This is the first study that has quantitatively evaluated the performance of the eRIC model and a FrOr model in the analysis of airway obstruction and the bronchodilator response in work-related asthma. The most exciting findings of this study were that (1) patients with WRA showed increased peripheral resistance, damping and hysteresivity when compared with controls, (2) fractional-order analysis outperformed standard FOT, as well as integer-order modeling in the diagnosis of respiratory changes in these patients, (3) the bronchodilator use in WRA resulted in increased dynamic compliance and reduced damping and peripheral resistance, and (4) standard FOT analysis outperformed integer and fractional-order modeling in the identification of the bronchodilator effects in these patients.
Table 1 shows that the two studied groups were of comparable age, height, and gender distribution. Although there were slight differences between the groups related to body mass, this parameter is not determinants in terms of alterations in respiratory impedance. We should highlight the fact that the main parameter that has a significant impact on the impedance – subject height [31] - was quite similar between the groups under study. The changes in volumes and flows observed in WRA patients before and after BD use (Table 2) were consistent with the involved physiopathology [32].
There is a consensus in the literature that FOT is in state of the art in the analysis of pulmonary function, contributing to increasing our knowledge about respiratory diseases, as well as in its diagnosis. However, only one study used this method to investigate WRA [3]. This study focused only on the evaluation of methacholine challenge and was also limited by the evaluation to just R0. Variables relating to respiratory reactance and respiratory modeling were not investigated. Supporting and adding new information to these previous results, Figure 3A shows an increase in the respiratory obstruction in WRA. This increase was more discriminating in the 4-16 Hz range, which resulted in increased values of R0 and R4 (Table 3, Figure 1 Supplement), as well as highly significant reductions in ventilation homogeneity (S and R4-R20). Considering the reactive changes (Figure 3B), WRA introduced more negative values in reactance in comparison with the control group, which resulted in significant changes in all of the reactive parameters (Table 3). These results are consistent with preliminary results in a smaller group [33] and can be explained by the presence of bronchoconstriction and inflammatory processes in asthmatics. These abnormalities reduce the diameter of the internal airways introducing increased airways resistance and changes in the time constants in the ventilatory process of these patients.
One interesting finding was that S, Xm, fr, Axt, and Axi presented fair values of AUC for clinical application (Table 7). These observations were in line with the usual interpretation of these parameters as being related to small airways disease [34-36] and the pattern of predominantly peripheral airway abnormalities in patients with mild obstruction, as may be characterized by the studied group.
Concerning the evaluation of the best methodology for calculating Ax, the correlations of Axi with spirometry (Table 5) and plethysmography (Table 6) were slightly higher than that obtained by Axt. Interestingly, the diagnostic accuracy of Axt in the identification of WRA respiratory abnormalities was higher than that observed in Axi (Table 7). It may be explained by the fact that, as can be seen in Figure 3B, the reactance curve is not a perfect triangle. The approximation of the reactance area by a triangle amplifies the differences observed among the curves, improving the performance of Axt. Accordingly, Table 9 shows that the performance of Axt in the identification of the changes due to BD use was also higher than that obtained by Axi. Thus, although using a less accurate method to estimate area, Axt is more accurate than Axi in terms of clinical use. This counterintuitive finding may help to elucidate the debate about the proper methodology for calculating Ax [8].
The bronchodilator use introduced a reduction in the resistance values and associated parameters (Figure 3A, Table 3, Figure 1 Supplement), as well as less negative values of respiratory reactance and parameters (Figure 3B, Table 3). These results are in close agreement with the reduction in airway obstruction and the improvement in ventilation homogeneity usually observed after BD use in these patients [32].
The effects of WRA and BD use in the parameters associated with the eRIC model are described in Figure 4. WRA does not introduce alterations in R, which indicates small changes in the central airways of the studies patients. This result is consistent with the data obtained using spirometry and plethysmography (Table 2), which described the presence of a predominantly small or moderate obstruction in the studied sample. BD use resulted in a reduction in R (Figure 4A). A possible explanation for this result may be the typical smooth muscle relaxation that occurs in these individuals. The resulting mean R values were smaller than that measured in controls. These findings are also in line with the predominantly small or moderate obstruction observed in the studied WRA population (Table 2).
