Hironi Makita

Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease.

RATIONALE Although the rate of annual decline in FEV1 is one of the most important outcome measures in chronic obstructive pulmonary disease (COPD), little is known about intersubject variability based on clinical phenotypes. OBJECTIVES To examine the intersubject variability in a 5-year observational cohort study, particularly focusing on emphysema severity. METHODS A total of 279 eligible patients with COPD (stages I-IV: 26, 45, 24, and 5%) participated. We conducted a detailed assessment of pulmonary function and computed tomography (CT) at baseline, and performed spirometry every 6 months before and after inhalation of bronchodilator. Smoking status, exacerbation, and pharmacotherapy were carefully monitored. Emphysema severity was evaluated by CT and annual measurements of carbon monoxide transfer coefficient. MEASUREMENTS AND MAIN RESULTS Using mixed effects model analysis, the annual decline in post-bronchodilator FEV1 was -32±24 (SD) ml/yr (n=261). We classified the subjects of less than the 25th percentile as Rapid decliners, the 25th to 75th percentile as Slow decliners, and greater than the 75th percentile as Sustainers (-63±2, -31±1, and -2±1 [SE] ml/yr). Emphysema severity, but not %FEV1, showed significant differences among the three groups. Multiple logistic regression analysis demonstrated that the Rapid decliners were independently associated with emphysema severity assessed either by CT or carbon monoxide transfer coefficient. The Sustainers displayed less emphysema and higher levels of circulating eosinophils. CONCLUSIONS Emphysema severity is independently associated with a rapid annual decline in FEV1 in COPD. Sustainers and Rapid decliners warrant specific attention in clinical practice.

Characterisation of phenotypes based on severity of emphysema in chronic obstructive pulmonary disease

Background: Airflow limitation in chronic obstructive pulmonary disease (COPD) is caused by a mixture of small airway disease and emphysema, the relative contributions of which may vary among patients. Phenotypes of COPD classified purely based on severity of emphysema are not well defined and may be different from the classic phenotypes of “pink puffers” and “blue bloaters”. Methods: To characterise clinical phenotypes based on severity of emphysema, 274 subjects with COPD were recruited, excluding those with physician-diagnosed bronchial asthma. For all subjects a detailed interview of disease history and symptoms, quality of life (QOL) measurement, blood sampling, pulmonary function tests before and after inhalation of salbutamol (0.4 mg) and high-resolution CT scanning were performed. Results: Severity of emphysema visually evaluated varied widely even among subjects with the same stage of disease. No significant differences were noted among three groups of subjects classified by severity of emphysema in age, smoking history, chronic bronchitis symptoms, blood eosinophil count, serum IgE level or bronchodilator response. However, subjects with severe emphysema had significantly lower body mass index (BMI) and poorer QOL scores, evaluated using St George’s Respiratory Questionnaire (SGRQ), than those with no/mild emphysema (mean (SD) BMI 21.2 (0.5) vs 23.5 (0.3) kg/m2, respectively; SGRQ total score 40 (3) vs 28 (2), respectively; p<0.001 for both). These characteristics held true even if subjects with the same degree of airflow limitation were chosen. Conclusions: The severity of emphysema varies widely even in patients with the same stage of COPD, and chronic bronchitis symptoms are equally distributed irrespective of emphysema severity. Patients with the phenotype in which emphysema predominates have lower BMI and poorer health-related QOL.

Relationship between improved airflow limitation and changes in airway calibre induced by inhaled anticholinergic agents in COPD

Background: Although airflow limitation improved by inhaled anticholinergic drugs varies among individuals with chronic obstructive pulmonary disease (COPD), the relationship between actual bronchodilation and improved pulmonary function and where in the lung such bronchodilation occurs remains unknown. A study was undertaken to determine the relationship between improved pulmonary function and changes in airway calibre at various sites in the airways in response to inhaled anticholinergic agents in patients with COPD using three-dimensional computed tomography (CT). Methods: CT scans were performed at deep inspiration and detailed pulmonary function tests before and 1 week after daily inhalations of tiotropium bromide in 15 patients with clinically stable COPD. The airway luminal area was examined at the third (segmental) to the sixth generations of eight bronchi in the right lung. Results: Bronchodilation was demonstrated by an overall average increase of 39% in the inner luminal area, and the mean (SE) forced expiratory volume in 1 s (FEV1) increased from 1.23 (0.11) l to 1.47 (0.13) l. The magnitude of bronchodilation was closely correlated with improved pulmonary function, particularly with that of FEV1 (r = 0.843, p<0.001). Such correlations were significant at the fourth to the sixth generation but not at the third generation of bronchi, and the slope of the regression lines became steeper from the third to the sixth generation. Conclusions: Inhaled anticholinergic agents induce overall bronchodilation which is in proportion to improvements in FEV1 in patients with COPD. Bronchodilation at the distal rather than the proximal airways is the determinant of functional improvement.

Exhaled Nitric Oxide – Is It Really a Good Marker of Airway Inflammation in Bronchial Asthma?

