Respiratory Medicine - Articles in Press

Preselection of patients at risk for COPD by two simple screening questions - Corrected Proof

Harald Kögler, Norbert Metzdorf, Thomas Glaab, Tobias Welte — 2010-02-08

Abstract: Background: The Burden of Obstructive Lung Disease study showed that in Germany, to confirm the diagnosis of chronic obstructive lung disease (COPD) in one subject, eight people ≥40 years of age have to be screened. The number-needed-to-screen (NNS) increased to 18 for identifying a patient with COPD≥GOLD stage II. These high numbers limit the cost-effectiveness of COPD screening by population spirometry. We investigated in a primary care setting whether using two simple questions regarding smoking status and presence of cough and/or dyspnea may help to preselect patients for proper diagnosis of COPD.Methods: A total of 1088 patients aged ≥40 yrs without a history of chronic lung disease, who were either current or ex-smokers and complained of cough and/or dyspnea, were examined by respiratory physicians. Spirometry was carried out to confirm COPD diagnosis and severity.Results: A total of 61.6% of patients were male. Mean smoking history was 31.8 pack-yrs. In 516 patients (47.4%), a diagnosis of COPD was confirmed. Among these, 379 (34.8% of total) had at least GOLD stage II COPD, while 89 (8.2% of total) had advanced disease (GOLD stages III/IV). COPD prevalence was significantly associated with age and the extent of cigarette smoke exposure.Conclusions: Two questions regarding smoking status and presence of cough and/or dyspnea enabled general practitioners to select patients at risk for COPD for subsequent spirometry. This preselection reduced the NNS to 2.1 for identifying a COPD patient, and to 2.9 for identifying a patient of at least GOLD stage II.

Effects of CPAP therapy on the sympathovagal balance and arterial stiffness in obstructive sleep apnea - Corrected Proof

2010-02-08

Summary: Objective: Increased arterial stiffness and sympathovagal imbalance are noted in patients with obstructive sleep apnea (OSA). It has been thought that continuous positive airway pressure (CPAP) therapy can have beneficial effects on the vascular function in such cases. However, it is not yet clear whether the improvement of sympathovagal balance by CPAP might be related to reduction of the arterial stiffness, independent of changes in the blood pressure.Methods: In 50 consecutive eligible patients with OSA (apnea–hypopnea index≥20/hour) receiving CPAP therapy, the brachial-ankle pulse wave velocity (baPWV), heart rate variability (LF, HF and LF/HF ratio), baroreceptor sensitivity (BRS), plasma levels of C-reactive protein (CRP), and endothelial function as assessed by changes in the forearm blood flow before and after reactive hyperemia (END) were measured before and after 3-months' CPAP therapy.Results: Significant decrease of the LF/HF ratio, plasma levels of CRP, baPWV and heart rate were observed after 3 months' CPAP therapy. The change in the baPWV following 3-months' CPAP therapy was significantly correlated with the change in the LF/HF ratio and mean blood pressure (MBP), but not with that of the BRS, CRP or END after the therapy. Multivariate linear regression analysis demonstrated a significant correlation between the change in the LF/HF ratio and that in the baPWV (beta=0.305, p=0.041), independent of the changes in the MBP, plasma CRP levels and heart rate.Conclusions: Improvement of the sympathovagal balance by CPAP therapy may be significantly related to decreased stiffness of the central to middle-sized arteries, independent of the changes in the blood pressure and vascular endothelial status.

Mechanical ventilation induces changes in exhaled breath condensate of patients without lung injury - Corrected Proof

2010-02-08

Summary: Introduction: Measurement of biomarkers in exhaled breath condensate (EBC) may be useful for monitoring lung inflammation and injury in mechanically ventilated patients. The aim of this study was to analyze changes in biomarkers of inflammation in EBC associated with prolonged mechanical ventilation.Methods: EBC samples were collected from critically ill patients weaning from mechanical ventilation without lung disease and from healthy nonsmokers. The following parameters were measured: pH after helium deaeration, nitrogen oxide and 8-isoprostane concentrations.Results: EBC was obtained from 10 patients and 20 controls. Ventilation time before the start of sample collection was 250 (85–714)h. The post-deaeration pH of EBC samples was significantly lower in ventilated patients than controls (7.50 [7.28–7.70] vs 8.07 [7.60–8.40]; P=0.008). Ventilation time before sample collection inversely correlated with pH (r=−0.636; P=0.048). A significantly higher concentration of nitrogen oxide (μM) was seen in ventilated patients vs controls (66.22 [22.26–83.13] vs 15.06 [10.73–23.30]; P=0.002), whereas levels of 8-isoprostane (pg/mL) were not significantly different between both groups (5.73 [4.0–11.4] vs 9.09 [6.63–11.43]; P=0.169). The nitrogen oxide concentration correlated negatively with dynamic compliance (r=−0.952; P<0.001) and positively with respiratory rate (r=0.683; P=0.029).Conclusions: EBC analysis is a non-invasive technique that can be used to monitor ventilated patients. Mechanically ventilated patients had higher EBC acidity and nitrogen oxide concentrations. Duration of ventilation correlated with breath condensate pH.

Bronchitis-like symptoms and proximity air pollution in French elderly - Corrected Proof

2010-02-03

Summary: Background: Our aim was to explore the association between respiratory health and proximity air quality in elderly.Methods: The prevalence of respiratory conditions was linked in 2104 individuals aged ≥65 years recruited in Bordeaux (3C Study) to home address concentrations of NO2, CO, SO2, fine particles (PM10), VOCs and benzene, estimated through a dispersion model combining data on background air pollution, traffic characteristics, and conditions of topographical and meteorological dispersion of air pollutants.Results: Mean [minimum; maximum] values of the annual concentrations (μg/m3) of proximity air pollutants were respectively: 28 [18; 72.2] for NO2, 420 [350; 1337] for CO, 7.5[5; 13.7] for SO2, 23.1 [19; 51] for PM10, 8.1 [0.01; 116.6] for VOCs and 1.8 [1.5; 6.9] for benzene. Using a binary logistic regression model, PM10 were significantly associated with usual cough (Odds-Ratio=1.33 (95% confidence interval: 1.00–1.77) for exposed compared to non-exposed) and SO2 with usual cough (1.55 (1.16–2.08)) and phlegm (1.45 (1.04–2.01)). We found a 10% and a 23% increase in usual cough for a 10μg/m3 increment in PM10 and a 1μg/m3 increment in SO2 respectively, and a 23% increase in usual phlegm for a 1μg/m3 increase in SO2. A sensitivity analysis showed similar results when considering 3-year proximity pollution. A more pronounced effect of SO2 and PM10 on usual cough and phlegm was observed in woman.Conclusions: Our assessment of exposure to proximity air pollution has shown an increased prevalence of bronchitis-like symptoms in elderly living in areas polluted by SO2 and PM10.

Two variants of occupational asthma separable by exhaled breath nitric oxide level - Corrected Proof

2010-02-03

Summary: Exhaled nitric oxide (FENO) has been used as a marker of asthmatic inflammation in non-occupational asthma, but some asthmatics have a normal FENO. In this study we investigated whether, normal FENO variants have less reactivity in methacholine challenge and smaller peak expiratory flow (PEF) responses than high FENO variants in a group of occupational asthmatics.Methods: We measured FENO and PD20 in methacholine challenge in 60 workers currently exposed to occupational agents, who were referred consecutively to a specialist occupational lung disease clinic and whose serial PEF records confirmed occupational asthma. Bronchial responsiveness (PD20 in methacholine challenge) and the degree of PEF change to occupational exposures, (measured by calculating diurnal variation and the area between curves score of the serial PEF record in Oasys), were compared between those with normal and raised FENO. Potential confounding factors such as smoking, atopy and inhaled corticosteroid use were adjusted for.Results: There was a significant correlation between FENO and bronchial hyper-responsiveness in methacholine challenge (p = 0.011), after controlling for confounders. Reactivity to methacholine was significantly lower in the normal FENO group compared to the raised FENO group (p = 0.035). The two FENO variants did not differ significantly according to the causal agent, the magnitude of the response in PEF to the asthmagen at work, or diurnal variation.Conclusions: Occupational asthma patients present as two different variants based on FENO. The group with normal FENO have less reactivity in methacholine challenge, while the PEF changes in relation to work are similar.

HSP47 in lung fibroblasts is a predictor of survival in fibrotic nonspecific interstitial pneumonia - Corrected Proof

2010-02-03

Summary: Background: The histopathologic pattern is currently the most important prognostic marker for idiopathic interstitial pneumonia (IIP). However, more highly sensitive markers are now required. Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and it has been demonstrated that HSP47 expression is significantly higher in the lung specimens of idiopathic UIP than in UIP associated with collagen vascular diseases (CVD). However, its expression in nonspecific interstitial pneumonia (NSIP), the other common pathological pattern of IIP, has not been well investigated. Therefore, the association between lung fibroblast HSP47 expression and prognosis in fibrotic NSIP was evaluated.Methods: Surgical lung biopsy specimens of 63 patients [idiopathic fibrotic NSIP=19, fibrotic NSIP associated with CVD=9, idiopathic UIP=26, and UIP associated with CVD=9] were reviewed, and a score for lung fibroblast HSP47 expression was assigned. These patients' clinical features and survival were also analyzed.Results: There was no significant difference in HSP47 expression between idiopathic fibrotic NSIP and fibrotic NSIP associated with CVD. The idiopathic fibrotic NSIP patients with higher HSP47 expression levels in their lung specimens had a poorer prognosis than patients with lower HSP47 expression levels.Conclusions: The present results suggest that lung fibroblast HSP47 expression may be a useful new prognostic marker for idiopathic fibrotic nonspecific interstitial pneumonia.

