Scanlon, Paul D.

Abstract Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose–effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).

Abstract Rationale Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown. Objectives To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care. Methods Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use. Measurements and Main Results Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71–1.38; P = 0.95). Conclusions Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897).

Rationale Proline–glycine–proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown. Objectives We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbations to test whether sputum levels of PGP were altered by treatment or associated with exacerbation frequency. Methods We collected remnant sputa from trial participants and assayed them in a blinded fashion for PGP, myeloperoxidase and matrix metalloproteinase (MMP)-9 and for the ability to generate PGP from collagen ex vivo . Once the parent trial was unblinded, the results were correlated with use of azithromycin or placebo and exacerbations in participants. Results Azithromycin treatment significantly reduced sputum levels of PGP and myeloperoxidase in patients with COPD, particularly with increased duration of therapy. We found no difference in sputum MMP-9 or PGP generation between participants taking azithromycin or placebo. Sputum PGP levels were highest around the time of an exacerbation and declined with successful treatment. Conclusions These data support a role for PGP in the airway and parenchymal neutrophilic inflammation that drives COPD progression and exacerbations, and provide new information on the anti-inflammatory properties of macrolides. PGP may have potential as a target for novel anti-inflammatory therapies in COPD and as a biomarker for clinical trials.

Abstract To demonstrate physiologic changes associated with asthma symptoms that many patients with asthma develop during exercise, we used sustained constant-load and interval exercise protocols with subjects breathing dry room temperature air. In constant-load exercise, subjects pedaled a stationary bicycle at 50% of their maximal power capacity for 36 min. In interval protocols, subjects pedaled at 60% of maximal capacity for 6 min and then 40% of maximal for 6 min; the 12-min cycle was repeated three times for a total exercise time of 36 min. Maximal expiratory flow versus volume maneuvers (MEFV) were obtained before, at 6-min intervals during, and at 5-min intervals after exercise. Changes in peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV1), and forced expiratory flow at 50% of pre-exercise vital capacity (FEF50) were compared with pre-exercise values. Within 15 min after a maximal 1-min incremental exercise protocol, mean flows decreased compared with pre-exercise (PEF, mean -22%, range -46 to 5%; FEV1, mean -21%, range -42 to -3%; FEF50, mean -41%, range -80 to 3%; all p < 0.05). There were no significant changes in MEFV flows until 18 min of constant-load exercise, when FEV1 and FEF50 fell (FEV1, mean -6%, range -15 to 2%; FEF50, mean -14%, range -32 to 6%; both p < 0.05), although changes in PEF were minimal and were not significantly different compared with pre-exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Microspheres of different sizes, 125 I-labeled antipyrine (I-Ap), and 42 KCl or 86 RbCl were injected into the aortic inflow of isolated, Langendorff, perfused, nonworking dogs hearts at blood flows of 1.3-4.8 ml/min g -1 . After 15 seconds to 5 minutes, the left ventricle was sectioned into about 300 ordered pieces, and the amount of each tracer was determined. For all tracers, the relative density of deposition was generally higher in the endocardial region, except in one heart in which the aortic pressure and the total coronary flow were low. The deposition of 42 K and that of I-Ap were essentially similar in three hearts over a large range of regional variation. This finding suggests either that both tracers were distributed in proportion to flow or that a small diminution in relative density of deposition of 42 K in high-flow regions due to lower transcapillary extraction was quantitatively similar to a decrease in the residual fraction of I-Ap in these same regions due to faster washout in the first 15-30 seconds after injection. Large microspheres were deposited preferentially in regions of high flow, exaggerating the apparent heterogeneity of regional flows. The distribution of the smaller microspheres was closer to that for I-Ap or 42 K.

Abstract Rationale The course of lung function decline for smokers with early airflow obstruction remains undefined. It is also unclear which early spirometric characteristics identify individuals at risk for rapid decline and increased mortality. Objectives To determine the association between spirometric measures and 5-year decline in FEV1 and 12-year mortality. Methods We analyzed longitudinal data from the Lung Health Study, a clinical trial of intensive smoking cessation intervention with or without bronchodilator therapy in 5,887 smokers with mild to moderate airflow obstruction. Participants were stratified into bins of baseline FEV1 to FVC ratio, using bins of 5%, and separately into bins of Z-score (difference between actual and predicted FEV1/FVC, normalized to SD of predicted FEV1/FVC). Associations between spirometric measures and FEV1 decline and mortality were determined after adjusting for baseline characteristics and time-varying smoking status. Measurements and Main Results The cohort was approximately two-thirds male, predominantly of white race (96%), and with mean age of 49 ± 7 years. In general, individuals with lower lung function by any metric had more rapid adjusted FEV1 decline. A threshold for differential decline was present at FEV1/FVC less than 0.65 (P < 0.001) and Z-score less than −2 (2.3 percentile) (P < 0.001). At year 12, 575 (7.2%) of the cohort had died. Lower thresholds of each spirometric metric were associated with increasing adjusted hazard of death. Conclusions Smokers at risk or with mild to moderate chronic obstructive pulmonary disease have accelerated lung function decline. Individuals with lower baseline FEV1/FVC have more rapid decline and worse mortality.