Background: The concentration of exhaled nitric oxide ([NO]) has been reported to reflect the inflammatory process of airways in patients with bronchial asthma, particularly when they are steroid naive. However, it is not fully understood whether it equally reflects the degree of airway inflammation in patients receiving inhaled corticosteroids, but whose symptoms are not necessarily well controlled. Objective: To examine whether the exhaled [NO] really reflects airway inflammation in patients with bronchial asthma, regardless of treatment with inhaled steroids. Methods: Exhaled [NO] was measured in patients with bronchial asthma (43 steroid treated and 32 steroid naive), chronic obstructive pulmonary disease (COPD) (n = 36), bronchiectasis (n = 10) and in control subjects (n = 26). We examined in each asthmatic group whether the exhaled [NO] correlated with parameters reflecting airway inflammation. Results: Exhaled [NO] was significantly correlated with symptom score, clinical severity, circulating eosinophil count, and the percentage of eosinophils in induced sputum in the steroid-naive asthmatics, but not in the steroid-treated asthmatics, although airway inflammation in this group was not well controlled, as evidenced by clinical symptoms and the higher percentage of eosinophils in induced sputum. Exhaled [NO] from the patients with COPD (6.2 ± 0.7 ppb) or bronchiectasis (5.4 ± 1.3 ppb) was not significantly increased compared with the controls (6.0 ± 1.0 ppb), and was significantly lower than in the asthmatic patients as a whole (19.0 ± 2.0 ppb). Conclusions: Although exhaled [NO] is a useful marker of airway inflammation for differential diagnosis and evaluation of severity in steroid-naive patients with bronchial asthma, it may not be as useful in steroid-treated patients.

Comparison of airway remodelling assessed by computed tomography in asthma and COPD

BACKGROUND Few studies have directly compared airway remodelling assessed by computed tomography (CT) between asthma and chronic obstructive pulmonary disease (COPD). The present study was conducted to determine whether there are any differences between the two diseases with similar levels of airflow limitation under clinically stable conditions. METHODS Subjects included older male asthmatic patients (n = 19) showing FEV(1)/FVC <70% with smoking history less than 5-pack/year. Age- and sex-matched COPD patients (n = 28) who demonstrated similar airflow limitation as asthmatic patients and age-matched healthy non-smokers (n = 13) were recruited. Using proprietary software, eight airways were selected in the right lung, and wall area percent (WA%) and airway luminal area (Ai) were measured at the mid-portion of the 3rd to 6th generation of each airway. For comparison, the average of eight measurements per generation was recorded. RESULTS FEV(1)% predicted and FEV(1)/FVC was similar between asthma and COPD (82.3 ± 3.3% vs. 77.6 ± 1.8% and 57.7 ± 1.6% vs. 57.9 ± 1.4%). At any generation, WA% was larger and Ai was smaller in asthma, both followed by COPD and then controls. Significant differences were observed between asthma and controls in WA% of the 3rd to 5th generation and Ai of any generation, while no differences were seen between COPD and controls. There were significant differences in Ai of any generation between asthma and COPD. CONCLUSIONS Airway remodelling assessed by CT is more prominent in asthma compared with age- and sex-matched COPD subjects in the 3rd- to 6th generation airways when airflow limitations were similar under stable clinical conditions.

Clinical features and determinants of COPD exacerbation in the Hokkaido COPD cohort study

Exacerbations are among the major factors that may affect the natural history of chronic obstructive pulmonary disease (COPD). The aim was to investigate the clinical characteristics and determinants of COPD exacerbations in our 5-year observational cohort study which had a very low exacerbation frequency. A total of 279 patients with COPD participated in the Hokkaido COPD cohort study, and 268 subjects who had clinical data for multiple visits were analysed. Exacerbation was defined in multiple ways: the patient’s subjective complaint, symptom definition, requiring prescription change, requiring antibiotic treatment, or requiring hospital admission. Exacerbation frequency (events per person per year) was 0.78±1.16, 0.24±0.47, 0.20±0.43, 0.13±0.28 and 0.06±0.19 for subjective complaint and symptom, prescription, antibiotic and hospital admission definitions, respectively. Exacerbation events did not significantly affect the annual decline in forced expiratory volume in 1 s. A high St George’s Respiratory Questionnaire total score, especially activity score, and a low body mass index were strongly associated with exacerbation-free survival, exacerbation frequency and development of recurrent exacerbations. Despite the low exacerbation frequency in our cohort, impaired health-related quality of life and weight loss were found to be independent risk factors for COPD exacerbations. Impaired health-related quality of life and weight loss are independent risk factors for COPD exacerbations http://ow.ly/qQRAG

Effects of IL-1beta, TNF-alpha, and macrophage migration inhibitory factor on prostacyclin synthesis in rat pulmonary artery smooth muscle cells.

Objective:  Cytokines have been implicated in the pathophysiology of pulmonary hypertension. We sought to explore the possibility that prostacyclin is a link.

