Department of Respiratory Medicine, Birmingham Heartslands Hospital, Birmingham B9 5SS, UK
Chlamydia pneumoniae is a ubiquitous Gram-negative bacterium, an obligate intracellular parasite with a unique developmental cycle, and a common respiratory pathogen in children as well as adults. 1 There is now an impressive body of evidence to show that C. pneumoniae contributes significantly to asthma and atheromatous vascular disease, which can be summarized as follows.
Wheezing is a common feature of chlamydial lung infections.
2 In a study of 365 adults with acute respiratory illness,
acute C. pneumoniae infection was diagnosed serologically in 19 patients (5.2%), of
whom nine (47.3%) reported wheezing.
3 A polyvalent C. pneumoniae antibody titre of
64 was associated with a high risk of wheezing, and there was a clear doseresponse
relationship between antibody titre and the occurrence of wheezing. Later diagnoses of asthmatic
bronchitis were made within 6 months of the presenting illness in 29.6% of patients with
antibody titres of
64 at recruitment, and in only 7% of matched controls (P <
0.05).
Antibodies to this organism were more likely to be found in adults with late-onset asthma but no
atopy (as judged by negative skin tests) than in those who were atopic, or whose asthma started
in childhood.
4 Other workers have also reported associations with
bronchial hyper-reactivity and chronic adult asthma, by serology,
5 PCR
6 and direct isolation.
7 Population-based work indicates that increasing C.
pneumoniae seroprevalence is correlated with increasing asthma prevalence.
8 The mechanism of this apparent association between C. pneumoniae infection and asthma is not clear, but presumably relates to chronic
bronchial inflammation. It has been suggested that bronchial hyper-reactivity may be caused by
anti-C. pneumoniae IgE antibodies (implying allergic sensitization).
9
Chronic coronary artery disease (CAD) and acute myocardial infarction (MI) have been associated with serological evidence of C. pneumoniae infection in many studies, 10,11,12 and other studies have demonstrated serological associations with cerebrovascular disease 13,14 and systemic hypertension. 15 Antibodies against the 40, 54, 60, 75 and 98 kDa outer membrane protein antigensof C. pneumoniae appear to be strongly associated with atherosclerosis, implying that they may be virulence factors. 16 There is abundant histological evidence of this infection in atherosclerotic coronary, 17 carotid 1819 and peripheral arteries. 20 C. pneumoniae has been cultured from atherosclerotic material, 21 and has been demonstrated by immunohistochemistry in three cell types known to be important in atherogenesis: namely, endothelial cells, macrophages and smooth muscle cells, 22 all of which support C. pneumoniae growth in vitro. 23 In animal models, chlamydiae disseminate at an early stage, within macrophages to peripheral blood mononuclear cells, lymph nodes, spleen and thymus, 24 in which they can be shown to multiply. Using PCR and immunocytochemistry, C. pneumoniae has been shown to spread preferentially to cardiovascular tissue, 25 where infection is followed by arterial lesions that resemble atherosclerosis. 26
Theories about the mechanism of this association have been concerned chiefly with two areas: the immune response and inflammatory cells, and lipid metabolism. 27 Infection with C. pneumoniae induces a marked increase in cholesteryl ester synthesis in vitro in human monocyte-derived macrophages incubated with low-density lipoproteins, producing the foam cells that are characteristic of early atherosclerosis. 28 Serological evidence of previous C. pneumoniae infection is also associated with a pro-atherogenic serum cholesterol profile. 29 An intriguing association between atherosclerosis and immunization by heat-shock proteins has been reported; it may therefore be speculated that the 57 kDa heat-shock protein (hsp) of C. pneumoniae, an anologue of the 60 kDa Escherichia coli hsp, 30 might play a part in atherogenesispossibly by influencing the balance of fibroblast-derived cytokines.
