European Journal of Cardiovascular Medicine

Chronic Obstructive Pulmonary Disease (COPD) is one of the top 3 causes of death world wide and 90% of these occur in low and middle income countries.^[1-3] It is defined as a heterogenous lung condition characterized by chronic respiratory symptoms (dyspnea, cough, sputum production and/or exacerbation) due to abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction.^[1]

The burden of COPD is projected to increase in coming decades due to continued exposure to COPD risk factors and the ageing of the world’s population. There is significant economic burden associated with the disease. However, the estimate of the prevalence of COPD in a country is low when only the respiratory symptoms are determined by a questionnaire. Objective measurement of lung function by spirometry is needed to investigate the true prevalence of COPD.^[4] Spirometry is required to make the diagnosis; the presence of a post-bronchodilator Forced expiratory volume in 1 second / Forced vital capacity (FEV1/FVC) < 0.701^[5] confirms the presence of persistent airflow limitation and thus of COPD. The goals of COPD assessment are to determine the severity of the disease, including the severity of airflow limitation, the impact on the patient’s health status, and the risk of future events. Spirometric classification of airflow limitation classify COPD in 4 grades on the basis of post bronchodilator FEV1/FVC ratio <0.70 and Forced expiratory volume in 1 second (FEV1).^[1,5] In spirometric evaluation, some patients find it difficult to empty their lungs completely thus, making it difficult to reach their FVC. The end of test criteria which is defined by less than 20 ml change in final 2 seconds of the maneuver, is sometimes difficult to achieve for patients with airflow obstruction.^[6,7] Failure to achieve an end of test plateau results in underestimation and misclassification of FVC.

Forced expiratory volume in 6 seconds (FEV6) is easy to execute, the total spirometric time duration and spirometric complications such as syncope are reduced.^[8] FEV6 is a cheap, effective measure which can be used as a primary screening tool. Various studies have shown that one can use FEV1/FEV6 and FEV6 as an alternative for FEV1/FVC and FVC for detection of airflow obstruction and restriction respectively.^[9-11] Values of FEV1/FEV6 as 73% and FEV6 as 82%, can be used as valid alternatives to FEV1/FVC 70% and FVC 80% as fixed cut off terms for detection of obstructive and restrictive spirometric pattern in adults.^[12] The specificity of FEV6 as a marker in patients with mild airflow obstruction has been questioned in various studies, stating that FEV1/FEV6 is more reliable in diagnosing moderate to severe airflow obstruction. FEV6 and FVC have shown a linear correlation in patients with reversible and irreversible airflow obstruction in various studies. It has also been stated that the difference between FEV6 and FVC increases with increasing severity of obstruction which could be a draw back in replacing FVC with FEV6 as it can result in further misclassification.^[6]

COPD is characterized by chronic airflow limitation that is partially reversible post bronchodilatation. Post bronchodilatation response in COPD is reflected as a change in FVC which is an indicator of relief of air trapping.^[13-15] However, in order to assess the bronchodilatation response in only FVC, change in forced expiratory time (FET) should be evaluated.^[13,16] The standardization of FET is problematic.^[13] FEV6 has been shown to increase significantly when the change in FVC was not caused by longer exhalation time. Thus we can hypothesise that FEV6 would produce better repeatability and end of test measure as compared to FVC.^[13,17]

We aimed to determine the reliability of FEV1/FEV6 as a marker of diagnosing obstruction with respect to FEV1/FVC and then determine the relation of FEV6 and FVC with increasing severity of obstruction and change in FVC and FEV6 post bronchodilatation in COPD.

It is a cross-sectional study of patients attending a Pulmonary laboratory for Spirometry at a tertiary care hospital conducted over a period of 18 months duration (from November 2014 to June 2016). The study was reported as per the STROBE guidelines.

Setting

The study was conducted in the pulmonary function testing laboratory at Jaslok Hospital and Research Centre, Mumbai with patients having obstructive defect on spirometry with no significant post bronchodilator reversibility.

Study Population

A total of 111 adult patients of age more than 35 years with history of smoking or long term environmental exposure and symptoms suggestive of obstructive airway disease were scheduled for spirometry and further evaluation.

