A Research On The Application Of The Bronchodilator Test Defined By FVC In COPD Patients

BACKGROUNChronic obstructive pulmonary disease(COPD)is a disease characterized by persistent airflow obstruction which is not fully reversible and is usually progressive and is associated with elevated chronic inflammatory responses to noxious particles or gases in the airways.The prevalence of COPD is skyrocketing,according to the survey results of Wang et al in 2012,the prevalence rate of COPD among people over 40 years old in China is 13.7%,up 67%compared with 10 years ago.COPD has become a chronic disease on a par with hypertension and diabetes.The bronchodilator test plays a crucial role in the management of COPD,e.g.the diagnosis of COPD is confirmed in cases with forced expiratory volume in the first second(FEV1)/forced vital capacity(FVC)ratios below 0.7 after bronchodilator administration.Flow response after bronchodilator inhalation is universally and frequently used as an indicator for assessing responsiveness in general practice.However,in clinical practice,we found that,in moderate to severe COPD cases,flow response may be poor,yet the response in terms of volume can be relatively favorable,which is probably due to a reduction in hyperinflation.At present,the characteristics and differences between the changes of FEV1 and FVC after bronchodilator test in COPD patients have not attracted enough attention.In the evaluation of bronchodilator test in COPD patients,people pay more attention to the changes of FEV1 but ignore the changes of FVC.The first question to answer in the pulmonary function test is do the subjects have ventilatory defects?If so,what type of disorder is it,restrictive,obstructive,or mixed abnormalities?In clinical practice,we found that FVC decreased before bronchodilator test in some COPD patients,and increased to the normal range after inhalation of bronchodilator.This indicated that these patients did not have restrictive abnormalities and their decreased vital capacity(VC)might be caused by gas trap and increase of residual volume(RV).For these cases,they could be diagnosed as obstructive abnormalities either than restrictive abnormalities.It is meaningful to interpret the result of lung function test correctly through such as a simple,safe,economic and convenient way.At present,there are few studies focus on the role of bronchodilator test in the differential diagnosis of the result of pulmonary function test in COPD patients.Total lung capacity(TLC)is equal to the sum of VC and RV.An increase in VC means a decrease in RV if the TLC remains the same.According to the American Thoracic Society/European Society of Respiratory Diseases(ATS/ERS)guidelines,increased RV/TLC(above the normal upper limit)indicates the presence of lung hyperinflation and reflects its severity.The significant increase of FVC in COPD patients after bronchodilator test was speculated to be related to the reduction of lung hyperinflation and RV.The relationship between RV/TLC and the changes in the FVC after bronchodilator test in COPD patients is unclear.COPD is heterogeneous in nature.COPD patients with similar FEV1 display different clinical manifestations,quality of life,exacerbation frequencies,and responses to treatment.Nowadays,COPD phenotyping is increasingly becoming a topic of interest to more and more physicians aiming at classifying patients into distinct clinical subgroups to initiate appropriate individualized care which may lead to a better prognosis and quality of life for patients.Recent research had proved eosinophilic inflammation dominated COPD is an important COPD phenotype.Its clinical characteristics are airway responsiveness(the change of FEV1),higher eosinophil counts,and higher FeNO concentrations.Although some studies were focused on the role of the change of FEV1 value after bronchodilator inhalation,but there are rarely studies about the role of the change of FVC value in COPD,and we are not clear about the relationship between the change and FeNO or eosinophil.Based on these grounds,this study’s objectives were as follows:1)to compare the FEV1 and FVC responses after administration of a bronchodilator in COPD patients 2)to evaluate the role of bronchodilator test in the differential diagnosis of the result of pulmonary function test in COPD patients 3)to compare the characteristics of COPD patients classified as FVC responders and non-responders during the bronchodilator test and to explore the relationship between the changes of FVC after bronchodilator test and the RV/TLC and the levels of fractional exhaled nitric oxide.This study can be divided into four parts.Part one Characteristics of the bronchodilator test in COPD patientsPURPOSETo compare the FEV1 and FVC responses after administration of a bronchodilator in patients with chronic obstructive pulmonary disease.METHODSA total of 1081 stable COPD patients(male 702,female 379)who performed bronchodilator test,aged 62.5±9.3(43-86)years were enrolled from Dec.2012 to Aug.2019.The severity of COPD was graded according to the Global initiative for chronic obstructive lung disease(GOLD)criteria.Changes in the FEV1 were expressed as 1)An absolute change relative to the baseline(△FEV1)and 2)A percentage change relative to the baseline(△FEV1%baseline).Changes in the FVC were expressed in a similar manner.The change of FEV1 and FVC(including absolute value and percentage)15 minutes after albuterol administration(400μg)were compared.Positive responses to the bronchodilator were defined as FEV1 and/or FVC increasing 12%from baseline and 200 ml or above.RESULTSAfter inhalation of albuterol,FEV1 increased 190 ml with a 16.31%improvement on average compared with baseline and FVC increased 370 ml with a 16.86%improvement on average.The rate of positive reversibility in FEV1 was 36.1%and the rate of positive reversibility in FVC was 56.1%.The improvement of FEV1 decreased as the GOLD stage was more severe.On the contrary,the improvement of FVC was increased in those with more severe GOLD