Tracheostomy in patients with long-term mechanical ventilation: A survey - Corrected Proof

2010-02-01

Summary: Background: Tracheostomy is increasingly performed in intensive care units (ICU), with many patients transferred to respiratory ICU (RICU). Indications/timing for closing tracheostomy are discussed.Aim and Method: We report results of a one-year survey evaluating: 1) clinical characteristics, types of tracheostomy, complications in patients admitted to Italian RICU in 2006; 2) clinical criteria and systems for performing decannulation, and outcome of patients undergoing tracheostomy (number decannulated; number non-decannulated/non-ventilated; number non-decannulated/ventilated; dead/lost patients).Results: 22/32 RICUs replied. There were 846 admissions of 719 patients (Mean age 64,3 (±14.2) years, 489 (68%) males). Causes of admission were: acute respiratory failure with underlying chronic co-morbidities 176 (24.4%); exacerbation of Chronic Obstructive Pulmonary Disease 222 (34.4%); neuromuscular diseases 200 (27.8%); surgical patients 77 (10.7%); thoracic dysmorphism 28 (3.8%); obstructive sleep apnea syndrome 16 (2.2%). Percutaneous tracheostomies were 65.9%. Major complications after tracheostomy were 2%. 427 tracheostomies were evaluated for decannulation: 96 (22.5%) were closed; 175 patients (41%) were discharged with home mechanical ventilation; 114 patients (26.5%) maintained the tracheostomy despite weaning from mechanical ventilation and 42 patients (10%) died or lost.The clinical criteria chosen for decannulation were: stability of respiratory conditions, effective cough, underlying diseases and ability to swallow. The systems for evaluating feasibility of decannulation were: closure of tracheostomy tube; laryngo-tracheoscopy; use of tracheal button and down-sizing.Conclusions: There were few major complications of tracheostomy. A substantial proportion of patients maintain the tracheostomy despite not requiring mechanical ventilation. There was no agreement on indications and systems for closing tracheostomy.

Association between polymorphism of glutathione S-transferase P1 and chronic obstructive pulmonary disease: A meta-analysis - Corrected Proof

Fugui Yan, Chengshui Chen, Jiyong Jing, Wen Li, Huahao Shen, Xiangdong Wang — 2010-02-01

Summary: Background: It was proposed that glutathione S-transferase P1 (GSTP1) gene involved in detoxification of electrophilic substances may be related with lung function. The present study aimed at investigating the correlation between GSTP1 105Val/Val genotype and chronic obstruct pulmonary disease (COPD) using a meta-analysis of existed studies.Methods: The Embase, Ovid, and PubMed databases were searched to identify eligible studies published before October 1, 2009. Data were extracted using standardized forms and the pooled odds ratios (ORs) with 95% confidence intervals (CI) were assessed by a model of fixed- or random effects.Results: The values of odds ratios(ORs) for COPD were 0.634 (95%CI 0.426–0.943, p = 0.025) in GSTP1 Ile/Ile, 0.625 (95%CI 0.418–0.935, p = 0.022) in GSTP1 Ile/Val, and 0.633 (95% CI 0.430–0.933, p = 0.021) in both, as compared to GSTP1 Val/Val, respectively. The individuals with GSTP1 105Ile/Ile, Ile/Val, and both have about 37% reduction in the odds of COPD, as compared to individuals with GSTP1 105Val/Val.Conclusions: The GSTP1 105Val/Val genotype is suggested to be a genetic contributor to COPD susceptibility, which should be furthermore clarified by studies with large sample sizes and careful control for age, sex, ethnicity, and cigarette smoking.

The MRC dyspnoea scale by telephone interview to monitor health status in elderly COPD patients - Corrected Proof

2010-01-29

Summary: Dyspnoea is the most common symptom associated with poor quality of life in patients affected by Chronic Obstructive Pulmonary Disease (COPD). While COPD severity is commonly staged by lung function, the Medical Research Council (MRC) dyspnoea scale has been proposed as a more clinically meaningful method of quantifying disease severity in COPD. We wished to assess whether this scale might also be useful during telephone surveys as a simple surrogate marker of perceived health status in elderly patients with COPD.We conducted a comprehensive health status assessment by telephone survey of 200 elderly patients who had a physician diagnosis of COPD. The telephone survey contained 71 items and explored such domains as educational level, financial status, living arrangements and social contacts, co-morbid illness, and the severity and the impact of COPD on health status. Patients were categorized according to the reported MRC score: mild dyspnoea (MRC scale of 1), moderate dyspnoea (MRC scale of 2 and 3), or severe dyspnoea (MRC of 4 and 5). Deterioration in most of the recorded indicators of health status correlated with an increasingly severe MRC score. This was most evident for instrumental activities of daily living (IADL), perceived health and emotional status, pain-related limitations, limitations in social life, hospital admissions in preceding year and prevalence of most co-morbidities.The MRC dyspnoea scale is a reliable index of disease severity and health status in elderly COPD patients which should prove useful for remote monitoring of COPD and for rating health status for epidemiological purposes.

Prognosis of COPD patients requiring frequent hospitalization: Role of airway infection - Corrected Proof

2010-01-27

Summary: Rationale: A subgroup of patients with chronic obstructive pulmonary disease require frequent hospitalization because of exacerbations of the disease. We hypothesized that airway infection by non-usual pathogens is a major factor driving hospitalization needs in these patients.Objectives: 1) To describe the clinical and functional characteristics of a cohort of COPD patients requiring ≥2 hospitalizations per year; 2) to determine prospectively their microbiological pattern during exacerbations; and, 3) to analyze the prognostic value of several clinical, functional and microbiological variables with respect to hospitalizations and mortality.Methods: Open cohort study of 116 COPD patients who had been hospitalized at least twice during the last 12 months. Patients were followed for an average of 21 months.Measurements and main results: Clinical data, forced spirometry and 6min walking distance were determined, and the BODE index was calculated, at the time of inclusion in the study. During follow-up, sputum culture was obtained during exacerbations, and hospitalization and mortality were collected every two months. Mean age was 71 yrs, and 94% of patients were male. Main findings show that: 1) not all patients had severe disease according to either the degree of airflow limitation or the BODE index; 2) non-usual pathogens, mainly Pseudomonas aeruginosa, other gram-negative non-fermentative rods and Enterobacteriaceae, were isolated among 71.1% of the sputum obtained during exacerbations; and, 3) these pathogens were associated with poor prognosis and frequent hospitalization.Conclusions: Airway infection by non-usual pathogens appears to be a key driver of frequent hospitalizations and mortality in COPD.

On-line monitoring of lung mechanics during spontaneous breathing: a physiological study - Corrected Proof

2010-01-25

Summary: Background: Monitoring the mechanics of breathing in patients with advanced chronic obstructive lung diseases prior to lung transplantation is useful to characterize changes in the mechanical properties of the lungs. On-line methods of monitoring immediately process the data for clinical decisions. However, the few available methods are so far limited to monitor respiratory mechanics in ventilator-dependent patients. We investigated whether on-line monitoring of the lung mechanics, including intrinsic PEEP, was feasible in spontaneously breathing patients.Methods: In 9 stable patients with chronic obstructive pulmonary disease (COPD) and 11 with cystic fibrosis (CF) undergoing the procedure for the lung transplantation waiting list, we applied 2 methods of on-line monitoring (modified recursive least squares, RLS and modified multiple linear regression methods, SLS) of intrinsic PEEP (P0), dynamic lung elastance (ELdyn) and inspiratory resistance (RLinsp), and compared them with an off-line graphical analysis (GA), our reference technique.Results: In CF patients, there was no difference between methods, while in COPD, the median values of ELdyn and RLinsp were significantly different between GA/SLS and GA/RLS, respectively (Dunn's, p<0.05). However, the correlation was very high for all comparisons, particularly for ELdyn (R>0.98) and RLinsp (R>0.93). Moreover, Bland–Altman plots showed that the mean differences were consistently low and the intervals of agreement reasonable.Conclusions: Our study suggests that on-line methods are reliable for monitoring lung mechanics in spontaneous breathing patients with severe lung diseases and could help clinicians in their decision-making process.

Thoracic ultrasound for pleural effusion: Delays and cost associated with departmental scanning - Corrected Proof

K. Bateman, D.G. Downey, T. Teare — 2010-01-25

Summary: Pleural effusion is a common clinical condition on medical wards and the majority of cases undergo pleural aspiration or chest drain insertion as a diagnostic or therapeutic procedure. The use of a thoracic ultrasound scan (USS) improves diagnostic yield for pleural fluid aspiration and reduces complications and USS is increasingly recommended prior to all pleural aspirations or drains and ‘real time’ scanning which, as well as potentially reducing delays, enhances the safety of the procedure. In many U.K hospitals a thoracic USS is still routinely performed in the radiology department. We reviewed radiology records and case notes from hospital in-patients to assess potential delays and associated costs with departmental thoracic USS and to identify cases where physician-led portable USS would potentially have improved the patient's journey.We demonstrated delays resulting in significant financial costs to the hospital of an estimated £17, 880 per annum. However, the cost to the patient is also significant, both in terms of patient experience (many of whom will have an underlying diagnosis of metastatic carcinoma and with a limited life expectancy) but also patient safety. Respiratory physicians are increasingly recognising the importance of portable thoracic USS to guide pleural procedures and there has been increasing use of physician-led portable thoracic USS. Hospitals should be encouraged to fund both portable thoracic USS equipment but it is also crucial that training in this area is properly supported.

