Minimal clinically important differences in COPD lung function

The FEV1 is widely used by physicians in the diagnosis, staging, treatment, monitoring, and establishing prognosis for patients with COPD. The MCID is the smallest difference which patients perceive as beneficial and which would mandate a change in patient management. A precise MCID for FEV1 has not been established. In attempt to establish a MCID for predose or trough FEV1, several limitations need to be addressed. There are issues such as reproducibility, repeatability, acceptability, variability, placebo effect, and equipment effects. Patient factors, such as baseline level of FEV1, albuterol reversibility, diurnal variation, influence the results. Nonetheless, using anchoring techniques, a change in pre dose FEV1 of about 100 mL can be perceived by patients, correlates with fewer relapses following exacerbations and is in the range usually achieved with bronchodilators approved for COPD. In the future, consistent reporting of spirometric variables, such as a predose FEV1 and other outcomes, can be incorporated into a more quantitative effort to establish the MCID. Also distributional/statistical methods may be useful in determining the MCID FEV1.     

Minimum Clinically Important Difference in Diffusing Capacity of the Lungs for Carbon Monoxide Among Patients with Severe and Very Severe Chronic Obstructive Pulmonary Disease

Background: The minimum clinically important difference (MCID) for diffusing capacity of the lungs for carbon monoxide (DLCO) has not yet been solidly established. Methods: We used the dataset of surgical cohort of National Emphysema Treatment Trial. Briefly, severe and very severe chronic obstructive pulmonary disease (COPD) patients who were candidate for volume reduction surgery and who could provide sufficient data at 12-month follow-up were included. We used two anchor methods using 6-minute walk distance (6MWD. MCID = 40 m) and forced expiratory volume in 1 sec (FEV₁. MCID = 100 ml) as anchors, and two distribution methods. We proposed MCID with a median of estimated values. We estimated MCID for DLCO in raw value and % change from the baseline independently. Results: The surgical cohort included 356 patients, whose average age was 66.6 ± 5.5 years, and the average % predicted FEV₁ was 27.8 ± 7.3%. The estimated MCID for DLCO in raw value and % change from the baseline were as follows: anchor method (average, 6MWD) 1.2 ml/min/mmHg, 17%; anchor method (average, FEV₁) 0.7 ml/min/mmHg, 11%; anchor method (receiver operating characteristic, 6MWD) 1.1 ml/min/mmHg, 10%; anchor method (receiver operating characteristic, FEV₁) 1.2 ml/min/mmHg, 3%; distribution method (0.3 units of standard deviation), 0.9 ml/min/mmHg, 11%; distribution method (standard error of measurement), 1.1 ml/min/mmHg. The median of these values was 1.1 ml/min/mmHg and 11%. Conclusion: We estimated the group-level MCID for DLCO for patients with severe and very severe COPD patients as 1.1 ml/min/mmHg and 11% of baseline DLCO.     

Detection and prevalence of chronic obstructive pulmonary disease in a cardiovascular clinic: evaluation using a hand held FEV₁/FEV₆ meter and questionnaire

Background and objective: COPD is one of the leading causes of morbidity and mortality worldwide, and its prevalence continues to increase. Although spirometry is indispensable for the diagnosis of COPD, other simple and reliable tools are necessary for screening of COPD because spirometry is not widely available. This study investigated the usefulness of a combination of an electronic FEV₁/FEV₆ meter (PiKo‐6) with a COPD questionnaire as a screening method in patients with cardiovascular diseases. Methods: The PiKo‐6 and the COPD questionnaire of the International Primary Care Airways Group were used to screen patients attending a cardiovascular outpatient clinic. Patients with FEV₁/FEV₆ < 70% were defined as having airflow limitation. Patients diagnosed with airflow limitation underwent spirometry. Using data from the PiKo‐6 and the COPD questionnaire, patients were assigned to a COPD group or a non‐COPD group. The relationship between PiKo‐6 measurements and spirometry was also evaluated. Results: Among 753 patients, 82 (10.9%) showed airflow limitation when assessed with the PiKo‐6. Of these patients, 79 (10.5%) were assigned to the COPD group. FEV₁, FEV₆ and FEV₁/FEV₆, as measured with the PiKo‐6, correlated significantly with FEV₁, FVC and FEV₁/FVC, respectively, as measured by spirometry (r = 0.865, 0.751 and 0.57). Among the cardiovascular comorbidities, heart failure and ischaemic heart disease showed slightly stronger associations with airflow limitation (13.8% and 12.5%, respectively). Conclusions: Combination of the PiKo‐6 with a COPD questionnaire may be a useful and feasible method of identifying undiagnosed COPD patients attending a cardiovascular outpatient clinic.     