Functional single nucleotide polymorphisms of the CCL5 gene and nonemphysematous phenotype in COPD patients

It was previously reported that the gain-of-function -28 guanine allele of the promoter single nucleotide polymorphism (SNP; cytosine to guanine substitution of nucleotide -28 (-28C>G)) in the CC chemokine ligand 5 gene (CCL5) was associated with susceptibility to late-onset asthma in patients who developed asthma at age ≥40 yrs. The clinical diagnosis of chronic obstructive pulmonary disease (COPD) includes emphysema and small airway disease, and upregulation of CCL5 has been described in the airways of patients with COPD. It was hypothesised that CCL5 has a genetic impact upon the variable expression of emphysema in patients with COPD. Patients with COPD were studied (n = 267). All of the patients underwent pulmonary high-resolution computed tomography (CT), and visual scoring (CT score) was performed to determine emphysema severity. Three SNPs of CCL5 were genotyped, including -403G>A, -28C>G and 375T>C. A significant difference was found in CT score according to CCL5 genotype; the -28G allele was inversely associated with CT score. When the analysis was confined to 180 patients with bronchial reversibility of <15%, even stronger evidence for this association was noted. Functional single nucleotide polymorphisms in the CC chemokine ligand 5 gene were associated with milder emphysema. Together with previous findings, the present study may identify the CC chemokine ligand 5 gene as part of a common pathway in the pathogenesis of late-onset asthma and chronic obstructive pulmonary disease with milder emphysema.

Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities

Background and objectives Chronic obstructive pulmonary disease (COPD) is responsible for significant morbidity and mortality worldwide. We evaluated the characteristics of stable COPD patients in the pulmonology clinics of seven Asian cities and also evaluated whether the exposure to biomass fuels and dusty jobs were related to respiratory symptoms, airflow limitation, and quality of life in the COPD patients. Methods This cross-sectional observational study recruited 922 COPD patients from seven cities of Asia. The patients underwent spirometry and were administered questionnaires about their exposure to cigarette smoking, biomass fuels, and dusty jobs in addition to respiratory symptoms and health related quality of life. Results Of the patients, there appeared to be variations from city to city in the history of exposure to biomass fuels and dusty jobs and also in respiratory symptoms of cough, phlegm, wheeze, and dyspnea. These symptoms were more frequent in those COPD patients with a history of exposure to biomass fuels than without and those with a history of exposure to dusty jobs than without (P < 0.01 for all comparisons). Airflow limitation was more severe in those COPD patients with a history of exposure to biomass fuels than without (52.2% predicted versus 55.9% of post-bronchodilator forced expiratory volume in 1 second [FEV1], P = 0.009); quality of life was poorer in those with exposure to biomass fuels than without (40.4 versus 36.2 of the St George’s Respiratory Questionnaire [SGRQ] total score, P = 0.001). Airflow limitation was more severe in those COPD patients with a history of exposure to dusty jobs than without (51.2% predicted versus 57.3% of post-bronchodilator FEV1, P < 0.001); quality of life was poorer in those with dusty jobs than without (41.0 versus 34.6 of SGRQ score, P = 0.006). Conclusion In Asian cities, the characteristics of COPD patients vary and the history of exposure to biomass fuels or dusty jobs was related to frequency of symptoms, severe airflow limitation, and poor quality of life.

Beta2-adrenergic receptor polymorphisms as a determinant of preferential bronchodilator responses to β2-agonist and anticholinergic agents in Japanese patients with chronic obstructive pulmonary disease

Background Previous studies have shown that polymorphisms in the &bgr;2-adrenergic receptor gene (ADRB2) may influence bronchodilator response (BDR) to both &bgr;2-agonists and anticholinergics, possibly by intracellular cross-talk, but in opposite ways, in the Japanese population. We hypothesized that the preferential response to either class of bronchodilators might be determined by ADRB2 polymorphisms in patients with chronic obstructive pulmonary disease (COPD). Objective To examine the association of ADRB2 polymorphisms and preferential BDR to &bgr;2-agonists and anticholinergics in patients with COPD. Design and participants The participants had been enrolled in the Hokkaido COPD cohort study. BDR to either class of bronchodilators (salbutamol or oxytropium, 0.4 mg) was measured every 6 months for 2 years. Considering the variation of BDR within and between days, mean values of postbronchodilator increases in forced expiratory volume in 1 s (&Dgr;FEV1) for the two agents measured at two different visits were initially used for the primary analysis (N=189). To confirm the results of the primary analysis, &Dgr;FEV1 measured at a single visit was also used for secondary analyses. Results Although a significant correlation between BDRs to salbutamol and to oxytropium was observed (P<0.001, r=0.36), there were individuals who responded preferentially to one of the two agents. When the participants were classified into two groups based on the bronchodilator causing the better response (salbutamol-dominant group and oxytropium-dominant group), Arg allele was significantly more common in the oxytropium-dominant group than in the salbutamol-dominant group (0.001