Chronic obstructive pulmonary disease is a common condition and a major cause of mortality. COPD is characterized by irreversible airflow obstruction. The physiological abnormalities observed in COPD are due to a combination of emphysema and obliteration of the small airways in association with airway inflammation. The predominant cells involved in this inflammatory response are CD8+ lymphocytes, neutrophils, and macrophages. Although eosinophilic airway inflammation is usually considered a feature of asthma, it has been demonstrated in large and small airway tissue samples and in 20%–40% of induced sputum samples from patients with stable COPD. This airway eosinophilia is increased in exacerbations. Thus, modifying eosinophilic inflammation may be a potential therapeutic target in COPD. Eosinophilic airway inflammation is resistant to inhaled corticosteroid therapy, but does respond to systemic corticosteroid therapy, and the degree of response is related to the intensity of the eosinophilic inflammation. In COPD, targeting treatment to normalize the sputum eosinophilia reduced the number of hospital admissions. Whether controlling eosinophilic inflammation in COPD patients with an airway eosinophilia will modify disease progression and possibly alter mortality is unknown, but warrants further investigation.
COPD; sputum eosinophilia; corticosteroids
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that is not fully reversible; symptoms include chronic cough, sputum production, and dyspnea with exertion. An estimated 50% of the 24 million adults in the USA who have COPD are thought to be misdiagnosed or undiagnosed. Factors contributing to this include a low awareness of COPD and the initial symptoms of the disease among the general population, acceptance of these symptoms as a consequence of aging or smoking, some symptomatic similarity to asthma, and failure of health care personnel to use spirometry for diagnosis. Increased familiarization with COPD diagnosis and treatment guidelines, and proactive identification of patients with increased risk of developing COPD through occupational, environmental, or lifestyle exposures, will assist in a timely, accurate diagnosis and effective treatment, which will consequently improve patient outcomes. This review addresses the issues surrounding the diagnosis and misdiagnosis of COPD, their consequences, and how COPD can be better managed within primary care, including consideration of COPD care in patient-centered medical home and chronic care models.
primary care; undiagnosed; misdiagnosed; chronic care model; patient-centered medical home
Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease of the lung caused primarily by exposure to cigarette smoke. Clinically, it presents with progressive cough, sputum production, dyspnea, reduced exercise capacity, and diminished quality of life. Physiologically, it is characterized by the presence of partially reversible expiratory airflow limitation and hyperinflation. Pathologically, COPD is a multicomponent disease characterized by bronchial submucosal mucous gland hypertrophy, bronchiolar mucosal hyperplasia, increased luminal inflammatory mucus, airway wall inflammation and scarring, and alveolar wall damage and destruction. Management of COPD involves both pharmacological and nonpharmacological approaches. Bronchodilators and inhaled corticosteroids are recommended medications for management of COPD especially in more severe disease. Combination therapies containing these medications are now available for the chronic management of stable COPD. The US Food and Drug Administration, recently, approved the combination of budesonide/formoterol (160/4.5 μg; Symbicort™, AstraZeneca, Sweden) delivered via a pressurized meter dose inhaler for maintenance management of stable COPD. The combination also is delivered via dry powder inhaler (Symbicort™ and Turbuhaler™, AstraZeneca, Sweden) but is not approved for use in the United States. In this review, we evaluate available data of the efficacy and safety of this combination in patients with COPD.
inhaled steroid; bronchodilator; β2-agonist; lung function; quality of life; COPD exacerbations
Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow limitation and airway inflammation, accompanied by decreased health status. It is still unknown which factors are responsible for the impaired health status in COPD. We postulated that airway inflammation negatively contributes to health status in COPD.
In 114 COPD patients (99 male, age: 62 ± 8 yr, 41 [31–55] pack-years, no inhaled or oral corticosteroids, postbronchodilator FEV1: 63 ± 9% pred, FEV1/IVC: 48 ± 9%) we obtained induced sputum and measured health status (St. George's respiratory questionnaire (SGRQ)), postbronchodilator FEV1, hyperinflation (RV/TLC), and airway hyperresponsiveness to methacholine (PC20). Sputum was induced by hypertonic saline and differential cell counts were obtained in 102 patients.
