Expiratory Flow Limitation and Its Relation to Dyspnea and Lung Hyperinflation in Patients with Chronic Obstructive Pulmonary Disease: Analysis Using the Forced Expiratory Flow-Volume Curve and Critique

Background: Tidal expiratory flow limitation (tEFL) is defined as absence of increase in air flow during forced expiration compared to tidal breathing and is related to dyspnea at rest and minimal exertion in patients with chronic airflow limitation (CAL). Tidal EFL has not been expressed as a continuous variable (0% - 100%) in previous analyses. Objective: To relate the magnitude of tEFL to spirometric values and Modified Medical Research Council (MMRC) score and Asthma Control Test (ACT). Methods: Tidal EFL was computed as percent of the tidal volume (0% - 100%) spanned (intersected) by the forced expiratory-volume curve. Results: Of 353 patients screened, 192 (114 M, 78 F) patients (136 with COPD, 56 with asthma) had CAL. Overall characteristics: (mean ± SD) age 59 ± 11 years, BMI 28 ± 7, FVC (% pred) 85 ± 20, FEV1 (% pred) 66 ± 21, FEV1/FVC 55% ± 10%, RV (% pred) 147 ± 42. Tidal EFL in patients with tEFL was 53% ± 39%. Using univariate analysis, strongest correlations were between tEFL and FVC and between tEFL


Introduction
Tidal expiratory flow limitation (tEFL) is defined as absence of increase in air flow during forced expiration effort compared to tidal breathing and correlates with dyspnea at rest better than it does with FEV 1 [1] [2] [3]. Tidal EFL is also closely associated with dynamic hyperinflation in patients with chronic airflow limitation [3] [4] and increased ventilatory demand which potentially stresses cardiopulmonary reserves in patients with advanced airflow limitation [5]. Symptoms of chronic dyspnea vary, however, in patients with similar levels of airflow limitation as assessed by spirometry. In particular, FEV 1 has been found to have a weak correlation with dyspnea [3] [4] while assessment of tEFL has been shown to associate closely with dyspnea [3] [4].
Tidal EFL was first described as part of the evaluation of forced expiratory flow-volume (FEFV) curves in the 1960's [6] [7]; subsequent research has shown this approach to be unreliable because of variability in static lung recoil and airway resistance following a deep inspiration, and time-dependent lung emptying and viscoelastic forces in the lung [1]. A simple method to detect tEFL, the negative expiratory pressure (NEP) technique, developed in the mid-1990s by Koulouris and colleagues [2], avoids certain technical challenges of the FEFV curve.
However, NEP requires specialized equipment for recording (not commercially available) and requires steady quiet breathing which is sometimes not possible because of subject anxiety. The operator of the testing apparatus has to remain hidden in order to avoid cortical input that might alter the subject's breathing pattern. Meanwhile, analysis of the forced expiratory flow-volume curve as part of spirometry remains the standard by which respiratory function and impairment are assessed in community and academic settings. Assessment of the magnitude of tEFL using the FEFV would provide additional evidence for its association with dyspnea. We are not aware of any quantitative analysis of association of the FEFV-generated tEFL with commonly used indices of dyspnea in patients with nonreversible and reversible airflow limitation.  [11]. Severity of COPD was graded based on GOLD 2017 staging [12]. Symptoms in patients with asthma were graded using the ACT score [13].

Tidal Expiratory Flow Limitation
Patients were instructed to breathe quietly for 5 minutes or until the tidal volume remained steady (not more than 10% variation). After performing a maximal inspiration to total lung capacity followed by an immediate expiration, spirometric maneuvers were performed as per ATS guidelines [14]. Only

Statistical Analysis
Continuous variables were expressed as means and SD or medians (range), depending on normality of distribution. Spearman correlations were used to assess associations between lung function, MMRC and ACT score [16]. Differences amongst physiologic variables based on MMRC and ACT scores were assessed using analysis of variance (ANOVA) controlled for age, gender and BMI with Bonferroni correction. Separate correlation analyses were conducted for patients with BMI ≥ 30 mg/kg 2 and those with BMI < 30 kg/m 2 . A p < 0.05 was taken as indicating significant differences amongst cohorts.

