Patterns of retention of particulate matter in lung tissues of COPD: potential role in disease progression. S.H. Ling, J.E. McDonough, J.V. Gosselink, W.M. Elliott, S. Hayashi, J.C. Hogg, S.F. Van Eeden. Chest. 2011 Jun 9. [Epub ahead of print].
BACKGROUND: Particulate matter (PM) has previously been shown to be present in lung tissues of smokers and urban dwellers. This study was designed to quantify the burden of PM in different lung tissues of subjects with chronic obstructive pulmonary disease (COPD) and determine its relationship to disease severity.
METHODS: Surgical lung tissue samples from non-smokers (controls) were compared to those from smokers with normal spirometry and subjects in the four other categories of the GOLD classification of COPD severity using quantitative histological techniques.
RESULTS: PM was present in the lung parenchyma, blood vessels walls, airways, lymphoid follicles, and alveolar macrophages. The total burden of PM (volume fraction or Vv) in all tissues of the lung was higher in smokers than non-smokers (p < 0.001) and also in smokers with airflow obstruction compared the smokers with normal spirometry (p < 0.01). There was an incremental increase in total PM burden with increased COPD severity that peaked in GOLD 2 and then trended downward in GOLD 3+4 COPD. This same pattern of PM retention was also observed in alveolar walls. The total burden of PM in lung tissues correlated with a decline in FEV(1)/FVC, as well as pack years smoking. mRNA expression of fibrinogen (gamma chain) correlated with total lung burden of PM and burden of PM in lung parenchyma (r(2) = 0.22, p < 0.001).
CONCLUSIONS: We conclude that retained PM is widely distributed in lung tissues of subjects with COPD and that cigarette smoke exposure and airflow obstruction are associated to retention of PM in lung tissues. We attribute the downward trend in PM burden in severe COPD to either less deposition and retention or selective removal of PM containing tissues by emphysematous destruction.
Comments: It is quite clear that subjects with COPD continue to have evidence of inflammation and indeed progression of disease even after smoking cessation. In this study the investigators show the significant burden of particulate matter increases with disease severity up to Gold stage 2 then it actually seemed to be less intense with more advanced stages. There are many plausible explanations for this including as the authors suggest that patients with emphysema and more advanced diseases lose some of PM burden as they develop more extensive alveolar destruction, the site with the highest concentration of PM. Other possibilities to explain the reduced PM may be that patients with more advanced disease are older and have had more time for apoptosis and other mechanisms to reduce the lung burden of particulate matter. It was also interesting that aside from fibrinogen they did not find any significant association with PM burden and genes typically associated with lung tissue repair. This raises the question as to whether the particulate matter is relatively inert or if over time it has been detoxified in those with more advanced disease.
Comparative efficacy of indacaterol 150 μg and 300 μg versus fixed-dose combinations of formoterol + budesonide or salmeterol-+-fluticasone for the treatment of chronic obstructive pulmonary disease–a network meta-analysis. S. Cope, G. Capkun-Niggli, R. Gale, J.R. Jardim, J.P. Jansen. Int J Chron Obstruct Pulmon Dis 2011;6:329–44.
OBJECTIVE: To compare efficacy of indacaterol to that of fixed-dose combination (FDC) formoterol and budesonide (FOR/BUD) and FDC salmeterol and fluticasone (SAL/FP) for the treatment of chronic obstructive pulmonary disease (COPD) based on the available randomized clinical trials (RCTs).
METHODS: Fifteen placebo-controlled RCTs were included that evaluated: indacaterol 150 μg (n = 5 studies), indacaterol 300 μg (n = 4), FOR/BUD 9/160 μg (n = 2), FOR/BUD 9/320 μg (n = 3), SAL/FP 50/500 μg (n = 5), and SAL/FP 50/250 μg (n = 1). Outcomes of interest were trough forced expiratory volume in 1 second (FEV(1)), total scores for St. George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI). All trials were analyzed simultaneously using a Bayesian network meta-analysis and relative treatment effects between all regimens were obtained. Treatment-by-covariate interactions were included where possible to improve the similarity of the trials.
RESULTS: Indacaterol 150 μg resulted in a higher change from baseline (CFB) in FEV(1) at 12 weeks compared to FOR/BUD 9/160 μg (difference in CFB 0.11 L [95% credible intervals: 0.08, 0.13]) and FOR/BUD 9/320 μg (0.09 L [0.06, 0.11]) and was comparable to SAL/FP 50/250 μg (0.02 L [-0.04, 0.08]) and SAL/FP 50/500 μg (0.03 L [0.00, 0.06]). Similar results were observed for indacaterol 300 μg at 12 weeks and indacaterol 150/300 μg at 6 months. Indacaterol 150 μg demonstrated comparable improvement in SGRQ total score at 6 months versus FOR/BUD (both doses), and SAL/FP 50/500 μg (-2.16 point improvement [-4.96, 0.95]). Indacaterol 150 and 300 μg demonstrated comparable TDI scores versus SAL/FP 50/250 μg (0.21 points (-0.57, 0.99); 0.39 [-0.39, 1.17], respectively) and SAL/FP 50/500 μg at 6 months.
CONCLUSION: Indacaterol monotherapy is expected to be at least as good as FOR/BUD (9/320 and 9/160 μg) and comparable to SAL/FP (50/250 and 50/500 μg) in terms of lung function. Indacaterol is also expected to be comparable to FOR/BUD (9/320 and 9/160 μg) and SAL/FP 50/500 μg in terms of health status and to SAL/FP (50/250 and 50/500 μg) in terms of breathlessness.
