High-Resolution Computed Tomography Based Comparative Analysis of Asbestosis vs. Fibrotic Hypersensitivity Pneumonitis


 BackgroundAsbestosis and fibrotic hypersensitivity pneumonitis (FHP) are fibrotic interstitial lung diseases that develop secondary to inhalation exposure. The differential diagnosis is based on clinical evaluation of imaging findings, particularly in developing countries. We compared the imaging features between asbestosis and FHP to gain a better understanding of the differential diagnostic value of these conditions.MethodsThis comparative study included 204 patients with asbestosis and 74 patients with FHP. We compared patients’ clinical data and chest high-resolution computed tomography (HRCT) images obtained from a predesigned chart. The International Classification of HRCT for Occupational and Environmental Respiratory Diseases was used to categorize chest imaging findings in patients. Diagnostic tests were used to compare the imaging features of asbestosis and FHP.ResultsPatients with asbestosis were older and had a longer latent period until disease manifestation than those with FHP. Asbestosis was characterized by irregular and/or linear opacities, with lower lung preponderance, accompanied by ground-glass opacities and mosaic attenuation. Notably, 98.5% of patients with asbestosis showed benign pleural abnormalities, and >33% of these patients had diffuse pleural thickening with parenchymal bands and/or rounded atelectasis. Abnormalities of the mediastinal and diaphragmatic pleura were observed only in cases of asbestosis, and this finding showed high specificity for the diagnosis for asbestosis compared with that for FHP. Subpleural dots or diaphragmatic pleural abnormalities showed moderate sensitivity and high specificity for diagnosis of asbestosis compared with that for FHP. Interobserver reliability was good for evaluation of imaging findings including honeycombing, pleural calcification, lymphadenectasis, and lymph node calcification.ConclusionsHRCT-based imaging findings can distinguish between asbestosis and FHP to a certain extent, particularly with regard to subpleural dots and diaphragmatic pleural abnormalities that characterize the former.


Background
Asbestos is a natural crystalline silicate mineral that has various commercial and industrial uses, such as in re prevention and insulation. Asbestos is widely used in industrial production as well as in routine life; chrysotile bers is the most common form of asbestos that accounts for >90% of asbestos products used worldwide. The International Agency for Research on Cancer has classi ed asbestos as a group 1 carcinogen [1]. All types of asbestos are carcinogenic and can cause asbestos-related diseases (ARDs), and no safe level of exposure has been established [2,3] Evidence-based research shows that asbestos exposure is associated with benign pleural diseases, asbestosis, mesothelioma, as well as lung, ovarian, and laryngeal cancer [4]. According to worldwide estimates, 3,400 individuals die of asbestosis yearly [5].
Many countries have banned or strictly restricted the use of asbestos. However, it continues to be used in some countries, such as Brazil, Russia, India, Kazakhstan, and China. [

6] Data recorded in 2010 show that
China is the world's second largest producer and consumer of chrysotile [6]. ARDs show a long latent period (30-60 years) [7]. Iceland was the rst country to ban all types of asbestos in 1983. However, ARDs had already emerged and was prevalent over many years owing to the long latent period [8]. It is expected that the future burden of ARDs will be high in some developing countries that have not banned the use of asbestos. Owing to the long latent period, lack of accurate and complete history regarding asbestos exposure and lack of awareness among physicians often present a diagnostic challenge.
According to The American Thoracic Society (ATS) guidelines, asbestosis is similar to other diffuse pulmonary diseases and therefore needs to be differentiated from other pneumoconiosis, idiopathic pulmonary brosis (IPF), hypersensitivity pneumonitis (HP), and sarcoidosis, among other such conditions [9]. Prima facie, asbestosis and IPF are often indistinguishable with regard to imaging ndings. The brotic pattern observed in asbestosis is patchy in nature and mimics that of usual interstitial pneumonia (UIP) [10]. UIP typically presents as honeycombing with or without peripheral traction bronchiectasis or bronchiolectasis, predominantly in the subpleural and basal areas of the lungs [11]. Inhaled asbestos bers/particles are phagocytosed by macrophages and are transported to the pleura via the lymphatic channels. The inhaled particles are also deposited in the respiratory bronchioles and alveoli. Long-term deposition can lead to penetration of the distal interstitium of the lungs and directly the lungs [9]. Fibrotic HP (FHP) is histopathologically characterized by in ammation and brosis with a bronchiolocentric distribution, and pleural involvement is rare [12]. FHP usually represents an immune response of the body to antigen inhalation [13]. A lung biopsy de nitively distinguishes between asbestosis and FHP; however, obtaining su cient lung tissue samples is challenging, and the samples may not satisfactorily and accurately establish the histopathological diagnosis. Therefore, biopsy proven diagnosis is possible in only a few patients. In this study, we compared asbestosis and FHP with regard to the clinical data and chest high-resolution computed tomography (HRCT) ndings to gain a better understanding of the differential diagnostic value of these conditions to establish a practical method for HRCT-based differentiation between asbestosis and FHP.