Univariate analysis showed that SGRQ total and symptom score were positively associated with % sputum macrophages (r = 0.20, p = 0.05; and r = 0.20, p = 0.04, respectively). Multiple regression analysis confirmed these relationships, providing significant contributions of % sputum macrophages (B = 0.25, p = 0.021) and RV/TLC (B = 0.60, p = 0.002) to SGRQ total score. Furthermore, SGRQ symptom score was associated with % sputum macrophages (B = 0.30, p = 0.03) and RV/TLC (B = 0.48, p = 0.044), whilst SGRQ activity score was associated with % sputum macrophages (B = 0.46, p = 0.002), RV/TLC (B = 0.61, p = 0.015), and PC20 (B = -9.3, p = 0.024). Current smoking and FEV1 were not significantly associated with health status in the multiple regression analysis.
We conclude that worse health status in COPD patients is associated with higher inflammatory cell counts in induced sputum. Our findings suggest that airway inflammation and hyperinflation independently contribute to impaired health status in COPD. This may provide a rationale for anti-inflammatory therapy in this disease.
Background: An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear.
Methods: A randomised, double blind, crossover trial of placebo and mometasone furoate (800 µg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase.
Results: Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV1), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV1 increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV1 with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count.
Conclusions: An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV1 following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.
BACKGROUND AND OBJECTIVE:
Some studies show a decline of FEV1 only one month after withdrawal of inhaled corticosteroids (ICS), while others show no decline. We speculate that the presence of an asthma phenotype in the Chronic Obstructive Pulmonary Disease (COPD) population, and that its exclusion may result in no spirometric deterioration.
We performed a prospective clinical observation study on 32 patients who fulfilled the Global Initiative for Chronic Obstructive lung disease definition of COPD (Grade II-IV). They were divided into two phenotypic groups. 1. Irreversible asthma (A and B) (n = 13): A. Asthma: Bronchial biopsy shows diffuse thickening of basement membrane (≥ 6.6 μm). B. Airflow limitation (AFL) likely to be asthma: KCO > 80% predicted if the patient refused biopsy. 2. COPD (A and B) (n = 19): A. COPD: hypercapneic respiratory failure with raised bicarbonate, panlobular emphysema with multiple bullas, or bronchial biopsy showing squamous metaplasia and epithelial/subepithelial inflammation without thickening of the basement membrane. B. AFL likely to be COPD: KCO < 80% predicted.
The asthma phenotype was significantly younger, had a strong association with hypertrophy of nasal turbinates, and registered a significant improvement of FEV1 (350 ml) vs a decline of - 26.5 ml in the COPD phenotype following therapy with budesonide/formoterol for one year. Withdrawal of budesonide for 4 weeks in the COPD phenotype resulted in FEV1 + 1.33% (SD ± 5.71) and FVC + 1.24% (SD ± 5.32); a change of <12% in all patients.
We recorded no spirometric deterioration after exclusion of the asthma phenotype from a COPD group.
Asthma; COPD; radiology and other imaging; respiratory function tests
Many patients with breathlessness and chronic obstructive lung disease are diagnosed with either asthma, COPD, or—frequently—mixed disease. More commonly, patients with uncharacterized breathlessness are treated with therapies that target asthma and COPD rather than one of these diseases. This common practice represents the difficulty in distinguishing these disorders clinically, particularly in patients with a history that does not easily differentiate asthma from COPD. A common clinical scenario is an older former smoker with partially reversible or fixed airflow obstruction and evidence of atopy, demonstrating “overlap” features of asthma and COPD. We stress that asthma-COPD overlap syndrome becomes more prevalent with advancing age as patients respond less favorably to guideline-recommended drug therapy. We review the similarities and differences in clinical characteristics between these disorders, and their physiologic and inflammatory profiles within the context of the aging patient. We underscore the difficulties in differentiating asthma from COPD in current or former smokers, share our institutional experience with overlap syndrome, and highlight the need for new research to better characterize and investigate this important clinical phenotype.
Background: Chronic obstructive pulmonary disease (COPD) is a syndrome of chronic progressive airflow limitation which occurs as a result of chronic inflammation of the airways and lung parenchyma. However, the role of inhaled corticosteroids in the treatment of COPD is controversial. We hypothesised that inhaled corticosteroids reduce the progression of airflow limitation in COPD.