Peripheral resistance increased in WRA (Figure 4A), which could be attributed to inflammation and airway wall remodeling. These results are also likely to be related to airway smooth muscle shortening, which introduces peripheral constriction. It was interesting to note that, even after the BD use and a reduction in its value, the Rp of WRA patients remained higher than that observed in controls. This result is in contrast to the reduction of R to values smaller than those measured in controls (Figure 4A), which is probably related to the inflammatory effect of the disease.
Figure 4C shows that WRA introduced increased values of Rt. Considering that Rt=R+Rp [37] and that R was not increased in patients (Figure 4A), we can speculate that this increase was associated with the increase observed in the peripheral resistance (Figure 4B). This result reflects the fact that airway changes in asthma usually begin at the peripheral airways, and that the studied patients with WRA presented predominantly small or moderate obstruction (Table 2) so that they can be considered as in the early stages of the disease.
Respiratory inertance primarily describes the mass of gas that is moved during tidal breathing. It may be interpreted as an index related to pressure losses, as well, mostly due to the acceleration of the gas column in the central airways [8]. Respiratory inertance was reduced in WRA (Figure 4D), which can be explained by the concepts of choke points [38] and apparent inertance [39]. Usually, inertance integrates the inertial characteristics of the whole respiratory system. As the respiratory obstruction advances, the oscillatory signal used by FOT to assess the impedance is prevented from passing through the choke points. It precludes FOT from considering the lung beyond the choke point so that the measured inertance reflects the airways proximal to the choke points. As a result, we observed a reduction in the apparent mass of the gas measured by the FOT, in the associated pressure necessary for the acceleration of the gas, and consequently, in the measured inertance. This process is similar to that observed in the apparent compliance and results in an apparent inertance. In line with this interpretation, direct associations were observed between inertance and spirometric indexes of peripheral airway obstruction (Table 5). Further additional supports to this hypothesis was provided by the inverse relationship obtained between inertance and the Raw and the direct association observed with SGaw (Table 6). Bronchodilation does not cause a significant change in I (Figure 4D). Similar to S (Figure 1C supplement), R4-R20 (Figure 1G supplement), and Rp (Figure 4B), I remained distinct from the results obtained in the control group after BD use. These results probably reflect the irreversible inflammatory effect of the disease.
WRA introduced a decrease in C (Figure 4E). This finding is consistent with the work of Bhatawadekar and collaborators [40], which used a single compartment model fit to estimate Ers (1/Crs). These authors pointed out that Ers is associated with small airways, and potentially a very clinically useful measure in asthma. This parameter includes the lungs and bronchial wall compliances, the compliance of the chest wall/abdomen compartment, and the thoracic gas compression. Thus, this result may be related to airway remodeling and frequency dependence of dynamic compliance due to non-uniform ventilation. The deformation of the thoracic wall associated with lung hyperinflation also needs to be considered since it introduces an essential restrictive factor in the interaction between the lung and thoracic wall. In Figure 4E, it is also apparent that the use of bronchodilator resulted in a significant increase in C, which became similar to that presented in regular patients. These results further support the idea of the reduction in airway obstruction and the improvement in ventilation homogeneity after BD use in these patients.
Considering the diagnostic use of eRIC parameters, only Rp reached an adequate value for clinical use (Table 8). This finding is in close agreement with the interpretation of this parameter as reflecting peripheral airway resistance, and the presence of peripheral changes in our studied patients, which shows mainly mild obstruction (Table 2).
Recently, the concept of FrOr modeling of the respiratory system has received significant interest in the research community [24, 29, 41-43]. Theoretically, these emerging models present an improved sensitivity to pathologic changes, due to an improved ability to capture the characteristics of respiratory mechanics. In reviewing the literature, however, no data was found on the question of FrOr modeling in patients with WRA. The current study found increased values of G in WRA, presenting a significant reduction after BD use (Figure 5A). These findings broadly support the interpretation linking WRA with increased energy dissipation in the respiratory system [21], which may be explained by the increased airway obstruction and reduced respiratory compliance. This finding also supports evidence from clinical observations reporting increased respiratory work and dyspnea on small efforts in these patients. The reduction after BD use is also consistent with the reduction of dyspnea usually observed after BD use in these patients [1].