Oscillatory Positive Expiratory Pressure in Chronic Obstructive Pulmonary Disease

Evidence-based guidance for the use of airway clearance techniques (ACT) in chronic obstructive pulmonary disease (COPD) is lacking in-part because well-established measurements of pulmonary function such as the forced expiratory volume in 1s (FEV₁) are relatively insensitive to ACT. The objective of this crossover study was to evaluate daily use of an oscillatory positive expiratory pressure (oPEP) device for 21–28 days in COPD patients who were self-identified as sputum-producers or non-sputum-producers.

COPD volunteers provided written informed consent to daily oPEP use in a randomized crossover fashion. Participants completed baseline, crossover and study-end pulmonary function tests, St. George's Respiratory Questionnaire (SGRQ), Patient Evaluation Questionnaire (PEQ), Six-Minute Walk Test and ³He magnetic resonance imaging (MRI) for the measurement of ventilation abnormalities using the ventilation defect percent (VDP).

Fourteen COPD patients, self-identified as sputum-producers and 13 COPD-non-sputum-producers completed the study. Post-oPEP, the PEQ-ease-bringing-up-sputum was improved for sputum-producers (p = 0.005) and non-sputum-producers (p = 0.04), the magnitude of which was greater for sputum-producers (p = 0.03). There were significant post-oPEP improvements for sputum-producers only for FVC (p = 0.01), 6MWD (p = 0.04), SGRQ total score (p = 0.01) as well as PEQ-patient-global-assessment (p = 0.02). Clinically relevant post-oPEP improvements for PEQ-ease-bringing-up-sputum/PEQ-patient-global-assessment/SGRQ/VDP were observed in 8/7/9/6 of 14 sputum-producers and 2/0/3/3 of 13 non-sputum-producers. The post-oPEP change in ³He MRI VDP was related to the change in PEQ-ease-bringing-up-sputum (r = 0.65, p = 0.0004) and FEV₁ (r = –0.50, p = 0.009).

In COPD patients with chronic sputum production, PEQ and SGRQ scores, FVC and 6MWD improved post-oPEP. FEV₁ and PEQ-ease-bringing-up-sputum improvements were related to improved ventilation providing mechanistic evidence to support oPEP use in COPD. Clinical Trials # NCT02282189 and NCT02282202.     

The severity of airways obstruction as a determinant of treatment response in COPD

Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV₁) to decide when to initiate combination treatment with a long-acting β₂-agonist and an inhaled corticosteroid. Assessment of baseline FEV₁ as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 μg salmeterol (Sal), 500 μg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV₁ <50% and FEV₁ ≥50% predicted subgroups (n=949/513 respectively). Treatment effects on clinical outcomes – lung function, exacerbations, health status, diary card symptoms, and adverse events – were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV₁; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV₁ <50% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV₁; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV₁, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.     

Thymus and activation-regulated chemokine (TARC/CCL17) predicts decline of pulmonary function in patients with chronic obstructive pulmonary disease

