COPD: A Dust-Induced Disease?; C. E. Girod and T. E. King, Jr. (Chest 2005; 128(4):3055–3064).
Abstract: Various reports have demonstrated the importance of small airway inflammation in the development of airflow limitation and progression of COPD. This hypothesis proposes that the pathogenesis of COPD mirrors a chronic inhalational dust-induced disease. The putative inorganic dust in cigarette smoke is aluminum silicate or kaolinite, a common component of clay soils. Kaolinite has been recovered in the alveolar macrophages of smokers and has been reported as a constituent of tobacco products. The origin of kaolinite in tobacco products remains unknown, and possible potential sources are proposed. On inhalation, kaolinite deposition in the distal lung may promote macrophage accumulation within the terminal airways, leading to a respiratory bronchiolitis. In the susceptible smoker, important genetic, environmental, immunologic, and mechanical factors interact and modulate this small airway, inflammation, ultimately leading to the pathologic lesion of emphysema. Further studies into the effects of kaolinite on macrophage function and the subsequent development of respiratory bronchiolitis could lead to prevention of COPD at its precursor lesion.
Comments: Drs, Girod and King present a concise, yet compelling, summary of the evidence that the pathogenesis of COPD may be related to the inflammatory response and resultant respiratory bronchiolitis from exposure to aluminum silicate. The fact that inflammation may be induced by particulate components that remain resident in the lung and are slowly eliminated over time may explain the persistence and indeed increase in certain inflammatory markers following smoking cessation that have been reported in other studies. This study also reinforces the fact that there are 5%–10% of individuals with COPD who are non-smokers and develop the disease likely as a result of occupational and environmental exposures. The observations and hypotheses presented in this paper present a plausible link between these individuals and those who develop COPD as a result of cigarette smoking.
Epidemiological Relationships Between the Common Cold and Exacerbation Frequency in COPD; J. R. Hurst, G. C. Donaldson, T. M. Wilkinson, W. R. Perera, J. A. Wedzicha (J. Eur. Respir J. 2005; 26(5):846–852).
Abstract: Higher exacerbation incidence rates in chronic obstructive pulmonary disease (COPD) are associated with more rapid decline in lung function and poorer quality of life, yet the mechanisms determining susceptibility to exacerbation remain ill-defined. The same viruses responsible for common colds are frequently isolated during exacerbations. The current authors hypothesised that exacerbation frequency may be associated with an increased frequency of colds, and investigated whether increased exacerbation frequency was associated with increased acquisition of colds, or a greater likelihood of exacerbation once a cold has been acquired. A total of 150 patients with COPD completed diary cards recording peak expiratory flow, and respiratory and coryzal symptoms for a median 1,047 days. Annual cold and exacerbation incidence rates (cold and exacerbation frequency) were calculated, and the relationships between these variables were investigated. This analysis is based on 1,005 colds and 1,493 exacerbations. Frequent exacerbators (i.e., those whose exacerbation frequency was greater than the median) experienced significantly more colds than infrequent exacerbators (1.73 versus 0.94.yr(−1)). The likelihood of exacerbation during a cold was unaffected by exacerbation frequency. Patients experiencing frequent colds had a significantly higher exposure to cigarette smoke (46 versus 33 pack-yrs). Exacerbation frequency in chronic obstructive pulmonary disease is associated with an increased frequency of acquiring the common cold, rather than an increased propensity to exacerbation once a cold has been acquired.
Comments: This study demonstrates that subjects who have frequent exacerbations are more prone to colds and that subjects with frequent colds have higher levels of exposure to cigarette smoke. It suggests that there are characteristics of subjects with frequent exacerbations that make them more susceptible to respiratory tract infections of all kinds. Further study and understanding such factors may lead to novel therapeutic interventions to reduce exacerbations.
Roflumilast—An Oral Anti-Inflammatory Treatment for Chronic Obstructive Pulmonary Disease: A Randomised Controlled Trial; K. F. Rabe, E. D. Bateman, D. O'Donnell, S. Witte, D. Bredenbroker, T. D. Bethke (Lancet. 2005; 366 (9485): 563–571).