Methods: A comprehensive literature search was conducted and data were analysed using random effects methodology. The effect of inhaled steroids on annual change in forced expiratory volume in 1 second (FEV1) was determined for all trials, for trials with high dose treatment regimens, and for trials in subjects with moderate to severe airflow limitation.
Results: Data from eight controlled clinical trials of ⩾2 years were included (n=3715 subjects). Meta-analysis of all study data revealed that inhaled corticosteroids reduce the rate of FEV1 decline by 7.7 ml/year (95% confidence interval (CI) 1.3 to 14.2, p=0.02). Meta-analysis of studies with high dose regimens revealed a greater effect of 9.9 ml/year (95% CI 2.3 to 17.5, p=0.01) compared with the meta-analysis of all studies.
Conclusions: Inhaled corticosteroid treatment for ⩾2 years slows the rate of lung function decline in COPD. The effect observed with high dose regimens is greater than that with all regimens combined. These data suggest a potential role for inhaled corticosteroids in modifying the long term natural history of COPD.
BACKGROUND--Bacterial infections of the lower airways during an exacerbation in patients with asthma or chronic obstructive pulmonary disease (COPD) may be the cause of an exacerbation or the consequence of a viral infection or an increase in airways limitation. To determine whether bacterial infection is an important component in the pathogenesis of an exacerbation, the effects of antimicrobial treatment must be studied. METHODS--Patients with asthma or COPD seen in general practice were studied in a double blind randomised manner to investigate whether the antimicrobial drugs amoxicillin (500 mg three times daily), cotrimoxazole (960 mg twice daily), or a placebo, each when added to a short course of oral corticosteroids, can accelerate recovery from exacerbations. Patients were instructed to contact their own physician early in the morning when complaints of increased shortness of breath, wheezing, or exacerbations of cough with or without sputum production occurred. Treatment effects were evaluated over the next 14 days by studying symptom scores (wheeze, dyspnoea, cough with and without mucus production, and awakening with dyspnoea), peak expiratory flow values (PEF, expressed as % predicted), and sublingual temperature. Bacteriological study of the sputum was made at the onset of an exacerbation and 7, 21 and 35 days afterwards. RESULTS--Of 195 patients enrolled 71 (36%) contacted their physician for symptoms of an exacerbation. Symptoms improved in all three groups, improvements ranging from 0.54 to 0.75 points per day on a four point scale. PEF% predicted showed improvements in the three groups after the exacerbation, ranging from 0.34% to 0.78% predicted per day, finally returning to baseline values. Sublingual temperature did not change. Six of 71 patients consulted their physician because of a relapse between four and 24 days after the start of treatment. In only two of the 50 sputum samples, collected during an exacerbation, and which contained > or = 10(5) bacteria in culture sensitive to the chosen antibiotic given, did any benefit from antimicrobial treatment occur. During the recovery period sputum purulence improved irrespective of antibiotic treatment. CONCLUSIONS--Antibiotics given with a short course of oral prednisolone during an exacerbation do not accelerate recovery as measured by changes in peak flow and symptom scores in ambulatory patients with mild to moderate asthma or COPD when treated by their general practitioners. Moreover, antibiotics do not reduce the number of relapses after treating an exacerbation.