BackgroundThe deterioration of pulmonary function, such as FEV₁-decline, is strongly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). However, few investigations shed light on useful biomarkers for predicting the decline of pulmonary function. We evaluated whether thymus and activation-regulated chemokine (TARC), a Th2 inflammation marker, could predict rapid FEV₁-decline in COPD patients.MethodsWe recruited 161 patients with stable COPD and performed pulmonary function test once every six months. At the time of registration, blood tests, including serum levels of TARC were performed. We assessed the correlation between changes in parameters of pulmonary function tests and serum levels of TARC. The rapid-decline in pulmonary function was determined using 25th percentile of change in FEV₁ or FEV₁ percent predicted (%FEV₁) per year.ResultsIn the FEV₁-rapid-decline group, the frequency of exacerbations, the degree of emphysema, and serum levels of TARC was higher than in the non-rapid-decline group. When using %FEV₁ as a classifier instead of FEV₁, age, the frequency of exacerbations, the degree of emphysema and serum levels of TARC in the rapid-decline group was significantly greater than those in the non-rapid-decline group. In univariate logistic regression analysis, TARC was the significant predictive factor for rapid-decline group. In multivariate analysis adjusted for emphysema, serum levels of TARC are independently significant predicting factors for the rapid-decline group.ConclusionsTARC is an independent predictive biomarker for the rapid-decline in FEV₁. Measuring serum TARC levels may help the management of COPD patients by predicting the risk of FEV₁ decline.     

Two-month comparative study of tulobuterol aerosol versus fenoterol aerosol in patients with chronic obstructive lung disease

In this two month, double-blind, crossover study, the efficacy and safety of tulobuterol aerosol (400μg qid) was compared to fenoterol aerosol (400μg qid) in patients with chronic obstructive lung disease. Thirty-six (36) adults with reversible bronchospasm were enrolled. All patients were evaluable. On set of response was within 5 minutes for both drugs. Mean increases in FEV₁ were greater after tulobuterol than fenoterol at every time interval. Increases peaked at 30–60 minutes postdose. Duration of response was longer after tulobuterol with mean FEV₁ remaining >15% over baseline for at least 6 hours postdose. Mean predose FEV₁ values were significantly greater after 2 and 4 weeks of tulobuterol treatment compared with fenoterol. Despite these large increases, changes in mean FEV₁ from predose to 1 hour postdose at these visits were not significantly different between treatment groups. Results of plethysmography testing also indicated greater improvement after tulobuterol. In addition, improvement in pulmonary symptoms was more pronounced during tulobuterol therapy. Small changes in mean blood pressure occurred, with greater changes after fenoterol than after tulobuterol. Changes in mean pulse rate were significantly greater following fenoterol administration. No adverse reactions were reported during tulobuterol treatment; however, one patient experienced severe tremor, tachycardia, and sweating during fenoterol treatment and withdrew from the study prematurely. The results in this study indicate that tulobuterol aerosol is more effective than fenoterol aerosol in the treatment of patients with chronic obstructive lung disease, with fewer cardiovascular effects and no adverse reactions.     

Reduced Heart Rate Variability in Patients with Chronic Obstructive Pulmonary Disease Independent of Anticholinergic or β-agonist Medications

ABSTRACT

Reduced heart rate variability (HRV) is a predictor of poor outcome in several pathologies and in general population. Whether HRV is altered during normal daily activities or influenced by anticholinergic and β-adrenergic medications in chronic obstructive pulmonary disease (COPD) remains unknown. Forty-one clinically stable COPD patients and 19 healthy controls matched for age, sex and smoking history underwent a 24-hour ambulatory ECG recording during normal daily activities. HRV was assessed by standardized temporal and spectral analysis. COPD patients showed a reduced HRV (LF/HF ratio) compared with healthy controls (median [interquartile range]) during daytime (2.6 [1.5–3.8] vs. 3.5 [2.9–5.6]), nighttime (1.8 [1.1–4.3] vs. 4.2 [2.7–6.9]) as well as during the entire 24-hour (1.9 [1.5–3.4] vs. 3.9 [3.2–5.6]) recordings (all P < 0.005). There was no significant difference between the two groups in the time domain and in the low frequency or high frequency domain for the 24-hour period analysis. In COPD patients, the 24-hour LF/HF ratio positively correlated with forced expiratory volume in 1 second (FEV₁) (r = 0.342, P = 0.028) and negatively correlated with age (r = ?0.317, P = 0.044). In multiple regression analysis, LF/HF ratio was associated with FEV₁ (P = 0.05) but not with age (P = 0.08). There was no difference of HRV between patients using or not anticholinergic or β-agonist medications. These results demonstrate that COPD patients have a reduced sympatho-vagal balance compared with healthy subjects. HRV correlates with disease severity and does not seem to be influenced by anticholinergic or adrenergic medications.     

