Small Airway Pathology and Bronchoreversibility in Advanced Emphysema

ABSTRACT

Background: Poorly reversible airflow obstruction is a hallmark feature of chronic obstructive pulmonary disease (COPD). However, some COPD patients demonstrate significant bronchodilator reversibility (BDR). The pathologic features associated with the presence or absence of this phenomenon are not known. Methods: We analyzed 67 patients with advanced upper lobe predominant emphysema who underwent lung volume reduction surgery and divided them into 2 groups: the reversible group [BD(+)] had a >12% and >200 mL increase in FEV₁ or FVC with bronchodilator; the irreversible group [BD(?)] had a ≤12% and ≤20 mL increase in FEV₁ and FVC. We measured the epithelial height (EH) and areas of epithelium (EA), subepithelium (SEA), smooth muscle (SMWA), and total wall (TWA) of the small airways (<2 mm in internal diameter) in the resected specimens, and adjusted these measurements for basement membrane area (BMA) or perimeter (BMP). Results: Despite similar baseline characteristics, the BD(+) group had a smaller EH (0.036 mm vs. 0.042 mm, p = 0.005) and EH/BMP (0.012 vs. 0.014, p = 0.007), and a greater SMWA/BMA (0.491 vs. 0.430, p = 0.034) compared to the BD(?) group. In addition, EA trended to be smaller in the BD(+) group when compared to the BD(?) group (0.160 mm² vs. 0.184 mm², p = 0.06). In a subset of patients with consistent patterns of BDR on serial testing, the BD(+) group had greater SMWA/BMA (0.518 vs. 0.433, p = 0.049) and TWA/BMA (1.405 vs. 1.266, p = 0.036) compared to the BD(?) group. Conclusions: Small airway smooth muscle mass may play a role in determining BDR in severe emphysema.     

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)     

Inspiratory capacity and forced expiratory volume in the first second in exacerbation of chronic obstructive pulmonary disease

Object: Periodic exacerbations of symptoms are the major cause of morbidity, mortality and health care costs in patients with chronic obstructive pulmonary disease (COPD). Dyspnea is the major factor affecting the comfort of patients in the exacerbation of COPD. In this study, we aimed to compare the value of forced expiratory volume in the first second (FEV₁) and inspiratory capacity (IC) measured before and after treatment in exacerbations and in the improvement in dyspnea. Methods: Eighty‐seven patients (male/female, 80/7; mean age, 63 ± 7) with COPD exacerbation were included in this study. All subjects underwent spirometric tests on the first day and at the end of treatment. The subjects were asked to quantify the sensation of dyspnea that was described to them as a nonspecific discomfort associated with the act of breathing. The patients quantified dyspnea by pointing to a score on a large Borg scale from 0 to 10 arbitrary units. In the beginning and at the end of treatment, forced vital capacity (FVC), FEV₁, forced expiratory flow rate between 25% and 75% of FVC (FEF25–75), peak expiratory flow rate (PEF), IC and Borg score (BS) values were compared. Results: After treatment of COPD exacerbations, FEV₁, FEF25–75, PEF and IC significantly increased, and the BS significantly decreased compared to the initial values. The increase in IC was more significantly correlated with the improvement in BS compared with FEV₁. Admission and discharge day BS was negatively correlated with FEV₁, FEF25–75 and IC. Conclusion: We have shown a more dramatic improvement in IC compared with FEV₁ in patients treated as a result of acute exacerbation of COPD. These data suggest that IC may be more useful than FEV₁ during acute exacerbation of COPD. Moreover, IC better reflects the severity of dyspnea in these patients. Please cite this paper as: Yetkin O and Gunen H. Inspiratory capacity and forced expiratory volume in the first second in exacerbation of chronic obstructive pulmonary disease. The Clinical Respiratory Journal 2008; 2: 36–40.     

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.