BACKGROUND--Sputum analysis provides a non-invasive method of examining the airway secretions of subjects with asthma in order to better understand the inflammatory process. Increased proportions of eosinophils are generally seen in the sputum of subjects with asthma, especially when there is an exacerbation. An unexpected observation in the sputum of subjects with mild exacerbations of asthma is reported. METHODS--Thirty four consecutive subjects with symptoms consistent with a mild exacerbation of asthma were recruited for a treatment study. Inclusion criteria required persistent symptoms of chest tightness, dyspnoea, or wheezing for two weeks (without spontaneous improvement or alteration in dose of inhaled corticosteroid) and a forced expiratory volume in one second (FEV1) that was reversible to more than 75% predicted or known best to ensure the exacerbation was mild. Sputum (spontaneous or induced with hypertonic saline) from all subjects was examined for differential cell counts. Eosinophilic sputum was defined as > or = 4% eosinophils on two occasions or > 10% eosinophils once. Clinical characteristics, sputum differential counts, and measurements of airways obstruction were compared between the subjects with and without sputum eosinophilia. RESULTS--Almost half of the subjects (16 of 34) considered to have mildly uncontrolled asthma had no sputum eosinophilia. In comparison with the subjects who had sputum eosinophilia the non-eosinophilic group had less airways obstruction (FEV1% predicted 88% v 70%) and less severe airways hyperresponsiveness (PC20 methacholine 0.45 mg/ml v 0.13 mg/ml). There was no difference between the groups in the type or prevalence of symptoms, history of recent infections, smoking, relevant allergen exposure, or use of inhaled corticosteroid. CONCLUSIONS--Symptoms of mildly uncontrolled asthma are not always associated with eosinophilic airways inflammation as measured by sputum analysis. The causes and treatment of the non-eosinophilic condition require further investigation.
Sputum eosinophilia is observed frequently in patients with rhinitis. Sputum eosinophilia in patients with non-asthmatic allergic rhinitis has been suggested to be related to nonspecific airway hyperresponsiveness (AHR). However, the clinical significance of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR has not been determined. We conducted a retrospective study examining the influence of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR on pulmonary function and expression of fibrosis-related mediators.
Eighty-nine patients with moderate-to-severe perennial rhinitis without AHR were included. All underwent lung function tests (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), skin tests to inhalant allergens, methacholine bronchial challenge tests, and hypertonic saline-induced sputum to determine eosinophil counts. Sputum mRNA levels for transforming growth factor-β (TGF-β), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also examined. Patients were divided into two groups according to the presence of sputum eosinophilia (≥3%, eosinophilia-positive [EP] and <3%, eosinophilia-negative [EN] groups).
FEV1 was significantly lower (P=0.04) and FEV1/FVC tended to be lower (P=0.1) in the EP group than in the EN group. In sputum analyses, the MMP-9 mRNA level (P=0.005) and the ratio of MMP-9 to TIMP-1 expression (P=0.01) were significantly higher in the EP group than in the EN group. There was no significant difference in TGF-β mRNA expression between the two groups.
Sputum eosinophilia in patients with moderate-to-severe perennial rhinitis without AHR influenced FEV1 and the expression pattern of fibrosis-related mediators.
Sputum; eosinophil; rhinitis; forced expiratory volume; matrix metalloproteinase-9
Aims: To assess the occurrence of respiratory symptoms and signs of airflow limitations in a group of asphalt workers.
Methods: All 64 asphalt workers and a reference group of 195 outdoor construction workers from the same company participated in a cross-sectional study. Spirometric tests and a questionnaire on respiratory symptoms and smoking habits were administered. Respiratory symptoms and lung function were adjusted for age and smoking.
Results: The FEV1/FVC% ratio was significantly lower in the asphalt workers than in the referents. Symptoms of eye irritation, chest tightness, shortness of breath on exertion, chest wheezing, physician diagnosed asthma, and chronic obstructive pulmonary disease (COPD) were all significantly more prevalent among the asphalt workers.
Conclusion: In asphalt workers there is an increased risk of respiratory symptoms, lung function decline, and COPD compared to other construction workers.
Patients with chronic obstructive pulmonary disease (COPD) experience more problematic respiratory symptoms and have more trouble performing daily activities in the morning. The aim of this study was to assess the perception of COPD symptoms related to morning activities in patients with severe airflow limitation.
Data of 133 patients with severe airflow limitation were analyzed in a prospective, non-interventional study. A clinical symptom questionnaire was completed by patients at baseline. In patients having morning symptoms, defined by at least one or more prominent or aggravating symptom during morning activities, a morning activity questionnaire was also completed at baseline and following 2 months of COPD treatment.
The most frequently reported COPD symptom was breathlessness (90.8%). Morning symptoms were reported in 76 (57%) patients; these had more frequent and severe clinical COPD symptoms. The most frequently reported morning activity was getting out of bed (82.9%). The long acting muscarinic antagonist (odds ratio [OR], 6.971; 95% confidence interval [CI], 1.317 to 11.905) and chest tightness (OR, 0.075; 95% CI, 0.011 to 0.518) were identified as significantly related to absence of morning symptoms. There was no significant correlation between the degree of forced expiratory volume in 1 second improvement and severity score differences of all items of morning activity after 2-month treatment.
