RICERCA ITALIANA     

BRONCHIECTASIS IN COPD PATIENTS : PREVALENCE AND BACTERIAL COLONIZATION.

Università degli Studi di Milano

Abstract

Bronchiectasis is a chronic pulmonary disease characterized by an irreversible dilatation of the bronchi. The current view of the pathogenesis of bronchiectasis considers initial colonization of the lower respiratory tract by different microorganisms as the first step leading to an inflammatory response characterized by neutrophil migration within the airways and secondary secretion of a variety of tissue-damaging oxidants and enzymes such as neutrophil elastase and myeloperoxidase. Persistence of microorganisms in the airways because of impairment in mucus clearance may lead to a vicious circle of events characterized by chronic bacterial colonization, persistent inflammatory reaction, and progressive tissue damage.
The exact prevalence of bronchiectasis in COPD patients is not known. It would be important to assess the prevalence, the kind of bronchiectasis and the bacterial colonisation. These are all important features that can be related to the natural history of COPD and to the therapeutic management of patient with COPD and bronchiectasis. Recent data indicate that macrolide long-term treatment and inhaled steroids therapy are both associated with a reduced rate of exacerbation, bronchial colonization and inflammation
The present study will address, on a relatively large number of patients, the prevalence of bronchiectasis in COPD subjects using a multislice CT scan technique applied in all the units and centrally analysed by Unit 2 and 4. This analysis will determine the presence and the morphology of bronchiectasis. Bacterial colonization and inflammatory parameters will be evalutaed on blood and exhalate bronchial condensate. Concerning bacterial colonization molecular biology techniques (Qualitative PCR and quantitative real time PCR) will be applied (UO1). ELISPOT technique for the evaluation of specific immune response will be used (UO2). Electron and optical microscopy techniques will be applied on bronchial biopsy samples obtained in a subgroup of patients enrolled by UO 3. Patients enrolled by UO 5 will undergo cardiopulmonary stress testing and 6MWT. During the second study year, a randomized trial on patients with bronchiectasis will be performed. Patients will be randomized to receive a macrolide or inhaled steroids or standard of care for 6 months with a follow-up of 6 months. All the inflammatory, microbiologic and functional parameters decribed above will be recorded. A clinical and functional evaluation will be applied looking to number of exacerbations, quality of life, respiratory function parameters. <<<

Principal Investigator

Francesco BLASI Università degli Studi di MILANO

Research Objectives

The research programm aims are the following:
-definition of bronchiectasis prevalence in patients affected by chronic obstructive pulmonary disease. Only few data on this issue are present in the literature .
-After bronchiectasis patients identification, we will evaluate the pathophysiologic implications, and microbiologic and inflammatory features of this subgroup in comparison to non-bronchiectasis patients.
-The interventional phase of the research will address the effects of long-term treatments with inhaled steroids and antibiotic on the natural history of the disease and their pathophysiologic implications. <<<

Timescale

24 months

National and international background

Bronchiectasis is a chronic pulmonary disease characterized by an irreversible dilatation of the bronchi. The current view of the pathogenesis of bronchiectasis considers initial colonization of the lower respiratory tract by different microorganisms as the first step leading to an inflammatory response characterized by neutrophil migration within the airways and secondary secretion of a variety of tissue-damaging oxidants and enzymes such as neutrophil elastase and myeloperoxidase (1). Persistence of microorganisms in the airways because of impairment in mucus clearance may lead to a vicious circle of events characterized by chronic bacterial colonization, persistent inflammatory reaction, and progressive tissue damage.
Chronic obstructive pulmonary disease or COPD is characterised by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lung. The natural history of COPD is punctuated by acute exacerbations. COPD is a highly prevalent condition which generates a major consumption of resources. A large part of these resources goes to the treatment of exacerbations, which have also been shown to have a negative impact on the course of the disease and on mortality in these patients (2).
Although not all exacerbations are bacterial in origin, bacterial exacerbations are associated with the highest inflammatory response in the bronchi (3). Recurrent exacerbations with associated bronchial inflammation have an impact on patient quality of life (4) and accelerate the decline in pulmonary function of patients with COPD (5). Therefore, prevention of exacerbations should be a main objective in the management of COPD.
Evidence for antibiotics used as prophylaxis in COPD is not recent and stems from 1950s-1960s. A recent Cochrane review in 2003 (6) found 29 such studies out of which 9 studies were included in the review. Many of the studies recruited men who were in the workforce, hence the study population were likely to have mild to moderate disease. This contrasts with more recent studies using inhaled steroids and antibiotics, which show a much greater benefit in more severe disease. Conclusions of the review were that a small reduction in the frequency of exacerbations was observed with prophylactic antibiotics but this was not statistically significant. The authors added that due to the change in the prevalence of resistant bacteria these studies would have to be repeated in the current environment. Due to the lack of recent data, guidelines from respiratory societies do not currently advocate the use of antibiotics in a prophylactic manner. Recently the FDA has also suggested that future trials of antibiotic usage in chronic bronchitis could explore the potential of intermittent suppressive therapy (7).