     

The effect of age on bronchodilator responsiveness

The relationship between age and bronchodilator responsiveness (BDR) in children has not been studied using objective parameters. The aim of this study was to seek such a relationship in young asthmatic children using dose—response curves (DRC). Fourteen asthmatic subjects (age 3–9 years) with a forced expiratory volume in 1 sec (FEV₁) less than 80% predicted were studied after being trained to use a spirometer reliably. Each subject completed a DRC by inhaling 5 doses of salbutamol (albuterol) at 15 min intervals until a cumulative total of 6.84 mg of salbutamol had been administered. FEV₁, forced vital capacity (FVC), and forced expiratory flow at mid vital capacity (FEF_25?75) were measured before and after each nebulization. In addition, arterial oxygen saturation (Sa_O2) and heart rate (HR) were measured in some of the subjects. All lung function parameters, Sa_O2 and HR increased significantly between baseline and completion of the DRC. A significant age effect on BDR was detected in FEV₁ and FVC, with older children showing a greater response than young ones. The response had plateaued after the maximum dose in the younger but not in the older children. These findings suggest that the level of response to a bronchodilator increases significantly with increasing age in young asthmatics. © 1993 Wiley-Liss, Inc.     

Acute bronchodilator responsiveness in subjects with and without airflow obstruction in five Latin American cities: The PLATINO study

BackgroundAcute bronchodilator responsiveness is an area of discussion in COPD. No information exists regarding this aspect of the disease from an unselected COPD population. We assessed acute bronchodilator responsiveness and factors influencing it in subjects with and without airway obstruction in an epidemiologic sample.MethodsCOPD was defined by GOLD criteria (post-bronchodilator FEV₁/FVC < 0.70). In this analysis, subjects with pre-bronchodilator FEV₁/FVC <0.70 but ≥0.70 post-bronchodilator were considered to have reversible obstruction. Bronchodilator responsiveness after albuterol 200 μg was assessed using three definitions: a) FVC and/or FEV₁ increment ≥12% plus ≥200 mL over baseline; b) FEV₁ ≥ 15% increase over baseline; and c) FEV₁ increase ≥10% of predicted value.ResultsThere were 756 healthy respiratory subjects, 481 subjects with reversible obstruction and 759 COPD subjects. Depending on the criterion used the proportion of person with acute bronchodilator responsiveness ranged between 15.0–28.2% in COPD, 11.4–21.6% in reversible obstructed and 2.7–7.2% in respiratory healthy. FEV₁ changes were lower (110.6 ± 7.40 vs. 164.7 ± 11.8 mL) and FVC higher (146.5 ± 14.2 mL vs. ?131.0 ± 19.6 mL) in COPD subjects compared with reversible obstructed. Substantial overlap in FEV₁ and FVC changes was observed among the groups. Acute bronchodilator responsiveness in COPD persons was associated with less obstruction and never smoking.ConclusionsOver two-thirds of persons with COPD did not demonstrate acute bronchodilator responsiveness. The overall response was small and less than that considered as significant by ATS criteria. The overlap in FEV₁ and FVC changes after bronchodilator among the groups makes it difficult to determine a threshold for separating them.     

Clinical impact of forced vital capacity on exercise performance in patients with chronic obstructive pulmonary disease

BackgroundForced vital capacity (FVC) has been suggested to be a good biomarker for decreased exercise performance in patients with chronic obstructive pulmonary disease (COPD). However, as FVC is highly correlated with forced expiratory volume in 1 second (FEV₁), the relationship between FVC and exercise capacity should be assessed within the category of FEV1, i.e., COPD severity. However, this was not considered in previous studies. Thus, limited data are available on the association between reduced FVC and exercise capacity measured by 6-min walk distance (6MWD) based on COPD severity.MethodsWe performed a cross-sectional study using data from the Korean COPD Subgroup Study (KOCOSS) cohort. We evaluated 1,386 patients with moderate (n=895) and severe-to-very severe (n=491) COPD. Reduced FVC was defined as FVC <80% predicted and short 6MWD as <350 m. Multivariable logistic regression was used to evaluate the association between reduced FVC and short 6MWD.ResultsThere were no significant differences in respiratory symptoms and quality of life between the patients with reduced FVC and those with preserved FVC. However, patients with reduced FVC had shorter 6MWD (30.5 cm in moderate and 34.5 cm in severe-to-very severe COPD) and higher BODE index scores than those with preserved FVC. The cubic spline model revealed 6MWD peaked around 93% predicted of FVC in moderate COPD, whereas FVC showed a positive association with 6MWD in severe-to-very severe COPD. Multivariable analyses showed that reduced FVC was significantly associated with short 6MWD in both moderate [adjusted odds ratio (aOR) =1.44, 95% confidence interval (CI): 1.03–2.02] and severe-to-very severe (adjusted OR =1.55, 95% CI: 1.01–2.40) COPD.ConclusionsReduced FVC was significantly associated with shorter 6MWD in moderate-to-very severe COPD patients, suggesting that reduced FVC might be reflective of 6MWD-measured exercise capacity in moderate-to-very severe COPD.     