Fifty-seven percent of COPD patients with severe airflow limitation have morning symptoms that limit their morning activities. These patients also have more prevalent and severe COPD symptoms. The results of this study therefore provide valuable information for the development of patient-reported outcomes in COPD.
Perception; Morning; Symptoms; Activities; Chronic obstructive pulmonary disease
Sputum cell counts have identified inflammatory subtypes of bronchitis in relatively small numbers of subjects with asthma, chronic obstructive pulmonary disease (COPD) and chronic cough in research studies. The prevalence of different subtypes of bronchitis in routine clinical practice, however, has not been reported.
To examine the heterogeneity of bronchitis and its relationship to the severity of airflow obstruction.
A retrospective cross-sectional survey based on a computerized database of spontaneous or induced sputum cell counts examined in a large university tertiary respiratory outpatient clinic.
The database contained 4232 consecutive sputum records from 2443 patients with chronic cough (39%), asthma (37%), asthma with COPD (9%), COPD (13%) and bronchiectasis (3%). Total and differential cell counts were obtained from 86% of successful sputum samples. Induced sputum provided more viable samples than spontaneous expectorate. Approximately one-third of patients with asthma and one-fifth of patients with COPD experience eosinophilic bronchitis. Asthmatic patients with moderate to severe airflow obstruction had a greater number of sputum eosinophils. There was a significantly higher number of total cell counts and percentage of neutrophils in the sputum of COPD patients with moderate and severe airflow obstruction than in those with mild airflow obstruction.
There is heterogeneity in the cellularity of sputum in various airway diseases. Patients with clinically stable airway diseases may have high sputum cell counts. During exacerbations, more patients may experience neutrophilic bronchitis. Severity of airflow obstruction is associated with eosinophilic bronchitis in patients with asthma, and neutrophilic bronchitis in patients with nonasthmatic COPD.
Asthma; Bronchitis heterogeneity; Clinical practice; COPD; Sputum cell counts
The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD) in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are observed in central airways, small airways and alveolar space. The proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance, systemic inflammation, apoptosis and ineffective repair. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec) to FVC (forced vital capacity) ratio <0.70. COPD is characterized by an accelerated decline in FEV1. Co morbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure), hypertension, metabolic diseases (diabetes mellitus, metabolic syndrome and obesity), bone disease (osteoporosis and osteopenia), stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline. The assessment of COPD is required to determine the severity of the disease, its impact on the health status and the risk of future events (e.g., exacerbations, hospital admissions or death) and this is essential to guide therapy. COPD is treated with inhaled bronchodilators, inhaled corticosteroids, oral theophylline and oral phosphodiesterase-4 inhibitor. Non pharmacological treatment of COPD includes smoking cessation, pulmonary rehabilitation and nutritional support. Lung volume reduction surgery and lung transplantation are advised in selected severe patients. Global strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease guidelines recommend influenza and pneumococcal vaccinations.
Airflow limitation; air pollution; bronchodilators; chronic obstructive pulmonary disease; exacerbations; lung; pulmonary rehabilitation; smoking
Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD.
Twenty-eight patients (age 58 ± 7.8 yr, packyears 40 ± 15.5, post-bronchodilator FEV1 77 ± 14.0%predicted, no inhaled steroids ≥4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum.
There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline-induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL-8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum.
In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD.
Netherlands Trial Register (NTR): NTR1283
Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing.
In a 52-week, randomized, double-blind, placebo-controlled study, 911 subjects with moderate-to-severe COPD managed without ICS received MF-DPI 800 μg QD PM, MF-DPI 400 μg BID, or placebo. The change from baseline in postbronchodilator forced expiratory volume in 1 second (FEV1), total COPD symptom scores, and health status as well as the percentage of subjects with a COPD exacerbation were assessed. Adverse events were recorded.
