A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Cardiopulmonary correlates of cognition in systemic lupus erythematosus.

OBJECTIVE: We aimed to evaluate the relationship between cognitive dysfunction and lung function, exercise endurance, and self-reported activity levels in patients with systemic lupus erythematosus (SLE). BACKGROUND: Cognitive dysfunction is present in 20%-60% of SLE patients. No studies to date have investigated the inter-relationships between cardiopulmonary factors and cognition in this population. METHODS: Thirty-seven SLE patients without overt neuropsychiatric histories and 16 healthy controls completed neuropsychological testing, measures of lung function, exercise capacity (distance walked during a timed walk test,(1) maximal oxygen uptake(2)), and exercise questionnaires. RESULTS: Thirty-two percent of SLE patients demonstrated cognitive impairment. Cognitive impairment was correlated with Six-Minute Walk Distance (6MWD) (r = 0.37, p = 0.02) and certain measures of lung function. Also, in SLE patients, self-reported physical activity was correlated with 6MWD (p = 0.012), but none of the more complex measures of physical activity (VO2max). CONCLUSIONS: Patients with mild SLE disease activity have cognitive dysfunction associated with certain objective markers of exercise capacity and activity levels. The lack of associations between self-report activity and VO2max suggests the possibility that multiple factors mediate the relationships between perceived and actual physical ability. Additional studies are needed to better understand the relationship between cognition and physical activity in patients with SLE.

The minimal important difference of exercise tests in severe COPD.

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4-6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St George's Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohen's effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1-20.1 m), 24.2 m (95% CI 23.4-25.4 m), 24.6 m (95% CI 23.4-25.7 m) and 26.4 m (95% CI 25.4-27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0-2.4 W), 3.2 W (95% CI 3.0-3.4 W), 3.2 W (95% CI 3.0-3.4 W) and 3.3 W (95% CI 3.0-3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26 ± 2 m for 6MWD and 4 ± 1 W for MCEC for patients with severe COPD.

Candidate genes for COPD in two large data sets.

Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.

Prevalence and clinical correlates of bronchoreversibility in severe emphysema.

Chronic obstructive pulmonary disease (COPD) exhibits airflow obstruction that is not fully reversible. The importance of bronchoreversibility remains controversial. We hypothesised that an emphysematous phenotype of COPD would be associated with decreased bronchoreversibility. 544 patients randomised to the medical arm of the National Emphysema Treatment Trial formed the study group. Participants underwent multiple measurements of bronchoreversibility on a mean of four sessions over 1.91 yrs. They were also characterised by measures of symptoms, quality of life and quantitative measures of emphysema by computed tomography. Mean baseline forced expiratory volume in 1 s (FEV(1)) in this patient population is 24% predicted. 22.2% of patients demonstrated bronchoreversibility on one or more occasions using American Thoracic Society/European Respiratory Society criteria. Few patients (0.37%) had bronchoreversibility on all completed tests. Patients who demonstrated bronchoreversibility were more likely to be male, and have better lung function and less emphysema. 64% of patients demonstrated large (> or =400 mL) changes in forced vital capacity (FVC). In a severe emphysema population, bronchoreversibility as defined by change in FEV(1) is infrequent, varies over time, and is more common in males and those with less severe emphysema. Improvements in FVC, however, were demonstrated in the majority of patients.

Outcomes for COPD pharmacological trials: from lung function to biomarkers.

The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD.

The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44 +/- 13% pred): 96 patients received 18 microg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patient's maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105 +/- 40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9 +/- 0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.

Quality of life measured with a generic instrument (Short Form-36) improves following pulmonary rehabilitation in patients with COPD.