Significant Bronchodilator Responsiveness and “Reversibility” in a Population Sample

ABSTRACT

Chronic Obstructive Pulmonary Disease (COPD) is defined by being “not fully reversible”, most guidelines recommend measurement of lung function after the administration of a bronchodilator. The objective of this study was to compare bronchodilator responsiveness (significant improvement in the FEV₁ or FVC) to full-, partial- or “inverse’” reversibility in obstruction status in a population-based sample in Southeastern Kentucky. The study population was selected using random digit dialing of an adult population in Southeastern Kentucky as part of the Burden of Lung disease (BOLD) project. Lung function was assessed using spirometry pre- and post-bronchodilation. Subjects presence and severity of COPD was classified using modified Global Obstructive Lung Disease (GOLD) criteria. We examined the relation between changes in “obstruction” status (based on the FEV₁/ FVC of 0.7) and the presence of “significant bronchodilator responsiveness” (based on ≥ 12% improvement in the FEV₁ or the FVC). The final population with acceptable pre- and post-bronchodilator spirometry included 440 participants. 32/440 subjects (7.3%) changed from obstructed to unobstructed (full-reversibility), 19/440 (4.3%) changed from unobstructed to obstructed (“inverse”-reversibility), 389/440 (88.4%) had either no-change or partial-reversibility, and 65/440 (14.8%) had bronchodilator responsiveness. Among those with full-reversibility, only 9/32 (28.1%) had bronchodilator responsiveness, whereas among subjects with “inverse”-reversibility, 10/19 (52.6%) had bronchodilator responsiveness. Among all subjects with bronchodilator responsiveness, only 19/65 (29.2%) changed categories. Our findings suggest that significant bronchodilator responsiveness is not the same as “reversibility” of “obstruction”, even though these terms are often used interchangeably.     

Spirometric Thresholds for Diagnosing COPD: 0.70 or LLN,Pre- or Post-dilator Values?

Abstract

In absence of a gold standard for chronic obstructive pulmonary disease (COPD) it remains difficult to compare the true diagnostic characteristics of the forced expiratory volume in 1 second to the forced vital capacity (FEV₁/FVC) <0.70 and < lower limit of normal (LLN). COPD is a clinical diagnosis, based on symptoms signs and lung function results combined, and an expert panel assessment would be an adequate reference standard. We compared the diagnostic properties of FEV₁/FVC <LLN and <0.70 against this panel diagnosis: 342 participants, aged >50, consulting for persistent cough, but without physician-diagnosed COPD, were prospectively enrolled. All underwent extensive history taking, physical examination, spirometry and diffusion testing. An expert panel, including a board certified respiratory physician, assessed all diagnostic information to determine the presence or absence of COPD and served as reference standard. Then, 104 participants were diagnosed with COPD by the panel. The reproducibility of the panel diagnosis was high (kappa of 0.94). Sensitivity estimates of <0.70 were significantly higher than that of <LLN (0.73 and 0.47, respectively, p < 0.001). The fixed approach was less specific than the LLN (0.95 and 0.99, respectively, p < 0.001). There was no significant difference in diagnostic property when using pre- or post-bronchodilator FEV₁/FVC (p = 0.615). In a symptomatic primary care population, the FEV₁/FVC <0.70 was more accurate to detect COPD.     

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.     

Association of serum vitamin D levels with disease severity,systemic inflammation,prior lung function loss and exacerbations in a cohort of patients with chronic obstructive pulmonary disease (COPD)

BackgroundVitamin D deficiency has been associated with chronic disorders including chronic obstructive pulmonary disease (COPD) but the relationships with inflammation, exacerbations and disease progression remain unclear.MethodsIn this monocentric cross-sectional observational study we analyzed the disease status, systemic inflammation, prior exacerbation frequency and loss in lung function in relation to serum 25-hydroxyvitamin D (25-OHD) levels in a cohort of 94 patients with COPD. Serum 25-OHD, C-reactive protein, interleukin-6 and tumor necrosis factor-α were quantified. Exacerbation frequencies and sunlight exposure were assessed. These parameters were analyzed in correlation to the current forced expiratory volume in 1 s (FEV₁), the individual average 3-year FEV₁ decline and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage.ResultsWe observed fair correlation between serum 25-OHD and the current FEV₁ (r=0.38, P<0.001). Furthermore, mean serum 25-OHD was significantly altered between patients of GOLD stages I–IV (P=0.013). There was weak negative correlation of 25-OHD and the average annual change of the FEV₁ (r=−0.26, P<0.05). Furthermore, we observed fair negative correlation between 25-OHD and C-reactive protein (r=−0.32, P<0.01) as well as weak negative correlation with interleukin-6 (r=−0.23, P<0.05). While the exacerbation frequency significantly differed between GOLD stages (P=0.04), there was no direct association between exacerbations and 25-OHD levels.ConclusionOur data confirm frequent vitamin D deficiency in COPD and point out correlations between 25-OHD levels, systemic inflammation, disease severity and progression.     

