Diagnostic performance of lung volumes in assessment of reversibility in chronic obstructive pulmonary disease

Reversibility measured by spirometry in chronic obstructive pulmonary disease (COPD) is defined as an increase in forced expiratory volume in first second (FEV1) that is both more than 12% and 200 mL above the pre-bronchodilator value in response to inhaled bronchodilators. FEV1 only may not fully reverberate the changes caused by reduction in air trapping or hyperinflation. To date, the studies that examined the effect of inhaled bronchodilators (BD) on residual volume (RV) and total lung capacity (TLC) are limited. This study was carried out to assess the differences between flow and volume responses after bronchodilator reversibility testing in patients with different COPD GOLD stages (GOLD stage I to stage IV). Spirometry and whole body plethysmography were done before and 15 min after inhalation of 400 μg salbutamol. Majority (53.3%) of cases were volume responders, 18.7% were flow responders, 20% were flow and volume responders, and 8% were non responders. Significant increase in Δ FEV1% was found in 15% of cases while 55% showed a significant increase in Δ FVC (P= < 0.001). Mean difference of Δ FVC (L) post BD was significantly increased with advancing GOLD stage (P= 0.03). A cutoff point > 20% for Δ RV% had 70% sensitivity and 60% specificity and > 12% for Δ TLC% showed 90% sensitivity and 45% specificity for prediction of clinically significant response to BD based on FEV1. A cutoff point > 18% for Δ RV% had 78% sensitivity and 29% specificity and > 14% for Δ TLC% had 50% sensitivity and 70% specificity for prediction of clinically significant response to BD based on FVC. ΔFEV1 underestimates the true effect of bronchodilators with advancing GOLD stage. Measurement of lung volumes in addition to the standard spirometric indices is recommended when determining bronchodilator response in COPD patients.


Background
Spirometry is the most commonly used method for assessment of airflow limitation in COPD. Reversibility in COPD is defined by an improvement in FEV1 that is both greater than 0.2 L and 12% above the prebronchodilator (pre-BD) FEV1 value [1]. Forced expiratory volume in one second (FEV1) is the parameter used by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.
Lung volumes are potentially useful parameters in detecting response to inhaled bronchodilators, yet they are not used frequently despite having important clinical implications [10].
Static hyperinflation is considered a risk factor for mortality [18]. Dynamic hyperinflation increases work of breathing [19] and has reversibility parameters which correlate with the inspiratory capacity (IC) but not with the FEV1 [15,20].
There are a significant number of patients whose total lung capacity (TLC) and residual volumes (RV) exhibit bronchodilator-responsiveness even if their FEV1 or FVC do not.
This study aimed to assess the differences between flow and volume responses after bronchodilator reversibility testing in patients with different COPD GOLD stages (GOLD stage I to stage IV).

Methods
This prospective cohort study included 300 patients (228 males and 72 females) who presented to the outpatient clinic during the period from May 2018 to May 2020. Informed consent was taken from all patients who participated in the study. This study was approved by the research ethics committee of the Faculty of Medicine.

Inclusion criteria
The diagnosis of COPD was established by clinical assessment and spirometric tests according to the GOLD 2017 guidelines [1]. Patients were asked to omit short-acting inhaled bronchodilators for at least 8 h, and long acting beta-agonists for at least 12 h. The technique of spirometry and whole body plethysmography were demonstrated and a trial run of these tests were performed until reasonable technique and consistent reproducible readings were obtained.
3. Reversibility test was done by inhalation of shortacting B2-agonist (400 μg salbutamol). Spirometry and whole body plethysmography were performed again 15 min after the bronchodilator (BD) was inhaled. The presence of a post-BD FEV1/FVC ratio < 0.7 confirms the presence of persistent airflow limitation. Bronchodilator response was expressed as a percentage and an absolute change in milliliters of the baseline values. FEV1 (flow responders) and FVC (volume responders) responsiveness were defined by >12% and >200 mL improvement of baseline values [23,24]. 4. GOLD staging. Patients were classified according to the severity of air flow obstruction into: GOLD I: FEV1 ≥ 80% of predicted GOLD II: FEV1 ≤ 50-< 80% of predicted GOLD III: FEV1 ≤ 30-< 50% of predicted GOLD IV: FEV1 < 30% of predicted

Statistical analysis
Data was collected and analyzed using SPSS (Statistical Package for the Social Science, version 20, IBM, and Armonk, New York). Continuous data was expressed in form of mean ± SD and range while nominal data was expressed in the form of frequency (percentage). Chi 2 test was used to compare the nominal data of different groups while continuous data of two groups were compared with Student t test, and ANOVA test was used in case of more than two groups. Correlation of mean differences of FEV1 and FVC with RV and TLC was assessed by Pearson correlation. Level of confidence was kept at 95% and P value was significant if < 0.05.

