OM-85 BV for COPD

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Exacerbations of chronic obstructive pulmonary disease (COPD) are a vexing subject. They occur often in patients with COPD and contribute substantially to the costs and reduced quality of life that characterize the disease, and are a major health problem because COPD is so common. However, we know less about them than we should. The cause of exacerbations is not known, though it is believed that infections of the airways frequently play an initiating role. It is not clear why some patients have frequent exacerbations while others do not. The influence of exacerbations on the course of the disease is also not clear; while death can occur during and perhaps because of an exacerbation, the best available data (1) suggests that exacerbation frequency does not influence the gradual decline in ventilatory function thought to be the hallmark of COPD. Treatment of exacerbations is empirical and bolstered by relatively few carefully controlled studies of adequate size; systemic steroids (2) and antibiotics (3) both appear to produce real benefit and constitute the backbone of therapy along with appropriate management of derangements of arterial blood gases.

In this issue of the American Journal of Respiratory and Critical Care Medicine, Collet and coworkers (4) report results that may represent a real advance in exacerbation management. In a prospective, randomized, double-blind placebo-controlled clinical trial, they found that patients with COPD had fewer hospitalizations when they were given OM-85 BV, an immunostimulatory agent, than when they were not. OM-85 BV is not a new drug, having apparently been available in Europe for some 20 years. It consists of extracts of eight kinds of bacteria thought to be important in respiratory infections and is administered orally. Its potential role in COPD has been studied previously, but published data have not been compelling and have tended to show that the incidence of exacerbations was reduced, which is not what Collet and colleagues found. This pedigree does not seem promising, so the study of Collet and colleagues merits close attention.

The investigators set out to examine the incidence of exacerbations, which is difficult. In patients with COPD, exacerbations occur with a frequency of approximately 0.1 per patient-month of observation (3, 4), so that a large group of patients must be followed for considerable periods to accumulate enough exacerbations to analyze. This requirement is further emphasized by the fact that exacerbation frequency varies widely among patients for reasons that are not readily discernible, but may relate to symptomatic definitions having different meanings to different patients. Collet and coworkers recruited 381 patients and followed them up for 6 months; this is a substantial series. To do this they used 12 clinical centers, so that patient numbers at some centers were smalla weakness largely vitiated by the fact that only 10 nurses saw the patients and collected the data. Presumably, the nurses were trained so that their execution of the protocol varied little. At randomization, the average patient had moderate to severe COPD, and the drug and placebo groups were similar. Follow up was very good, with 95% of the requisite patient contacts successfully completed. With similar patients at baseline and good follow up, differences between treatment groups were likely ascribable to the treatments being tested.

Exacerbations were defined in terms of symptoms, as changes in sputum quality or quantity plus one other symptom, plus evidence that the symptoms were regarded as "significant" by the patients. Examples of significance included unscheduled medical contacts and antibiotic use. One suspects that the latter were much more common than the former. Data regarding exacerbations were collected retrospectively by the nurses during regularly scheduled visits or telephone contacts. One can quibble with this; it seems likely that direct observation of the patients at the onset of exacerbations would have improved the sensitivity and/or specificity of the diagnosis. In any event, no difference in the incidence of exacerbations was observed between treatment groups. Indeed, it appears that the incidence differed so little that the investigators chose to do a careful "interim" analysis before embarking on the second year of the study. It was this analysis that revealed treatment related differences in hospitalization results.

These results are striking. In the placebo group 23.2% of the patients were hospitalized for a respiratory problem, while this was true for 16.2% of patients who had received OM-85 BV. The mean length of stay for respiratory hospitalizations was 11.3 days in patients on placebo and 6.4 days in those on OM-85 BV. While neither of these differences attained conventional levels of statistical significance, when multiplied to give the average aggregate hospitalization for each treatment group, the difference was significant by both statistical and clinical criteria: total days of hospitalization for respiratory problems in patients on OM-85 BV amounted to only about 45% of those of the control group. Whether a patient had been hospitalized or not was presumably ascertained by the nurses during scheduled contacts and was therefore retrospective, but it seems unlikely that hospitalizations were missed due to forgetfulness on the part of patients who were contacted on a monthly basis. Hospital charts were obtained and examined by a blinded panel of qualified people to determine the cause of the event. Finally, all hospitalizations were analyzed as well as those thought to be due to respiratory disease, and the difference in "non-respiratory" hospital days also favored OM-85 BV. The overall results were not due to atypical performance by a single large clinic, but were representative of results from essentially all clinics with substantial enrollment. Thus, the results seem robust, and bear on a clinical issue of great importance to the well-being of both the individual patient and the health care system as a whole.