Bronchodilator efficacy of tiotropium–formoterol via single pressurized meter dose inhaler (pMDI) versus tiotropium alone in COPD

BackgroundBronchodilators form the main stay of treatment for COPD. When symptoms are not adequately controlled with one bronchodilator, addition of another bronchodilator is recommended. We have recently developed a combination of tiotropium and formoterol in a single pressurized metered dose inhaler (pMDI) (Cipla Ltd., India). The aim of this study was to compare the bronchodilator effects of a single dose of 18 mcg of tiotropium versus a single dose of a combination of 18 mcg tiotropium plus 12 mcg formoterol administered via a pMDI in subjects with moderate-to-severe COPD.Study design44 COPD subjects were enrolled in this randomized, double-blind, multi-centre, cross-over study. 18 mcg tiotropium and 18 mcg tiotropium plus 12 mcg formoterol were administered via pressurized metered dose inhalers on two separate days. FEV₁, FVC and Inspiratory capacity (IC) were measured before, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 h after the study drugs were administered.ResultsCompared with tiotropium alone, a combination of tiotropium plus formoterol showed a faster onset of bronchodilator response (p < 0.01 for FEV1 and FVC), a greater mean maximum change in FEV1 (p = 0.01) and FVC (p = 0.008) and greater AUC_0–24h values for FEV₁, FVC and IC. Trough FEV₁ and FVC values were also greater in the combination group.ConclusionA combination of tiotropium plus formoterol administered via a single inhaler produced a superior bronchodilator response than tiotropium alone over a period of 24 h.     

Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial

Background and objective: Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions. We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4‐year COPD trial. Methods: Subgroup analysis from a randomized, double‐blinded, placebo‐controlled trial of tiotropium 18 µg daily in COPD. Primary end‐point was rate of decline in FEV₁. Secondary end‐points included spirometry at individual time points, health‐related quality of life (St George's Respiratory Questionnaire), exacerbations and mortality. Results: Of 5992 patients, 362 were from Asian centres (100 from Japan). Mean age 66 years, 95% men, 13% current smokers, BMI: 21 kg/m²; post‐bronchodilator FEV₁: 44% predicted; St George's Respiratory Questionnaire total score: 44 units. No treatment effect was observed for rate of decline in FEV₁ although annual decline was less in Asian patients. Morning pre‐bronchodilator FEV₁ and forced vital capacity improved in Asian patients (P < 0.05). Tiotropium reduced number of exacerbations (rate ratio (95% confidence interval (CI)): 0.73 (0.57–0.94)). Hazard ratios (95%CI) for exacerbations and hospitalized exacerbations (tiotropium/control) were 0.81 (0.62–1.05) and 0.85 (0.61–1.19), respectively. St George's Respiratory Questionnaire total score improved by 1.5–6.1 units (P < 0.05 for months 18, 24, 30 and 36) with tiotropium. Fatal events occurred in 34 tiotropium (18.5%) and 42 control (23.6%) patients. Conclusions: In COPD patients from Asia, tiotropium improves lung function, improves health‐related quality of life and reduces exacerbations over 4 years of treatment.     