The current study observed values of H in controls (Figure 5B) similar to that obtained previously [26, 27]. In contrast with the results previously reported in non-specific asthma [29], mild obstruction in patients with WRA introduced a highly significant reduction in H. This provides evidence that asthma resulting from occupational exposure results in more aggressive changes in terms of the elastic properties of the respiratory system than in the average of asthmatics. These findings may have essential implications in the development of objective methods for the differential diagnosis between WRA and non‐work related asthma.
It is also interesting to point out that H was also reduced in mild patients with other obstructive diseases, including chronic obstructive pulmonary disease [27], and silicosis [44], but not in asbestos-exposed workers with mild abnormalities [26]. This difference may be attributed to the restrictive nature of the asbestosis. It is a compelling finding since it provides another evidence that H may help in the differential diagnosis of work-related respiratory diseases.
Perhaps the most interesting finding in FrOr analysis was the increase in η values observed in patients with WRA (Figure 5C). It is in close agreement with the involved physiology, reflecting chronic airway inflammation and remodeling, which predisposes the lung to a more heterogeneous pattern of peripheral airway constriction. A comparison between the present results and those of a preliminary study, including all asthma phenotypes [29], confirms the ability of this parameter to describe the presence of heterogeneous peripheral ventilation in the specific phenotype of WRA. Additional supports of this interpretation are provided by other studies performed recently in patients with sickle cell anemia [28], chronic obstructive pulmonary disease [23, 27], and asbestos-exposed workers [26]. The hysteresivity increases with the hysteresis area of the pressure-volume loop [45], which associates this parameter with the work of breathing [21, 22]. Correlation analysis was consistent with this interpretation, describing inverse associations with spirometric indexes of airway obstruction, and direct associations with Raw (Tables 5 and 6, respectively). These findings indicate that η clearly describes the respiratory abnormalities in WRA, which are characterized by increased respiratory work [1].
Another interesting finding was the absence of changes in η values as a consequence of BD use (Figure 5C). This result is in contrast with the reduction observed in G after BD use (Figure 5A) and provided additional evidence of the association between η and peripheral abnormalities. Among FrOr parameters, η presented the highest correlations with spirometric and plethysmographic parameters of airway obstruction (Tables 5 and 6, respectively).
The range of measured values in asthmatics was reduced after BD use (Figures 4 and 5). Patients with mild airway obstruction (61%) mainly compose the studied group of asthmatics. However, there are also 29% of patients with moderate and 10% with severe obstruction. This may explain the observed large range of measured values in asthmatics before BD use. After BD use, the airway obstruction tends to be reduced, and the respiratory system properties of the asthmatics tends to be closer to normal, reducing the range of measured values in these patients (Figures 4 and 5).
It is now well established that fractional-order dynamic behavior may be linked to fractal structure, implying that properties of both function and structure are fundamentally interconnected [46]. It has been shown that recurrent fractal geometry may result in fractional-order terms [15]. In the particular case of the bronchial tree of normal subjects, a highly complex fractal structure is observed, in which the presence of self-similarity in its spatial structure is closely linked to a healthy lung function. In contrast, diseased lung presents asymmetry as a result of inhomogeneities due to the physiopathological process. The bronchial tree of a patient with WRA shows progressive loss of complexity in its spatial structure related to inflammation, airway remodeling, bronchoconstriction, edema, and fluid accumulation in the airways [47]. In line with these principles, previous studies from our laboratory demonstrate a consistent reduction in respiratory impedance complexity with increased airflow obstruction in a preliminary group, including all asthma phenotypes [48]. Further studies in similar groups of asthmatic subjects showed a significant increase in η and G with airway obstruction [29], indicating that these parameters are inversely related to respiratory complexity in these patients. It was hypothesized that the increase observed in η and G may be explained, at least partially, by the reduction in the complexity of the spatial structure of the airway tree of patients with asthma. Figure 5A and C provide further support to this hypothesis, extending this evidence to the specific case of WRA.