Criteria

Patients who came for Spirometry in the outpatient department of the hospital during 18 months period from November 2014 to June 2016 ​​​​​

Inclusion criteria

We included patients who were more than 35 years of age, had a post bronchodilator spirometry showing FEV1/FVC <0.70 (as per GOLD guidelines 2024) [1] along with a post bronchodilator reversibility in FEV1 or FVC of <200ml and <12% and had clinical symptoms suggestive of COPD.

Exclusion Criteria

Patient refusal was the only exclusion criteria for our study.

Sample Size

After a priority power analysis of previous data and a correlation co-efficient derived in the previous studies, a sample size of minimum 100 patients with obstructive airway defect with insignificant post bronchodilator reversibility was required.

In our study we have studied 111 patients.

Procedure

Patients who were suspected clinically to have COPD, which was based on patient’s symptoms, long standing history of smoking, second hand exposure to tobacco smoke or Chollah smoke, further underwent spirometry testing to confirm the diagnosis of COPD.

Pulmonary Function Testing

The following tests were performed

Forced Vital Capacity (FVC), FVC%, Forced Expiratory Volume in one second (FEV1), FEV1%, FEV1/FVC%, Forced expiratory volume in 6 seconds (FEV6) and FEV1/FEV6%.

Each pulmonary function test was expressed as a percentage of the predicted values based on age, sex, height, weight and body surface area according to the Indian community reference values.^[18] Spirometry measurements were performed with mass flow sensor (MS-PFT OF JAGGER COMPANY) by a trained person according to the guidelines of the ATS. Three acceptable maneuvers were performed for each spirometric reading and the spirometric measurement with the largest sum of FEV1 and FVC was chosen for final analysis. FEV6 was also taken from that maneuver itself.

Patients who had a post bronchodialtor FEV1/FVC ratio of <0.70 were included in the study and were then further classified into different GOLD grades as per post bronchodilator FEV1% of mild (>/=80%), moderate (>/=50% to <80%), severe (>/=30% to < 50%) and very severe (<30%) airflow obstruction.^[1]

Statistical Analysis

Sensitivity analysis was used to compare FEV1/FEV6% to FEV1/FVC% for diagnosing airflow obstruction. Pearson's correlation coefficient was used for studying correaltion between FVC and FEV6, FEV1/FVC and FEV1/FEV6 and post bronchodilator values of FVC1 and FEV6. Analysis of variance (ANOVA) was use to study the relation of FVC and FEV6 in different severities of disease. The difference between FEV1/FVC% and FEV1/FEV6% was studied with two tailed p value analysis.

A total of 111 patients meeting the eligibility criteria for the study were recruited as study population. All the patients were diagnosed cases of chronic obstructive lung disease depending on the GOLD criteria. The characteristics of the study population based on the age and Body Mass Index (BMI) are presented in table no 1.

The gender ratio of the recruited study population was 1.7:1 with 70 male and 41 female patients of COPD. The mean age of the study population was 63.12 ± 10.97 years with similar mean age among male and female patients (62.34 ± 11.02 years and 62.99 ± 10.99 respectively). The mean BMI of the male, female and the total study population was 24.57 ± 4.93, 24 ± 4.96, 24.58 ± 4.95 kg/square meters respectively.

Based on their FEV1 % of the predicted as per GOLD criteria (table 2), it was observed that most of the patients were with moderate severity (n=44, 39.7% = ~40%). The moderate severity frequency was followed by severe in a total of 34 patients, mild in 28 patients and very severe in 5 patients.

As only cases were enrolled in the patients, we evaluated the sensitivity of the FEV1/FEV6 towards identifying the obstructive lung disease cases. Out of a total of 111 study participants with FEV1/FVC ratio less than 70% as diagnostic criteria, the sensitivity of FEV1/FEV6 ratio (with fixed cutoff of 73%) towards identifying obstructive cases was determined as 97.3% with a range of 92.3 to 99.44%. We could not determine the specificity and predictive values of the FEV1/FEV6 ratio as we did not enrol the control population in the study. The relationship between the FEV6 and FVC was studied in the study population to establish if the FEV6 showed a similar pattern as FVC in these patients of obstructive disease.

The correlation of FVC and FEV6 at different volumes before and after bronchodilator use (figure 1, figure 2) was carried out using Pearson's correlation coefficient.