Real-world Safety and Efficacy of Indacaterol Maleate in Patients with Chronic Obstructive Pulmonary Disease: Evidence from the Long-term Post-marketing Surveillance in Japan

Objective Evidence concerning the safety and efficacy of indacaterol maleate in a real-life setting is limited. The objective of this post-marketing surveillance was to evaluate the real-life safety and efficacy of indacaterol maleate in Japanese patients with chronic obstructive pulmonary disease (COPD). Methods This was a 52-week post-marketing surveillance conducted between April 2012 and December 2018. The safety endpoints included the incidence of adverse events (AEs), serious adverse events (SAEs), and adverse drug reactions (ADRs). The efficacy endpoints included the physician-reported global evaluation of treatment effectiveness (GETE), change from baseline in the COPD assessment test (CAT) results, forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and %FEV₁ following 4, 12, 26, and 52 weeks of indacaterol administration. Results Of the 1,846 enrolled patients, 1,726 were included in the safety and efficacy analyses. The mean age of the patients was 72.5 years old. Cough, pneumonia and COPD worsening were the most common AEs reported, while pneumonia (1.04%) was the most common SAE, and cough (1.68%) was the most common ADR. GETE showed that 69.70% of patients achieved an excellent/good/moderate response following indacaterol treatment. The CAT score decreased, and lung function parameters (FVC, FEV₁ and %FEV₁) improved across all the COPD stages following treatment with indacaterol. Conclusion Indacaterol showed a favorable safety and tolerability profile in Japanese patients with COPD without new safety signals observed in real-life settings. These findings demonstrated that indacaterol is an effective maintenance treatment in real-life practice for Japanese patients with COPD.     

Long-term safety of Prolastin®-C,an alpha1-proteinase inhibitor,in Japanese patients with alpha1-antitrypsin deficiency

BackgroundSafety and pharmacokinetics (PK) of alpha₁-proteinase inhibitor, modified process (Alpha-1 MP), was evaluated in a clinical trial of Japanese patients with alpha₁-antitrypsin deficiency (AATD). The present study aimed to evaluate the long-term safety of weekly intravenous infusions of 60 mg/kg Alpha-1 MP in Japanese patients with AATD.MethodsThis was a multi-center, open-label extension (OLE) study that enrolled adult patients with AATD, who had completed the preceding safety and PK clinical trial. Patients were administered with Alpha-1 MP (60 mg/kg) weekly, for 52 weeks, and this could be renewed annually. Alpha1-MP trough levels (C_min) were evaluated, and safety endpoints include: treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs potentially related to Alpha-1 MP, chronic obstructive pulmonary disease (COPD) exacerbations, laboratory parameters, vital signs, and pulmonary function tests (forced expiration volume in 1 s [FEV₁] and forced vital capacity [FVC]).ResultsFour patients underwent Alpha-1 MP intravenous infusions at a mean (SD) of 210.8 (9.54) for 213 weeks (four years), with a C_min of 55.73 (4.99) mg/dL. A total of fifty-four TEAEs were reported in four patients, in which most of them were mild (n = 52, 96.3%). Two patients had five SAEs, and all were unrelated to treatment. Three mild TEAEs were potentially related to treatment with Alpha-1 MP. No clinically significant findings in laboratory parameters, COPD exacerbations, or vital signs were observed. There were no identifiable differences in FEV₁ and FVC throughout the study period.ConclusionsLong-term weekly intravenous infusions of 60 mg/kg Alpha-1 MP are generally safe and well-tolerated in Japanese patients with AATD.Clinicaltrials.govNCT02870348; JAPIC CTI: JapicCTI-163194.     

A meta-analysis on the efficacy of oral theophylline in patients with stable COPD

Background

Theophylline is a nonspecific inhibitor of phosphodiesterases that, despite exerting bronchodilator and anti-inflammatory effects, is a third-line therapy rarely used to treat chronic airflow limitation. We wished to evaluate the efficacy of oral theophylline as measured by improvements in trough (pre-dose) or peak (post-dose) FEV₁ and FVC in patients with clinically stable COPD.

Design

Meta-analysis of randomized, placebo-controlled trials reported as of June 2005 in which theophylline was orally administered to stable COPD patients and the functional evaluations included pre- and post-theophylline values for FEV₁ and FVC.

Results

A total of 18 trials were included in the meta-analysis. The weighted mean differences (WMD) with 95% confidence intervals (95% CI) for improvement over placebo in trough FEV₁ and FVC were 0.108L (0.053–0.163) and 0.186L (0.036–0.336), respectively, while peak FEV₁ and FVC improved by 0.096L (0.044–0.147) and 0.242L (0.11–0.374), respectively.

Conclusions

Treatment with oral theophylline improves both trough and peak FEV₁ and FVC in clinically stable COPD patients. These results support previously reported benefits of theophylline in COPD.     