Alveolar and bronchial exhaled nitric oxide in chronic obstructive pulmonary disease - Corrected Proof

An Lehouck, Claudia Carremans, Kristien De Bent, Marc Decramer, Wim Janssens — 2010-01-25

Summary: Background: Fractional exhaled NO (Fe,NO) has yielded inconsistent results in COPD. Measuring exhaled NO at multiple flow rates however, allows to dissect exhaled NO in an alveolar (CAlv,NO) and bronchial (J'aw,NO) fraction, which are claimed to better reflect the bronchial and alveolar inflammation in COPD. We examined whether the use of Fe,NO, CAlv,NO and J'aw,NO may contribute to the clinical diagnosis of COPD.Methods: One hundred and fifty one patients were included in this case–control design: 28 healthy nonsmokers, 39 healthy smokers, 55 COPD nonsmokers and 29 COPD smokers. Prior to spirometry, exhaled NO was measured at three different flow rates (50, 100 and 200ml/s; NIOX-FLEX) from which Fe,NO, CAlv,NO and J'aw,NO were calculated.Results: Mean Fe,NO, mean CAlv,NO and mean J'aw,NO of healthy individuals were not significantly different from COPD patients and none of these variables correlated with FEV1. In both healthy and COPD patients, current smoking significantly reduced Fe,NO, J'aw,NO and CAlv,NO. Multivariate analysis demonstrated that in contrast to gender, age, BMI, GOLD stage and the use of inhaled corticosteroids, current smoking was the only variable affecting CAlv,NO. (p=0.0115)Conclusion: We conclude that similar to single breath exhaled NO, exhaled NO at different flow rates does not contribute to the diagnosis of COPD in standard respiratory practice.

Pulmonary hypertension in lung diseases: Survey of beliefs and practice patterns - Corrected Proof

2010-01-22

Summary: Introduction: Pulmonary hypertension can be associated with decreased functional capacity and poor prognosis in patients with parenchymal lung diseases (PLD). Yet, little attention has been given to current beliefs and practice patterns.Methods: An 18-question survey was submitted electronically to members of four Networks of the American College of Chest Physicians.Results: Analyzable responses were received from 453 physicians. Most (95%) respondents reported testing for PH in patients with PLD using transthoracic echocardiography (TTE) or right-heart catheterization (RHC) and believed that PH could occur in the absence of severe compromise in pulmonary function (70%) and hypoxemia (50%). Approximately 30% of physicians reported not performing RHC to confirm a diagnosis of PH before initiating therapy. Most respondents (92%) felt that medical therapy was effective and the medication of first choice was either bosentan or sildenafil. Most respondents believed that treating PH in these patients improves quality of life (63%) and dyspnea (67%), but were less sure about the impact on functional capacity and survival.Conclusions: Approximately 30% of physicians do not perform RHC to confirm this diagnosis prior to initiating therapy. Despite relatively little supportive evidence, most physicians treat with vasoactive medications and believe that medical therapy confers benefit.

Pharmacotherapy for pulmonary sarcoidosis: A delphi consensus study - Corrected Proof

Amanda C. Schutt, Wendy M. Bullington, Marc A. Judson — 2010-01-20

Summary: Background: Most issues concerning pharmacotherapy of pulmonary sarcoidosis have not been resolved in clinical trials. The objective was to survey sarcoidosis experts concerning the treatment of pulmonary sarcoidosis and attempt to reach a consensus by these experts using a Delphi method.Methods: A 6-item questionnaire was developed. Experts were identified at the Diffuse Lung Disease Network at the annual CHEST meeting in October 2008. Three rounds of questionnaires were presented to the experts. Respondent feedback and supporting literature was incorporated into the questionnaires of subsequent rounds.Results: Experts reached a consensus concerning the following issues: (a) corticosteroids are the initial therapy of choice; (b) initial use of inhaled corticosteroids are not recommended; (c) methotrexate was the preferred second-line drug; (d) 40mg of daily prednisone equivalent was the maximum dose recommended for the treatment of acute pulmonary sarcoidosis; (e) tapering to 10mg of daily prednisone equivalent for chronic pulmonary sarcoidosis was considered a successful taper. The experts could not resolve the following issues: (a) the initial corticosteroid dose for the treatment of acute pulmonary sarcoidosis; (b) the decision and timing of corticosteroid therapy in a patient with mild, Stage 2 pulmonary sarcoidosis.Conclusions: This Delphi study revealed that sarcoidosis experts reached a consensus concerning several aspects of the treatment of pulmonary sarcoidosis; these could be considered as appropriate approaches to therapy. Other issues concerning the therapy of pulmonary sarcoidosis remain unresolved by experts, and are areas where further clinical research could be directed.

Poor lung function and tonsillectomy in childhood are associated with mortality from age 18 to 44 - Corrected Proof

2010-01-15

Summary: Background: The aim of this analysis was to examine associations between lung health in childhood and mortality between ages 18 and 44 years in the Tasmanian Longitudinal Health Study (TAHS).Methods: The 1961 Tasmanian birth cohort who attended school in 1968 (n=8583) were linked to the Australian National Death Index (NDI) to identify deaths. Additional deaths were notified by families through a 37 year follow-up postal questionnaire. Information on lung health at age 7 years and on potential confounders was obtained from the original 1968 TAHS survey and school medical records. Cox proportional hazards modelling was used to assess determinants of mortality.Results: A total of 264 (3%) deaths were identified. The principal causes of death were external injury (56.1%, n=97) and cancer (17.9%, n=31). Males were more likely than females to have died (p=<0.1). Only two (1.1%) participants had died from respiratory conditions. Having an FEV1<80% predicted at 7 years of age was associated with a 2-fold increased incidence of death. Tonsillectomy before age 7 years was associated with a 1.5-fold increase in mortality (p=0.05); being male with a 3.6-fold increase in mortality (p=0.0001); and repeated chest illnesses at age 7 years causing >30 days confinement in the last year, was associated with a 2.2-fold increase in mortality (p=0.03).Conclusions: Childhood lung health appears to be associated with increased mortality in adulthood, perhaps by affecting the ability to survive trauma, major illnesses and other physical stresses.

A single dose of Sildenafil does not enhance FeNO: A randomised, cross-over and placebo-controlled study - Corrected Proof

Thomas Rothe, Werner Karrer, Christian Schindler — 2010-01-15

Summary: Monitoring of asthma control can be performed with different means including measurement of the concentration of nitric oxide (NO) in exhaled air. Due to its action on the NO-metabolism; we hypothesized that the intake of Sildenafil might augment and falsify the NO-values in exhaled air of subjects taking the drug to treat erectile dysfunction.This randomised, placebo-controlled cross-over study including 10 male non-asthmatic volunteers taking a single dose of 50 mg Sildenafil did not confirm this assumption in non-asthmatic subjects. We cannot think of any reason why asthmatics should behave differently.On the basis of these results, it does not seem necessary to ask asthma patients with elevated NO-values if they had taken any selective inhibitor of the cGMP-specific phosphodiesterase Type 5 as Sildenafil prior to the test.

Elevated 1, 25-dihydroxyvitamin D levels are associated with protracted treatment in sarcoidosis - Corrected Proof

Dashant Kavathia, John D. Buckley, Dhanwada Rao, Benjamin Rybicki, Robert Burke — 2010-01-13

Summary: Background: Active vitamin D metabolite, 1, 25-dihydroxyvitamin D, has pleomorphic effects on both innate and acquired immunity. Sarcoid granuloma derived 1, 25-dihydroxyvitamin D leads to hypercalcemia, but the association of 1, 25-dihydroxyvitamin D with the clinical phenotype of the disease is currently unknown.Objective: To determine the relationship between serum 1, 25-dihydroxyvitamin D levels and the degree of sarcoidosis disease chronicity.Design: Serum 1, 25-dihydroxyvitamin D levels were measured and associated with sarcoidosis activity and phenotypes as assessed by Sarcoidosis Severity Score and Sarcoidosis Clinical Activity Classification respectively.Results: Fifty nine patients were recruited with 44% having a sub-acute onset, and the chronic disease phenotype. There was no significant difference in serum 1, 25-dihydroxyvitamin D levels by chest radiograph stage (p = 0.092) nor did the levels correlate with the Sarcoidosis Severity Score (r = −0.16; p = 0.216). Serum 1, 25-dihydroxyvitamin D levels were associated with patients requiring repeated regimens of systemic immunosuppressive therapy or >1 year of therapy (SCAC Class 6). Increasing quartiles of serum 1, 25-dihydroxyvitamin D level was associated increased odds of the chronic phenotype (OR 1.82, 95% CI, 1.11, 2.99, p = 0.019). The majority (71%) of the patients with levels >51 pg/mL required chronic immunosuppressive therapy as defined by SCAC class 6.Conclusions: In patients with sarcoidosis, elevated 1, 25-dihydroxyvitamin D levels are associated with chronic treatment needs.

Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients - Corrected Proof

2010-01-11

Summary: The rapid increase in the elderly population is leading to a corresponding increase in the number of people requiring medical care. To date no comparative study between community-acquired pneumonia (CAP) and nursing home-acquired pneumonia (NHAP) has been reported in the very elderly non-intubated patients. The present study was undertaken to compare the clinical characteristics and microbial etiology between CAP and NHAP in elderly patients ≥85-years old. There were 54 patients with NHAP and 47 with CAP. Performance status was significantly worse in the NHAP than in the CAP group. Among all patients, the most frequent pathogens were Chlamydophilia pneumoniae followed by Streptococcus pneumoniae, Mycoplasma pneumoniae influenza virus and Staphylococcus aureus. The frequency of S. peumoniae was significantly higher in NHAP patients than in CAP patients after adjusting for age and sex. Physical activity, nutrition status and dehydration were significant prognostic factors of pneumonia among all patients. In-hospital mortality was significantly higher in NHAP than in CAP after adjusting for age and sex. This study demonstrated that the etiology and clinical outcome differ between CAP and NHAP patients in the very elderly non-intubated population.

Development and validation of the Asthma Life Impact Scale (ALIS) - Corrected Proof

2010-01-07

Summary: Background: Current asthma patient-reported outcome (PRO) measures focus on symptoms and functioning and may not capture the holistic impact of asthma on the quality of life of the patient.Objective: To develop a PRO measure capturing the overall impact of asthma on patient's quality of life.Methods: Items for the Asthma Life Impact Scale (ALIS) were generated from patients with asthma during interviews in the UK and focus groups in the US. The ALIS was tested with UK and US asthma patients during cognitive debriefing interviews and included in large, two-administration, validation studies in the UK and US.Results: Issues raised by asthma patients during interviews (n = 39 patients) and focus groups (n = 16 patients) were included in the draft ALIS. Cognitive debriefing interviews with 29 UK and US asthma patients showed that the scale was relevant and comprehensive. 140 UK and 185 US asthma patients participated in the validation study. The analysis showed that the ALIS measures a single construct, namely the overall impact of asthma on patients' quality of life. Internal consistency (Cronbach's Alpha) was high (UK = 0.94; US = 0.92) as was test-retest reliability (UK = 0.93; US = 0.83). Patients reporting worse general health or more severe asthma had significantly higher ALIS scores (p < 0.001) (indicating greater negative impact of asthma). Correlations with the Asthma Quality of Life Questionnaire were moderate to high.Conclusions: The final 22-item ALIS is unidimensional, reliable and valid, and a valuable tool for comprehensively assessing the holistic impact of asthma from the patient's perspective.

Correlation between airflow limitation and airway dimensions assessed by multidetector CT in asthma - Corrected Proof

2010-01-06

Summary: Background: Asthma is characterized by variable airflow obstruction and airway wall thickening. Multidetector-row computed tomography (MDCT) is useful for the evaluation of airway wall structural changes in asthma. The objective of the study is to assess the relationship between airflow limitation and airway dimensions from the third to fifth generation bronchi in asthma using MDCT.Methods: Thirty-eight subjects with asthma underwent MDCT to measure the airway wall area (WA) and luminal area (Ai), WA and Ai corrected by body surface area (BSA), up to the fifth generation of the apical bronchus (B1) and the posterior basal bronchus (B10) of the right lung.Results: WA/BSA, WA percentage (WA%) and Ai/BSA in the fifth generation were significantly correlated with forced expiratory volume in 1 s (FEV1)% predicted. The correlation coefficients between WA% and FEV1% predicted increased when tracking the airways from the third to the fifth generation (r=−0.25, p>0.05; r=−0.40, p<0.01; r=−0.63, p<0.001 for B1; r=−0.23, p>0.05; r=−0.47, p<0.01; r=−0.69, p<0.001 for B10). At the generation 5, WA% was greater and Ai/BSA was smaller in severe asthma than mild-to-moderate asthma.Conclusion: These results suggest that airway flow limitation in asthma is closely related to the more distal airways (third to fifth generation).

Spirometry guidelines influence lung function results in a longitudinal study of young adults - Corrected Proof

2010-01-04

Summary: Rationale: End of test criteria can influence spirometry results. Epidemiology studies initiated before adoption of the 1987 American Thoracic Society (ATS) guidelines typically used a 1 or 2 s plateau on the volume-time curve, not a minimum test duration of 6 s, to terminate a test.Objectives: To determine the effect of changing guidelines on FEV1, FVC and FEV1/FVC during a longitudinal study of young adults.Methods: Spirometry was performed on participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Values obtained at entry and 2, 5 and 10 years later using accepted procedures were re-evaluated using the 2005 ATS–ERS guidelines, which were in effect for the year 20 exam. Generalized estimating equations were used to adjust tests with short exhalations that were acceptable by then current end of test criteria.Results: The percentage of participants at years 0, 2, 5, and 10 with exhalations less than 6 s but with an acceptable plateau was 33%, 29%, 9%, and 2%, respectively. Exhalations less than 6 s occurred more frequently in younger and female participants, and were associated with lower FVC and higher FEV1/FVC. For short exhalations the adjusted FVC was 47 ml and 110 ml higher than the measured FVC when 6 and 8 s exhalation times were used.Conclusions: In longitudinal studies of young adults, changing end of test criteria may affect lung function, especially among younger and female participants. Determining adjusted values for tests with short exhalations may better represent the lung health of participants.

Bronchodilatory effects of aclidinium bromide, a long-acting muscarinic antagonist, in COPD patients - Corrected Proof

2009-12-31

Abstract: Background: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist bronchodilator currently in Phase III clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacodynamics, pharmacokinetics, safety and tolerability of ascending doses of aclidinium bromide in patients with COPD.Methods: This double-blind, randomised, placebo-controlled, crossover study was conducted in patients with moderate to severe COPD (forced expiratory volume in 1s [FEV1] <65% predicted). Patients were randomly assigned to one of four treatment sequences of aclidinium bromide 100, 300, 900μg and placebo with a washout period between doses. The primary outcome was area under the FEV1 curve over the 0–24h time interval.Results: Seventeen patients with COPD were studied. Mean FEV1 over 24h was 1.583L for placebo, and 1.727L, 1.793L and 1.815L for aclidinium bromide 100, 300 and 900μg, respectively (p<0.001 vs. placebo, all doses). Significant changes from baseline in FEV1 were detected 15min post-dose for aclidinium bromide 300 and 900μg, with a peak effect 2h post-dose (all doses). Aclidinium bromide was undetected in plasma. The majority of adverse events was unrelated to study medication and did not result in discontinuation.Conclusion: Aclidinium bromide 100–900μg produced sustained bronchodilation over 24h in patients with COPD.

Non-response in epidemiological studies – How to cope with it? - Corrected Proof

Per S. Bakke — 2009-12-28

This issue of Respiratory Medicine contains one paper that addresses non-response in community studies of respiratory disorders, a second paper on this subject was published in a recent issue. As the authors of both papers point out the response rates in epidemiological studies have been on the decline at least for the last three decades. This is seen regardless of disorder examined, geographical area or age of the study population. Does this imply that we are heading towards a scenario where epidemiological studies are no longer regarded as a valid research tool?

Comparison of eNO and histamine hyperresponsiveness in diagnosing asthma in new referrals - Corrected Proof

P. Munnik, I. van der Lee, J. Fijn, L.J. van Eijsden, J-W.J. Lammers, P. Zanen — 2009-12-28

Summary: The mainstay of the diagnosis of asthma is the presence of reversible airway obstruction. Exhaled NO levels are increased in asthma, in close relationship with the amount of airway inflammation, and may be used for monitoring the disease and adjusting therapy. In this study we investigated the role of eNO as a diagnostic for asthma, compared with the FEV1-reversibility and the PC20 (20% decrease of the FEV1 in the bronchial histamine provocation test), in two independent centers, on an unselected population. ENO measurements were performed with chemoluminesence technique in one center and with an electrochemical device in the other. Only after correction for so-called nuisance factors (allergy, use of inhaled steroids, recent infection, smoking, sex and the use of nitrate food) the eNO appeared as a diagnostic with equal power as the FEV1-reversibility and the PC20.Therefore, screening for asthma in our study population, with the eNO measurement, is a simple, fast and safe strategy.

Gender influences health-related Quality of Life in IPF - Corrected Proof

2009-12-25

Summary: Background: HRQL in IPF patients is impaired. Data from other respiratory diseases led us to hypothesize that significant gender differences in HRQL in IPF also exist.Methods: Data were drawn from the NIH-sponsored Lung Tissue Research Consortium (LTRC). Demographic and pulmonary physiology data along with MMRC, SF-12, and SGRQ scores from women vs. men were compared with two-sample t-tests. Multivariate linear regression was used to examine the association between SF-12 component scores and gender while adjusting for other relevant variables.Results: The study sample consisted of 147 men and 74 women. Among several baseline variables, only DLCO% predicted differed between women and men, (43.7 vs. 38.0, p=0.03). In general, men exhibited lower (better) MMRC scores (1.7 vs. 2.4, p=0.02), particularly those with milder disease as measured by DLCO% predicted. In an adjusted analysis, SF-12 PCS scores in men were lower (worse) than women (p=0.01), an effect that was more pronounced in men with greater dyspnea scores. In a similar analysis, SF-12 MCS scores in women were lower than men (worse) (48.3 vs. 54.4, p=0.0004), an effect that was more pronounced in women with greater dyspnea scores.Conclusions: Significant gender differences in HRQL exist in IPF. As compared to women, men reported less severe dyspnea, had worse SF-12 PCS scores, but better SF-12 MCS scores. Dyspnea appears to have a greater impact on the physical HRQL of men and the emotional HRQL of women. An improved understanding of the mechanism behind these differences is needed to better target interventions.

Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: The MONtelukast In Chronic Asthma (MONICA) study - Corrected Proof

2009-12-23

Summary: Bronchial asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) or both, necessitating additional treatment. Patients ≥18years (n=1681) with mild-to-moderate asthma received oral montelukast 10mg added to ICS or ICS+LABAs, and were followed for 6months in a prospective, open-label observational study. The primary endpoint was change in Asthma Control Test (ACT) score. Secondary endpoints included mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) and FEV1/PEF. Mean ACT scores improved from 14.6±4.6 (baseline) to 19.4±4.4 (month 6; p<0.0001). Using ACT score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 (17.6 and 21.7%, respectively); the percentage of patients with well controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 (47.5 and 11.4%, respectively). The mini-AQLQ score (mean±SD) improved from 4.0±1.1 to 5.3±1.1 (p<0.0001); FEV1 increased from 2.46±0.89 to 2.60±0.92L (p<0.0001). Treatment with montelukast was generally well tolerated. In patients insufficiently controlled with ICS or ICS+LABAs, daily add-on montelukast improved both asthma control and asthma-related quality of life. Clinicaltrials.gov registry number NCT00802789.

Association of the CCR3 gene polymorphism with aspirin exacerbated respiratory disease - Corrected Proof

2009-12-21

Summary: Introduction: Aspirin hypersensitivity represents two distinct clinical syndromes, such as aspirin exacerbated respiratory disease (AERD) and aspirin-intolerant chronic urticaria/angioedema (AICU) which have different clinical phenotypes resulting from different genetic backgrounds in a Korean population. Persistent eosinophilic inflammation in airway is a characteristic feature of AERD and chemokine CC motif receptor 3 (CCR3) plays an important role in eosinophilic infiltration into the asthmatic airway.Objectives: The main objective of this study is to investigate the association between CCR3 gene polymorphisms and aspirin hypersensitivity, including AERD and AICU.Methods: CCR3 mRNA expression was measured after an aspirin provocation test by real-time PCR. In total, 330 patients with aspirin hypersensitivity (191 AERD and 139 AICU) and 217 normal healthy controls (NC) were genotyped for two CCR3 promoter polymorphisms (-520T/G and -174C/T), and the functional effects of the polymorphisms were analyzed applying a luciferase reporter assay and an electrophoretic mobility shift assay.Results: CCR3 mRNA expression was significantly increased after aspirin provocation in AERD patients (P=0.002) but not in AICU patients. An in vitro functional study showed that the reporter construct having a -520G allele exhibited significantly higher promoter activity compared with the construct having a -520T allele in human myeloid (U937), lymphoid (Jurkat), and mast (HMC-1) cell lines (P<0.001). We found -520G and -174T specific bands on EMSA.Conclusion: This result suggests that the CCR3 genetic polymorphisms may contribute to the development of the AERD phenotype and may be used as a genetic marker for differentiating between the two major aspirin hypersensitivity phenotypes.

Chest low-dose computed tomography in neutropenic acute myeloid leukaemia patients - Corrected Proof

2009-12-17

Summary: Background: We aimed to compare chest low-dose computed tomography (LDCT) with chest radiography (CXR) in the assessment of febrile acute myeloid leukaemia neutropenic patients.Methods: A prospective non-randomized study was carried out between 30 May, 2003 and 3 June, 2004 in consecutive neutropenic patients who required imaging of the thorax and were treated for acute myeloid leukaemia. Each patient had a baseline 2-view chest radiograph followed by LDCT. Both the CXR and the LDCT studies were blindly and independently reviewed by two chest radiologists.Results: Forty patients were enrolled: 24 male and 16 female, mean age 53.5years (range 18–83) and an average neutrophil count of 0.78×109/L. Patients had CXR within a mean of 40min from the LDCT. Overall, 31 (77.5%) of 40 CXR were abnormal, whereas LDCT detected abnormalities in 38 (95%) of 40 patients. LDCT demonstrated three times the number of lung nodules as CXR and twice as many ground-glass opacities. Lung consolidation was detected similarly using both techniques, but LDCT demonstrated more extensive and multi-focal consolidation. The majority of nodules detected only on LDCT were subcentimetre in diameter. The additional information provided by LDCT led to an alteration in the clinical management of 11 (27.5%) of 40 patients.Conclusion: LDCT is a useful tool in the initial investigation of suspected pulmonary complication in neutropenic patients. This is supported by the additional information it provides to the CXR with reduced radiation when compared to conventional CT.

Co-existence of COPD and left ventricular dysfunction in vascular surgery patients - Corrected Proof

2009-12-14

Summary: Background: The co-existence between chronic obstructive pulmonary disease (COPD) and heart failure has been previously described. However, the co-existence between COPD and subclinical left ventricular (LV) dysfunction, without the presence of heart failure symptoms, is less well understood. This study determined the relationship and clinical relevance of COPD and subclinical LV dysfunction in vascular surgery patients.Methods: 1005 consecutive vascular surgery patients were included in which COPD was determined using spirometry and LV function using echocardiography. Mild COPD was defined as FEV1≥80% of predicted+FEV1/FVC-ratio<0.70. Moderate/severe COPD was defined as FEV1<80% of predicted+FEV1/FVC-ratio<0.70. Systolic LV dysfunction was defined as LV ejection fraction <50% and diastolic LV dysfunction was diagnosed based on E/A-ratio, pulmonary vein flow and deceleration time. Multivariate regression analyses were used to evaluate the impact of COPD and LV dysfunction on all-cause mortality. The mean follow-up time was 2.2±1.8 years.Results: Both, mild and moderate/severe COPD were associated with increased risk for subclinical LV dysfunction with odds ratio of 1.6 (95%-CI=1.1–2.3) and 1.7 (95%-CI=1.2–2.4), respectively. mild- or moderate/severe COPD in combination with LV dysfunction was associated with increased risk for all-cause mortality (mild: hazard ratio 1.7; 95%-CI=1.1–3.6, moderate/severe: hazard ratio 2.5; 95%-CI=1.5–4.7).Conclusions: COPD was associated with increased risk for subclinical LV dysfunction. COPD+subclinical LV dysfunction was associated with increased risk for all-cause mortality compared to patients with COPD+normal LV function. Echocardiography may be useful to detect subclinical cardiovascular disease and risk-stratify COPD patients undergoing vascular surgery.

Chronic cough in upper airway diseases - Corrected Proof

J.B. Watelet, T. Van Zele, G. Brusselle — 2009-12-14

Summary: Background: The epidemiological, pathophysiological and clinical links between upper and lower airways are nowadays clearly demonstrated. Most of asthmatics are suffering from rhinitis while up to 40% of rhinitic patients have asthma. Asthmatics and COPD patients are also prone to develop concomitant chronic rhinosinusitis (CRS).This study aimed to determine the predictive value of cough for concomitant asthma in patients suffering from upper airway diseases.Methods: This cross-sectional study described a group of 143 consecutive patients suffering simultaneously from common upper and lower airway disorders. Both ENT-specialists and respiratory physicians consecutively examined the patients in Ghent University Hospital from October 2004 till October 2006. This study was based on the demographic characteristics, upper and lower airway conditions.Results: Forty-seven percent of the patients included in the study were males and the mean age of studied population was 43.6years. The major complaint was chronic cough. When present, patients with chronic cough have an increased risk of suffering from a concomitant asthma in both allergic rhinitis (OR=5.8) and CRS with nasal polyps (OR=10.4), but not in CRS without polyps.Conclusions: Chronic cough was found to be a key symptom of associated asthma in allergic rhinitis and CRS with nasal polyps. Interestingly, chronic cough in CRS without nasal polyps did not show the same predictive value: this suggests different pathophysiological mechanisms.

Plasma ammonia response to incremental cycling and walking tests in COPD - Corrected Proof

L.D. Calvert, M.C. Steiner, M.D. Morgan, S.J. Singh — 2009-12-09

Summary: Objective: It is well documented that plasma ammonia accumulates during exercise under conditions of metabolic stress. Metabolic stress (when skeletal muscle ATP supply fails to meet demand) occurs at low work rates during cycling in patients with COPD, but not been described during walking. Walking is an important activity for many patients with COPD and is commonly prescribed in pragmatic outpatient pulmonary rehabilitation programmes. In this study we explored whether metabolic stress occurs during incremental walking at the low work rates these patients achieve.Methods: Twenty-nine subjects with stable COPD [mean(SD) age 68(7)years, FEV1 50(19)% predicted] performed maximal cardiopulmonary exercise tests on a cycle ergometer and treadmill. Plasma ammonia concentration was measured at rest, 1 and 2min of exercise, peak exercise and 2min recovery.Results: Subjects achieved mean(SD) cycle work rate of 57(20)W with VO2max 15.5(4.6)ml/min per kg, and treadmill distance 284(175)m with VO2peak 16.8(4.2)ml/min per kg. Plasma ammonia concentration rose significantly (p<0.001) with walking [mean(SEM) change 24.7(3.8)μmol/l] and cycling [mean(SEM) change 35.2(4.3)μmol/l], but peak exercise ammonia was lower in walking (p<0.01). In a subgroup of subjects (n=7) plasma ammonia did not rise during either cycling or walking despite similar lactate rise and peak exercise indices.Conclusion: Our data indicate that failure of muscle ATP re-synthesis to meet demand and development of metabolic stress can occur during walking in COPD patients at the low work rates these patients achieve. This may therefore be a factor contributing to exercise limitation independent of ventilatory limitation.

