A Simple Measure to Assess Hyperinflation and Air Trapping: 1-Forced Expiratory Volume in Three Second / Forced Vital Capacity

Background: Several recent studies have suggested that 1 minus-forced expiratory volume expired in 3 seconds / forced vital capacity (1-FEV3/FVC) may be an indicator of distal airway obstruction and a promising measure to evaluate small airways dysfunction. Aims: To investigate the associations of 1-FEV3/FVC with the spirometric measures and lung volumes that assess small airways dysfunction and reflects hyperinflation and air trapping. Study Design: Retrospective cross-sectional study. Methods: Retrospective assessment of a total of 1110 cases who underwent body plethysmographic lung volume estimations between a time span from 2005 to 2012. Patients were assigned into two groups: firstly by FEV1/FVC (FEV1/FVC <70% vs. FEV1/FVC ≥70%); secondly by FEV3/FVC < lower limits of normal (LLN) (FEV3/FVC < LLN vs. FEV3/FVC ≥ LLN). Spirometric indices and lung volumes measured by whole-body plethysmography were compared in groups. Also the correlation of spirometric indices with measured lung volumes were assessed in the whole-study population and in subgroups stratified according to FEV1/FVC and FEV3/FVC. Results: Six hundred seven (54.7%) were male and 503 (45.3%) were female, with a mean age of 52.5±15.6 years. Mean FEV3/FVC and 1-FEV3/FVC were 87.05%, 12.95%, respectively. The mean 1-FEV3/FVC was 4.9% in the FEV1/FVC ≥70% group (n=644) vs. 24.1% in the FEV1/FVC <70% group (n=466). A positive correlation was found between 1-FEV3/FVC and residual volume (r=0.70; p<0.0001), functional residual capacity-pleth (r=0.61; p<0.0001), and total lung capacity (r=0.47; p<0.0001). 1-FEV3/FVC was negatively correlated with forced expiratory flow25-75 (r=−0.84; p<0.0001). The upper limit of 95% confidence interval for 1-FEV3/FVC was 13.7%. 1-FEV3/FVC showed significant correlations with parameters of air trapping and hyperinflation measured by whole-body plethysmography. Importantly, these correlations were higher in study participants with FEV1/FVC <70% or FEV3/FVC < LLN compared to those with FEV1/FVC ≥70% or FEV3/FVC ≥ LLN, respectively. Conclusion: 1-FEV3/FVC can be easily calculated from routine spirometric measurements. 1-FEV3/FVC is a promising marker of air trapping and hyperinflation. We suggest that 1-FEV3/FVC is complementary to FEV1/FVC and recommend clinicians to routinely report and evaluate together with FEV1/FVC during spirometry.

The ratio of the forced vital capacity (FVC) that is not yet expired within the first 3 seconds of a forced exhalation is expressed with the following formula: 1 minus-forced expiratory volume in third seconds (1-FEV 3 ) / FVC (1,2). Originally, Hansen et al. (3) showed that 1-FEV 3 /FVC may be used for the evaluation of small airways, may be an indicator of the distal expiratory obstruction and was more sensitive than forced expiratory flow (FEF) 25-75 % in evaluating small airways (3). In chronic obstructive pulmonary diseases (COPD), although small airways are mainly involved, larger airways are also affected due to a number of factors, including the loss of ciliated epithelial cells, squamous metaplasia, thickening of the basement membrane, mucous gland hypertrophy and hyperplasia (4). All these factors contribute to irreversible obstruction mainly caused by progressive air trapping, which is a prominent feature of COPD. Both the peripheral and proximal airways are also affected not only in COPD but also in asthma. The forced expiratory volume in the first second (FEV 1 ) mainly reflects large airways obstruction, and for FEV 1 to become abnormal a significant amount of small airways must be affected (5). Later fractions of forced exhalation those occur after FEV 1 , such as FEV 3 was proposed to be more sensitive to reductions in terminal expiratory flow (1,3). For that reason, FEV 3 , FEV 3 /FVC ratio and 1-FEV 3 /FVC were suggested to better assess small airways disease (3,(6)(7)(8). Therefore, both in asthma and COPD, 1-FEV 3 /FVC may be an indicator of small airways dysfunction and air trapping. In order to detect the presence of air trapping in the lungs, lung volumes should be measured to determine the total lung capacity and the residual volume. However, since these methods are associated with increased medical costs and require sophisticated equipment, they are not widely utilized. However, 1-FEV 3 /FVC value can be readily calculated by the widely available standard spirometric examination, and thus may help to detect air trapping in patients with obstructive pulmonary disease. In order to test this hypothesis, the present study aimed to investigate the associations of 1-FEV 3 /FVC in obstructive lung diseases and its relationship with the spirometric measures and lung volumes that assess small airways dysfunction, which reflects hyperinflation and air trapping.