Spirometry and body plethysmograpghy parameters among enrolled patients before and after bronchodilators
There was a significant increase in FEV1 (L) and FEV1% predicted after BD with mean difference 0.06 ± 0.29L and 6.56 ± 6.27%, respectively. Also, after BD, the FVC (L) and FVC% predicted were significantly increased with mean difference 0.06 ± 0.67L and 8.88 ± 7.09%, respectively.
There was a significant increase in the IC% predicted and the RV (L) after BD with mean difference was 5.16 ± 14.54% and 0.76 ± 3.49L, respectively. The RV/TLC significantly increased after BD with 9.13 ± 14.60 mean difference. All other parameters showed no significant changes after BD (Table 2).
Pre-BD parameters among enrolled patients based on type of response It was noticed that volume responders (only FVC response to BD) had significantly lower FEV1 (L and % predicted), FVC (L and % predicted), and FEV1/FVC ratio in comparison to other types of response ( Table 3).

Distribution of patients based on percentage of change in FEV1
Based on percentage of change in FEV1 after BD, it was noticed that 15% of patients showed a significant increase (12% increase calculated from the pre-BD value and a 0.2 L increase), 80% of patients showed a nonsignificant increase and 5% of patients had no change in FEV1 after BD ( Table 4).

Distribution of patients' based percentage of change in FVC
Based on percentage of change in FVC after BD, it was noticed that majority (55%) of patients showed significant increase. Non-significant increase was noticed in   (Table 5).

Relation between percentage of change in FEV1 and FVC
There were significant differences between percentage of FEV1 and that of FVC. It also shows that the number of patients who showed significant reversibility response of FVC was much higher than those who showed the same response of FEV1 after bronchodilator (55% and 15%, respectively). In contrast, number of patients who showed insignificant reversibility response of FEV1 was much higher than those who showed the same response of FVC after bronchodilator (80% and 42%, respectively) ( Table 6).

Mean differences of FEV1 and FVC based on GOLD stage among enrolled patients
It was noticed that mean difference of Δ FEV1 (L) after bronchodilator was significantly (P=0.01) decreased with advancing GOLD stage while mean difference of Δ FVC (L) post bronchodilator was significantly increased with advancing GOLD stage (P= 0.03) ( Table 7).

Accuracy of Δ RV and Δ TLC in prediction of significant response based on FEV1
At cutoff point > 20%, Δ RV had 70% sensitivity and 60% specificity with overall accuracy was 61% for prediction of clinical significant response to BD based on FEV1. Also, at cutoff point > 12%, Δ TLC had 90% sensitivity and 45% specificity with 50% overall accuracy for prediction of clinically significant response to BD based on FEV1 (Table 8, Fig. 1).

Accuracy of Δ RV and Δ TLC in prediction of significant response based on FVC
At cutoff point > 18%, percentage of change in RV had 78% sensitivity and 29% specificity with overall accuracy was 55% for prediction of clinical significant response to BD based on FVC.
Also, at cutoff point > 14%, percentage of change in TLC had 50% sensitivity and 70% specificity with overall accuracy was 64% for prediction of clinical significant response to BD based on FVC (Table 9, Fig. 2).    (Table 11).

