Affiliations: Chandigarh, India
Dr. Jindal is Professor and Head of Pulmonary and Critical Care Medicine, Postgraduate Institute of Medical Education and Research.
Correspondence to: S.K. Jindal, MD, FCCP, Professor and Head, Department of Pulmonary Medicine, Postgraduate Institute of Medical, Education & Research, Chandigarh, India
Bronchoreversibility in COPD has remained a matter of debate ever since the known association of tobacco smoking with its pathogenesis and progression. What has remained enigmatic is the observation that not all smokers demonstrate a similar susceptibility to the decline in lung function and that bronchoreversibility in COPD patients is demonstrable only in a subgroup of patients. However, it is important to identify this subgroup of patients for making treatment decisions.
It has been proposed1that smokers with an allergic diathesis have a greater predisposition to develop severe and chronic airflow obstruction, what was popularly known as the “Dutch hypothesis.” Airway narrowing developed in hyperreactive individuals as the primary abnormality as a result of exposure to smoking or other environmental pollutants. This was contrary to the “British hypothesis,” which proposed chronic mucus hypersecretion as a marker of recurrent bronchial infections leading to chronic obstruction of the airways.2However, the infection hypothesis has been shown to be misconstrued by the findings of several subsequent reports.3 There was no demonstrable relationship shown between exacerbations of infections or their treatment and lung function decline.3–4
The Dutch hypothesis supported an implied relationship of asthma with COPD. Despite the known differences between COPD and asthma, smokers who show accelerated decline in FEV1 have marked similarities with asthma patients. There were earlier reports5–6 on demonstrable bronchial hyperreactivity, peripheral blood eosinophilia, and raised serum IgE levels in smokers compared to nonsmokers. Furthermore, the presence of eosinophils in peripheral blood was also shown to correlate with ventilatory impairment.5 Similar observations have been made in several studies.7–8 Eosinophilic inflammation of the airways in patients thus has been clearly defined in a subset of COPD patients. This is also the group of patients who are likely to show reversibility of airway obstruction with therapy with bronchodilators and/or antiinflammatory drugs, such as the corticosteroids.9
In this issue of CHEST (page 375), Perng et al have reported a significant relationship of bronchodilator reversibility in smoking-related COPD patients with sputum eosinophilia. Nonreversibility was associated with raised levels of neutrophils interleukin-8 and albumin in the sputum. It has been proposed that the assessment of inflammatory characteristics of induced sputum can be used to assess the bronchodilatory responsiveness in COPD patients.
Inflammation in COPD patients is complex and relatively more poorly understood than in asthma patients. The presence of inflammatory cells, proteolytic enzymes, and oxidative stress results in continued damage to the airways as well as to the alveolar walls.10The presence of almost all types of inflammatory cells, including the neutrophils, lymphocytes of both T and B origin, and alveolar macrophages, has been demonstrated in emphysema patients.11 These cells are responsible for the release of different cytokines, lipids, and growth factors that act as inflammatory mediators to cause damage.
The presence of eosinophils in the BAL fluid and bronchial biopsy specimens of COPD patients has been convincingly shown in many recent studies, although some investigators have failed to demonstrate their presence.12–13 The role of eosinophils in the pathogenesis of COPD also has been questioned, and it is proposed that the presence of eosinophils may only indicate the presence of coexisting asthma.9,14
The neutrophilic inflammation that occurs in response to noxious inhalational exposures of substances such as the tobacco smoke in COPD patients is corticosteroid-resistant.10 This is in sharp contrast to the situation with asthma patients, who are highly responsive to corticosteroids. COPD is primarily a disease of the peripheral airways and the lung parenchyma, while asthma involves all airways, but predominantly the intermediate and larger sized bronchi.
One might also postulate that COPD patients who show reversibility of airways obstruction are either asthmatic or atopic, and that they develop some degree of fixed obstruction due to prolonged inhalational insults, especially tobacco smoking. This group of patients are therefore liable to respond to treatment with both bronchodilators and corticosteroids, as has been shown in the article by Perng et al. The concept is somewhat analogous to the redefinition of the Dutch hypothesis, although several difficulties do continue to bother investigators.
The development of airway obstruction in smokers with atopy or asthma occurs earlier and in a more severe form than in other persons. But the clinical response of smokers to bronchodilator treatment is better. For example, the long-term improvements in dyspnea, health-related quality of life, and pulmonary function following 1 year of therapy with inhalational tiotropium were more pronounced in this group of patients than in those showing no bronchodilatory responsiveness.15 The reversibility of airflow obstruction also has been shown to be a predictor of better survival time in several studies.14–16
The presence of bronchodilatory reversibility in patients with eosinophilic inflammation who have COPD has practical and therapeutic implications. This group of patients needs to be clinically identified and more aggressively treated, in a similar manner to that of patients of bronchial asthma. But this does not bring us any nearer to the understanding of the pathogenesis of COPD, since patients who have predominant neutrophilic inflammation show no reversibility. These patients are generally nonresponsive to most treatments and continue to progress to respiratory failure. This is the group of “true COPD” patients who continue to pose a challenge.
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