Figure 1: Correlation between FVC and FEV6 before bronchodilator use

Figure 2: Correlation between FVC and FEV6 after bronchodilator use

A strong correlation was observed between FVC and FEV6 with a Pearson’s correlation coefficient of 0.9983 (95% confidence interval: 0.9975 to 0.9988) for pre bronchodilator use and 0.9982 (95% confidence interval: 0.9973 to 0.9987) for post bronchodilator use. The scatter plots of FVC and FEV6 were almost overlapping throughout the sample size and also demonstrated a similar trend at various volumes of the FVC and FEV6. Thus a change in FVC predicted almost 100% change in FEV6 and vice versa.

Relationship of FEV6 and FVC in different disease severities was calculated using Analysis of Variance (ANOVA). Both FVC and FEV6 decreased with increasing disease severity (Table 3). This decrease was statistically significant for all classes of disease severity with a significant p value of less than 0.0001.

Effect of bronchodilation with respect to change in FVC and FEV6 was then calculated using Pearson's correlation coefficient (figure 3). Both FVC and FEV6 demonstrated a similar and parallel trend after bronchodilator use. The correlation for this relationship was very strong (Pearson’s r= 0.9632 with 95% confidence interval of 0.9468 to 0.9746 and p value of <0.0001). The trend was parallel and overlapping to each other throughout the study population both at negative and positive values of change after bronchodilator use (figure 3)

Figure 3: Correlationship of change in FVC and change in FEV6 after bronchodilator use

Figure 4: Mean FEV1/FVC and FEV1/FEV6 of the study population

As there was close relationship of FVC and FEV6 in the results mentioned above, we analyzed the correlation between FEV1/FVC and FEV1/FV6. The mean FEV1/FVC% of the study population was 60.61 ± 8.03 % and FEV1/FV6% was 62.32 ± 7.8% (figure 4). The two tailed p value between these two ratios was 0.1099 (Not significant). A strong correlation of r= 0.9893 with 95% confidence interval of 0.9844 to 0.9927 (figure 5) was then observed between FEV1/FVC and FEV1/FEV6 throughout the study population and at different percentages of these ratio.

Figure 5: Correlation between FEV1/FVC and FEV1/FEV6 in the study population. The strong correlation can be observed from the close and parallel scatter plot in the figure

Spirometry is a corner stone for diagnosing various respiratory diseases and it is always dependent on patient effort and cooperation. The maximum possible effort is required and may be predisposed to inter-subject variabilities especially to reach FVC. However, various studies have shown FEV6 to be a good substitute to FVC^[19] which needs to be given more emphasis. To perform FVC maneuver patients are required to empty their lungs completely, which is a tedious process and may take up to 20 seconds. Thus, it can be exhausting for older or impaired individuals or those who have severe respiratory diseases.^[7] Airflow obstruction is defined by a FEV1/FVC ratio <0.7.^[1] Therefore, any wrong values in the measurement of either of these values will result in misclassification. The 1994 ATS recommendation which is still used for validation, stated that, to produce a valid FVC measurement, each maneuver should last until a plateau is achieved on the volume-time graph ^[20]. Patients with airway obstruction often fail to meet the end of test criteria defined by a less than-20 ml change in the final two seconds of the maneuver.^[6,7] The standard FVC is also dependent on expiratory time and effort which poses a challenge to perform for individuals with airway obstruction and with increasing age.^[13] These problems associated with performing FVC have sparked an interest in identifying an alternative for FVC, preferably a test that requires a shorter exhalation and that has discrete end of test criterion. In the year of 2000, the National Lung Health Education Program^[21] had proposed using forced expired volume in 6 seconds (FEV6) and the FEV1/FEV6 ratio as a surrogate for FEV1/FVC and FVC values. Although, Its validity in diagnosing and assessing the severity of the obstructive lung disease has been studied in the past but the data in Indian patients is limited. With this background to support the existing evidence and to study FEV6 as an alternative to FVC in spirometry, we conducted this cross-sectional observational study to establish FEV6 as a correlated parameter in COPD severity and diagnosis in Indian patients.