Not only exacerbations, but bronchial colonisation itself may injure the lung tissues. Studies using bronchoscopic techniques have demonstrated that aproximately 50% of patients with moderate to severe COPD are chronically colonised by potentially pathogenic microorganisms in significant concentrations (8). Chronic colonisation of the respiratory tract in COPD induces a chronic sub-clinical inflammatory process that results in the release of bacterial and host inflammatory substances that further injure the already damaged respiratory epithelium (9). Furthermore, the intensity of the inflammatory response is directly related to the bacterial load in the lower airways (10). This on-going, sub-clinical destruction of the tracheo-bronchial tree is perhaps most evident in the host's inability to deal with minor respiratory viral infections and environmental irritants, which clinically manifest as exacerbations. Therefore, it is reasonable to propose, that the primary focus of antibacterial therapy should not be the exacerbation, but minimizing the chronic, progressive destruction of the respiratory tract that results from the chronic bacterial colonization. On the other hand, there is growing evidence of a relationship between a greater bacterial load in the airways in the stable phase and a steeper decline in pulmonary function (11), which suggest a deleterious role of bronchial colonization in the evolution of COPD. In addition, bronchial colonisation is a demonstrated risk factor for frequent and more severe exacerbations (12), which, in turn, provoke increased impairment in pulmonary function.
Previous studies have shown an increased of several cytokines in these diseases, as interleukin-6 (IL-6) levels, IL-8 and TNF-a. (13,14)
These studies show that inflammatory markers can be detected in the respiratory tract using invasive techniques such as bronchoaleolar lavage or less invasive techniques such as induced sputum. However, these procedures cannot be repeated within a short period of time because they may induce an inflammatory response themselves and are relatively unacceptable for the patients
Exhaled condensate may contain molecules coming from the mouth (oral cavity and oropharynx), tracheobronchial system and alveoli, but their proportional contribution is still not clear. It is assumed that airway surface liquid becomes aerosolised during turbulent airflow and that the content of the condensate reflects the composition of airway surface liquid, although large molecules may not aerosolise as efficiently as those that are small and soluble (15).
Different studies have shown an increased levels of several inflammatory markers in the exhaled breath condensate of patients with many chronic respiratory disorders (16-19)
A strong correlation between the levels of CO2 and O2 in exhaled fluid and exhaled breath suggests that aerosol particles exhaled in human breath reflect the composition of the bronchoalveolar extracellular lining fluid (20).
In this respect, analysis of exhaled breath condensate may be useful as a non-invasive way of monitoring pulmonary conditions. Although simple and well accepted by patients, this technique has mainly been used for analysis of nitric oxide metabolites, 8-isoprostane, hydrogen peroxide, and various proinflammatory cytokines. Proteomic investigation (21) has enabled characterization of biological fluids, including serum, urine, cerebrospinal fluid, and bronchoalveolar lavage fluid (www. expasy.org). Although proteomic technology has been applied to exhaled breath condensate (22,23), prior studies have not identified proteins by mass spectrometry or other methods (24). Applying this technique our group recently demonstrated that the protein composition of exhaled breath condensates from smokers contained more than three times as much keratin as did condensates from non-smokers (25).
The exact prevalence of bronchiectasis in COPD patients is not known. It would be important to assess the prevalence, the kind of bronchiectasis and the bacterial colonisation. These are all important features that can be related to the natural history of COPD and to the therapeutic management of patient with COPD and bronchiectasis. Recent data indicate that macrolide long-term treatment and inhaled steroids therapy are both associated with a reduced rate of exacerbation, bronchial colonization and inflammation (26,27). <<<