Study design
This comparative study included two groups and conforms to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines [14].

Patient selection
We recruited 341 patients with asbestosis and 158 patients with HP, who were newly diagnosed at Beijing Chaoyang Hospital between January 2006 and December 2016. Asbestosis was diagnosed based on the International Labor Organization classi cation criteria after multidisciplinary discussions [9,15]. FHP was diagnosed based on the diagnostic criteria of HP [13,16]. In ammatory HP and FHP were classi ed based on the criteria. Patients with uncontrolled pneumonia, tuberculosis, autoimmune diseases, heart failure, severe liver and kidney dysfunction, malignant tumors, unavailability of HRCT data, and those with in ammatory HP and acute exacerbation of HP were excluded from the study. All patients completed a standardized questionnaire regarding their occupational and environmental history; all jobs throughout an individual's working life were considered. This study was approved by the Institutional Ethics Committee for Human Research, Beijing Chaoyang Hospital. Written informed consent was obtained from all participants involved in the research.
High-resolution computed tomography HRCT was performed using the following parameters: 0.625-mm sections, 1-s scan time, and a 10-mm interval in the apex-base scans with both lungs visualized in the eld of view. A respiratory imaging expert and an occupational disease expert independently evaluated the HRCT imaging ndings in patients with asbestosis and HP. The characteristics and distribution of lesions and the HRCT scores were determined after discussion. The International Classi cation of HRCT for Occupational and Environmental Respiratory Diseases (ICOERD) criteria were used to describe the chest imaging ndings in each lung, which was divided into three zones extending between the apex and base [17]. Following is the overall distribution for each side and zone of the thorax: upper arch of the aorta and the area superior to it, middle arch of the aorta extending inferiorly to the inferior pulmonary vein, lower inferior pulmonary vein and lower region including the diaphragm. The upper, middle and lower lung regions on each side were scored using a 4-point scale (0, 1, 2, and 3), and the total score was calculated as the sum of the 6 lung regions. The scores range between 0 and 18. Lesions evaluated included rounded opacities, irregular and/or linear opacities, inhomogeneous attenuation, honeycombing, emphysema, large opacities, pleural abnormalities, subpleural dots, coarse honeycombing, and a three-density pattern. Based on the 2013 ATS/European Respiratory Society guidelines for the diagnosis of idiopathic interstitial pneumonias [18], chest HRCT patterns were classi ed into UIP, nonspeci c interstitial pneumonia (NSIP), organizing pneumonia (OP), and unclassi able interstitial pneumonia (unclassi able IP).

Statistical analysis
All statistical analyses were performed using the SPSS Statistics software, V.25 (IBM Inc, Chicago, Illinois, USA). The median with interquartile range was used for descriptive analysis, mean±standard deviation was used for continuous variables, and counts with percentages were used for categorical variables. The t-test, Mann-Whitney U test, Chi-squared test, and Fisher's exact test were used for intergroup comparison. Diagnostic tests were used to determine the predictive value of HRCT imaging ndings to distinguish between asbestosis and FHP. The con dence interval of likelihood ratios was calculated using the Simmel method [20]. The kappa coe cient (κ) was used to evaluate interobserver reliability of imaging ndings, which was de ned as follows: poor (0.00<κ≤0.20), fair (0.20<κ≤0.40), moderate (0.40<κ≤0.60), good (0.60<κ≤0.80), and excellent (0.80<κ≤1.00) [21]. All comparisons were two-sided, and P value <0.05 was considered statistically signi cant.

