Is Chlamydia pneumoniae Important in Asthma?
The First Controlled Trial of Therapy Leaves the Question Unanswered

Sebastian L. Johnston, Ph.D.

National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science Technology and Medicine, London, U.K.

	ARTICLE

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Chlamydia pneumoniae is a new respiratory pathogen, discovered in 1986 (1). Serologic studies indicate the prevalence of infection with C. pneumoniae to be high, with the majority of adults having evidence of past infection (2). Although many infections are believed to be asymptomatic (3), C. pneumoniae infection is clearly related to atypical pneumonia (4) and possibly ischemic heart disease (5). Serologic studies have also associated this organism with some exacerbations of asthma (6), though further studies using direct detection techniques are needed to more precisely define its role in asthma exacerbations.

Of perhaps more interest are data implicating C. pneumoniae in new-onset asthma in adulthood (7, 8) and in the pathogenesis of chronic stable asthma: serologic studies suggest a role for C. pneumoniae in the pathogenesis of severe asthma (9) and a dose-response relationship between the serologic response to C. pneumoniae and the severity of asthma (10). Although all these studies have been based on serologic tests, which cannot reliably differentiate between past, recent, and current infection and which may be cross-reactive with other Chlamydia species, they do provide some evidence that C. pneumoniae may play a role in new-onset and chronic stable asthma in adults.

The role of C. pneumoniae infection in stable childhood asthma was investigated using the polymerase chain reaction (PCR) to confirm the presence of the organism in nasal aspirate specimens. There was a high prevalence of chronic low-grade C. pneumoniae infection when asymptomatic (28%) and a relationship between local C. pneumoniae-specific IgA and asthma severity in terms of exacerbation frequency (11). These data implicate C. pneumoniae infection in asthma pathogenesis, however there are no published studies using direct detection to investigate the presence of C. pneumoniae in the lower airways of either adults or children to confirm whether C. pneumoniae plays a role in the pathogenesis of chronic stable asthma. Despite the inconclusive data on the possible role of C. pneumoniae in the pathogenesis of chronic stable asthma, this edition of the journal contains a report of the first randomized, placebo-controlled trial on the effect of therapy against C. pneumoniae in this setting (pp. 536-541) (12).

To propose a causal relationship between an infectious agent and a chronic disease, either the agent must provoke an abnormal immunopathologic host response to infection in susceptible subjects (for which there is no evidence in the case of C. pneumoniae and asthma), or three requirements should be met: the agent should be detected at increased frequency in subjects with the disease compared with normal subjects; its presence should bear a relationship with disease severity; and successful therapy directed against the agent should have clinical benefit in the disease. Although, with regard to C. pneumoniae, the first two requirements have not been met, the authors of this study are to be congratulated for being the first to investigate the third requirement.

The study investigated adult subjects with chronic stable asthma with serologic evidence of C. pneumoniae infection. The double-blind, placebo-controlled treatment was roxithromycin 150 mg twice a day for 6 wk and subjects were then followed for 6 mo to determine whether any benefit associated with treatment was maintained after cessation of therapy. There was a small but significant improvement in evening peak expiratory flow at the end of therapy (difference between treatment and placebo groups: 12 L/min [3% predicted], p < 0.02). However, this was not maintained during the follow-up period off treatment as both groups had similar lung function again at 6 mo. There were trends in favor of treatment, but no significant benefit, in terms of symptoms and quality of life.

Possible interpretations of these data are that treatment of C. pneumoniae infection resulted in the clinical benefit observed at the end of treatment, but that reinfection after cessation of treatment resulted in the loss of benefit during follow-up. However, because there was no direct evidence of infection and macrolides are known to possess anti-inflammatory activities unrelated to their antimicrobial activity, it is equally possible that the treatment benefit resulted from anti-inflammatory activity in patients who were not actively infected with C. pneumoniae. Unfortunately, it is only possible to speculate about these possibilities, as the study design did not include demonstration by direct detection (culture and/or PCR) that the subjects were infected at recruitment, whether treatment eradicated the organism, and whether cessation of treatment was followed by reestablishment of infection. Similarly, the study did not include a control group of asthmatic patients with asthma of similar severity but without serologic evidence of C. pneumoniae infection to determine whether observed effects were a result of anti-inflammatory activity.

Thus, of the important questions relating to the role of C. pneumoniae in stable asthma (whether C. pneumoniae is detected at increased frequency in asthmatic compared with normal subjects, whether its presence bears a relationship with disease severity, and whether successful antimicrobial therapy has clinical benefit), the first two have not yet been properly addressed and the last remains unanswered by the present study. Although roxithromycin did appear to have some clinical benefit in these patients with stable asthma, its effects were small and only apparent during continued therapy. Use of macrolide antibiotics is therefore not recommended for stable asthma in clinical practice until further studies identify patient groups that respond to therapy, how long therapy is required, what the cost/benefit ratio of treatment is, and what the costs are in terms of emergence of resistant bacteria. There is also an urgent need for carefully designed controlled studies to investigate the possible role of C. pneumoniae in new-onset asthma, where if proven, the potential benefits of treatment may be greater than in stable chronic disease.

The main achievements of the present study are to further raise the issue of the possible role of C. pneumoniae in asthma and to point to aspects of study design that need to be carefully considered in future similar studies (it is acknowledged that when the foregoing study was designed, PCR detection was only available in a very small number of research laboratories). Most importantly, such studies should include direct evidence of infection at recruitment, direct investigation of eradication of infection, investigation of possible reinfection using the extended follow-up employed in this study, and preferably a control group of non-infected patients of similar severity to assess any anti-inflammatory component of treatment.

	References

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