We enrolled 111 cases of diagnosed chronic obstructive lung disease depending on the GOLD criteria^[1] and performed a systemic analysis to define variations in FVC and FEV6 in different disease severities and later correlate to establish if FVC and FEV6 followed a liner relationship with each other in the total population as well as in different severities of the disease. For our study population with a mean approximate age of 63 years and BMI of approximately 24kg/sq.m, almost 70% of the patients had moderate to severe COPD. The FVC and FEV6 showed similar trend in various severities of the disease (p>0.05) displaying a close relationship to each other both before and after the administration of the short acting bronchodilator. From mild to very severe COPD, the FEV6 decreased in parallel with FVC showing a strong correlation in all severities of COPD. By establishing the strength and direction of relationship between the FVC and FEV6, we could partially overcome the fact of not using control population in the study population for comparison. Followed by this analysis, we determined if FEV1/FEV6 ratio showed a similar behaviour of distribution in the study population as that of FEV1/FVC. We determined this relationship very strong with a coefficient of correlation of 0.9893 (p<0.0001). Thus it meant that a change in FEV1/FVC predicted almost 99% similar directional change in FEV1/FEV6. This analysis was supported by the sensitivity of FEV1/FEV6 ratio to diagnose COPD cases in our study population. The sensitivity was 97.3% with only 3 false positive cases in whom the FEV1/FVC was almost near the 70%. All three patients had moderate airflow obstruction.

The sensitivity of the FEV1/FEV6 with respect to FEV1/FVC in our study was slightly higher than Swanney et al.^[9] and Vandervoorde et al.^[10] who reported the sensitivity of 95% and 94% respectively. Both these studies compared the FEV6 and FVC in obstructive as well as restrictive patterns in cases and matched controls. Both these studies also established a very high specificity of FEV1/FEV6 in diagnosing as well as screening the obstructive lung diseases (97.4% and 93.1% respectively). A meta-analysis by Ji-yong Jing et al.^[4] showed a sensitivity of FEV1/FVC6 of 89% with a very high specificity of 98%. Hiroyuki Kishi et al.^[19] observed a sensitivity of 93.2% with 98.5% specificity of FEV1/FEV6 ratio towards obstructive pattern of lung disease. Malolan et al.^[6] demonstrated a 100% sensitivity and 100% specificity of FEV1/FEV6 in COPD patients. Singh et al.^[22] conducted a study in India where they reported the sensitivity of FEV1/FEV6 for diagnosing obstruction in stage 1 and stage 2 COPD subgroup was 88.88% and 98%, respectively, while it was 100% in stages 3 and 4. The findings of Singh et al. echo the findings of our study as we reported a sensitivity of 100% in stages 3 to 4 of the COPD. Aghili et al. showed FEV1/FEV6 had sensitivity of 95.5% and specificity of 99.4%.^[23] As it can be established by these higher sample size population survey based studies, the specificity of FEV1/FEV6 is consistently high approximately 98% or more. Our study supports the current literature with high sensitivity of FEV1/FEV6 in obstructive lung disease. Swanney et al.^[9] also found the reliability of FEV1/FEV6 as the ratio was more reproducible in multiple tests compared to FEV1/FVC.

Singh et al.^[22] also mentioned that the value of FEV1/FEV6 < 73% could be considered as a valid alternative for FEV1/FVC < 70% as a fixed cutoff point for the detection of airflow obstruction in adults. The authors also emphasized that these cutoff terms should be used cautiously, specially outside the middle-aged population. If we do consider a cut off of 73% of FEV1/FEV6 for the diagnosis of COPD, the sensitivity of FEV1/FEV6 almost approximates 100% in our study, thus we express coherence to the findings of Singh et al. The closest correlation as our study was reported by Lundgren et al.^[24] The authors reported a correlation of FEV1/FEV6 with FEV1/FVC with r = 0.99 (p < 0.0001). Bhatt et al.^[25] in 2014 also reported similar findings that FEV1/FEV6 < 0.73 could be used as a substitute for FEV1/FVC < 0.70 to diagnose obstructive airway disease and that FEV1/FEV6 < 0.73 was associated with emphysema which was detected via computed tomography measures, poor quality of life and increased frequency of exacerbations even when FEV1/FVC ratio was normal (i.e≥ 0.70). They demonstrated FEV1/FEV6 to be superior to FEV1/FVC for the diagnosis of COPD-related morbidity.