Patients' demographic characteristics
We analyzed the data of 204 patients with asbestosis and 74 patients with FHP ( Figure 1). Supplemental Table 1 shows demographic data of the study population. The age at diagnosis was younger, and the exposure time and latent period were shorter in patients with FHP than in patients with asbestosis (P<0.05). We observed no statistically signi cant intergroup difference in smoking habits. Of the 204 patients with asbestosis, 125 (61.3%) were employed in occupations associated with asbestos products, and 79 (38.7%) patients processed asbestos at home.

Pulmonary Function Test Results
Lung volume parameters including FVC% predicted (pred.), FEV1% pred., and small airway velocity indices including PEF% pred., MEF75% pred., MEF50% pred., and MEF25% pred. were lower in patients with asbestosis than in patients with FHP (P<0.05 in all cases); however, no statistically signi cant intergroup difference was observed in TLC% pred., RV% pred., DLCO SB% pred., partial pressure of oxygen, and the composite physiologic index (P >0.05 in all cases) ( Table 1). Comparisons of high-resolution computed tomography ndings between asbestosis and brotic hypersensitivity pneumonitis The scores of irregular and/or linear opacities were lower in the asbestosis than in the FHP group (4.0 [2.0-8.0] vs. 8.5 [6.0-12.0], P<0.001) ( Table 2). The prevalence of subpleural lines <5 mm from the pleura (26.0% vs. 6.8%, P<0.001) and subpleural dots (56.9% vs. 13.5%, P<0.001) was higher in the asbestosis than in the FHP group. With regard to the distribution of irregular and/or linear opacities, the lower lung area was more commonly involved in the asbestosis group (Supplemental gure 1), whereas the middle and upper areas were more commonly involved in the FHP group. The percentage of peripheral involvement was higher in the asbestosis than in the FHP group (76.0% vs. 35.1%, P<0.001). Basal honeycombing was common in the asbestosis and upper lung honeycombing was common in the FHP group. Inhomogeneous attenuation was more common in the FHP group. Ground-glass opacities were detected in 123 (60.3%) patients with asbestosis and in 69 (93.2%) patients with FHP (P<0.001). We observed no signi cant intergroup difference in the percentage of mosaic perfusion and three-density pattern (P>0.05 in all cases) (Supplemental gure 2). With regard to pleural abnormalities, parenchymal bands, rounded atelectasis (Supplemental gure 3), and visceral, mediastinal, and diaphragmatic pleural abnormalities were observed only in the asbestosis group (Table 3). Prevalence of NSIP and OP was lower (P<0.05) and unclassi able IP was higher in the asbestosis than in the FHP group (P<0.05). No signi cant intergroup difference was found in UIP (P>0.05) ( Table 4).   Comparisons of the predictive value of high-resolution computed tomography ndings between the asbestosis and brotic hypersensitivity pneumonitis groups HRCT showed high sensitivity (0.94) and low speci city (0) for detection of interlobular opacities and high speci city (0.88, 0.86, and 0.92) but low or moderate sensitivity (0.27, 0.57, and 0.09) for detection of subpleural lines, subpleural dots, and honeycombing, respectively in asbestosis (Table 5). HRCT showed high speci city (0.80 and 0.82, respectively) but low sensitivity (0.22 and 0.15, respectively) for detection of mosaic attenuation and three-density pattern in asbestosis. HRCT showed moderate sensitivity (0.59) for detection of parietal pleural abnormalities and low speci city (0.23) for differential diagnosis in asbestosis. Visceral, mediastinal, and diaphragmatic pleural involvement and pleural effusion are speci c signs associated with asbestosis, and HRCT showed sensitivities of 0.40, 0.32, 0.59, and 0.09, respectively for the detection of these features. Detection of subpleural dots and diaphragmatic pleural abnormalities showed high predictive value for diagnosis of asbestosis vs. FHP (Table 5 and 6). The PPV represents the patients who were diagnosed as asbestosis. Abbreviations: HRCT, highresolution computed tomography; PPV, positive predictive value; NPV, negative predictive value; +LR, positive likelihood ratio; -LR, negative likelihood ratio; CI, con dence interval. The PPV represents the patients who were diagnosed as asbestosis. Abbreviations: HRCT, highresolution computed tomography; PPV, positive predictive value; NPV, negative predictive value; +LR, positive likelihood ratio; -LR, negative likelihood ratio; CI, con dence interval.