Mometasone furoate administered via a dry powder inhaler 800 μg QD PM and 400 μg BID significantly increased postbronchodilator FEV1 from baseline (50 mL and 53 mL, respectively, versus a 19 mL decrease for placebo; P < 0.001). The percentage of subjects exacerbating was significantly lower in the pooled MF-DPI groups than in the placebo group (P = 0.043). Subjects receiving MF-DPI 400 μg BID reported a statistically significant (19%) reduction in COPD symptom scores compared with placebo (P < 0.001). Health status as measured with St. George's Respiratory Questionnaire (SGRQ) improved significantly in all domains (Total, Activity, Impacts, and Symptoms) in the pooled MF-DPI groups versus placebo (P ≤ 0.031). MF-DPI treatment was well tolerated.
Once-daily MF-DPI improved lung function and health status in subjects with moderate-to-severe COPD and was comparable to BID MF-DPI.
To determine the accuracy of the history and selected elements of the physical examination in the diagnosis of chronic obstructive pulmonary disease (COPD).
Independent blind comparison of the standard clinical examination (evaluating the accuracy of history, wheezing, and forced expiratory time [FET]) with spirometry. The gold standard for diagnosis of COPD was a forced expiratory volume at 1 second (FEV1) below the fifth percentile (adjusted for patient height and age).
Seven sites in 6 countries, including investigators from primary care and secondary care settings.
One hundred sixty-one consecutive patients with varying severity of disease (known COPD, suspected COPD, or no COPD) participated in the study.
One hundred sixty-one patients (mean age 65 years, 39% female, 41% with known COPD, 27% with suspected COPD, and 32% normal) were recruited. Mean (±SD) FEV1 and forced vital capacity were 1,720 (±830) mL and 2,520 (±970) mL. The likelihood ratios (LR) for the tested elements of the clinical examination (and their P values on χ2 testing) were: self-reported history of COPD, 5.6 (P < .001); FET greater than 9 seconds, 6.7 (P < 0.01); smoked longer than 40 pack years, 3.3 (P = .001); wheezing, 4.0 (P < .001); male gender, 1.6 (P < .001); and age over 65 years, 1.6 (P = .025). The accuracy of these elements was not appreciably different when reference standards other than FEV1 below the 5th percentile were applied. Only 3 elements of the clinical examination were significantly associated with the diagnosis of COPD on multivariate analysis: self-reported history of COPD (adjusted LR 4.4), wheezing (adjusted LR 2.9), and FET greater than 9 seconds (adjusted LR 4.6). Area under the receiver operating characteristic curve for the model incorporating these 3 factors was 0.86.
Less emphasis should be placed on the presence of isolated symptoms or signs in the diagnosis of COPD. While numerous elements of the clinical examination are associated with the diagnosis of COPD, only 3 are significant on multivariate analysis. Patients having all 3 of these findings have an LR of 33 (ruling in COPD); those with none have an LR of 0.18 (ruling out COPD).
chronic obstructive pulmonary disease; clinical examination; spirometry; diagnosis
Exacerbations of chronic obstructive pulmonary disease (COPD) are natural events in the progression of the disease, and are characterised by acute worsening of symptoms, especially dyspnoea. These heterogeneous events follow increased airway inflammation, often due to infection, and lead to decreased airflow and increased lung hyperinflation relative to stable COPD. Although exacerbation frequency generally increases as COPD progresses, some patients experience frequent exacerbations (≥2 per year) independently of disease severity. Exacerbations, especially frequent exacerbations, are associated with impaired health-related quality of life, reduced physical activity and poor disease prognosis.
The cornerstone of pharmacotherapy for stable COPD is long-acting bronchodilators, including the long-acting β2-agonists (LABAs) and long-acting anti-muscarinic agents (LAMAs) alone or combined with inhaled corticosteroids (ICS). While ICS treatment can potentially reduce the risk of exacerbations, clinical studies have demonstrated the efficacy of LABAs and LAMAs in reducing COPD symptoms, primarily by reducing lung hyperinflation secondary to reduced airway resistance. Sustained reduction in lung hyperinflation may in turn lessen dyspnoea during an exacerbation. Indeed, recent studies suggest that bronchodilators may also reduce the incidence of, or prevent, exacerbations.
Using data from recent studies, this review explores the evidence and possible mechanisms through which bronchodilators may prevent exacerbations.