STUDY OBJECTIVES: The purpose of this study was to evaluate the effects of a 3-week comprehensive pulmonary rehabilitation program on quality of life as measured by the Short Form-36 (SF-36) in patients with COPD. DESIGN AND SETTING: We report on the outcomes of 37 consecutive patients referred for pulmonary rehabilitation at a respiratory specialty medical center. PATIENTS: Thirty-seven patients (mean age, 66 years) with COPD and severe airflow limitation (mean +/- SE FEV(1), 29.6 +/- 1.8% of predicted) were studied. INTERVENTIONS: Rehabilitation consisted of a 3-week pulmonary rehabilitation program incorporating 12 exercise sessions, each of which included bicycle ergometer exercise training, upper-extremity training, strength training, and stretching, along with psychosocial counseling and education. MEASUREMENTS AND RESULTS: The Health Status Index (SF-36) and 6-min walk test were completed before and after rehabilitation. There was an improvement in five of the nine quality-of-life subscales of the SF-36 following pulmonary rehabilitation. Although there was an improvement in functional capacity as measured by the 6-min walk, there was no correlation between improvement in quality of life and improvement in functional capacity. There was no correlation between FEV(1) and improvement in walk distance, but there was a correlation between FEV(1) and improvement in SF-36 physical function and energy/fatigue subscales. CONCLUSION: Health-related quality of life assessed by the SF-36, a general measure of quality of life, improves following an intensive 3-week pulmonary rehabilitation program. Use of the SF-36 allows comparison of the results of pulmonary rehabilitation to therapeutic interventions in patients with other medical disorders.

Improved exercise performance following lung volume reduction surgery for emphysema.

Lung volume reduction surgery (LVRS) for emphysema has been suggested to improve patient lung function and activity. The short-term impact of LVRS on exercise performance was evaluated using maximal and submaximal steady-state exercise testing in 27 patients with severe hypoxemic chronic obstructive pulmonary disease (COPD), along with measurements of patient function, dyspnea, and quality of life. LVRS significantly improved exercise performance, due to ventilatory improvements associated with increased ventilatory reserve, enhanced tidal volume recruitment, and improved alveolar ventilation. Preoperative measurements of ventilatory reserve and dead space ventilation during exercise testing were closely associated with improved exercise performance. Improvements in patient dyspnea, walk distances, and quality of life also occurred following LVRS and were associated with improvements in exercise performance. Surgical mortality from LVRS was low (4%), but short-term all-cause mortality was increased (19%). Short-term mortality was associated with reduced expiratory muscle strength and markedly elevated dead space ventilation. We conclude that LVRS produces significant improvements in exercise performance, dyspnea, and quality of life in selected patients with COPD. Physiologic prediction of patients most likely to survive for an extended period and have significant benefit following LVRS may also be possible.

Acute exacerbations of chronic bronchitis: an international comparison.

The prevalence of chronic bronchitis is between 3% and 17% in most developed countries. However, higher rates in the range of 13 to 27% are encountered in less developed areas of the world. Acute exacerbations of chronic bronchitis (AECB) have usually been defined as the presence of increases in cough/sputum, sputum purulence, and dyspnea. However, recent investigations suggest that the severity of AECB may be divided into three stages based on the history of the patient: (1) previously healthy individuals; (2) patients with chronic cough and sputum and infrequent exacerbations; and (3) persons with frequent exacerbations or more severe chronic airflow limitation. Therapy for patients with less severe AECB include older and less expensive broad-spectrum antibiotics, while newer agents are indicated for patients with the most severe stage of AECB.

Core body temperature is normal in chronic fatigue syndrome.

BACKGROUND: Subjects with chronic fatigue syndrome (CFS) frequently report symptoms of subnormal body temperature and low-grade fever. We conducted a study to determine whether CFS subjects manifest any abnormality of core body temperature (CBT) that might help explain their fatigue. METHODS: Continuous 24-hour recordings of CBT measured every 5 min were performed in 7 subjects meeting the Centers for Disease Control definition of CFS. Three additional groups were studied: normal controls, subjects with seasonal allergy, and subjects with major depression. Subjects (n = 7) in each group were age-, sex-, and weight-matched to the CFS group and had normal basal metabolic rates, thyroid function, and 24-hour urinary free cortisol excretions. CBT was measured with an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. Each pill was factory-calibrated to +/- 0.1 degree C and field-calibrated with a water bath calibration prior to use. RESULTS: The 24-hour mean calibration-adjusted CBTs of each group were not significantly different (control: 37.00 +/- 0.17 degrees C; CFS: 37.04 +/- 0.31 degrees C; allergy: 37.15 +/- 0.18 degrees C; depression: 37.16 +/- 0.18 degrees C). Similarly, the mean peak and trough circadian temperatures were not statistically different. The mean 24-hour profile of CBT for each group showed a similar circadian rhythm. In simultaneously collected blood samples, each group showed a similar circadian profile of serum cortisol with a peak occurring at 08:00. CONCLUSIONS: Subjects with CFS have normal CBT despite frequent self-reports of subnormal body temperature and low-grade fever.

Quantitative chest computed tomography as a means of predicting exercise performance in severe emphysema.

RATIONALE AND OBJECTIVES: We assessed the value of quantitative high-resolution computed tomography (CT) as a diagnostic and prognostic tool in smoking-related emphysema. METHODS: We performed an inception cohort study of 14 patients referred with emphysema. The diagnosis of emphysema was based on a compatible history, physical examination, chest radiograph, CT scan of the lung, and pulmonary physiologic evaluation. RESULTS: As a group, those who underwent exercise testing were hyperinflated (percentage predicted total lung capacity +/- standard error of the mean = 133 +/- 9%), and there was evidence of air trapping (percentage predicted respiratory volume = 318 +/- 31%) and airflow limitation (forced expiratory volume in 1 sec [FEV1] = 40 +/- 7%). The exercise performance of the group was severely limited (maximum achievable workload = 43 +/- 6%) and was characterized by prominent ventilatory, gas exchange, and pulmonary vascular abnormalities. The quantitative CT index was markedly elevated in all patients (76 +/- 9; n = 14; normal < 4). There were correlations between this quantitative CT index and measures of airflow limitation (FEV1 r2 = .34, p = 09; FEV1/forced vital capacity r2 = .46, p = .04) and between maximum workload achieved (r2 = .93, p = .0001) and maximum oxygen utilization (r2 = .83, p = .0007). CONCLUSION: Quantitative chest CT assessment of disease severity is correlated with the degree of airflow limitation and exercise impairment in pulmonary emphysema.

Collaborative self-management strategies for patients with respiratory disease.

The effectiveness of collaborative self-management of respiratory disorders has been most clearly demonstrated in asthma. In both adults and children with severe asthma requiring emergency care and hospitalizations, collaborative self-management can decrease not only the need for emergency care and hospitalization but also time lost from work and school, thereby increasing the patients' ability to be full and active participants in the community. Collaborative self-management is best provided in a comprehensive program that includes ready access to healthcare professionals, education, behavioral therapy, and peak-flow monitoring. The relative value of each of these components and the value of single components applied simultaneously is unclear. In some studies, asthma symptoms and medication adherence have also improved following implementation of collaborative self-management. The available data indicate that collaborative self-management should be considered as a potential therapeutic adjunct in the management of every patient with asthma and should be routinely employed with patients who have severe disease as defined by emergency room use and hospitalizations. Additional investigations should be conducted in patients with other respiratory diseases to define the role of collaborative self-management. Nonetheless, state-of-the-art medical care and the nature of the patient-physician relationship in the 1990s dictates that collaborative self-management be routinely employed in the optimal outpatient management of any individual who is interested in participating in his or her own healthcare. However, individualization of the practitioner-patient relationship is necessary. Not all patients desire to play an active role in their illness and its management. The personality, attitudes, and desires of individuals in assisting in their own management must be assessed. Theory would suggest that patients who do not appear to have an interest in self-management may have low self-efficacy that may be increased by educational efforts. Improved self-efficacy and active participation in disease management may result in beneficial outcomes. It is clear that the physician-patient relationship has changed over the past decade. As patients have been empowered to act in their own best interests, the physician's role as an educator and facilitator has become more prominent than ever. Even if medical investigations had not demonstrated any beneficial effects of collaborative self-management, patients have the right to participate in decisions affecting their healthcare and are increasingly exercising that right. Respiratory care practitioners are in a unique position to enhance collaborative self-management. In the home environment, RCPs can foster smoking cessation and serve as a liaison between patients and physicians.(ABSTRACT TRUNCATED AT 400 WORDS)

Respiratory tract infection complicating transtracheal oxygen therapy.

Transtracheal oxygen is generally well tolerated in patients with chronic hypoxemia. Minor complications are common, but there are few reports of serious respiratory tract infections associated with transtracheal oxygen therapy. We describe four patients with interstitial lung disease who had frequent lower respiratory tract infections requiring hospitalization after initiation of transtracheal oxygen therapy.

COPD: management and rehabilitation.

Chronic obstructive pulmonary diseases include emphysema, chronic bronchitis and asthma. Patients with mild disease may remain asymptomatic for many years. In patients with a sedentary lifestyle, 60 percent of lung function may be lost before shortness of breath occurs during daily activity. Spirometry may detect mild to moderate airflow obstruction in asymptomatic patients. Goals of therapy include reduction of airflow obstruction, prevention or treatment of complications, and improvement in quality of life.