Emitted dose and lung deposition of inhaled terbutaline from Turbuhaler at different conditions - Corrected Proof

Mohamed E. Abdelrahim — 2009-12-09

Summary: Turbuhaler has a very high resistance hence patient inhalation flow when using it would be low.The total emitted dose (TED) of 500μg terbutaline sulphate from a Bricanyl Turbuhaler was determined using a range of inhalation flows (10–60L min−1) with inhalation volume of 2 and 4L using a DPI sampling apparatus after one and two inhalations.The relative lung and systemic bioavailability of terbutaline from Bricanyl Turbuhaler when used by healthy subjects and COPD patients were determined after one and two inhalations at slow and fast inhalation flows using a novel urinary terbutaline pharmacokinetic method.The TED resulted from the one and two inhalations increased significantly (p<0.05) with the increase of the inhalation flow at both 2 and 4L inhalation volumes. The relative lung and systemic bioavailability after one inhalation at fast inhalation flow were significantly higher (p<0.01) than at slow inhalation flow in both healthy subjects and patients. Also the healthy subjects results were significantly higher (p<0.05) than the COPD patients after one inhalation.However after two inhalations there was no significant difference between slow and fast inhalation flow or healthy subjects and COPD patients.Hence it is essential to inhale twice and as deep and hard as possible from each dose of Turbuhaler for patients with low inspiratory flow and limited inhalation volume as they may not receive much benefit from one inhalation.

Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension - Corrected Proof

Adriano R. Tonelli, Hassan Alnuaimat, Kamal Mubarak — 2009-12-09

Summary: Pulmonary arterial hypertension (PAH) encompasses a number of diseases responsible for a specific set of hemodynamic findings during right heart catheterization. During initial workup, pulmonary vasodilator testing is performed. A positive acute pulmonary vasodilator test predicts better survival and response to calcium channel blocker (CCB) therapy.There is lack of consensus on the preferred agent for determining acute pulmonary vasoreactivity. The ACCP guidelines and the 4th World Symposium on Pulmonary Hypertension support the use of intravenous epoprostenol or nitric oxide (NO) as the preferred agents for pulmonary vasodilator testing.A decrease in the mean pulmonary artery pressure by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output is currently considered a positive pulmonary vasodilator test. A positive test by the current recommended criteria is observed in about 10-15% of patients with idiopathic PAH. Approximately half of these patients will experience long-term benefits with CCBs. A positive test may select patients with an earlier or less aggressive form of disease, which may carry a better prognosis. A positive vasodilator test is observed very infrequently in patients with pulmonary arterial hypertension other than idiopathic PAH or anorexigen associated PAH.This article reviews the literature regarding pulmonary vasodilator testing and use of CCB therapy in patients with PAH, while identifying the gaps in knowledge concerning this diagnostic procedure.

COPD health care in Sweden – A study in primary and secondary care - Corrected Proof

2009-12-07

Summary: Objectives: To map out-patients with Chronic Obstructive Pulmonary Disease (COPD) with special reference to patients suffering from acute exacerbations, and to describe COPD health care structure and process in Swedish clinical practice in a real life setting.Design: Retrospective, non-interventional, epidemiological survey.Setting: 141 hospital based out patient clinics (OPC, n=30) and primary health care clinics (PC, n=111) were included in the structure evaluation.Subjects: 1004 COPD diagnosed patients from 100 of the centres (OPC, n=26) participated in the process evaluation.Methods: All Swedish OPC (n=40) and a random sample of 180 PC were asked to answer a questionnaire regarding COPD care. In addition, data from 10 randomly selected patients with a documented COPD disease were analysed from the centres.Results: Spirometers were available at all OPCs and at 99% of the PCs. Spirometry had been performed in 52% of PC-patients and in 89% of OPC-patients during the last 2 years prior to the study. More severe patients, as judged by investigator and lung function data, were treated at OPCs than at PCs. Physiotherapists, occupational therapists and dieticians were available at >80% of centres. Exacerbation rate was higher at PCs without a specialized nurse, 2.2/year versus 0.9/year at centres with a specialized nurse.Conclusions: Special attention to COPD, marked by a specialised nurse in primary care improves the quality, as assessed by a lower number of exacerbations. The structure of COPD care in Sweden for diagnosed individuals seems satisfactory, but could be improved mainly through higher availability and educational activities.

Predictors for clinical trial participation in the rare lung disease lymphangioleiomyomatosis - Corrected Proof

2009-12-07

Summary: Background: Lymphangioleiomyomatosis (LAM) is a rare, progressive and frequently lethal cystic lung disease that almost exclusively affects women and has no proven therapies. An improved understanding of the pathogenesis has identified promising molecular targets for clinical trials. Although barriers, modifiers, and benefits for clinical trial participation in common diseases such as cancer have been studied, we are unaware of such evaluations concerning rare diseases.Methods: We performed a survey of a population-based registry of 780 LAM subjects in North America to identify predictors of trial participation. Logistic regression analysis evaluated the association of demographic and clinical features with trial participation.Results: 41 of 263 (16%) LAM patient respondents in North America had participated in a clinical trial. Age, disease duration, lack of any college education, use of oxygen therapy, and presentation without chest pain were associated with trial participation in unadjusted analyses. Multivariate analyses indicate that patient age was the strongest independent predictor for trial participation (OR=2.07, p=0.004 per decade greater of patient age). Common reasons reported against trial participation included not meeting enrollment criteria (44%), drug toxicity (25%), and stable disease (20%). The most frequent reason reported for trial participation was to help future patients (85%).Conclusions: Study entry criteria, drug toxicity, and stability of disease are barriers to trial enrollment among subjects with LAM. Older LAM patients and those with more advanced disease are more likely to have participated in clinical trials. Altruism is commonly a motivating factor.

Vocal cord dysfunction: Beyond severe asthma - Corrected Proof

2009-12-07

Summary: Background: Vocal cord dysfunction (VCD) is the abnormal adduction of the vocal cords during inspiration causing extrathoracic airway obstruction. VCD has been described as a confounder of severe asthma. The influence of VCD among less severe asthmatics has not been previously defined.Methods: We retrospectively reviewed the medical records of 59 patients with pulmonologist-diagnosed asthma who were referred for videolaryngostroboscopy (VLS) testing from 2006 to 2007.Results: A total of 44 patients had both asthma and VCD. 15 patients had asthma without concomitant VCD. Females were predominant in both groups. Overall, the majority of patients referred for VLS testing had mild-to-moderate asthma (78%) and 72% of these patients had VCD. Few patients from either group had “classic” VCD symptoms of stridor or hoarseness. Gastroesophageal reflux disease (GERD) and rhinitis were common in both groups.Conclusions: Vocal cord dysfunction occurs across the spectrum of asthma severity. There was a lack of previously described “classic” VCD symptoms among asthmatics. Symptoms were diverse and not easily distinguished from common symptoms of asthma, highlighting the need for a high index of suspicion for VCD in patients with asthma. Failure to consider and diagnose VCD may result in misleading assumptions about asthma control, and result in unnecessary adjustments of asthma medications. The high prevalence of GERD raises the question of the role of acid reflux in the pathogenesis of VCD in asthmatics.

Adenosine for vasoreactivity testing in pulmonary hypertension: A head-to-head comparison with inhaled nitric oxide - Corrected Proof

Edmundo C. Oliveira, Antonio Luiz P. Ribeiro, Carlos Faria Santos Amaral — 2009-12-04

Summary: Background: APVT is an invasive method recommended for symptomatic patients with PAH that permits the identification of the minority of patients (<20%) that may benefit from long-term calcium channel blockers. Adenosine has been indicated in guidelines as a vasodilator agent of choice for APVT, although it has not been directly compared with iNO, the gold standard for this test. The objective of the study was to compare adenosine with inhaled nitric oxide (iNO) for acute pulmonary vasoreactivity testing (APVT) in pulmonary arterial hypertension (PAH), in order to determine the efficacy and safety of the first in the clinical setting.Methods: The measurements of cardiac output, pulmonary and systemic resistance were done in the basal state and with a stepwise increase of the dose of each drug until either maximum dosage (adenosine: 500 μg/kg/min or iNO: 80 ppm) or side effects observed or a positive response were reached, according to current guidelines. The order of drugs used in each test was consecutively alternated during the study.Results: Six of the 39 studied patients (15%) presented a positive response to iNO; none to adenosine (p = 0.047, McNemar's test). Twenty-three patients (59%) did not reach the maximum dose of adenosine due to side effects, including bronchospasm, thoracic pain and bradycardia.Conclusions: APVT testing with adenosine was not able to detect PAH patients responsive to iNo and provoked frequent adverse effects. Adenosine should not be used as a vasodilator drug in APVT.