A new staging strategy for chronic obstructive pulmonary disease

Background:

The best method for expressing lung function impairment is undecided. We tested in a population of patients with chronic obstructive pulmonary disease (COPD) whether forced expiratory volume in 1 second (FEV₁) or FEV₁ divided by height squared (FEV₁/ht²) was better than FEV₁ percent predicted (FEV₁PP) for predicting survival.

Method:

FEV₁, FEV₁PP, and FEV₁/ht² recorded post bronchodilator were compared as predictors of survival in 1095 COPD patients followed for 15 years. A staging system for severity of COPD was defined from FEV₁/ht² and compared with the Global Initiative for Obstructive Lung Disease (GOLD) staging system.

Result:

FEV₁/ht² was a better univariate predictor of survival in COPD than FEV₁ and both were better than FEV₁PP. The best multivariate model for predicting survival included FEV₁/ht², age and sex. Comparing the GOLD stages with the FEV₁/ht² groups found that survival was more coherent within each FEV₁/ht group than it was within each GOLD stage. FEV₁/ht² had 60% more people in its most severe group than the severest GOLD stage with these extra subjects having equivalently poor survival and had 155% more in the least severe group with equivalent survival. GOLD staging misclassified 51% of subjects with regard to survival.

Conclusion:

We conclude that GOLD criteria using FEV₁PP do not optimally stage COPD with regard to survival. An alternative strategy using FEV₁/ht² improves the staging of this disease. Studies which stratify COPD patients to determine the effect of interventions such as drug trials, rehabilitation, or management guidelines should consider alternatives to the GOLD classification.     

Lack of Benefit of Continuous Positive Airway Pressure on Lung Function in Patients with Overlap Syndrome

Obstructive sleep apnea (OSA) has been shown to be an inflammatory stimulus and may potentially result in a deterioration in the respiratory status of patients with coexistent chronic obstructive pulmonary disease (COPD) (overlap syndrome). We hypothesized that with treatment of OSA, there would be an improvement in coexistent COPD in overlap patients. We also sought to characterize overlap patients by comparing them with patients with either OSA or COPD alone. We performed a retrospective study of patients who attended a university-affiliated Veterans Affairs hospital. Demographic and clinical data were obtained from the medical charts and pharmacy records for the preceding two years and for the two years following the initiation of continuous positive airway pressure (CPAP) therapy. Overlap patients had moderately severe sleep apnea (AHI 28.6 ± 4.2) and moderately severe COPD (FEV₁= 1.94 ± 0.10 L). The prevalence of overlap syndrome in COPD patients was 11.9%, and 41% in OSA patients. Overlap patients who were compliant with CPAP therapy experienced a greater decrease in FEV₁, percent predicted FEV₁, percent decrease in FEV₁, FVC, percent predicted FVC, and percent decrease in FVC when compared with noncompliant patients. A very strong correlation was found between the average hours of CPAP use per day and the percent decrease in FEV₁ (r = 0.69, p = 0.003). There was a similar strong correlation for the decrease in FEV₁ and percent predicted FEV₁. OSA is common in COPD patients; similarly, COPD is common in OSA patients. Treatment of OSA with CPAP therapy in patients with overlap syndrome may not lead to an improvement in the coexistent COPD.     

What Predicts Change in Pulmonary Function and Quality of Life in Asthma or COPD?

Information about predictors of decline in pulmonary function (forced expiratory volume in 1 second [FEV₁]) or health-related quality of life (HRQoL) in patients with asthma or (chronic obstructive pulmonary disease [COPD]) might help to determine those who need additional care. A 2-year prospective cohort study was conducted among 380 asthma and 120 COPD patients. In both asthma and COPD patients, a 2-year change in FEV₁ was only weakly associated with a 2-year change in HRQoL (r =. 0.19 and 0.24, respectively). In both groups, older age, living in an urban environment, and a lower peak expiratory flow rate (PEFR) at baseline were associated with a decline in FEV₁. Additional predictors of FEV₁ decline were greater body weight, less chronic cough or sputum production, and less respiratory symptoms in asthma patients and current smoking in COPD patients. A decline in HRQoL was associated with older age, non-compliance with medication, more dyspnea, and a lower PEFR in asthma patients and with male gender, lower education, lower body weight, more dyspnea, and more respiratory symptoms in COPD patients. Our results show that FEV₁ and HRQoL appear to represent different disease aspects influenced by different predictors.     

