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Conclusions

Coronary artery disease and cerebro-vascular stroke are among the commonest causes of death world wide. Any new approach to the prevention of these conditions would be enormously attractive, not least to physicians, research grant seekers and antibiotic manufacturers. Since the temptations are great, any change in the preventive management of these conditions in apparently healthy people must be rigorously supported by hard evidence over sufficient follow up time if mistakes in other fields are not to be repeated [see: Sackett, 2002; Lagro-Janssen et al., 2003 on hormone replacement therapy]. Meanwhile, a key question is whether C. pneumoniae plays a causal role in these conditions, or is simply associated with them because it has a predilection for damaged tissue (the hitch-hiker hypothesis).

Classically, evidence for acute infection and disease causality has been enshrined in fulfilment of so-called Koch's postulates . These, among other things, state that the organism should be recoverable from the site of the disease, should be capable of inducing similar disease in appropriate experimental animals etc. The special features of C. pneumoniae that make it a candidate as a cause for coronary artery disease are summarised in the figure. 

[MEW comment: Chlamydiologists tend to focus on chlamydiae.  It is important not to forget  that other infections, with good reason, are also implicated in the pathogenesis of coronary artery disease. The work of Espinola-Klein et al., 2002 and of Ruprecht et al., 2001, who showed a dose-related effect of increasing infectious disease burden seems to me the right conceptual approach, although I have problems with the methodology].

C. pneumoniae has only occasionally, but not consistently, been isolated by culture from atheromatous arteries  making Koch's postulates of disease causality difficult to fulfil. It has been questioned whether Koch's postulates are appropriate as criteria for the role of infection in the causation of chronic disease [Shor et al., 1998] .  These last authors refer to an earlier paper by Hill 1965, which suggests that disease associations might be tested for causality on the basis of strength, consistency, temporarilty, coherence, analogy and biological gradient. On this basis there is no doubt that there is a consistent association of C. pneumoniae with coronary artery disease. Consistency of association with chronic neurological diseases remains to be established. The strength of the association with coronary artery disease had an odds ratio of approximately 1.5, in a recent meta-analysis of prospective serological studies. However, it is paradoxical that, while the original association between C. pneumoniae infection and coronary heart disease was discovered by serology, the largest and most powerful recent studies show a weak or minimal effect [see: serological evidence]. In contrast, an odds ration of approximately 20 overall has been reported for the direct detection of the organism by PCR or immunocytochemistry in diseased cardiovascular tissue [Danesh et al., 2000]. Some of the reasons for this huge discrepancy are summarised below, together with the potential implications for ongoing studies of the possible preventable effect of anti-chlamydial antibiotics on coronary artery disease:

Overall, it seems most likely that the contribution of C. pneumoniae to coronary artery disease is more accurately reflected by the extensive prospective serological studies, (which indicate a weak association), rather than by the pathology studies, which indicate an extremely strong association, which, were it true, should by now be self-evident from other data. 

In terms of temporality it is feasible that C. pneumoniae might be a cause or significant exacerbating factor in  atherosclerosis, as the organism is found in cardiovascular tissue relatively early in life, in teenage persons [Taylor-Robinson & Thomas, 1998]. Evidence of a biological gradient is more controversial. This laboratory found little association between the distribution of C. pneumoniae DNA within an individual and the severity of atheromatous disease [Thomas et al., 1999]. However others have reported such differences [see direct detection].  

In terms of coherence and analogy, experimental studies at the cellular level and in animals certainly suggest mechanisms by which C. pneumoniae might cause atherosclerosis or precipitate coronary heart disease as a result of persisting local antigenic stimulation. Many of these effects seem to be attributable to the inflammatory and immunomodulatory effects of lipopolysaccharide and are thus unlikely to be specific to C. pneumoniae. The extent to which infection might trigger lipid core formation in atheromatous plaque or cause actual plaque rupture and thrombosis leading to acute coronary heart disease has not been adequately researched. For reviews on the role of C. pneumoniae in coronary artery disease see Kalayoglu et al., 2002; Ngeh et al., 2002; Leinonen & Saikku., 2002.