The correlation of FEV1/FEV6 with FEV1/FVC in our study was very strong (r=0.99). Singh et al.^[22] demonstrated a similar correlation suggesting similar behaviour of both FEV6 and FVC parameters in the COPD patients. Malolan et al.^[6] also demonstrated a linear correlation between FVC and FEV6 in all subjects, along with the difference in means to be statistically significant in all patients. After a comprehensive correlation analysis of FEV6 and FVC with disease severity, pre bronchodilator and post bronchodilator changes as well as between the FEV1/FEV6 and FEV1/FVC in our study, we propose that the behaviour of the trend of FEV6 and FVC is strongly related to each other and these changes are always correlated irrespective of the severity of the disease or the use of bronchodilator.

FVC is a more difficult maneuver to reproduce than FEV6, especially in patients with air trapping which is the same population in which researchers have criticized the accuracy of FEV1/FEV6 in diagnosing airflow obstruction.^[26] Patients who have significant air trapping attain their equal pressure point earlier and more peripherally before they can empty their lungs completely. Therefore, they have FVC lower than expected for age, creating a falsely high FEV1/FVC, which would be less likely to occur if FEV6 is used.^[25] Applying FEV1/FEV6 instead of FEV1/FVC could be very useful in the context of primary care, where spirometry can be used as a screening tool for the early detection of COPD in a high-risk population, ie, smokers 45 years of age and subjects with respiratory symptoms. Using FEV6 instead of FVC is easier for the patient and the technician, especially for older patients and those with severe respiratory diseases.^[21] There is a more precise end-of-test definition.^[21] It is also seen that FEV6 is more reproducible than FVC.^[9] Shorter maneuvers reduce the risk of syncope and as FEV6 estimation is shorter in duration to FVC estimation, it could be a potential advantage of FEV6 estimation^[21] and also the fact that FEV6 reduces the overall time to perform a test, it becomes a more convenient method. The ease of performing FEV6 manoeuvre with its reduced variability gives it a statistical advantage in diagnosing airway obstruction. Along with the numerous advantages of FEV6 which have been discussed in our study, using FEV6 as a surrogate for FVC would also result in an easier performance of spirometry manuver as patients would not have to blow for 15 to 20 seconds to achieve a valid FVC value. This will be helpful in older and impaired patients. The requirement of data storage space will also reduce with a shorter expiratory time which is an important issue for smaller, portable spirometers.

The limitations of the study mainly include inclusion of only the cases in the study. As the control group of non COPD patients was not present for the analysis, we could not analyze the exact specificity and predictive values of the FEV6 and FEV1/FEV6 ratio for diagnosis. This limitation was partially overcome by the comprehensive correlation analysis of the FEV6 with FVC in multiple independent variables such as severity of the disease, FEV1% predicted, and bronchodilator use. As the specificity of the test is uniformly established in the literature to be more than 98% while having multiple variations in sensitivity, our study adds to the existing literature for the sensitivity of FEV1/FEV6 in diagnosis of COPD especially in the Indian scenario. We did not estimate the reproducibility of the FEV1/FEV6 in the study population which also can be one of the limitations. The findings of the study may be extrapolated to the population with similar baseline characteristics only but we could identify similar means and standard deviations with other studies too. The study being a single center study, a potential selection bias towards the study population could be present. A multiple center study aimed at screening of high risk individuals for COPD with comparison to matched control is required to validate the observations of our study to a larger population.

In summary, as per consensus statement by the Office Spirometry for Lung Health Assessment in Adults from National Lung health Education program,^[21] a feasible testing and follow-up strategy should minimize the false-positive and false-negative rates, is relatively simple and affordable, should be safe and includes an action plan that minimizes potential adverse effects. As per the results of our study and specificity data from the literature, FEV6 as an alternate to FVC appears sensitive, specific, safer and reproducible for the diagnosis of COPD. These criteria make FEV1/FEV6 an effective measure for the screening of obstructive lung diseases.

In our study, FEV1/FEV6 had a sensitivity of 97.3% and correlated strongly with FEV1/FVC in different disease severity. FEV1/FEV6 is a sensitive and reliable marker which shows strong correlation with FEV1/FVC for diagnosing obstructive airway disease in COPD patients and can be used as an alternative indicator for disease screening especially in primary health care where advanced spirometers are generally not available. FEV6 showed a linear correlation with FVC in increasing disease severity in our study indicating that it can be substituted for FVC as a marker for restrictive lung disease. Both FVC and FEV6 showed a similar trend pre and post bronchodilation with no statistical difference amongst the two in any stage of COPD.

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