Background: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD. Methods. This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting; 1411 patients with COPD were randomly assigned roflumilast 250 μg (n = 576), roflumilast 500 μg (n = 555), or placebo (n = 280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat. Findings. 1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the roflumilast 250 μg group, and 124 (22%) from the roflumilast 500 μg group. Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 μg (by 74 mL [SD 18]) and roflumilast 500 μg (by 97 mL [18]) compared with placebo (p < 0.0001). Improvement in health-related quality of life was greater with roflumilast 250 μg (−3.4 units [0, 6]) and roflumilast 500 μg (−3.5 units [0, 6]) than with placebo (−1.8 units [0, 8]), although the differences between treatment groups were not significant. The mean numbers of exacerbations per patient were 1.13 (2.37), 1.03 (2.33), and 0.75 (1.89) with placebo, roflumilast 250 μg, and roflumilast 500 μg, respectively. Most adverse events were mild to moderate in intensity and resolved during the study. Interpretation. Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.
Comments: It is clear that COPD involves an inflammatory response that is distinct from that of asthma and is less responsive to corticosteroids. While the role and relative contribution of airway inflammation in the pathogenesis of the airway and parenchymal changes that occur in COPD remain to be fully elucidated, investigators have begun to look at novel agents such as PDE4 inhibitors like Roflumilast that may better target the inflammatory component. The improvements in FEV1 are modest though statistically significant in this study of over 1000 subjects on either 500 or 250 μg of Roflumilast versus 280 subjects on placebo. In contrast to pivotal studies that have been recently published examining LABA/ICS or long acting anticholinergics in treatment of COPD this study excluded patients with greater than 12% reversibility at baseline, which may explain the relatively modest improvements in FEV1. It should be noted that a greater number of patients withdrew in the treatment arms 17% in the 250 μg group, 22% in the 500 μ g group versus 11% in the placebo group. Diarrhea was the most common adverse event felt attributable to the study medication over placebo. Studies of longer duration and with broader outcome measures are required to clarify the potential role of this class of drugs in COPD.
Effect of 1-Year Smoking Cessation on Airway Inflammation in COPD and Asymptomatic Smokers; B. W. Willemse, N. H. Ten Hacken, B. Rutgers, I. G. Lesman-Leegte, D. S. Postma, W. Timens (Eur. Respir. J. 2005; 26(5):835–845).
Smoking cessation is the only treatment in patients with chronic obstructive pulmonary disease (COPD) effective in slowing down disease progression. Its effect on airway inflammation in COPD is unknown, although cross-sectional studies suggest ongoing inflammation in ex-smokers. To elucidate the effect of smoking cessation on airway inflammation, 28 smokers with COPD (mean age: 55 yrs; forced expiratory volume in 1 second: 71% predicted) and 25 asymptomatic smokers with normal lung function (aged 50 yrs) were included in a 1-yr smoking cessation programme. Effects of smoking cessation on airway inflammation were investigated in bronchial biopsies (baseline, 12 months) and sputum samples (baseline, 2, 6 and 12 months). In the 12 candidates with COPD who successfully ceased smoking, airway inflammation persisted in bronchial biopsies, while the number of sputum neutrophils, lymphocytes, interleukin (IL)-8 and eosinophilic-cationic-protein levels significantly increased at 12 months. In the 16 asymptomatic smokers who successfully quitted, inflammation significantly reduced (i.e., number of sputum macrophages, percentage of eosinophils and IL-8 levels) or did not change. The current authors suggest that the observed persistent airway inflammation in patients with chronic obstructive pulmonary disease is related to repair of tissue damage in the airways. It remains to be elucidated whether this reflects a beneficial or detrimental effect.
Comments: Willemse and colleagues address a very important issue with regard to the impact of smoking cessation on airway inflammation. This is one of the few prospective studies to examine the change in airway inflammatory characteristics following smoking cessation. It is interesting to note that the patients with COPD who successfully quit smoking for the 12-month period had an increase in certain inflammatory markers in sputum and no change in bronchial biopsies, while the asymptomatic smokers had a decrease in certain inflammatory markers in the sputum. The authors offer several hypotheses as possible explanations for their observations that vary from increased elimination rates of inflammatory cells following smoking cessation to the possibility of cigarette smoke containing anti-inflammatory factors. This is a very important observation and needs to be studied further to assist in clarifying the role of airway inflammation in airway remodeling in COPD. Such work is key to understanding the potential value of developing novel targeted anti-inflammatory therapy for COPD.