Usefulness of the CAT,LCOPD, EQ-5D and COPDSS Scales in Understanding the Impact of Lung Disease in Patients with Alpha-1 Antitrypsin Deficiency

Alpha-1-antitrypsin deficiency (AATD) is an inherited disorder responsible for early onset emphysema associated with a significant impairment of health-related quality of life (HRQoL). Our aim was to assess the usefulness of different instruments to evaluate the HRQoL in patients with AATD compared to non-AATD COPD. Observational, cross-sectional study in which all patients filled out a series of questionnaires: the COPD severity score (COPDSS), the EuroQoL 5-Dimensions (EQ-5D), the Living with COPD (LCOPD) and the COPD Assessment Test (CAT).

A total of 96 patients were included, 35 with AATD (mean age 56.5 yrs, 57.1% male and mean FEV₁(%) 48.7% and 61 non-AATD COPD (70.3 yrs, 80.3% men and FEV₁(%) 47%. The questionnaire scores were similar, with a tendency towards worse scores in AATD for the EQ-5D (VAS) (64.8 (20.2) vs. 71.6 (17.1); p = 0.08). The correlations between the different scores and FEV1(%) were significant in both groups for COPDSS and LCOPD, but not for CAT and EQ-5D. In general, the correlations of scores with FEV₁(%) were stronger for AATD compared with non-AATD COPD patients: COPDSS r = ?0.570, p < 0.01 for AATD and r = ?0.260, p < 0.05 for COPD; LCOPD r = ?0.502, p < 0.001 for AATD and r = ?0.304, p < 0.05 for non-AATD COPD.

Patients with AATD have a similar degree of HRQoL impairment as older subjects with non-AATD COPD and showed a stronger correlation between HRQoL measurements and lung function impairment compared with non-AATD COPD. This may be related to the characteristics of the disease in these patients who are usually younger, with less co-morbidity and lower smoking consumption.     

Plasma homocysteine is elevated in COPD patients and is related to COPD severity

Background:

Although recent studies have found that total plasma homocysteine (tHCY) and chronic obstructive pulmonary disease (COPD) are both risk factors for cardiac disease, there have been few studies of plasma homocysteine levels in COPD patients. We tested the hypothesis that total plasma homocysteine (tHCY) would be elevated in patients diagnosed with COPD compared with controls.

Methods:

We studied 29 COPD outpatients and 25 asymptomatic subjects (controls) over age 55 years with measurement of forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), St. Georges Respiratory Questionnaire (SGRQ) score, tHCY and serum C-reactive protein (sCRP).

Results:

There was no difference between controls vs. COPD patients in mean age or gender but mean (SD) FEV₁ was 2.25 (0.77) vs 1.43 (0.60) L; FEV₁% predicted 76.1 (17.2) vs 49.1 (16.3) p < 0.001 in both cases. Median (IQR) tHCY was 8.22 (6.63, 9.55) in controls vs 10.96 (7.56, 13.60) micromol/l for COPD, p = 0.006 and sCRP 0.89 (0.47, 2.55) vs 2.05 (0.86, 6.19) mg/l, p = 0.023. tHCY(log) was also higher in (r, p) smokers (0.448, 0.001), patients with low FEV₁% (−0.397, 0.003), males (0.475, <0.001), but high SGRQ Total score (0.289, 0.034), and high sCRP (0.316, 0.038). tHCY(log) was independently related to (regression coefficient, p) sCRP(log) (0.087, 0.024), male gender (0.345, <0.001) and presence of COPD (0.194, 0.031). Median (IQR) tHCY GOLD Stage I and II 8.05 (7.28, 11.04), GOLD Stage III and IV: 11.83(9.30, 18.30); p = 0.023.

Conclusions:

Plasma homocysteine is significantly elevated in COPD patients relative to age and sex-matched controls and is related to serum CRP and COPD severity.     