Comments: Indacaterol is a once daily long acting beta agonist that will add to the options for treating COPD. The results of this study suggesting that it is at least not inferior to any of the combination formulations with regard to largely measures of bronchodilation indicates that it may be useful in patients with milder disease without a significant history of exacerbations. The study's results are difficult to interpret however given that the trials studied were not direct head to head comparisons and that there could many differences between trials in terms of patient selection and other factors that render the comparisons suboptimal.
Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. A. Oaseem, T.J. Wilt, S.E. Weinberger, N.A. Hanania, G. Criner, T. van der Molen, D.D. Marciniuk, T. Denberg, H. Schunemann, W. Wedzicha, R. Macdonald, P. Shekelle; for the American College of Physicians, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society. Ann Intern Med. 2011 Aug 2;155(3):179-191.
DESCRIPTION: This guideline is an official statement of the American College of Physicians (ACP), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), and European Respiratory Society (ERS). It represents an update of the 2007 ACP clinical practice guideline on diagnosis and management of stable chronic obstructive pulmonary disease (COPD) and is intended for clinicians who manage patients with COPD. This guideline addresses the value of history and physical examination for predicting airflow obstruction; the value of spirometry for screening or diagnosis of COPD; and COPD management strategies, specifically evaluation of various inhaled therapies (anticholinergics, long-acting β-agonists, and corticosteroids), pulmonary rehabilitation programs, and supplemental oxygen therapy. Methods: This guideline is based on a targeted literature update from March 2007 to December 2009 to evaluate the evidence and update the 2007 ACP clinical practice guideline on diagnosis and management of stable COPD. Recommendation 1: ACP, ACCP, ATS, and ERS recommend that spirometry should be obtained to diagnose airflow obstruction in patients with respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). Spirometry should not be used to screen for airflow obstruction in individuals without respiratory symptoms (Grade: strong recommendation, moderate-quality evidence). Recommendation 2: For stable COPD patients with respiratory symptoms and FEV(1) between 60% and 80% predicted, ACP, ACCP, ATS, and ERS suggest that treatment with inhaled bronchodilators may be used (Grade: weak recommendation, low-quality evidence). Recommendation 3: For stable COPD patients with respiratory symptoms and FEV(1) <60% predicted, ACP, ACCP, ATS, and ERS recommend treatment with inhaled bronchodilators (Grade: strong recommendation, moderate-quality evidence). Recommendation 4: ACP, ACCP, ATS, and ERS recommend that clinicians prescribe monotherapy using either long-acting inhaled anticholinergics or long-acting inhaled β-agonists for symptomatic patients with COPD and FEV(1) <60% predicted. (Grade: strong recommendation, moderate-quality evidence). Clinicians should base the choice of specific monotherapy on patient preference, cost, and adverse effect profile. Recommendation 5: ACP, ACCP, ATS, and ERS suggest that clinicians may administer combination inhaled therapies (long-acting inhaled anticholinergics, long-acting inhaled β-agonists, or inhaled corticosteroids) for symptomatic patients with stable COPD and FEV(1)<60% predicted (Grade: weak recommendation, moderate-quality evidence). Recommendation 6: ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe pulmonary rehabilitation for symptomatic patients with an FEV(1) <50% predicted (Grade: strong recommendation, moderate-quality evidence). Clinicians may consider pulmonary rehabilitation for symptomatic or exercise-limited patients with an FEV(1) >50% predicted. (Grade: weak recommendation, moderate-quality evidence). Recommendation 7: ACP, ACCP, ATS, and ERS recommend that clinicians should prescribe continuous oxygen therapy in patients with COPD who have severe resting hypoxemia (Pao(2) ≤55 mm Hg or Spo(2) ≤88%) (Grade: strong recommendation, moderate-quality evidence).
Comment: It is interesting to note that in these guidelines supported by ATS and ERS that the cutoff of < 60% predicted is being used as opposed to previous guidelines that used cut offs of 50 to 80% predicted and < than 50% predicted for certain treatment options such as long acting bronchodilators or use of corticosteroids for exacerbations respectively. It is instructive and helpful to see this consensus statement from these major societies understanding that guidelines are only guidelines and we still need to individualize patient care.
Treating the systemic effects of chronic obstructive pulmonary disease. C.F. Vogelmeier, E.F. Wouters. Proc Am Thorac Soc. 2011 Aug;8(4):376-9.
Many patients with chronic obstructive pulmonary disease (COPD) also suffer from other disorders that are considered to be comorbidities and that may have a major impact on morbidity and mortality. So far, it is not clear if these diseases in the context of COPD need specific drugs or if patients diagnosed with COPD should receive certain medications to prevent the development of systemic effects of COPD. Cachexia may be caused by many contributing factors and thus may prove to be very difficult to reverse. For the treatment of osteoporosis in patients with COPD, treatment recommendations have been published. COPD is associated with reduced systemic levels of vitamin D, which has not only calcemic, but also extracalcemic effects that may play a role in the development of COPD and its consequences. Available evidence suggests that statins have a high potential, although definitive studies have not been published yet. Physical inactivity may be a major cause for systemic inflammation. In turn, exercise training may be an effective form of therapy. Although smoking cessation is very effective, it is not successful in the majority of cases.
Comment: It is now generally accepted that patients who develop lung disease as a result of cigarette smoking are also at increased risk of developing several extrapulmonary manifestations either as comorbidities or complications of their lung disease. This is a very concise yet instructive review of the underlying pathogenesis and potential interventions that can be instituted to mitigate the development of these systemic effects.