Relation of MMRC to BMI, tEFL, Lung Function in Patients with Nonreversible Chronic Airflow Limitation
Of the 192 patients, 136 were diagnosed with nonreversible chronic airflow limitation and 56 with asthma (airflow limitation with reversibility). BMI progressively increased with MMRC (Table 1); mean BMI was highest in the group exhibiting MMRC 4 (30 kg/m 2 , p < 0.0001). As can be seen in Table 1, a progressive increase in the number of patients with each MMRC score is noted in just the GOLD D patients. By contrast, no patients in GOLD A had MMRC scores of 3 or 4.  Figure 5 and Figure 6 also show close associations between tEFL and RV and RV/TLC although the associations were 2 to 7 orders of magnitude less than for FEV 1 and FVC.      Table 2 shows the same variables listed according to ACT score in 56 patients with asthma; ACT scores were subdivided into segments of 5. Only 2 patients reported no or minimal symptoms with exertion. Amongst lung function variables, only the RV/TLC exhibited significant differences amongst cohorts (p < 0.03, Figure 7). Associations between tEFL and spirometric values were not statistically significant. ACT scores were higher in patients with mean BMI ≥ 28 kg/m 2 (p < 0.00014) and RV/TLC values > 40% (p < 0.03). Despite the increase in air trapping, IC and IC/TLC did not change significantly over the range of ACT scores.

Discussion
The main findings in this study are that: 1) in patients with chronic nonreversible airflow limitation, tEFL was associated most closely with FEV 1 , FEV 1 /FVC, FVC, slow VC, RV and RV/TLC, 2) in these patients, tEFL increased as MMRC Open Journal of Respiratory Diseases  increased, 3) in patients with asthma, the ACT score was most closely associated with air trapping and tEFL, but not other lung functions, and 4) in both groups, BMI was associated with increase in perception of dyspnea and/or functional limitation.
In patients with nonreversible flow limitation, the degree of tEFL was negatively related to spirometric values, findings similar to other studies of COPD [2] [3] [4] [17], bronchiectasis [2] [4] and cystic fibrosis [18]; all of which employed the NEP technique. Similarly, we found that hyperinflation, as reflected by increases in RV and RV/TLC, was positively related to tEFL. We did not find an association between IC (and IC/TLC) and tEFL, in part because of the opposing effects of obesity which increased with MMRC in this group. In the studies of Koulouris et al. [4] and Holland et al. [18] IC was significantly reduced in the presence of tEFL; in contrast to our study, however, BMI did not differ amongst their seated non-tEFL and tEFL groups. Furthermore, hyperinflation is not just dependent on presence of tEFL [19]. Other contributing factors include loss of elastic recoil [20] [21], narrowing of upper and lower airways [22] [23], small airway closure [24] and post-inspiratory diaphragmatic braking activity [25].