Accuracy Of High-resolution Computed Tomography Based Diagnosis
HRCT images tended to show inconsistencies in the evaluation of rounded opacities, irregular and/or linear opacities, intralobular opacities, subpleural lines, subpleural dots, ground-glass opacities, and centrilobular emphysema. HRCT showed moderate diagnostic accuracy for rounded atelectasis, mediastinal and diaphragmatic pleural involvement, calci cation of the mediastinal pleura, and pleural effusion. Notably, HRCT showed good diagnostic accuracy for honeycombing, pleural calci cation, calci cation of pleura on the chest wall and diaphragmatic pleura, as well as lymphadenopathy and calci cation. Other signs were poor. The interobserver reliability was good for classi cation of UIP, NSIP, and unclassi able IP based on chest HRCT imaging patterns.

Discussion
This retrospective comparative study included 204 patients with asbestosis and 74 patients with FHP who underwent chest HRCT and pulmonary function tests. Patients with asbestosis were older and had a longer latent period than those with FHP. Asbestosis was characterized by irregular and/or linear opacities, with basal preponderance, accompanied by ground-glass opacities, and mosaic attenuation. Pleural abnormalities were observed in 98.5% of patients with asbestosis and of these, >33% of patients had diffuse pleural thickening with parenchymal bands and rounded atelectasis. Mediastinal and diaphragmatic pleural involvement occurred only in asbestosis, and HRCT showed high speci city for the detection of these pleural abnormalities for the diagnosis of asbestosis. HRCT showed moderate sensitivity and high speci city for detection of subpleural dots and diaphragmatic pleural abnormalities to distinguish between asbestosis and FHP.
Pleural plaque formation represents the most common pathological lesion in asbestos-induced pleural abnormalities [9]. In a study that investigated individuals with asbestos exposure, 50% of the participants showed pleural plaques, which is an important feature of asbestosis [9]. Pleural in ammation, collagen deposition, and calci cation may occur following exposure, and these changes manifest as pleural plaques even at low levels of asbestos exposure [9]. Reportedly, the combined rate of asbestosis and pleural plaque formation was 82.7-95% [9]. Fibrotic bands and peribronchiolar and alveolar brosis often coexist with pleural plaques; however, the association is not absolute [23]. In this study, the percentage of asbestosis-induced pleural abnormalities was signi cantly higher than that of FHP-induced pleural lesions. Pleural abnormalities (particularly the visceral type) are a distinctive manifestation of asbestosis, which is also referred to as diffuse pleural thickening. Visceral pleural thickening includes parenchymal band formation and rounded atelectasis. Pleural thickening tends to occur bilaterally and is patchy, although it may be unilateral in 33% of patients [9]. Studies have shown that parenchymal bands and diffuse pleural thickening are often associated with visceral pleural brosis. Parenchymal bands are known to be of diagnostic value in asbestosis complicated by pleural disease [24]. Rounded atelectasis is caused by thickening of the visceral pleura and collapse of the central lung parenchyma and is often associated with in ammatory pleural disease and may mimic a tumor on chest radiography.
FHP tends to primarily affect the middle and upper lungs and is characterized by decreased lobule density, decreased blood ow, and centrilobular nodules [25]. Asbestosis mainly occurs in the lower segments of the lungs. Akira et al [26]. reported that asbestosis affected the lower segments of the lungs in 78 (98%) of the 80 patients investigated in the study, and only 2 patients showed ndings in the upper lungs. Lower lung involvement in asbestosis is attributable to the fact that asbestos bers easily enter the terminal bronchioles. Owing to the effect of gravity, asbestos bers are deposited in the lower lung, leading to the typical pattern of distribution observed in cases of asbestosis. Previous studies have shown that 94%, 85%, and 26% of patients