24-hour bronchodilation following a single dose of the novel β(2)-agonist olodaterol in COPD

Background

Current guidelines recommend long-acting bronchodilators as maintenance therapy in COPD when symptoms are not adequately controlled with short-acting agents. Olodaterol is a novel long-acting β₂-adrenoceptor agonist with a pre-clinical profile that suggests 24-h bronchodilation may be achieved with once-daily administration.

Objective

To assess dose- and time-response in terms of bronchodilator efficacy, and to evaluate pharmacokinetics, safety and tolerability of single doses of olodaterol administered via Respimat^® Soft Mist™ Inhaler in COPD patients.

Methods

A single-center, double-blind, placebo-controlled, 5-way crossover study including 24-h spirometry (FEV₁, FVC), safety, tolerability and pharmacokinetics (in a subset of patients) following dosing of olodaterol 2 μg, 5 μg, 10 μg and 20 μg; the washout period between test-days was at least 14 days. Primary endpoint of the study was the 24-h post-dosing FEV₁. Patients participating in the pharmacokinetic assessments continued in an open-label extension phase to establish pharmacokinetics of olodaterol 40 μg.

Results

36 patients were assigned to treatment; mean baseline prebronchodilator FEV₁ was 1.01 L (37% predicted normal). All doses of olodaterol provided significantly greater bronchodilation compared to placebo in 24-h FEV₁ post-dose (p < 0.001); a clear dose–response relationship was observed, with values ranging from 0.070 L for olodaterol 2 μg to 0.119 L for olodaterol 20 μg. Similarly, olodaterol was superior to placebo (p < 0.001) in peak FEV₁ (0.121 L to 0.213 L) and average FEV₁ both during the daytime (0–12 h; ranging from 0.099 L to 0.184 L) and night-time (12–24 h; ranging from 0.074 L to 0.141 L). FVC results were consistent with those observed for FEV₁. Pharmacokinetic evaluation of the peak plasma concentrations and renal excretion suggested no obvious deviation from dose-proportionality over the investigated dose range of 2 μg–40 μg; in most patients, no plasma levels could be detected following the 2 μg dose. All treatments were well tolerated with no apparent dose relation in terms of adverse events.

Conclusions

Olodaterol appears to be a promising long-acting β₂-adrenoceptor agonist,with bronchodilation maintained over 24 h that offers an opportunity for once-daily dosing in patients who require maintenance bronchodilator therapy for the management of COPD symptoms.     

What is the difference between FEV1 change in percentage predicted value and change over baseline in the assessment of bronchodilator responsiveness in patients with COPD?

Background

Several criteria are clinically applied in the assessment of significant bronchodilator responsiveness in chronic obstructive pulmonary disease (COPD). The present study aimed to investigate the differences in various degree of severity of COPD among these criteria.

Methods

After 400 micrograms of salbutamol administered via spacer by metered dose inhaler (MDI), forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) changes (including percentage change, absolute change and absolute change in percentage predicted value) were retrospectively analysed in 933 stable patients with mild-to-very-severe COPD. Significant bronchodilator responsiveness was assessed using American Thoracic Society and European Respiratory Society (ATS-ERS) criterion based on FEV₁ or/and FVC (both ≥12% increase over baseline and ≥200 mL) and FEV₁ percentage predicted criterion (≥10% absolute increase in percentage predicted FEV₁) in different grades of COPD.

Results

Of the patients [age 66.8 years, baseline FEV₁ 974 mL (39.3% predicted) and FVC 2,242 mL], mean improvements were 126 mL in FEV₁ and 265 mL in FVC; 21.4% and 45.3% met ATS-ERS criterion based on FEV₁ and FVC, respectively; and 13.5% met FEV₁ percentage predicted criterion. The responsive ratios of ATS-ERS criterion based on FEV₁ to FEV₁ percentage predicted criterion in grade I, II, III and IV of COPD were 0.95^:1.26^:2.53^:6.00, respectively (P<0.01 in grade II and P<0.001 in grade III). As the degree of severity increased, the mean improvement of FEV₁ was reduced; on the contrary, that of FVC was increased.