Conclusion

Atheromatous plaque is commonly colonised with C. pneumoniae and this organism, among others, is thereby associated with coronary artery disease. Studies in animals have shown the potential of  C. pneumoniae to exacerbate coronary heart disease, but there is  little evidence as to whether this has any clinical significance in human disease. Future research needs to focus on the possibility that C. pneumoniae and other chronic bacterial pathogens may trigger acute coronary events, such as plaque rupture. Unfortunately, the present antibiotic trials may prove to lack sufficient power to answer these key issues and one major clinical trial has been abandoned for lack of positive results. In the overall context of risk factors for coronary artery disease it seems likely that the importance of C. pneumoniae and other bacteria as a trigger may be relatively small. Nevertheless coronary heart disease is an extremely common cause of death. Moreover any effect of bacterial infections on heart disease are potentially preventable. Even a small role for bacterial infections could be very significant in public health terms and as Leinonen and Saikku 2002 point out, the ultimate proof of a causal relationship would be the demonstration that C. pneumoniae vaccination can prevent disease. Meanwhile we can settle for clear demonstrated benefit of antibiotic in preventing coronary artery disease over a substantial follow up period. It is vital that the relationship of infection to coronary artery disease continues to be an active area for medical research.  

Data on the role of C. pneumoniae on other chronic diseases are sparse and, frequently, contradictory. It is therefore premature to draw any firm conclusions in this area.

[MEW] August 2004

NEXT: Infections index

Danesh, J., Whincup, P., Walker, M., Lennon, L., Thomson, A., Appleby, P.,  Wong, Y., Bernades-Silva, M. & Ward, M. E. (2000). Chlamydia pneumoniae IgG titres and coronary heart disease: prospective study and meta-analysis. British Medical Journal 2000;321:208-13.    Full article  

Espinola-Klein, C. et al.,  (2002). Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation 105, 15 - 21.

Hill, A. R. (1965). The environment and disease: association or causation? Proceedings of the Royal Society of Medicine 58, 295 - 300.

Kalayoglu, M. V., Libby, P. & Byrne, G. I. (2002). Chlamydia pneumoniae as an emerging risk factor in cardiovascular disease. JAMA. 288, 2724 - 2731. Full article

_{Lagro-Jenssen, T., Rosser, W. W. & van Weel, C. (2003). Commentary: Breast cancer and hormone replacement therapy: up to general practice to pick up the pieces. Lancet 362, 414 - 415.}

Leinonen, M. & Saikku, P. (2002). Evidence for infectious agents in cardiovascular disease and atherosclerosis. Lancet Infectious Disease 2, 11 - 17.

Ngeh, J., Anand, V. & Gupta, S. (2002). Chlamydia pneumoniae and atherosclerosis -- what we know and what we don't. Clinical Microbiology and Infection 8, 2 - 13.

Rupprecht, H. J. et al., (2001). Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. Circulation 104, 25 - 31. [Herpes viridae were particularly important].

Sackett, D. L. (2002). The arrogance of preventive medicine. Canadian Medical Association Journal 167, 363 - 364. Full article . Should be compulsory reading ;-)

Shor, A., Phillips, J. I., Ong, G., Thomas, B. J., Taylor-Robinson, D.. (1998). Chlamydia pneumoniae in atheroma: consideration of criteria for causality. Journal of Clinical Pathology 51, 812 - 817. Full article     

Taylor-Robinson D. & Thomas, B. J. (1998). Chlamydia pneumoniae in arteries: the facts, their interpretation, and future studies. Journal of Clinical Pathology 51, 793 - 797. Full article   [Good critical review]

Thomas, M., Wong, Y., Thomas, D., Ajaz, M., Tsang, V., Gallagher, P. J. et al. (1999). Relation between direct detection of Chlamydia pneumoniae DNA in human coronary arteries at postmortem examination and histological severity (Stary grading) of associated atherosclerotic plaque. Circulation 99, 2733 - 2766. Full article