COPD and CSE+COPD groups and the effect of sex on the phenotype of COPD. Third, we did not recruit GOLD stage III participants. Fourth, due to insufficient sample size, no comparison was made between groups of GOLD stage I and GOLD stage II for patients with BSE+COPD, and no comparison between BSE COPD and CSE COPD patients with the same GOLD stage. Future subgroup study based on GOLD stage will add show more value to the effect of BSE on lung CT findings.

In summary, this study focused on individuals with BSE living in an underdeveloped rural area of China. It showed that otherwise healthy individuals exposed to BSE had reduced pulmonary small vessel area and airway remodeling, while patients with BSE and COPD had more severe emphysema, airway remodeling, and reductions in pectoralis muscle change, as well as relatively slower declines in lung function. More investigations are thus needed regarding the specific phenotypes of BSE COPD patients in different stage of GOLD.