Conclusions

Compared with FEV₁ percentage predicted criterion, ATS-ERS criterion based on FEV₁ as well as FVC, the later in particular, detected a larger percentage of patients with significant responsiveness. The increasing difference was relevant as a function of the severity of airflow obstruction.KEY WORDS : Airflow obstruction, bronchodilator responsiveness, chronic obstructive pulmonary disease (COPD), forced vital capacity (FVC), forced expiratory volume in one second (FEV₁)     

The Diagnostic Importance of a Reduced FEV1/FEV6

Abstract

Background: On spirometry the FEV₁/FEV₆ ratio has been advocated as a surrogate for the FEV₁/FVC. The significance of isolated reductions in either the FEV₁/FEV₆ or FEV₁/FVC is not known. Methods: First-time adult spirograms (n = 22,837), with concomitant lung volumes (n = 12,040), diffusion (n = 14,154), and inspiratory capacity (n = 12,480) were studied. Four groups were compared. 1) Only FEV₁/FEV₆ reduced (n = 302). 2) Only FEV₁/FVC reduced (n = 1158). 3) Both ratios reduced (n = 6593). 4) Both ratios normal (n = 14,784). Results: In patients with obstructed spirometry (either a reduced FEV₁/FVC and/or FEV₁/FEV₆), 3.8% only had a reduced FEV₁/FEV₆, while 14.4% only had a reduced FEV₁/FVC. The mean FEV₁ was lower when both ratios were reduced. The group with only a reduced FEV₁/FEV₆, compared to only the FEV₁/FVC reduced, had a lower FEV₁, FVC, BMI, Expiratory Time, and IC (p values < 0.0001). DLCO was also lower (p = 0.005), and the FEV₁/FVC and RV/TLC were higher (p values < 0.0001). When the patients with only a reduced FEV₁/FEV₆ had a subsequent spirogram, 60% had a reduced FEV₁/FVC when their mean expiratory times were 3.5 seconds longer. Ninety percent of this group had strong clinical evidence of airways obstruction. Conclusions: The FEV₁/FEV₆ is not as sensitive as the FEV₁/FVC for diagnosing airways obstruction, but in the presence of a normal FEV₁/FVC, subjects have greater physiologic abnormalities than when only the FEV₁/FVC is reduced. The FEV₁/FEV₆ ratio should not replace the FEV₁/FVC as the standard for airways obstruction, but there is benefit including this measurement to identify individuals with greater air trapping and diffusion abnormalities.     

Proventil HFA Prevents Exercise-Induced Bronchoconstriction in Children

Short-acting inhaled beta₂-agonists used just prior to exercise are an effective method for preventing exercise-induced bronchoconstriction (EIB) in children. This was a randomized, single-blind, placebo-controlled, four-period crossover study that compared the effectiveness of albuterol formulated in hydrofluoro-alkane-134a (HFA) to albuterol formulated in chlorofluorocarbons (CFCs) and to placebo in protecting asthmatic children age 6-11 from EIB. Patients self-administered either HFA albuterol, two different CFC albuterol products, or placebo 30 min prior to exercise challenge. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 min after the exercise challenge was completed. The smallest percent change from the predose forced expiratory volume in 1 sec (FEV₁) after exercise challenge was similar for the three active treatments, and each of the active treatments was significantly better than placebo. Each active treatment had significantly fewer patients unprotected from EIB (unprotected defined as having ≥20% fall in FEV, after exercise challenge) than placebo. Changes in heart rate, blood pressure and electrocardiogram     

Acute Effect of Bronchodilator on Intrathoracic Airway Wall Compliance in COPD Patients

Purpose

In patients with chronic obstructive pulmonary disease (COPD), bronchial responsiveness after acute administration of short acting bronchodilators is conventionally assessed by measuring the improvement of forced expiratory volume in the first second (FEV₁) during a maximal forced expiratory maneuver. This study aimed to measure the variation of intrathoracic airway wall compliance (AWC) after acute administration of short acting beta-2 agonist in COPD patients since this might influence the final modification of airway caliber during maximal expiratory effort and the resulting bronchodilation as inferred by FEV₁ changes.