with asbestosis presented with subpleural dots, subpleural lines, and mosaic perfusion, respectively [27]. Among the 204 patients with asbestosis secondary to chrysotile ber exposure investigated in our study, 56.9%, 27.5%, and 22.1% of patients showed subpleural dots, subpleural lines, and mosaic perfusion on chest HRCT. Subpleural dot and line formation may be associated with chrysotile bers, which are more likely to get deposited at the distal end of the airways during respiration. Histopathologically, subpleural dots represent peribronchiolar nodular brosis involving the alveolar ducts [28]. Bronchiolar wall thickening and attened and collapsed alveoli manifest as subpleural lines [29].
Uneven pulmonary perfusion due to airway or vascular disease is referred to as a mosaic attenuation pattern. Mosaic attenuation is an important CT-based imaging nding that aids in detection of IPF and diagnosis of FHP [30]. Asbestosis affects the small airways [31], and it is unclear whether mosaic attenuation can successfully distinguish between asbestosis and FHP. In this study, we observed no statistically signi cant difference in the percentage of mosaic attenuation between the asbestosis and FHP groups. HRCT showed that inhomogeneous attenuation was observed in up to 64.2% of patients with asbestosis, in addition to ground-glass opacities and mosaic attenuation; speci cally 68.9% of patients with mosaic attenuation showed a "three-density pattern" sign. Radiologist Webb rst described the "three-density pattern" sign, which refers to an imaging nding of low-density lobules, preserved lobules, and air trapping [30]. A survey-based study by Delphi emphasizes the signi cance of this sign for the diagnosis of FHP [32]. Asbestosis is histopathologically characterized by peribronchiolar and subpleural brosis. A few patients may present with UIP-type lesions, usually accompanied by benign pleural abnormalities, and asbestos bodies may be identi ed in the lung tissue [22,33]. In the present study, unclassi able IP was commonly observed in cases of asbestosis. FHP represents a lung allergy caused by exposure to various antigens, and the imaging ndings may manifest as UIP, NSIP, OP, bridging brosis, or central bronchiolar brosis with bronchiolar metaplasia.
Following are the limitations of this study: (a) The single-center retrospective study design (204 and 74 patients with asbestosis and FHP, respectively) may be associated with a selection bias. (b) The small sample size and the small number of patients with some imaging patterns may have affected the statistical results. (c) We compared only asbestosis and FHP in this study. Asbestosis also needs to be differentiated from other occupational interstitial lung diseases. (d) HRCT showed poor sensitivity and high speci city for detection of subpleural lines, subpleural dots, honeycombing, mosaic attenuation, and a three-density pattern. Therefore, asbestosis and FHP still have the value of differential diagnosis. (e) The cumulative exposure is broadly represented by the duration of asbestos exposure, and eld monitoring data are unavailable for patients with chrysotile exposure.

Conclusions
This study highlights the similarities and differences in chest imaging ndings between patients with asbestosis and FHP; we observed that pleural abnormalities, parenchymal bands, and rounded atelectasis showed high diagnostic value for asbestosis. In addition to representing a serious occupational health concern in China, asbestos exposure causes environmental pollution and is a threat to human health. Owing to the long latent period, the health hazards associated with asbestos tend to persist even after being banned in several regions. It is necessary to improve the diagnostic accuracy of modalities, particularly of chest imaging ndings, to facilitate early diagnosis and prompt initiation of comprehensive treatment. Further large-scale studies are warranted to identify prevention measures and to provide evidence to support a complete ban on the production and use of asbestos. Availability of data and material

Abbreviations
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.