Side effects of OMV were largely innocuous, amounting to a slight preponderance of gastrointestinal upset in OM-85 BV patients as opposed to control. OM-85 BV did not have consistent significant effects on steady state symptoms, quality of life, or lung function, which is not surprising, given the duration of the study. Collet and coworkers point out that their results may not be at serious variance with previous studies noting a decreased incidence of exacerbations, since their sensitivity may have been great enough to detect mild exacerbations in OM-85 BV treated patients that other studies missed.

If we accept that the study of Collet and colleagues was well done, what are its implications both in terms of our knowledge of COPD and of clinical practice? OM-85 BV does not appear to be a bacterial vaccine but is thought to function by activating pulmonary macrophages, increasing the ratio of CD4 to CD8 lymphocytes, and changing the level of a variety of cytokines in the lung. The changes are thought to be indicative of an increased level of host defense against a wide variety of pathogens including both viruses and bacteria (5). Thus, the protective effect of OM-85 BV implicates infection as an important player in the pathogenesis of exacerbations but does not indicate a specific class of infectious agent. If OM-85 BV in fact prevents severe exacerbations, it will be of great interest to see if it is capable of altering the course of COPD. That is, this agent may allow us to quantitate the influence of exacerbations upon the gradual, remorseless loss of lung function that is the defining characteristic of the disease. Perhaps one cautionary, though speculative, note should be made in this regard. Macrophages are also activated by cigarette smoke, and at least one theory in regard to the pathogenesis of emphysema revolves around lung destruction by mechanisms apparently designed to fight infection. Long-term studies of OM-85 BV may be of more than theoretical interest.

Should we begin to treat COPD patients with OM-85 BV? On the basis of the results of Collet and coworkers, which is to our knowledge the most rigorous study available, it would be very difficult to criticize someone who did just that. I am unaware of the price of OM-85 BV; but it seems unlikely that it is high enough to cancel the cost savings implicit in a halving of hospital days. As used by Collet and coworkers, OM-85 BV is relatively easy to administer, so it is likely that patient compliance would be as good as it is with theophylline therapy, for example. On the other hand, one is reluctant to recommend a significant change in therapy on the basis of a single study, even one as good at that of Collet and coworkers. I hope that this excellent study is repeated, and I believe that an examination of the long term effects of OM-85 BV in COPD would be worthwhile.

Faculty of Medicine
University of Manitoba
Winnipeg, Manitoba, Canada

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	References

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1. Fletcher, C. M., R. Peto, C. M. Tinker, and F. E. Speizer. 1976. Natural History of Chronic Bronchitis and Emphysema. Oxford University Press, Oxford.

2. Albert, R. K., T. R. Martin, and S. W. Lewis. 1980. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann. Intern. Med 92: 753-758 .

3. Anthonisen, N. R., J. Manfreda, C. P. W. Warren, E. S. Hershfield, G. K. M. Harding, and N. A. Nelson. 1987. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann. Intern. Med 106: 196-204 .

4. Collet, J. P., S. Shapiro, P. Ernst, P. Renzi, T. Ducruet, A. Robinson, et al . 1997. Effect of an immunostimulating agent on acute exacerbations and hospitalizations in COPD patients. Am. J. Respir. Crit. Care Med 156: 1719-1724 [Abstract/Free Full Text].

5. Emmerich, B., K. Pachmann, D. Milatovic, and H. P. Emslander. 1992. Influence of OM-85 BV on different humoral and cellular immune defense mechanisms of the respiratory tract. Respiration 59(Suppl. 3): 19-23.