A caveat is necessary. The associations of C. pneumoniae infection with human disease at first depended heavily on serology, principally micro-immunofluorescence. This technique is bedevilled by a high level of operator error, 31 and by cross-reactions with Mycoplasma pneumoniae (owing to contamination of antigen preparations) 32 and other chlamydiae. 33 The associations of C. pneumoniae with asthma and ischaemic heart disease are now widely accepted, but only because of confirmatory evidence from other techniques, such as PCR. Such evidence suggests that arterial disease is more reliably correlated with the presence of C. pneumoniae than with other infectious agents. 17
If these associations are important, can we identify individuals at risk of asthma or
atheromatous vascular disease who should be targeted for anti-chlamydial therapy? The answer
is: possibly, in the future. To survive within macrophages, chlamydiae must not elicit a TH1-type CD4 lymphocyte response, such as would be promoted by
interferon-.
34 In human C. pneumoniae infection, the
expression of interferon-
mRNA is predominantly associated with antigen
recognition in the context of the HLA DR4 molecule.
35 The reported association of previous C. pneumoniae infection with a pro-atherogenic serum cholesterol profile
29 also appears to apply particularly in the presence of
certain HLA DR molecules.
11 People with particular HLA class II genotypes might
therefore be at a higher risk of chronic C. pneumoniae-associated disease.
Evidence for the efficacy of antibiotics in asthma is sparse, but is accumulating. Macrolides have long been reported to ameliorate chronic asthma 36 and to reduce bronchial histamine responsiveness. 37 Hahn et al. 38 gave clarithromycin or azithromycin for 616 weeks to three poorly controlled adult asthmatics with serological evidence of recent C. pneumoniae infection. Following treatment, all three patients were able to discontinue oral steroids, and remained well on inhaled anti-asthma therapy only for 324 months. 38 The same investigators also treated 46 stable chronic asthmatics for 39 weeks with doxycycline, azithromycin or erythromycin. Over 6 months (on average), there was complete resolution of asthma in four patients who had developed it after C. pneumoniae infection. Of the remaining 42 patients, three had complete remission and 18 major clinical improvement. 39
With respect to CAD, in a comparison of 3315 patients with a single episode of acute
myocardial infarction and 13,139 age- and sex-matched controls with no apparent risk factors for
cardiovascular disease, previous use of a tetracycline or quinolone antibiotic (but not a
macrolide) was associated with 30% and 55% reductions, respectively, in the risk of myocardial
infarction.
40 In a prospective, double-blind, randomized,
placebo-controlled trial in 202 patients with unstable angina or non-Q-wave myocardial
infarction, 30 days' roxithromycin treatment led to a significant reduction in severe
recurrent myocardial ischaemia over 6 months.
41 In 60 men surviving MI with persisting C.
pneumoniae antibody titres of 1:64, randomly assigned to 36 days'
azithromycin or placebo, treatment with azithromycin (in 40 patients) led to significant falls in C. pneumoniae IgG titres and adverse cardiovascular events.
42 In contrast, 4 months' doxycycline treatment in 34
men with previous coronary bypass and mild hypertension or moderate hypercholesterolaemia
had no effect on C. pneumoniae antibodies or coronary heart disease risk factors.
43
Such trials continue to provoke scepticism. Firstly, the complete eradication of chlamydial infection by antibiotics remains difficult or impossible, even when antibiotics with good in-vitro activity are given in high doses for long periods. 44,45 MICs of azithromycin have been shown to increase during treatment in vivo. 46 In cell cultures, following exposure to high concentrations of azithromycin and doxycycline, viable C. pneumoniae can repeatedly be recovered after further passages without antibiotics. 47 Secondly, it seems clear that the pathological foundations of asthma and atheromatous vascular disease are laid in early childhood, when `fatty streaks' first appear. 48 It seems intuitive that anti-chlamydial treatment later in life would arrive too late to undo such changes. Finally, immunological processes have long been considered important in CAD and acute MI. 49 A high level of immunological activity against C. pneumoniae is seen in atherosclerosis, 50 and perivascular inflammation is enhanced by intra-peritoneal immunization with convalescent or hyperimmune sera. 51 Bactericidal agents might be expected to have only marginal effect on such immunological processes. Even so, therapeutic strategies directed at suppressing C. pneumoniae infection continue to excite interest, and surely deserve to be tested on a large scale for respiratory and cardiovascular prophylaxis.
Notes
* Tel: +44-121-766-6611; Fax: +44-121-772-0292
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