MATERIALS AND METHODS
A retrospective assessment of a total of 1110 participants with at least three acceptable spirometric manoeuvres who underwent body plethysmographic lung volume estimations (ZAN 500 Plethysmography, nSpire, Germany) between 2005 and 2012 at the Pulmonary Function Test Laboratory was carried out. Repeated tests of same person were excluded (according to duplicated name, surnames and identity card numbers). None of the authors have reported a conflict of interest prior to the study. The pulmonologists reviewed all of the pulmonary function tests on a daily basis. The technicians were trained in whole-body plethysmography techniques, and the laboratory supervisor also checked all the steps involved in the test procedures in terms of adherence to the American Thoracic Society and American Thoracic Society/European Respiratory Society guidelines (9)(10)(11)(12). The whole-body plethysmography device was calibrated daily according to manufacturer's guidelines and biological quality control was performed on a monthly basis. Patients younger than 18 years of age were excluded, and only pre-bronchodilator test results were utilized. 1-FEV 3 /FVC was calculated electronically by whole-body plethysmography for each patient; this can also be calculated by spirometers. 1-FEV 3 /FVC estimation: After FEV 3 and FEV 3 /FVC measurements were obtained from records of the patients, 1-FEV 3 /FVC was calculated to show the remaining unexhaled vital capacity ratio in the lung at the end of the 3 rd second There is controversy regarding appropriate criteria to define airflow obstruction by using the fixed threshold of 70% or the lower limits of normal (LLN) for the FEV 1 /FVC ratio (13). In the present study, firstly, we defined airflow obstruction by using the fixed threshold of 70% for the FEV 1 /FVC ratio by using pre-bronchodilator spirometry (14,15). Patients were assigned into either the group with FEV 1 /FVC <70% or the group with FEV 1 /FVC ≥70%. The two groups were compared in terms of FVC, FEV 1 , FEV 1 /FVC, FEF 25-75 , inspiratory capacity (IC), total lung capacity (TLC), residual volume (RV), RV/TLC, thoracic gas volume at functional residual capacity (FRC-pleth), FEV 3 , FEV 3 /FVC, and 1-FEV 3 /FVC. Secondly, in order to assess whether FEV 3 /FVC (accordingly, 1-FEV 3 /FVC) provides additional information on air trapping and hyperinflation to that of FEV 1 /FVC, we analysed correlations of FEV 3 /FVC abnormality. We defined FEV 3 /FVC abnormality by using the redefined LLN criteria for FEV 3 / FVC (16). Analyses were performed separately, for the whole study population, and the subgroups, including individuals with FEV 3 /FVC < LLN and FEV 3 /FVC ≥ LLN.

Statistical analyses
Statistical analyses were performed using Statistical Package for Social Sciences (SPSS) software version 21.0 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp.) Continuous variables were expressed as mean ± standard deviation, whereas categorical variables were shown as the number and percentage of cases. Means and medians were compared using Student's t-test or Mann-Whitney U-test, depending on the normality distribution of data. A p value <0.05 was considered an indication of statistical significance. In addition, the correlations between variables were tested using Spearman's correlation analysis. The study protocol was approved by the Ethics Board (Approval No: 83045809/604.01/02-346067).