Economic implications of comorbid conditions among Medicaid beneficiaries with COPD - Corrected Proof

Pei-Jung Lin, Fadia T. Shaya, Steven M. Scharf — 2009-12-03

Summary: Objectives: To characterize a comprehensive comorbidity profile and to explore the economic implications of comorbidity among patients with chronic obstructive pulmonary disease (COPD).Methods: This retrospective cohort study analyzed medical claims from the Maryland Medicaid database. We employed a 1:2 case–control design to select COPD patients (n=1388) and demographically matched controls (n=2776) aged 40 to 64 years with 24 months of continuous enrollment. Odds ratios were employed to compare comorbidity differences, including 17 conditions defined by the Charlson Comorbidity Index (CCI) and 6 additional conditions commonly observed in COPD patients. We estimated the incremental medical utilization and medical cost by specific condition.Results: Compared with the controls, Medicaid COPD patients had higher comorbidity burden and were more likely to have myocardial infarction, congestive heart failure, cerebrovascular disease, peptic ulcer, mild liver disease, hypertension, sleep apnea, tobacco use, and edema. COPD patients on average had 24% more medical claims (81.4 vs. 65.4, p<0.001) and were 33% more expensive than controls ($7603 vs. $5732, p<0.001). Ten conditions defined by the CCI as well as hypertension, tobacco use, and edema were associated with incremental medical utilization and cost in COPD patients; depression was associated with incremental medical utilization but not cost.Conclusions: The high burden of comorbidity in COPD patients translates into additional medical utilization and cost. Effective disease management and treatment protocols are needed to reduce comorbidity burden. The development of a COPD-specific comorbidity measure may be used to identify high-risk subgroups and to predict utilization and cost.

Usefulness and safety of double endoscopy in children with gastroesophageal reflux and respiratory symptoms - Corrected Proof

2009-12-02

Summary: Background: Management of children with gastroesophageal reflux disease (GORD) and difficult-to-treat (D-T-T) respiratory symptoms may include double fiberoptic, airway and oesophago-gastro-duodenoscopies (DE). A study was performed to evaluate the usefulness and safety of DE in children with severe GORD and D-T-T respiratory symptoms.Methods: A 3-year retrospective review of records of children who underwent DE under general anaesthesia was performed: the relevant clinical information obtained and the occurrence of complications in the 72h following the DE.Results: Inflammatory changes of the airways were found at bronchoscopy in 40 out of the 60 children: bronchoalveolar lavage (BAL) demonstrated positive lipid-laden alveolar macrophages (LLAM), neutrophilic inflammation or both, respectively in 9, 12 and 16 patients. BAL bacterial cultures were positive in 2 patients with elevated airway neutrophilia. Structural airway abnormalities, explaining not GOR-related D-T-T respiratory symptoms were identified in 11 patients. Oesophagoscopic findings supporting GORD were detected in 32/60 children and confirmed by consistent histological changes in oesophageal mucosal biopsies (OEB) in 27.The frequency of complications, all minor, was low during the procedure and in the following 72h. They included mild desaturation, stridor or bronchospasm, vomiting, dysphagia and hyperthermia requiring antibiotic treatment in 1 patient. No “new onset” complication was observed after 48h following DE. The time-dependent hazard of complications was significantly higher for patients with a history of onset of respiratory symptoms early in life (≤2 years of age) (p=0.038).Conclusion: DE can be useful in the clinical evaluation of children with D-T-T respiratory symptoms and GORD and is associated with low frequency of mild complications when performed by appropriately trained and experienced personnel.

Deficiency of pulmonary Vα24 Vβ11 natural killer T cells in corticosteroid-naïve sarcoidosis patients - Corrected Proof

2009-12-02

Summary: Invariant natural killer T (NKT) cells might contribute to the amplified and prolonged T-cell immune response that characterizes sarcoidosis. Therefore, we want to investigate the frequency and distribution of pulmonary invariant NKT cells in corticosteroid-naïve patients with sarcoidosis. We used multi-parameter flow cytometry with antibodies against CD3, CD4, CD8, CD14, CD19, CD45, CD16/56, TCR Vα24, and TCR Vβ11, on bronchoalveolar lavage fluid (BALF), to examine the frequency and distribution of pulmonary invariant NKT cells in 47 newly diagnosed sarcoidosis patients and in 8 control subjects. The frequencies of BALF Vα24 Vβ11 invariant NKT cells were significantly lower in patients with sarcoidosis in comparison to control subjects. Moreover, lower invariant NKT cell frequencies in patients with sarcoidosis significantly correlated with exaggerated BALF lymphocytosis and CD4 T cell responses. This study demonstrated a pulmonary deficiency in the frequency of a subset of T cells with immunoregulatory function in patients with sarcoidosis.

Low-dose fluticasone propionate with and without salmeterol in steroid-naïve patients with mild, uncontrolled asthma - Corrected Proof

2009-11-30

Summary: Background: The role of combination ICS/LABA as initial controller therapy in mild, persistent asthma is uncertain. Therefore, the objective of this study was to compare the efficacy of initial controller therapy with fluticasone propionate (FP) 100μg twice daily to the efficacy of fluticasone propionate/salmeterol xinafoate (FSC) 100/50μg twice daily in patients with persistent asthma symptoms while using as-needed SABA alone.Methods: This randomized, double-blind, parallel-group study was conducted at 45 general practice and 15 specialist centers. A total of 526 adult patients were randomized to receive FP or FSC for 24weeks. The primary efficacy endpoint was change in morning peak expiratory flow (PEF) from baseline. Secondary efficacy endpoints included symptom- and rescue-free days; asthma exacerbation rate; asthma-related health-care utilization; and the onset of effect. Safety was assessed by monitoring adverse events.Results: Mean morning PEF was significantly greater in the FSC versus the FP group (P<0.001); this greater effect was evident as early as the first week of treatment (P<0.001). The percentages of symptom-free days and rescue-free days in the FSC group were 7.7% (P=0.009) and 8.4% (P=0.001) higher than the FP group, respectively. Trends toward lower exacerbation-related health care-utilization for FSC versus FP were not statistically significant and exacerbation rates were not significantly different. The incidence of adverse events was low with both treatments.Conclusions: :Treatment with FSC was a more effective initial controller therapy than FP monotherapy in ICS-naïve patients who had uncontrolled asthma while using as-needed SABA alone.

Association of COPD with carotid wall intima-media thickness in vascular surgery patients - Corrected Proof

2009-11-30

Summary: Introduction: There is increasing evidence that non-invasive imaging modalities such as ultrasonography may be able to detect subclinical atherosclerotic lesions, and as such may be useful tools for risk-stratification. However, the clinical relevance of these observations remains unknown in patients with COPD. Therefore we investigated the association between COPD and carotid wall intima-media thickness (IMT) in patients undergoing vascular surgery and its relationship with mortality in these patients.Methods: Carotid wall IMT was measured in 585 patients who underwent lower extremity, aortic aneurysm or stenosis repair. Primary study endpoint was increased carotid wall IMT which was defined as IMT≥1.25mm. Secondary study endpoints included total and cardiovascular mortality over a mean follow-up of 1.5 years.Results: Thirty-two percent of patients with mild COPD and 36% of the patients with moderate/severe COPD had increased carotid wall IMT, while only 23% had an increased carotid wall IMT in patients without COPD (p<0.01). COPD was independently associated with an increased carotid wall IMT (OR 1.60; 95% CI 1.08–2.36). Among patients with COPD, increased carotid wall IMT was associated with an increased risk of total (HR, 3.18 95% CI 1.93–5.24) and cardiovascular mortality (HR 7.28, 95% CI 3.76–14.07).Conclusions: COPD is associated with increased carotid wall IMT independent of age and smoking status. Increased carotid wall IMT is associated with increased total and cardiovascular mortality in patients with COPD suggesting that carotid wall measurements may be a good biomarker for morbidity and mortality in these patients.

Rhinitis in subjects with work-exacerbated asthma - Corrected Proof

2009-11-30

Summary: Objectives: This study aimed at characterizing the nature, severity, and timing of nasal and ocular symptoms in subjects with work-exacerbated asthma (WEA).Methods: Among the 363 subjects referred to a tertiary-care hospital for the investigation of work-related asthma symptoms, 105 subjects who demonstrated non-specific bronchial hyperresponsiveness to histamine, but a negative response to a specific inhalation challenge with the suspected occupational agent(s) were considered as having WEA. Their characteristics were compared with those of 172 subjects with occupational asthma (OA), ascertained by a positive response to a specific inhalation challenge.Results: A high proportion of subjects with WEA (83%) and OA (90%) reported at least one nasal symptom at work. Sneezing/itching and rhinorrhea were more frequent in subjects with OA (78% and 70%, respectively) than in those with WEA (61%, p = 0.004 and 57%, p = 0.038, respectively), while post-nasal discharge was more common in WEA (30%) than in OA (18%, p = 0.019). Nasal symptoms were less severe in WEA (median [25th–75th percentiles] global severity score: 4 [2–6]) as compared to OA (5 [4–7], p < 0.001). Nasal symptoms preceded less frequently those of asthma in subjects with WEA (17%) than in subjects with OA (43%, p = 0.001).Conclusions: Nasal symptoms are highly prevalent in subjects with WEA, although their clinical pattern differs from that found in OA. Further investigations of the health and socio-economic impacts of upper airways symptoms in WEA are required to improve the understanding and management of this common condition.