Critique of Use of the Forced Expiratory Flow-Volume Curve
One of the main criticisms of using the FEFV in the determination of tEFL has been variability in lung volume history dependent on preceding deep inspirations and time-dependent lung emptying and viscoelastic forces in the lung [1].
We attempted to maintain consistent the viscoelastic properties during respiratory by asking subjects to take in the deepest breath they could prior to rapid expiration. Lung deflation occurs faster following rapid inflation as the elastic energy stored in thoracic structures is greater with rapid rather than with slow inspiration. This phenomenon was first described by Mortola et al. [26] who found that holding the breath after a maximal inspiration resulted in slower passive lung deflation. Eisaa et al. [27] and Guerin et al. [28] confirmed this finding in subsequent studies and explained it by noting that the elastic recoil pressures of the lung and chest wall gradually decrease as a result stress relaxation.
In asthmatics, deep breathing is an effective means of reversing bronchoconstriction [29] [30]. In an in vitro model of human airways, Lavoie et al. [31] found that reversal of bronchoconstriction depends on the degree of tidal expansion and is inversely related to the severity of bronchoconstriction. In our asthmatic patients, we attempted to maintain consistent bronchial tone and reactivity with maximal inspiration just prior to spirometric measurements; nevertheless these maneuvers did not prevent the heterogeneous distribution of lung function over the range of ACT scores in contrast to the distribution of lung function in COPD patients over the range of MMRC, suggesting that volume history and viscoelastic properties have different effects in asthmatics as opposed to emphysema and bronchiectasis which are characterized by parenchymal destruction.
Another criticism of using the FEFV curve has been the potential imprecision of superimposing the tidal flow-volume curve within the FEFV, because such alignment is made considering TLC as a fixed reference point [1] [2] [3]. We made no such assumption realizing that lung volumes may change slightly depending on volume and time history and viscoelastic properties. To ensure that the tidal curve was consistently related to the FEFV, equipment was checked for Open Journal of Respiratory Diseases leaks before testing began and subjects were monitored for maintaining a tight mouth seal and nose clip during respiratory maneuvers. In short, we recognized the finding of tEFL to be influenced by the very factors known to affect the "concept of expiratory flow limitation" [32].
Tidal EFL was absent in only 23 (17%) patients with nonreversible airflow limitation, and absent in 20 (36%) with asthma. The prevalence of tEFL in nonreversible FL patients was higher than others who used the NEP technique (36% -59% in stable COPD patients) [2] [17] [18]. Similarly, while tEFL was less frequent in our asthmatic patients than in patients with nonreversible airflow limitation, it was more prevalent than in another study of asthma that employed the NEP technique. Boczkowski et al. [33] reported that 6 of 13 (46%) asthmatic patients not exhibiting tEFL with the NEP technique would have been considered as having EFL by the FEFV method (ref. [33], Table 5). By contrast Filippelli et al. [34], using partial FEFV curves, found that half of their asthmatic patients exhibited tEFL, closer to our patients' prevalence of tEFL (64%). Again, differences can be attributed to volume and time history and time-constant inequalities within the lung [33] [35].  Table 1 shows that the ratio varied amongst cohorts, and only in ACT 0 -5 was RV/TLC was lowest at 34% (only 2 patients in this subcohort). Taking deep breaths just prior to performing spirometry was an attempt to make more consistent the lung history, but this maneuver is likely to have a more predictable effect in patients with COPD than in asthma.

Effects of Obesity
In general, as gas trapping increases, IC is expected to decrease with increasing tEFL. We did not find this to be the case, most likely because of the counteracting effect of obesity displacing the diaphragm more cephalad, thereby reducing the end-expiratory lung volume from its hyperinflated state. Use of the FEFV curve avoids a potential error associated with the negative expiratory pressure technique in obese patients: upper airway collapse and a false comparison with Open Journal of Respiratory Diseases the immediately previous control spontaneous tidal expiration [36] [37]. As an alternative method, Ninane and colleagues [38] described the use of manual compression of the abdominal wall to demonstrate flow limitation during spontaneous breathing in different body positions in healthy subjects and patients with COPD. Despite the inherent caveats of the forced expiratory flow-volume curve, we nevertheless found that dyspnea worsened as air trapping increased, particularly in individuals with nonreversible airflow limitation.
There were limitations to our study. By employing spirometry instead of the body box to measure flow and volume, compression artifacts likely resulted in underestimation of the true maximal airflow and therefore an increase in the prevalence of tEFL [39]. This error would be magnified with increase in RV and airflow resistance. Therefore in patients with chronic airflow limitation undergoing spirometry, the error in measured expiratory flow at (for example) 50% VC could amount to as much as 50%, depending on the degree of air trapping (ref. [39], Figure 4). This would have contributed to the overestimation of tEFL in our patients. Plethysmography, however, has its own limitations. Gas compression is reduced at lower lung volumes in airflow limitation. Furthermore, with severe airway obstruction, FRC and RV can be overestimated because of a lag in transmission of alveolar pressure to the mouth [40] [41] and compliance of the upper airway [42] during panting. Finally, obesity causes a reduction in expiratory reserve volume and a shift of the tidal curve towards RV, resulting in a reduction of this error by promoting tEFL.

Conclusion
Dyspnea is closely associated with tEFL, spirometric values and hyperinflation, particularly in patients with nonreversible airflow limitation. In patients with asthma, tEFL does not change significantly as ACT score increases, likely because of opposing effects of obesity and variability in airway remodeling. Air trapping and a BMI of <30 kg/m 2 are strongly associated with expiratory flow limitation in patients with both reversible and chronic airflow limitation. Tidal EFL is of higher prevalence using the FEFV curve than historical values of tEFL using the negative expiratory pressure technique mainly because of volume and time history and volume inequalities within the lung. Nevertheless, while the magnitude and frequency of tEFL are greater with FEFV, relationships between tEFL, symptoms and lung function are similar to those obtained by the negative expiratory pressure technique.