DISCUSSION
In the present study, we report that the fraction of FVC that has not been expired at the end of the first three seconds of the FVC (1-FEV 3 /FVC), is significantly increased in patients with a FEV 1 /FVC below 70%. Both groups, including FEV 1 / FVC <70% and FEV 3 /FVC < LLN subjects, had significantly increased hyperinflation and air trapping with regard to RV, RV/ TLC, TLC compared to FEV 1 /FVC ≥70% and FEV 3 /FVC ≥ LLN groups, respectively. We also showed that 1-FEV 3 /FVC significantly correlates with measures of hyperinflation and air trapping in the whole study population as well as in subgroup analyses, including FEV 1 /FVC <70% and FEV 3 /FVC < LLN subjects. Small airways are major contributors to airflow limitation in asthma and COPD (17). Air trapping and premature airway closing are accepted as useful surrogates to assess and quantify small airways obstruction. RV and RV/TLC ratios are useful and widely accepted measures of hyperinflation and air trapping (18).
The earliest change associated with airflow obstruction is a reduction in the terminal portion of the spirogram, even though the initial part of the spirogram is barely affected (9). In this context, later fractions of forced exhalation, i.e. those that occur after the first second of exhalation, such as FEV 3 , were proposed to define reductions in terminal expiratory flow (1,3). FEV 3 and FEV 3 /FVC were introduced in the last three decades, first by Crapo et al. (19) in 1981, followed by Miller et al. (20,21) in 1985. Later on, Hansen et al. (16) introduced the concept of 1-FEV 3 /FVC to identify the increased fraction of the long-time-constant lung units as a measure of late expiratory fraction in their study utilizing data from a smokers and neversmokers population of the Third National Health and Nutrition Examination Survey (22). Our study shows that 1-FEV 3 / FVC is a promising spirometric parameter that correlates with markers of air trapping and hyperinflation. 1-FEV 3 / FVC can be easily calculated by using standard spirometry through the measurement of FEV 3 at the 3 rd second of the forced expiratory manoeuvre. We suggest that 1-FEV 3 /FVC may be used to assess the presence of hyperinflation and air trapping, especially in settings where the lung volumes cannot be measured. Furthermore, FEV 3 /FVC LLN criteria define a group with significantly worse spirometric indices (FEV 1 , FEV 3 , FEV 1 /FVC, FEF 25-75 ), and increased RV, RV/TLC, TLC compared to FEV 3 /FVC ≥ LLN subjects. Previously, FEV 3 /FVC and 1-FEV 3 /FVC were reported to be superior to FEF 25-75 in the assessment of expiratory airflow limitation, since FEF 25-75 can be misleading, with a high rate of false-negative and false-positive results (3,22). We observed that FEF 25-75 had a high correlation with 1-FEV 3 /FVC in the total study population as well as in subgroup analyses. Interestingly, we found that FEF 25-75 had a higher correlation with RV/TLC and IC than that of 1-FEV 3 /FVC, whereas 1-FEV 3 /FVC had a higher correlation with RV, TLC and FRCpleth than that of FEF 25-75 . But as we did not define normality vs. abnormality according to LLN for FEF 25-75 , our analysis did not allow a comparison of our results with previous findings. In addition to these results, we also observed that not only FEV 3 /FVC but also FEV 1 /FVC was negatively correlated   (3). Current studies and our own are still unable to answer the question of which ratio is better, 1-FEV 3 /FVC or the FEV 1 /FVC, in diagnosing expiratory airflow obstruction.
The potential strengths of this study include the fact that the pulmonary function test laboratory where all of the tests were performed is the most comprehensive and qualified laboratory in the country, accepting referrals for whole-body plethysmography from more than 40 hospitals. For that reason, we believe our analysis reflects a wide range of a patient profile based on reliable measurements. However, its retrospective design with a lack of detailed history of smoking and other exposures, limited us in investigating the effect of smoking on spirometric measures effects of smoking on spirometric measures. In addition, our database does not include the necessary information regarding the medication history of the study participants. This was another limitation of our study. Nevertheless, whether the FEV 3 /FVC ratio translates into clinically meaningful disease-centred outcomes needs to be evaluated in further observations, together with clinical and radiologic features.

CONCLUSION
1-FEV 3 /FVC can be easily calculated from routine daily spirometric measurements. 1-FEV 3 /FVC is a promising marker of air trapping and hyperinflation. We suggest that 1-FEV 3 /FVC is complementary to FEV 1 /FVC and recommend clinicians routinely report this measurement and evaluate it together with FEV 1 /FVC during spirometry..