Methods

In a group of 10 patients suffering from COPD, intrathoracic AWC was measured at middle (50% of Forced Vital Capacity (FVC) and low (75% of FVC) lung volumes using the interrupter method during forced expiratory maneuver in basal conditions and after acute inhalation of albuterol (salbutamol) (400 mcg by MDI). Ten healthy subjects were examined similarly as a control group.

Results

Lower values of baseline intrathoracic AWC at both lung volumes were found in COPD patients (1.72?±?0.20 ml/cmH₂O and 1.08?±?0.20 ml/cmH₂O, respectively) as compared to controls (2.28?±?0.27 ml/cmH₂O and 1.44?±?0.22 ml/cmH₂O, respectively) (p?<?0.001). In COPD patients, AWC increased significantly at both lung volumes after salbutamol, amounting to 1.81?±?0.38 ml/cmH₂O and 1.31?±?0.39 ml/cmH₂O, respectively (p?<?0.01), but the relative change was not different from that observed in controls.

Conclusion

In COPD patients, AWC is reduced compared to controls, but after bronchodilator, the intrathoracic airways become more compliant. The consequent increased collapsibility under high positive pleural pressure could limit the airway caliber improvement seen after bronchodilator, as assessed by the FEV₁ changes during the forced expiratory maneuver, underestimating the effective bronchodilation achieved in these patients.

     

Impaired Carbon Monoxide Diffusing Capacity is the Strongest Predictor of Exercise Intolerance in COPD

Abstract

Background: Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD) and forced expiratory volume in one second (FEV₁) is the traditional metric used to define the severity of COPD. However, there is dissociation between FEV₁ and exercise capacity in a large proportion of subjects with COPD. The aim of this study was to investigate whether other lung function parameters have an additive, predictive value for exercise capacity and whether this differs according to the COPD stage. Methods: Spirometry, body plethysmography and diffusing capacity for carbon monoxide (DLCO) were performed on 88 patients with COPD GOLD stages II-IV. Exercise capacity (EC) was determined in all subjects by symptom-limited, incremental cycle ergometer testing. Results: Significant relationships were found between EC and the majority of lung function parameters. DLCO, FEV₁ and inspiratory capacity (IC) were found to be the best predictors of EC in a stepwise regression analysis explaining 72% of EC. These lung function parameters explained 76% of EC in GOLD II, 72% in GOLD III and 40% in GOLD IV. DLCO alone was the best predictor of exercise capacity in all GOLD stages. Conclusions: Diffusing capacity was the strongest predictor of exercise capacity in all subjects. In addition to FEV₁, DLCO and IC provided a significantly higher predictive value regarding exercise capacity in COPD patients. This suggests that it is beneficial to add measurements of diffusing capacity and inspiratory capacity when clinically monitoring COPD patients.     

Onset of Effect of Aclidinium,a Novel,Long-Acting Muscarinic Antagonist,in Patients with COPD

ABSTRACT

Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium. This was a double-blind, double-dummy, multicenter, crossover study in COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV₁) ≥30% and <60% predicted. On study days, patients received single doses of aclidinium 200 μg, tiotropium 18 μg, or placebo. Serial spirometry was conducted from 10 minutes to 3 hours post-dose. The primary variable was the percentage of patients with an increase in FEV₁ of ≥10% above baseline at 30 minutes post-dose. Other assessments included change from baseline in FEV₁ and dyspnea over 3 hours post-dose. A total of 115 patients entered the study. Significantly more patients had an increase in FEV₁ of ≥10% above baseline at 30 minutes with aclidinium and tiotropium versus placebo (49.5% and 51.8% versus 13.8%; p < 0.0001). At 30 minutes, the relative increase from baseline in FEV₁ was significantly higher for aclidinium and tiotropium versus placebo (12% and 11% versus 3%; p < 0.0001). Aclidinium and tiotropium also significantly increased FEV₁ (p < 0.01) and improved the perception of dyspnea compared with placebo at all measured time points from 10 minutes to 3 hours post-dose. In conclusion, aclidinium provided effective bronchodilation, similar to that seen with tiotropium, with significant improvements compared with placebo observed from 10 minutes post-dose.