Severity of Airflow Obstruction in Chronic Obstructive Pulmonary Disease (COPD): Proposal for a New Classification

Current classifications of Chronic Obstructive Pulmonary Disease (COPD) severity are complex and do not grade levels of obstruction. Obstruction is a simpler construct and independent of ethnicity. We constructed an index of obstruction severity based on the FEV₁/FVC ratio, with cut-points dividing the Burden of Obstructive Lung Disease (BOLD) study population into four similarly sized strata to those created by the GOLD criteria that uses FEV₁. We measured the agreement between classifications and the validity of the FEV₁-based classification in identifying the level of obstruction as defined by the new groupings. We compared the strengths of association of each classification with quality of life (QoL), MRC dyspnoea score and the self-reported exacerbation rate. Agreement between classifications was only fair. FEV₁-based criteria for moderate COPD identified only 79% of those with moderate obstruction and misclassified half of the participants with mild obstruction as having more severe COPD. Both scales were equally strongly associated with QoL, exertional dyspnoea and respiratory exacerbations. Severity assessed using the FEV₁/FVC ratio is only in moderate agreement with the severity assessed using FEV₁ but is equally strongly associated with other outcomes. Severity assessed using the FEV₁/FVC ratio is likely to be independent of ethnicity.     

Comparison of Oral and Depot Intra‐muscular Steroids in Assessing Steroid‐Responsiveness in COPD

Non‐compliance or euphoria may limit the usefulness of prednisolone tablets in assessing steroid‐responsiveness in chronic obstructive pulmonary disease (COPD). Depot intra‐muscular methyl‐prednisolone (imMP), producing a plateau steroid effect over two weeks, may be more reliable. Following two weeks of placebo, twenty‐seven COPD patients (mean FEV₁ 43% predicted) participated in a two‐week randomised, double‐blind, placebo‐controlled, parallel‐design trial taking either 120 mg imMP with placebo tablets or placebo injection with prednisolone 30 mg daily. After each period, post‐bronchodilator FEV₁, forced vital capacity (FVC), inspiratory capacity (IC) and six‐minute walking distance (6MWD) were assessed and patients completed both quality‐of‐life scores (St. George's 30 and Short Form 36) and mood scores (Hospital Anxiety and Depression scores and Altman's Self‐rating Mania Scale). There were no significant changes in 6MWD, quality of life or mood scores after either type of steroids and no change in lung function after imMP. By contrast, there were small mean improvements in lung function on oral prednisolone (mean FEV₁, FVC and IC increased by 100, 320 and 150 ml, respectively). Only the improvement in FVC was significantly greater after prednisolone compared with imMP. Single depot intra‐muscular injections of steroids have no advantage over oral daily prednisolone in testing steroid‐responsiveness in COPD patients.     

Postoperative outcome after coronary artery bypass grafting in chronic obstructive pulmonary disease

BACKGROUND:

It is uncertain if the presence and severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is predictive of surgical morbidity and mortality after coronary artery bypass grafting (CABG).

METHODS:

Retrospective study of patients who underwent CABG between 1998 and 2003 in a university-affiliated hospital for whom a preoperative spirometry was available. COPD was diagnosed in smokers or ex-smokers 50 years of age or older in the presence of irreversible airflow obstruction. Patients were divided into three groups depending on the spirometry: controls (forced expiratory volume in 1 s [FEV₁] 80% or more, FEV₁/forced vital capacity [FVC] greater than 0.7), mild to moderate COPD (FEV₁ 50% or more and FEV₁/FVC 0.7 or less) and severe COPD (FEV₁ less than 50% and FEV₁/FVC 0.7 or less).

RESULTS:

Among the 411 files studied, 322 (249 men, 68±8 years of age) were retained (controls, n=101; mild to moderate COPD, n=153; severe COPD, n=68). The mortality rate (3.0%, 2.6% and 0%, respectively) was comparable among the three groups. Patients with severe COPD had a slightly longer hospital stay than controls (mean difference 0.7±1.4 days, P<0.05). Pulmonary infections were more frequent in severe COPD (26.5%) compared with mild to moderate COPD (12.4%) and controls (12.9%), P<0.05. Atrial fibrillation tended to be more frequent in severe COPD than in the other two groups.

CONCLUSION:

Mortality rate associated with CABG surgery is not influenced by the presence and severity of airflow obstruction in patients with COPD. The incidence of pulmonary infections and length of hospital stay were increased in patients with severe COPD.