Bronchodilator; chronic obstructive pulmonary disease; dyspnoea; exacerbations; long-acting anti-muscarinic agent; long-acting β2-agonists
To determine whether the self-reported diagnosis of adults who present to the emergency department (ED) with an acute exacerbation of either asthma or chronic obstructive pulmonary disease (COPD) is validated by medical record review.
This is cross-sectional study of 78 consecutive adults, 55 years and older, presenting to 3 EDs with symptoms suggestive of an exacerbation of asthma or COPD. We used current spirometric guidelines for a “spirometrically validated” diagnosis of COPD (eg, postbronchodilator forced expiratory volume in 1 second/forced ventilatory capacity b70%). Patients without office spirometry result were classified with COPD using clinical validation based on at least one of the following: primary care physician diagnosis of COPD, chronic bronchitis, or emphysema in the medical record or chest radiography, chest computed tomography, or arterial blood gas (ABG) diagnostic of COPD.
Among 60 patients who self-reported diagnosis of COPD, 98% (95% confidence interval, 89-100) had clinically validated or spirometrically validated COPD. In addition, 83% (95% confidence interval, 59-96) of patients who reported either asthma only or no respiratory disease had clinically validated or spirometrically validated COPD. In no case was the chest radiograph or the ABG useful as a stand-alone test in establishing the diagnosis of COPD.
Patients 55 years and older presenting to the ED with acute asthma or COPD, even those with clinical symptoms but no diagnosis of COPD, are likely to have COPD. Clinicians should maintain a high index of suspicion for COPD when older asthma patients deny COPD.
Guidelines recommend inhaled corticosteroids (ICS) for patients with severe chronic obstructive pulmonary disease (COPD). Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity. The effect of withdrawing ICS from COPD patients in primary care is unknown.
In a pragmatic randomised, double-blind, placebo-controlled trial in 31 practices, 260 COPD patients stopped their usual ICS (median duration of use 8 years) and were allocated to 500 mcg fluticasone propionate twice daily (n = 128), or placebo (n = 132). Follow-up assessments took place at three monthly intervals for a year at the patients' practice. Our primary outcome was COPD exacerbation frequency. Secondary outcomes were time to first COPD exacerbation, reported symptoms, peak expiratory flow rate and reliever inhaler use, and lung function and health related quality of life.
In patients randomised to placebo, COPD exacerbation risk over one year was RR: 1.11 (CI: 0.91–1.36). Patients taking placebo were more likely to return to their usual ICS following exacerbation, placebo: 61/128 (48%); fluticasone: 34/132 (26%), OR: 2.35 (CI: 1.38–4.05). Exacerbation risk whilst taking randomised treatment was significantly raised in the placebo group 1.48 (CI: 1.17–1.86). Patients taking placebo exacerbated earlier (median time to first exacerbation: placebo (days): 44 (CI: 29–59); fluticasone: 63 (CI: 53–74), log rank 3.81, P = 0.05) and reported increased wheeze. In a post-hoc analysis, patients with mild COPD taking placebo had increased exacerbation risk RR: 1.94 (CI: 1.20–3.14).
Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration. Patients with mild COPD may be at increased risk of exacerbation after withdrawal.
BACKGROUND—Inhaled corticosteroids are known to be
beneficial for patients with asthma, but their role in treating
patients with stable chronic obstructive pulmonary disease (COPD)
remains controversial. A study was undertaken to determine whether
inhaled corticosteroids are of functional benefit in patients who did
not show improvement with a trial of oral corticosteroids.
METHODS—In phase I patients with stable COPD were
given a two week course of oral placebo followed by two weeks of
prednisone 40 mg per day in a single blind manner to distinguish
between responders and non-responders to oral corticosteroids. In phase
II a double blind, randomised, parallel group trial of inhaled
budesonide 1600 µg per day versus placebo was carried out in 79 non-responders to oral corticosteroids. The primary outcome measure was
forced expiratory volume in one second (FEV1), and
secondary outcome measures were exercise capacity, dyspnoea with
exertion, quality of life, peak expiration flow rate, and respiratory symptoms.