On the question of diagnostic use, this study found that η, obtained from FrOr modeling, reached a high diagnostic accuracy in identifying WRA abnormalities (Table 8). The comparison of the more accurate parameters obtained in traditional analysis, eRIC, and FrOr modeling showed that η was more accurate than Rp (Figure 6). These results corroborate the propositions of previous authors, who suggested that FrOr models have the potential to improve respiratory clinical science and practice [10, 16, 21]. Also in line with this proposition and the observed results, it is apparent from the data in Table 4 that the FrOr model provided an improved description of the measured impedance. Following the present results, previous studies have demonstrated that FrOr models provide a more suitable fitting than integer-order models [27, 29]. It could be associated with the nature of the FrOr models, whose flexibility allows these models to adjust to fractional values of 20 dB/decade. Integer-order models, however, are only able to adjust to integer multiples of 20 dB/decade.
These results are in keeping with previous studies, in which the detailed analysis offered by FrOr modeling improved our knowledge about several biomedical areas, including the properties of the arterial wall in brain aneurysms [51], the description of the red blood cell membrane mechanics [52] and the blood flow in the cranial network [53]. Similar improvements were also observed in modeling the viscoelastic nonlinear compressible properties of the lung [49], the blood ethanol concentration [50], and improving the chemotherapy used in cancer treatment [18].
The evidence presented in Table 8 and Figure 6 supports the notion that FrOr models may be useful in clinical use. The increase in diagnostic accuracy obtained in the present study (Figure 6) is in close agreement with improvements observed in the differentiation between malignant and benign breast lesions detected on X-ray screening mammography [51], cancer detection [52], screening for hemodialysis patients [53], differentiation of low- and high-grade pediatric brain tumors [54], and Parkinson’s Disease severity assessment [55].
Regarding these aspects, an initially unexpected result was observed from data in Tables 9 and 10 and Figure 7. In contrast to the results observed in the identification of changes in respiratory mechanics in WRA, there was no evidence that the parameters obtained from the FrOr model were more accurate than the traditional FOT parameters to identify the respiratory effects of BD use. When these results are analyzed more carefully, it can be observed that the highest accuracy observed among the traditional FOT parameters (Table 9) was obtained by R4, which is related to central airway obstruction. Among model parameters (Table 10), the most accurate was R. This eRIC model parameter also reflects mainly central airway resistance. Both results are in close agreement with the spirometric and plethysmographic changes observed after BD use in the present study (Table 2), which described changes associated mainly to central airways. These results are in line with the recent work of Bhatawadekar and collaborators [40] investigating the bronchodilator response in asthma. Thus FrOr parameters were not the most adequate to diagnose these changes because these parameters are more related to peripheral airways, while the observed BD responses are involved with more central airways.
The findings in this study are subject to at least three limitations. First, the present work is limited to patients with WRA. This focus allowed us to investigate this specific phenotype, clarifying the use of FOT and respiratory modeling in this critical disease. However, many other types of asthma exhibit different features. Therefore, further studies are needed to assess these specific disorders.
Secondly, one could argue that the bronchodilator analysis was limited to evaluate the adequacy of the studied parameters to reflect the respiratory changes due to BD use. A comparative analysis of a group of BD responders and non-responders using spirometry as a reference and including the administration of placebo and BD medication in a large sample of patients could establish cut-off points for changes in parameters derived from FOT models. It has important practical application and should, therefore, be addressed in future studies.
Finally, the present study investigated a relatively small sample size. Although this limitation was minimized using the LOOCV method, it is still a limitation, and additional studies, including a more significant number of subjects, are necessary. The present analysis, however, significantly contributes to the essential debates in the literature concerning the proper methodology for calculating Ax [8], the use of FOT in occupational health [8], particularly in WRA [3], as well as introduced respiratory modeling in this disease.