Treatment with a peroxisomal proliferator activated receptor gamma agonist has a modest effect in the allergen challenge model in asthma: A randomised controlled trial - Corrected Proof

2009-11-30

Summary: Purpose: A considerable body of non clinical evidence has accumulated to support peroxisomal proliferator-activated receptor gamma agonists as candidate anti-inflammatory drugs in asthma. We utilized rosiglitazone as a tool compound in the inhaled allergen challenge model of asthma.Methods: A single centre, double-blind, randomised, placebo controlled, two period cross-over study. Subjects received rosiglitazone 4mg and placebo twice daily for 28 days in random order. On day 28, inhaled allergen challenge was performed 1hour post-dose. A methacholine challenge was performed on day 29 and an adenosine monophosphate challenge on day 14. Exhaled nitric oxide was measured on days 1, 14, 28, 29. Blood was collected pre dose on days 1, 14 and 28 and analysed for markers associated with PPAR activity and systemic markers of inflammation.Results: The late asthmatic reaction (LAR) change from post saline FEV1 from 4–10 hrs post allergen on day 28 was statistically significant for the weighted mean LAR. The difference in weighted mean was 0.06 L (95% CI 0.01 to 0.11) which equates to a 15% attenuation of the response during placebo treatment. This was accompanied by trends in other markers of efficacy and anti-inflammatory activity but none were considered major effects.Discussion: Treatment with a PPARγ agonist (rosiglitazone) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma. Based on the results of this study, PPARγ agonist monotherapy is unlikely to represent a clinically useful intervention in human asthma.Registered with www.clinicaltrials.gov (NCT00318630).

Breath-by-breath quantification of progressive airflow limitation during exercise in COPD: A new method - Corrected Proof

2009-11-23

Summary: During heavy exercise in chronic obstructive pulmonary disease (COPD), dynamic airways compression leads to a progressive fall in intrabreath flow. This is manifested by concavity in the spontaneous expiratory flow–volume (SEFV) curve. We developed a method to quantify the SEFV curve configuration breath-by-breath during incremental exercise utilizing a computerized analysis. The flow signal was digitized at 100Hz. For each breath's SEFV curve, points of highest flow () and end-expiration () were identified to define a rectangle's diagonal. Fractional area within the rectangle below the SEFV curve was defined as the “rectangular area ratio” (RAR); RAR <0.5 signifies concavity of the SEFV. To illustrate the utility of this method, time courses of RAR during incremental exercise in 12 healthy and 17 COPD individuals (FEV1 %Pred.=39±12) were compared. SEFV in healthy individuals manifested progressively more convex SEFV curves throughout exercise (RAR=0.56±0.08 at rest and 0.61±0.05 at peak exercise), but became progressively more concave in COPD patients (RAR=0.52±0.08 at rest and 0.46±0.06 at peak exercise). In conclusion, breath-by-breath quantification of SEFV curve concavity describes progressive shape changes denoting expiratory flow limitation during incremental exercise in COPD patients. Further studies are warranted to establish whether this novel method can be a reliable indicator of expiratory flow limitation during exercise and to examine the relationship of RAR time course to the development of dynamic hyperinflation.

Mass of intercostal muscles associates with risk of multiple exacerbations in COPD - Corrected Proof

2009-11-23

Summary: Background: The potential role of decreased respiratory muscle mass, if any, in mediating the susceptibility to exacerbation in COPD patients has not been determined. We hypothesized that a decrease in respiratory muscle mass is associated with increased risk of multiple hospital admissions due to acute exacerbations of the disease.Methods: Eligible cases and controls (n=20) were identified from records of our department's pulmonary clinic. Ten subjects diagnosed with COPD (males, 66±7yr, Body Mass Index (BMI)=26±4kg/m2) were identified as fragile patients. Fragility was defined as four or more admissions in the previous year due to severe exacerbations of the disease. Fragile patients were matched with 10 non-fragile controls, defined as COPD patients who had required only one admission due to exacerbation of the disease. Criteria for 1:1 matching included ethnicity, gender, age, BMI, degree of airflow obstruction (i.e., FEV1), comorbidity and chronic treatment. Multiple computed tomography (CT) scan slices were obtained to assess area and attenuation coefficients of multiple upper limb, thorax, abdomen and lower limb muscles.Results: CSA of intercostal and abdominal muscles was significantly decreased in fragile COPD patients (right side intercostals, mean relative difference (MRD)=−14%, p=0.010; OR (95% CI)=2.2 (1.1–4.8), p=0.021; left side, MRD=−13%, p=0.007; OR=2.2 (1.1–4.5), p=0.027). CSA and attenuation coefficients of all other muscle compartments showed no statistical differences between the two study groups but showed the same trend. Strength of the inspiratory and expiratory muscles did not differ between the two study groups.Conclusions: This study shows that the risk for multiple admissions due to a COPD exacerbation associates with a marked decrease in the CSA of the intercostal muscle compartment.

How often is diagnosis of COPD confirmed with spirometry? - Corrected Proof

2009-11-20

Summary: Background: Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality worldwide. Diagnosis is customarily confirmed with spirometry, but there are few studies on documented spirometry use in everyday clinical practice.Methods: In a cross-sectional survey and study of the medical records of primary and secondary care COPD patients aged 18–75 in a Swedish region, patients with COPD were randomly selected from the registers of 56 primary care centres and 14 hospital outpatient clinics. Spirometry data at diagnosis ±6 months were analyzed.Results: From 1114 patients with COPD, 533 with a new diagnosis of COPD during the four-year study period were identified. In 59% (n=316), spirometry data in connection with diagnosis were found in the medical records. Spirometry data with post-bronchodilator forced expiratory volume in 1s (FEV1)/ vital capacity (VC) ratios were available in 45% (n=241). FEV1/VC ratio <0.70 were found in 160 patients, which corresponds to 30% of the patients with a new diagnosis. Lower age, female gender, current smoking, higher body mass index (BMI) and shorter forced exhalation time were related to COPD diagnosis despite an FEV1/VC ratio of ≥0.70. The most common problem in the quality assessment was an insufficient exhalation time.Conclusions: Only a third of Swedish patients with COPD had their diagnosis confirmed with spirometry. Our data indicate that female gender, current smoking, higher BMI and short exhalation time increase the risk of being diagnosed with COPD without fulfilling the spirometric criteria for the disease.

Racial discordance in spirometry comparing four commonly used reference equations to the National Health and Nutrition Examination Study III - Corrected Proof

2009-11-20

Summary: Diagnosing lung function abnormalities requires application of the appropriate reference equation for a given patient population. Current guidelines recommend the National Health and Examination Study III data set for evaluating patients in the United States. In Caucasian patients, relying on older reference equations, as opposed to those derived from the NHANES III data set, will often result in a different interpretation of a patient's spirometry. The present study assessed whether similar discordance would occur in African–American patients.A cross-sectional analysis of African–American patients undergoing spirometry testing at our hospital was performed. Patients were classified as normal, restricted, obstructed or mixed based upon the ATS/ERS guidelines, using Crapo, Knudson, Morris, Glindmeyer, and NHANES III prediction equations. Differences in classification were evaluated.4463 subjects were identified, with a mean age of 49.6. Discordance in interpretation was most common when results from prediction equations by Morris, Knudson, and Glindmeyer were compared to NHANES III (24.6%, 26.4%, and 20.1%, respectively). Discordance was less common when comparing Crapo to NHANES III (12.8%). There was a tendency for Knudson, Morris and Glindmeyer to under classify restriction, and for Crapo, Morris, and Glindmeyer to over classify obstruction.There is significant discordance in interpretation when spirometry for African–American patients is referenced to equations published by Crapo, Morris, Knudson, and Glindmeyer, compared to NHANES III.

Responses to inhaled long-acting beta-agonist and corticosteroid according to COPD subtype - Corrected Proof

2009-11-18

Summary: Rationale: Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disorder in which a number of different pathological processes lead to recognition of patient subgroups that may have individual characteristics and distinct responses to treatment.Objectives: We tested the hypothesis that responses of lung function to 3 months of combined inhalation of long-acting beta-agonist and corticosteroid might differ among patients with various COPD subtypes.Methods: We classified 165 COPD patients into four subtypes according to the severity of emphysema and airflow obstruction: emphysema-dominant, obstruction-dominant, mild-mixed, and severe-mixed. The emphysema-dominant subtype was defined by an emphysema index on computed tomography of more than 20% and FEV1 more than 45% of the predicted value. The obstruction-dominant subtype had an emphysema index≤20% and FEV1≤45%, the mild-mixed subtype had an emphysema index≤20% and FEV1>45%, and the severe-mixed subtype had an emphysema index>20% and FEV1≤45%. Patients were recruited prospectively and treated with 3 months of combined inhalation of long-acting beta-agonist and corticosteroid.Results: After 3 months of combined inhalation of long-acting beta-agonist and corticosteroid, obstruction-dominant subtype patients showed a greater FEV1 increase and more marked dyspnea improvement than did the emphysema-dominant subgroup. The mixed-subtype patients (both subgroups) also showed significant improvement in FEV1 compared with the emphysema-dominant subgroup. Emphysema-dominant subtype patients showed no improvement in FEV1 or dyspnea after the 3-month treatment period.Conclusion: The responses to 3 months of combined inhalation of long-acting beta-agonist and corticosteroid differed according to COPD subtype.