RESULTS—Randomisation allocated 39 subjects to
inhaled corticosteroids and 40 to placebo. There was no difference in
the change in FEV1 from baseline between the treatment and
placebo groups; mean difference -12 ml (95% CI -88 to 63) at three
months and -4 ml (95% CI -95 to 87) at six months. The proportion
of patients with a 15% or greater improvement was no higher among
those receiving inhaled corticosteroids than in the placebo group at
any of the follow up visits. Changes in secondary outcomes were also no different.
even at high doses, were of no physiological or functional benefit in
these patients with advanced COPD.
oxide (NO) is involved in inflammation and host defence of the lung. It
has been found in increased concentrations in the airways in asthmatic
subjects but its levels in patients with chronic obstructive pulmonary
disease (COPD) have not been investigated. A study was undertaken to
determine whether markers of NO metabolism (NO in exhaled air, iNOS
expression in sputum cells, and nitrite + nitrate
(NO2-/NO3-) in sputum
supernatant) are increased in subjects with COPD, and whether they
correlate with inflammatory indices in induced sputum. The associations
of these markers with smoking were also assessed.
subjects with COPD (median age 66 years, median forced expiratory
volume in one second (FEV1) 63% predicted, eight current
smokers) and 16 healthy subjects (median age 63 years, median
FEV1 113% predicted, eight current smokers) participated in the study. NO was measured during tidal breathing and sputum was
induced by inhalation of hypertonic saline.
were observed between subjects with COPD and healthy controls in
exhaled NO excretion rate (median 5.15 and 6.25 nmol/min), sputum
macrophage iNOS expression (14% and 12%), and sputum supernatant
NO2-/NO3- (46 and
73 µM). NO in exhaled air correlated with the percentage of sputum
eosinophils in patients with COPD (rho = 0.65, p = 0.009) but not in
healthy individuals. Exhaled NO and supernatant
NO2-/NO3- levels were
lower in healthy smokers than in healthy non/ex-smokers.
findings indicate that NO metabolism is not increased in patients with
stable COPD. The close association between exhaled NO levels and sputum
eosinophils suggests a role for NO in airway inflammation in COPD.
Studies performed during exacerbations may clarify this role.
Patients with chronic obstructive pulmonary disease (COPD) demonstrate variable responses to inhaled corticosteroids (ICS). The factors contributing to this variability are not well understood. Data from patients with asthma have suggested that low 25-hydroxyvitamin D [25(OH)D] levels contribute to a lack of ICS response in asthma. The objective of this study was to determine whether serum levels of 25(OH)D were related to ICS responses in patients with COPD.
A total of 60 exsmokers with severe COPD (mean forced expiratory volume in one second [FEV1] 1.07 L, 36% of predicted) spent 4 weeks free of any ICS, followed by 4 weeks of ICS use (fluticasone propionate 500 μg twice daily). Spirometry was performed prior to and after 4 weeks of ICS use. Blood 25(OH)D levels were measured prior to ICS use and examined for relationships to changes in FEV1 following the 4 weeks of ICS use.
The mean 25(OH)D level was 23.3 ± 9.3 ng/mL. There was a high prevalence of vitamin D insufficiency (35%) and deficiency (40%). There was no relationship between baseline 25(OH)D and changes in FEV1 following 4 weeks of ICS.
Baseline 25(OH)D does not contribute to the variation in short-term FEV1 responses to ICS in patients with severe COPD.
COPD; androstadienes; anti-inflammatory agents; spirometry
Chronic obstructive pulmonary disease (COPD) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma. The aim of this study was to determine the proportion of adult subjects aged >50 years within each phenotypic subgroup of COPD, defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.7, in accordance with current international guidelines.
Adults aged >50 years derived from a random population-based survey undertook detailed questionnaires, pulmonary function tests and chest CT scans. The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis, emphysema and asthma, with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of 0.7.
A total of 469 subjects completed the investigative modules, 96 of whom (20.5%) had COPD. Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD. 18/96 subjects with COPD (19%) had the classical phenotypes of chronic bronchitis and/or emphysema but no asthma; asthma was the predominant COPD phenotype, being present in 53/96 (55%). When COPD was defined as a post-bronchodilator FEV1/FVC less than the lower limit of normal, there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema, chronic bronchitis or asthma phenotype.
This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder.