Validity of the Asthma Control Test Questionnaire Among Smoking Asthmatics.

BACKGROUND: Smoking asthmatics respond worse to existing asthma therapies and have more asthma symptoms and exacerbations. OBJECTIVE: We evaluated the Asthma Control Test (ACT) for assessing asthma control among smokers. METHODS: Adults with asthma who smoked were enrolled and followed for 6 weeks. The statistical properties, validity, and responsiveness of the ACT were evaluated. Physician global assessment (GS) of asthma was the "gold standard." RESULTS: A total of 151 participants were enrolled: 52% female and 48% male. The median (interquartile ranges) was 35 (27, 43) years for age, 11 (7, 18) for pack-years, and 16 (13, 20) for the ACT score. Participants self-identified as African American (49%), non-Hispanic whites (38%), and Hispanic whites (11%). Participants were classified as well controlled (24%), not well controlled (42%), or very poorly controlled (34%) at enrollment. Cronbach's alpha (95% confidence interval [CI]) for the ACT at enrollment was 0.81 (0.76, 0.85). The intraclass correlation coefficient (95% CI) for agreement of scores at enrollment and 6 weeks was 0.68 (0.57, 0.78) in participant with stable asthma (n = 93). ACT scores were associated with GS (P < .001). Area under the receiver operating characteristic (ROC) curve (95% CI) for an ACT cutoff score of ≤19 (not well controlled) was 0.76 (0.67, 0.84). The ACT score with the maximum area under the ROC curve was 18.6. CONCLUSIONS: The ACT questionnaire was reliable and discriminated between levels of asthma control in smoking asthmatics with similar sensitivity and specificity as nonsmoking asthmatics, which confirms its value as a tool for the management of asthma in this prevalent but understudied subgroup of subjects.

Recommendations for a Standardized Pulmonary Function Report. An Official American Thoracic Society Technical Statement.

BACKGROUND: The American Thoracic Society committee on Proficiency Standards for Pulmonary Function Laboratories has recognized the need for a standardized reporting format for pulmonary function tests. Although prior documents have offered guidance on the reporting of test data, there is considerable variability in how these results are presented to end users, leading to potential confusion and miscommunication. METHODS: A project task force, consisting of the committee as a whole, was approved to develop a new Technical Standard on reporting pulmonary function test results. Three working groups addressed the presentation format, the reference data supporting interpretation of results, and a system for grading quality of test efforts. Each group reviewed relevant literature and wrote drafts that were merged into the final document. RESULTS: This document presents a reporting format in test-specific units for spirometry, lung volumes, and diffusing capacity that can be assembled into a report appropriate for a laboratory's practice. Recommended reference sources are updated with data for spirometry and diffusing capacity published since prior documents. A grading system is presented to encourage uniformity in the important function of test quality assessment. CONCLUSIONS: The committee believes that wide adoption of these formats and their underlying principles by equipment manufacturers and pulmonary function laboratories can improve the interpretation, communication, and understanding of test results.

High Positive End-Expiratory Pressure Is Associated with Improved Survival in Obese Patients with Acute Respiratory Distress Syndrome.

BACKGROUND: In acute respiratory distress syndrome, minimizing lung injury from repeated collapse and reopening of alveoli by applying a high positive end-expiratory pressure improves oxygenation without influencing mortality. Obesity causes alveolar atelectasis, thus suggesting that a higher positive end-expiratory pressure might be more protective among the obese. We hypothesized that the effect of applying a high positive end-expiratory pressure on mortality from acute respiratory distress syndrome would differ by obesity status. METHODS: This was a retrospective analysis of 505 patients from the Assessment of Low tidal Volume and elevated End-expiratory volume to Obviate Lung Injury Trial, a multicenter randomized trial that compared a higher vs a lower positive end-expiratory pressure ventilatory strategy in acute respiratory distress syndrome. We examined the relationship between positive end-expiratory pressure strategy and 60-day mortality stratified by obesity status. RESULTS: Among obese patients with acute respiratory distress syndrome, those assigned to a high positive end-expiratory pressure strategy experienced lower mortality compared with those assigned to a low strategy (18% vs 32%; P = .04). Among the nonobese, those assigned to high positive end-expiratory pressure strategy experienced similar mortality with those assigned to low strategy (34% vs 23%; P = .13). Multivariate analysis demonstrated an interaction between obesity status and the effect of positive end-expiratory pressure strategy on mortality (P <.01). CONCLUSIONS: Ventilation with higher levels of positive end-expiratory pressure was associated with improved survival among the subgroup of patients with acute respiratory distress syndrome who are obese.

A Distinct Low Lung Function Trajectory from Childhood to the Fourth Decade of Life.

RATIONALE: Low maximally attained lung function increases the risk of chronic obstructive pulmonary disease irrespective of the subsequent rate of lung function decline. OBJECTIVES: We aimed to determine if there were individuals with a distinct, persistently low lung function trajectory in the CRS (Tucson Children's Respiratory Study). METHODS: The CRS, an ongoing birth cohort study, enrolled 1,246 participants between 1980 and 1984. Latent class linear mixed effects modeling of the ratio of FEV1 to FVC was used to identify distinct lung function trajectories among participants with two or more spirometry measurements between ages 11 and 32 years. MEASUREMENTS AND MAIN RESULTS: Among 599 participants with 2,142 observations, a model with two distinct trajectories (a low trajectory [n = 56; 9.3%] and a normal trajectory) fit the data significantly better than a model with only one trajectory (P = 0.0007). As compared with those with a normal trajectory, participants with a persistently low trajectory were more likely to have a history of maternal asthma (20.0% vs. 9.9%; P = 0.02); early life lower respiratory illness caused by respiratory syncytial virus (41.2% vs. 21.4%; P = 0.001); and physician-diagnosed active asthma at age 32 years (43.9% vs. 16.2%; P < 0.001). Individuals with a persistently low trajectory also demonstrated lower lung function as measured by average maximal expiratory flow at functional residual capacity during infancy and at age 6 years. CONCLUSIONS: A distinct group of individuals in a nonselected population demonstrates a persistently low lung function trajectory that may be partly established at birth and predisposes them to chronic obstructive pulmonary disease later in life.

COPD Overdiagnosis, Underdiagnosis, and Treatment.

This article serves as a CME-available enduring material summary of the following COPD9USA presentations: - "Spirometry Isn't for Screening - So What Is?" Presenter: David H. Au, MD, MS - "Diagnosis of COPD in a Primary Care Midwest Practice" Presenter: Barbara Yawn, MD, MSc - "What Happens in Primary Care Without Screening?" Presenter: Sandra G. Adams, MD, MS - "From Screening to Diagnosis to Management in a Busy Primary Care Practice"Presenter: Min Joo, MD - "Practical Considerations of How Phenotype and Genotype Can Affect Management Decisions" Presenter: Bartolome Celli, MD.

Older adults with chronic lung disease report less limitation compared with younger adults with similar lung function impairment.

RATIONALE: Disability guidelines are often based on pulmonary function testing, but factors other than lung function influence how an individual experiences physiologic impairment. Age may impact the perception of impairment in adults with chronic lung disease. OBJECTIVES: To determine if self-report of physical functional impairment differs between older adults with chronic lung disease compared with younger adults with similar degrees of lung function impairment. METHODS: The Lung Tissue Research Consortium provided data on 981 participants with chronic obstructive pulmonary disease and interstitial lung disease who were well characterized with clinical, radiological, and pathological diagnoses. We used multiple logistic regression to determine if responses to health status questions (from the Short Form-12 and St. George's Respiratory Questionnaire) related to perception of impairment differed in older adults (age ≥ 65 yr, n = 427) compared with younger adults (age < 65 yr, n = 393). MEASUREMENTS AND MAIN RESULTS: Pulmonary function was higher in older adults (median FEV1 %, 70) compared with younger adults (median FEV1 %, 62) (P < 0.001), whereas the median 6-minute-walk distance was similar between groups (372 m vs. 388 m, P = 0.21). After adjusting for potential confounders, older adults were less likely to report that their health limited them significantly in performing moderate activities (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.22-0.58) or climbing several flights of stairs (OR, 0.51; 95% CI, 0.34-0.77). The odds of reporting that their physical health limited the kinds of activities they performed were reduced by 63% in older adults (OR, 0.37; 95% CI, 0.24-0.58), and, similarly, the odds of reporting that their health caused them to accomplish less than they would like were also lower in older adults (OR, 0.39; 95% CI, 0.25-0.60). The OR for reporting that their breathing problem stops them from doing most things or everything was 0.35 (95% CI, 0.22-0.55) in older adults versus younger adults. CONCLUSIONS: Older adults with chronic lung disease were less likely to report significant impairment in their activities compared with younger adults, suggesting they may perceive less limitation.

Relationship between lung function impairment and health-related quality of life in COPD and interstitial lung disease.

BACKGROUND: Health-related quality-of-life (HRQL) measures have been correlated with lung function in patients with COPD and interstitial lung disease (ILD). However, different pathophysiologic mechanisms may influence how these distinct diseases affect HRQL, resulting in differing HRQL by pulmonary diagnosis among patients with similar severity of ventilatory impairment. METHODS: The National Heart, Lung, and Blood Institute Lung Tissue Research Consortium provided data on well-characterized participants with COPD (n = 576) and ILD (n = 405) at four clinical sites. Using multiple linear regression, we examined the effects of FEV1 (% predicted) and diagnosis (ILD vs COPD) on HRQL scores, including total St. George Respiratory Questionnaire (SGRQ) scores and Short Form-12 (SF-12) physical component summary (PCS) and mental component summary (MCS) scores. RESULTS: Participants with ILD had, on average, higher SGRQ scores (15.33 points; 95% CI, 12.46-18.19; P <.001) and lower SF-12 PCS scores (-4.73 points; 95% CI, -6.31 to -3.14; P <.001) compared with patients with COPD with similar FEV1 % predicted values, indicating worse HRQL. The specific diagnosis also modified the effect of FEV1 on the total SGRQ score (P = .003) and the SF-12 PCS score (P = .03). There was no relationship between lung function and SF-12 MCS scores. CONCLUSIONS: HRQL scores were worse for patients with ILD compared with patients with COPD with similar degrees of ventilatory impairment. Differences in dyspnea mechanism or in the rate of disease progression may account for these differences in HRQL.

Mortality in COPD: causes, risk factors, and prevention.

Chronic obstructive pulmonary disease (COPD) is a leading and increasing cause of death, the extent of which is underestimated as a consequence of underdiagnosis and underreporting on death certificates. Data from large trials, such as the Lung Health Study, Towards a Revolution in COPD Health (TORCH), Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT), European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP), and Inhaled Steroids in Obstructive Lung Disease (ISOLDE), have shown that the causes of death in patients with mild COPD are predominantly cancer and cardiovascular disease, but as COPD severity increases, deaths due to non-malignant respiratory disease are increasingly common. In practice, mortality of patients with COPD can be predicted by a variety of measures including: forced expiratory volume in one second (FEV(1)), the ratio of inspiratory and total lung capacities, exercise capacity, dyspnea scores, and composite indices such as the body-mass index (B), degree of airflow obstruction (O), degree of functional dyspnea (D), and exercise capacity (E) (BODE) index. Smoking cessation improves survival in COPD patients, and in select patients with advanced disease, oxygen therapy, lung volume reduction surgery, or lung transplantation may also improve survival.

Interpretation of pulmonary function test: issues and controversies.

Pulmonary function testing (PFT) serves many purposes in clinical practice, and in contrast to other laboratory measures, PFT results are often provided with a clinical interpretation. PFT interpretation depends on the clinical context, and multiple challenges influence PFT interpretation. Overall, the goal of PFT interpretation is to distinguish normal from abnormal, and this is affected by the selection of reference standards, as well as the arbitrary albeit not necessarily irrational choice of cut-off values. Controversies regarding PFT analysis may lead to important differences in interpretation. In this article, issues associated with the selection of reference standards are discussed, followed by a review of the controversies related to PFT interpretation in the diagnosis of obstructive ventilatory defect, restrictive ventilatory defect, gas transfer defect, and flow-volume loop abnormalities. Given the challenges facing PFT interpretation, no single interpretative algorithm is sufficient; rather, PFT interpretation requires a comprehensive approach including consideration of the clinical context, laboratory methodology, and reference standards and an understanding of the consequences of a normal or abnormal designation.

Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy.

Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF (19 to 21 months) rats to oxypurinol (1 mmol/L; n=4 and n=15, respectively) or placebo (n=3 and n=10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31+/-3% versus 67+/-3% in WKY, P<0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7+/-0.2 mm versus 7.0+/-0.4 mm in WKY, P<0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho-extracellular signal-regulated kinase were restored toward normal by oxypurinol (P<0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.

Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications.

There is substantial evidence that oxidative stress participates in the pathophysiology of cardiovascular disease. Biochemical, molecular and pharmacological studies further implicate xanthine oxidoreductase (XOR) as a source of reactive oxygen species in the cardiovascular system. XOR is a member of the molybdoenzyme family and is best known for its catalytic role in purine degradation, metabolizing hypoxanthine and xanthine to uric acid with concomitant generation of superoxide. Gene expression of XOR is regulated by oxygen tension, cytokines and glucocorticoids. XOR requires molybdopterin, iron-sulphur centres, and FAD as cofactors and has two interconvertible forms, xanthine oxidase and xanthine dehydrogenase, which transfer electrons from xanthine to oxygen and NAD(+), respectively, yielding superoxide, hydrogen peroxide and NADH. Additionally, XOR can generate superoxide via NADH oxidase activity and can produce nitric oxide via nitrate and nitrite reductase activities. While a role for XOR beyond purine metabolism was first suggested in ischaemia-reperfusion injury, there is growing awareness that it also participates in endothelial dysfunction, hypertension and heart failure. Importantly, the XOR inhibitors allopurinol and oxypurinol attenuate dysfunction caused by XOR in these disease states. Attention to the broader range of XOR bioactivity in the cardiovascular system has prompted initiation of several randomised clinical outcome trials, particularly for congestive heart failure. Here we review XOR gene structure and regulation, protein structure, enzymology, tissue distribution and pathophysiological role in cardiovascular disease with an emphasis on heart failure.