Editorials

Preventing exacerbations of chronic bronchitis and COPD

Two recent Cochrane reviews report effective regimens

Papers p 1271

Exacerbations of chronic obstructive pulmonary disease affect quality of life and the cost of managing the disease. Though the long term effects of hypersecretion on the deterioration of ventilatory function in patients with chronic obstructive pulmonary disease have been debated for many years,¹ recent data show a good correlation between hypersecretion and long term deterioration of ventilatory function in these patients.² This is why mucolytics, which seem to have an effect on hypersecretory exacerbations,³ might also influence disease progression in chronic obstructive pulmonary disease. Exacerbations are important events for patients with chronic bronchitis in that they negatively affect quality of life.¹ Exacerbations also have socio-economic consequences.² Therapies aiming at reducing the occurrence and severity of exacerbations are therefore of interest.

The Cochrane review in this week's issue of the BMJ reports a meta-analysis of drugs considered to have mucolytic effects (p 1271).³ Twenty two studies of 10 drugs were included. Treated patients showed a significant reduction over controls in the number of exacerbations (about 0.5 per 6 months) and number of days each exacerbation lasted. No difference in lung function or in adverse effects was seen.

The studies included in the review used different definitions for an exacerbation of chronic bronchitis. In some the presence of mucopurulent or purulent sputum was an obligatory criterion, while in others it was not. The presence of purulent sputum indicates that bacteria may be an important contributing factor to the exacerbation. Effects in studies with such definitions might suggest that the drug has a protective effect against bacterial colonisation and infection of the bronchi, while that is less clear for studies with other definitions.

The drug contributing most to the beneficial results in this review seems to be acetylcysteine (12 studies). However, the mucolytic activity of acetylcysteine is not well documented in chronic bronchitis,⁴ and after oral administration acetylcysteine cannot be shown in bronchial secretions.⁵ Another possible mechanism might be an antioxidative effect; this has been proposed because acetylcysteine or one of its metabolites, glutathione, is a free thiol. A similar substance with higher levels of free thiols did not, however, have any effect on the number of exacerbations,⁶ making the free thiol hypothesis unlikely.

Acetylcysteine treatment has been reported to be negatively related to intrabronchial bacterial presence in patients with chronic bronchitis,⁷ possibly because it reduces the ability of bacteria to adhere to epithelial cells.⁸ Oral therapy might thus theoretically reduce the presence of pathogens in the oropharyngeal cavity, the reservoir for bronchial bacterial colonisation and infection. Interestingly, however, application of  streptococci to the oropharynx after antibiotic therapy in children with repeated episodes of otitis led to a reduced rate of relapse.⁹ This indicates that a normal oropharyngeal flora is an important part of the defence against colonisation and infection of adjacent serous membranes. Ambroxol is another drug studied in this meta-analysis for which alternative explanations for its exacerbation-reducing effect can be envisaged. It is, for example, a secretagogue for surfactant, and surfactant contains substances with antibacterial properties.¹⁰ Ambroxol also has antioxidative properties.¹¹ There is therefore reason to doubt that the exacerbation-reducing effect of the drugs included in this meta-anlysis is due to their mucolytic effects.

The clinical use of acetylcysteine in patients with chronic bronchits and chronic obstructive pulmonary disease varies throughout Europe, probably because of different interpretations of single studies. This systematic reviewwith its overall finding of a protective effect on exacerbationsis therefore important. Because bacterial infection is an important cause of exacerbations in chronic bronchitis, antibiotic therapy has been the mainstay of therapy. This week's review, however, suggests that we should pay more attention to preventing exacerbations. Interestingly, other prophylactic measures have also been evaluated recently.

Orally administered bacterial lysates that stimulate immune defence have been used in southern Europe for several years. OM 85 BV, a lysate of eight pulmonary pathogens, has also been evaluated in a meta-analysis, which showed a reduction in exacerbations by 0.6 per 6 months.¹² A large and important study published recently also showed a reduction in hospital admissions in patients with chronic obstructive pulmonary disease after treatment with OM 85 BV.¹³ An oral "vaccine" of whole killed bacteria of non-typeable Haemophilus influenzae was evaluated in a recent Cochrane review of six clinical studies.¹⁴ The reviewers conclude that treatment in the autumn reduces the number and the severity of exacerbations of chronic bronchitis. Interestingly these therapeutic possibilities have provoked almost no interest in Scandinavian countries, possibly because none of the research has been performed in Scandinavia.

The present Cochrane report, together with that on oral vaccination with whole killed Haemophilus influenzae and the meta-analysis of treatment with OM 85 BV, indicates that different therapeutic regimes might be valuable in preventing exacerbations in chronic bronchitis and chronic obstructive pulmonary disease. This is interesting clinically as prophylaxis may be cost effective.¹² It is also of great theoretical interest and should stimulate studies on possible mechanisms, effects on health related quality of life, and prognosis..

Ann Ekberg-Jansson, scientist. 
Sven Larsson, professor. 
Claes-Göran Löfdahl, professor. 

Department of Allergology and Pulmonary Medicine, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden

Footnotes

   CGL has institutional support from AstraZeneca, GlaxoSmith Klein, and MSD and has received lecture fees from these companies and Boehringer-Ingelheim, Novartis, and Orion.