Discussion
COPD is a major cause of chronic morbidity and mortality throughout the world; many people suffer from this disease for years and die prematurely from it or it's complications. Globally, the COPD burden is projected to increase in the coming decades because of continued exposure to COPD risk factors and aging of the population [25].
Spirometry is required to make the diagnosis in this clinical context; the presence of a post-bronchodilator FEV1/FVC < 0.70 confirms the presence of persistent airflow limitation and thus of COPD in patients with appropriate symptoms and significant exposures to noxious stimuli [1].
Expiratory flow response after administration of a bronchodilator is widely and frequently used as an indicator for the degree of reversibility of airflow limitation in patients with COPD. In severe COPD, flow response after bronchodilator may almost be negligible. Bronchodilator response in terms of lung volumes has been addressed by several authors, as well as the relationship between flow response and volume response [26].
The current study included 300 patients (228 males and 72 females) who were recruited from the outpatient clinic during the period from May 2018 to May 2020. Patients are diagnosed as COPD according to GOLD guidelines 2017 (post bronchodilator FEV1/FVC 0.70 by spirometry).
The purpose of the study was to assess the differences between flow and volume responses after bronchodilator reversibility testing in patients with different COPD GOLD stages (GOLD stage I to GOLD stage IV) and to study the correlation between the bronchodilator response and the severity of the disease. The current study showed that most patients (44%) were classified as severe COPD (GOLD stage IV), whereas only 3 patients met the criteria for mild COPD (GOLD stage I).    Schermer et al. demonstrated that most patients (58.7%) were classified as moderate COPD (GOLD stage II), whereas only 45 (2%) patients met the criteria for very severe COPD (GOLD stage IV). This is possibly because patients in our locality delay seeking medical advice consequencing an advanced GOLD stage at presentation [27].
Falco et al. [28] conducted a retrospective study upon 594 patients with COPD and studied the differences in bronchodilator response regarding flow and the volume parameters in COPD patients at different GOLD stages. They reported that 33.5% of cases were females. In the current study, 24% of cases were female, possibly because smoking habits are more frequent among females in the western society.
Pisi et al. found that 16% of cases were volume responders, 8% were flow responders, and 7% were volume and flow responders [31].
Schermer et al. [27] assumed that the link between flow and volume responses would reverse along with the progression of COPD.
Da Costa et al. [32] agreed with Schermer et al. [27] who suggested that the response measured by FVC is greater at the most severe stages of the disease. The altered effect of lung inflation on airway caliber, due either to loss of lung elastic recoil or compression by enlarged (emphysematous) air spaces may explain the lack of sensitivity to bronchodilatation as assessed by changes in FEV1 in the more severe stages of COPD. Also, Vigna M et al. found that patients belonging to the first GOLD classes tend to be more responsive in terms of flow, a feature that is lost in severe forms, where a volume response prevails [33].
In line with the previous studies, Galal et al. [34] found that ΔFVC increased with the level of airflow obstruction. This volume response, that is increasing improvement in FVC with the level of airflow limitation, makes it a more sensitive parameter to measure the BDR than FEV1 that shows response decline as airways obstruction worsens. Similar findings were mentioned by Falco et al. [28], Pisi et al. [31], and Boni et al. [15] who concluded that the magnitude of Δ FEV1 decreased as the GOLD stage became more severe and the Δ FVC increased in the more severe GOLD stages.
Newton et al. [17] reported significant increases in FVC and IC and significant reduction in FRC, RV, and TLC following the administration of salbutamol in severely and moderately hyperinflated COPD patients although minority of patients showed significant improvements in FEV1. This was in agreement with the current results.
Cerveri et al. showed an inverse relationship between bronchodilators-induced increments in FEV1 and various indexes of emphysema, in spite of conspicuous increments of FVC. They concluded that isolated volume response to bronchodilators is a characteristic of severe emphysema involving more than 40% of lung parenchyma [35]. Jarenbäck et al. performed spirometry and body plethysmography at baseline and after bronchodilator. Their results stated that volume response does not follow the flow response (FEV1) and flow parameters were more significant in less advanced stage, whereas parameters reflecting volume response (FVC) were more prominent in patients with more severe stages of COPD [36]. Barjaktarevic et al. showed that mild COPD (GOLD I) was characterized by greater BDR in terms of FEV1 than   [37].
McCartney et al. [26] studied RV responsiveness at different thresholds for percentage change: 8, 10, 12, 15, and 20%. They concluded that the higher the threshold for RV responsiveness used, the fewer patients were responsive. At threshold for RV (8%), 21.3% of subjects had a RV reduction. At the highest threshold for RV (20%), 4.6% of their total patient population had a reduction in RV. Therefore, 7.7% of subjects currently characterized as being non responsive to bronchodilators have a 20% reduction in their residual volume. The total lung capacity in their study showed increasing response with increasing obstruction.
Measurements of lung volumes before and after bronchodilators added sensitivity when examining for bronchodilator responsiveness. Notably, in hyperinflated patients, the measurement of FVC before and after bronchodilator administration identified a response that may not be uncovered by the measurement of FEV1 alone.
In this study, there were significant changes regarding Δ FVC% in 55%, Δ RV% in 55%, and Δ TLC% in 16.7% of the studied patients after use of bronchodilators. This was concordant with the results of Vigna et al. who stated that FVC improvements after bronchodilator administration are related to the reduction in residual volume (RV), a parameter linked to the improvement in exercise tolerance and dyspnea perception [33].
Limitations of the study are, first, relatively small number of patients in GOLD stages I and II, because this category of patients generally do not ask for medical advice except in the cases of complications or exacerbations and this can be traced back to the culture of the community and that most patients are financially unable and do not pay attention to simple symptoms.
Second, addition of an anticholinergic agent was not a part of the bronchodilator reversibility testing. The use of salbutamol alone will probably not have achieved maximal bronchodilatation in all patients.
This study addressed a category of patients who were residual volume responders; this may put a light on a complementary approach in interpreting bronchodilator reversibility that includes RV to obtain a better understanding of how patients respond to bronchodilators.
In our opinion, more studies are needed to understand the difference between flow and volume responders in all phenotypes of COPD. Future studies should identify the reproducibility and most accurate cut-off values of these volume-based definitions that appear to be useful in defining the effect of bronchodilators in symptomatic COPD patients.
Studies examining the efficacy of new treatments also should pay closer attention to the effect on lung volumes. Further prospective studies examining the behavior of lung volumes after bronchodilator administration in patients with definite clinical diagnoses of COPD are required.

Conclusion
Measurement of lung volumes in addition to the standard spirometric indices is recommended when determining bronchodilator response in COPD patients. A significant proportion of COPD patients showed significant reductions in lung volumes after bronchodilator inhalation, despite classified as being nonresponsive based on spirometry results with minimal or no change in the FEV1.