stage.CONCLUSIONAfter administration of a bronchodilator,the improvement of FVC is more remarkable than FEV1 in patients with COPD,especially in those with advanced GOLD stages.The reversibility of COPD should also be assessed by FVC in addition to FEV1.Part two The differential diagnosis value of the bronchodilator test in the interpretation of pulmonary function test of COPD patientsPURPOSETo evaluate the role of bronchodilator test in the differential diagnosis of the result of pulmonary function test in COPD patientsMETHODSA total of 1081 stable COPD patients(male702,female 379)who performed bronchodilator test,aged 62.5±9.3(43-86)years were enrolled from Dec.2012 to Aug.2019.Changes in the FEV1 were expressed as 1)An absolute change relative to the baseline(△FEV1)and 2)A percentage change relative to the baseline(△FEV1%baseline).Changes in the FVC were expressed in a similar manner.The severity of COPD was graded according to the Global initiative for chronic obstructive lung disease(GOLD)criteria.Patients were further classified into three groups according to FVC:(Ⅰ)normal FVC group(N-FVC):Before-bronchodilator(BBD)and after-bronchodilator(ABD)FVC≥80%predicted(pred.);(Ⅱ)inconsistent FVC group(IC-FVC):BBD FVC<80%pred.,with ABD FVC≥80%pred.;(Ⅲ)limited FVC group(L-FVC):BBD and ABDFVC<80%pred.The characteristics were compared between groups.RESULTSForm GOLD stages 1 to 4,the ratio of BBDFVC%pred.<80%were 6.8%,52.6%,92.0%,and 99.2%,respectively,and ratio of ABDFVC%pred.<80%were 0%,16.5%,55.1%,92.2%,respectively.For the entire cohort,309 of 716(43.2%)with small BBD FVC achieved large ABD FVC after inhaling bronchodilator,suggesting that 43.2%patients had improvements of FVC ABD and the restrictive defect can be ruled out.FEV1,FVC,forced expiratory flow at 75%、50%of the FVC(MEF75、MEF50),and maximal mid-expiratory flow(MMEF)were successively reduced from N-FVC group,IC-FVC group to L-FVC group.More than 90%of N-FVC patients existed in GOLD stages 1 and 2,and 93.5%of IC-FVC patients belonged to GOLD stages 2 and 3,while L-FVC patients majorly existed in GOLD stages 3 and 4.Therefore,it is logically considered that COPD patients classified by FVC(from N-FVC to L-FVC)show the progressive development of COPD,similar to GOLD stages classified by FEV1CONCLUSIONBronchodilator test is a useful method for identifying pseudo-low FVC in patients with COPD.COPD patients classified by FVC(from N-FVC to L-FVC)show the progressive development of COPD,similar to GOLD stages classified by FEV1.Part three The relationship between RV/TLC and changes of FVC after bronchodilator test in COPD patientsPURPOSETo compare the characteristics of COPD patients classified as FVC responders and non-responders during the bronchodilator test and to explore the relationship between the RV/TLC and changes of FVC after bronchodilator test in COPD patientsMETHODSA total of 1081 stable COPD patients(male702,female 379)who performed bronchodilator test,aged 62.5 ±9.3(43-86)years were enrolled from Dec.2012 to Aug.2019.336 patients were simultaneously measured by DLCO single-breath method.The severity of COPD was graded according to the Global initiative for chronic obstructive lung disease(GOLD)criteria.Changes in the FEV1 were expressed as 1)An absolute change relative to the baseline(△FEV1)and 2)A percentage change relative to the baseline(△FEV1%baseline).Changes in the FVC were expressed in a similar manner.Positive responses to the bronchodilator were defined as FEV1 and/or FVC increasing 12%from baseline and 200 ml or above.The characteristics were compared between patients with and without significant bronchodilator responsiveness in terms of FVC.RESULTSPatients with significant FVC responsiveness displayed poorer lung function and higher RV/TLC compared with those without considerable FVC responsiveness.There is a discernible linear relationship between RV/TLC%predicate and FVC responsiveness to bronchodilator use(r=0.306,P=0.000).The application of bronchodilator responsiveness of FVC for detecting RV/TLC%predicated>120 in COPD patients exhibited relatively high sensitivity(65.8%)and specificity(60.0%).CONCLUSIONWe demonstrated that COPD patients with significant FVC responsiveness had poorer lung function than non-responders and established a simple method for detecting lung hyperinflation.Part four The relationship between fractional exhaled nitric oxide and changes of FVC after bronchodilator test in COPD patientsPURPOSETo explore the relationship between fractional exhaled nitric oxide and changes of FVC after bronchodilator test in patients of chronic obstructive pulmonary disease.METHODSA total of 346 COPD patients with exacerbation who underwent bronchodilator tests,fractional exhaled nitric oxide(FeNO)measurements and blood eosinophil counts were analyzed.Changes in the FEV1 were expressed as 1)An absolute change relative to the baseline(△FEV1)and 2)A percentage change relative to the baseline(△FEV1%baseline).Changes in the FVC were expressed in a similar manner.Positive responses to the bronchodilator were defined as FEV1 and/or FVC increasing 12%from baseline and 200 ml or above.The characteristics,FeNO levels,and blood eosinophil counts were compared between patients with and without significant bronchodilator responsiveness in terms of FVC.RESULTSPatients with significant FVC responsiveness displayed poorer lung function and higher FeNO levels compared with those without considerable FVC responsiveness(Z=-5.042 to-0.375,p=0.000-0.022).There is a discernible linear relationship between FeNO levels and FVC responsiveness to bronchodilator use(r=0.251,P=0.001).The application of bronchodilator responsiveness of FVC for detecting high FeNO levels in COPD patients exhibited relatively high sensitivity(61.8%)and specificity(86.7%).CONCLUSIONWe demonstrated that COPD patients with significant FVC responsiveness had higher FeNO levels than non-responders and established a simple method for detecting highFeNO values.FVC responders may be identified as a separate group of COPD patients.