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Chlamydiae are obligate intracellular bacteria of which there are 4 species: C. trachomatis, C. psittaci, C. pneumoniae and C. pecorum and were originally classified according to phenotype (Table 1). C. pneumoniae was first isolated in 1965 from a child’s conjunctiva during a trachoma vaccine trial in Taiwan [1] and was originally named TW-183. It was recognised not to be C. trachomatis because it failed to kill mice following intravenous injection [2] and it also failed to cause follicular conjunctivitis in monkeys. In fact, C. pneumoniae cannot be differentiated from C. psittaci on phenotype alone and originally, it was thought to be a C. psittaci strain. DNA and antigenic criteria are now used to differentiate C. pneumoniae from other species and its entire genome was sequenced in 1998 [3,4].

Although TW-183 was an ocular isolate as was another strain, IOL-127, which was obtained from Iran around the same time and which was subsequently shown to be C. pneumoniae [5], it was realised that TW-183 was a cause of respiratory rather than ocular infections. C. pneumoniae was first isolated in relation to respiratory tract disease from the pharynx of a University of Washington student presenting with pharyngitis in 1983. This isolate was labelled AR-39 (acute respiratory) but when it was recognised that it was the same as TW-183, C. pneumoniae obtained its first name, the "TWAR" organism. In a seminal study published in 1986, 13 of 386 students presenting with acute respiratory infections were found to have serological evidence of infection by TWAR and the organism was isolated from 8 students [6]. TWAR was formally recognised as a new chlamydial species in 1989 and renamed C. pneumoniae [7]. Numerous studies since then have confirmed C. pneumoniae as a respiratory pathogen but research has also associated this organism with several other respiratory and non-respiratory diseases of which coronary heart disease has caused the most interest. Other infections, such as syphilis and tuberculosis, are known to cause chronic, multi-systemic disease but the epidemiology of the diseases associated with C. pneumoniae do not have much in common (Table 2). In this review, the strength of evidence for C. pneumoniae as an important cause of chronic disease is examined.

Culture. As chlamydiae are intracellular bacteria, they cannot be grown by conventional techniques. C. trachomatis was first grown in chick embryos in 1957 and in HeLa 229 cell cultures in 1971 [8]. Initially, C. pneumoniae grew poorly in these preparations but techniques such as centrifugation of the organism onto cell culture monolayers [9] and other refinements as regards the culture medium [10] have improved results. Nevertheless, culture of C. pneumoniae is not a widely available technique and certain clinical samples such as sputum are toxic towards cell cultures. The implication is that diagnosis of C. pneumoniae infection has often been by non-culture techniques with the consequence that results are sometimes open to different interpretation [11].

Serology. Serology is perhaps the most widely used diagnostic tool in C. pneumoniae research. The microimmunofluorescence (MIF) test is the gold standard method for detecting antibodies to chlamydiae and was originally used to type the different C. trachomatis serovars [12]. Unfortunately, it is subjective [13], tedious to perform and not suitable for mass screening. Enzyme linked immunoassay (EIA) methods are objective, simple to perform and their results have been shown to correlate with those of MIF [14-16]. There are concerns that EIA methods are not as specific as MIF but MIF itself is not truly specific [14,17]. Nevertheless, for certain populations such as the middle aged men in cardiovascular studies, the prevalence of C. trachomatis and C. psittaci antibodies have been found to be low [18]. Perhaps the most contentious aspect of C. pneumoniae serology concerns not the methodology but whether the presence of antibodies measured at one time point indicates current or chronic infection or past exposure [11,19]. Unfortunately, there are insufficient long term studies of the antibody response following culture proven acute or chronic infection.

Polymerase chain reaction. The polymerase chain reaction (PCR) should be a specific and sensitive method for detecting the presence of C. pneumoniae DNA. However, clinical specimens such as blood vessels or brain are not generally available from live subjects and we have found that inhibitors of the PCR reaction are often present in atherosclerotic tissue [20,21]. A blinded, multicentre study involving nine experienced laboratories that have contributed significantly to the literature showed that when a clinical sample (blood vessel) was reported as being positive by one laboratory, the majority of other centres reported it as negative and the best concordance was only 25% [22]. This result is consistent with the idea that quantities of C. pneumoniae DNA in clinical specimens can be small leading to sampling errors [20,21,23]. However, 19% of negative controls in this study were reported as positive and it is possible that contamination can also be a significant problem.

Immunocytochemistry. Immunocytochemistry (ICC) has also been used for the detection of C. pneumoniae. In the case of atherosclerosis where there have been many studies that have used both PCR and ICC allowing comparison of their performance, ICC tends to find more evidence for C. pneumoniae but samples positive by one technique are not necessarily positive by another [11]. This could indicate that ICC is more sensitive although it has been suggested that C. pneumoniae antigen rather than viable organism is present [24]. It has been observed that the results of ICC depend on the antibody used [25] and the obvious concern is that non-specific staining occurs [21,26,27]. It was reported in one study that there was a correlation between the severity of atherosclerosis and the presence of C. pneumoniae when ICC was used [28]. However, PCR showed that the prevalence of C. pneumoniae in samples with mild atherosclerosis was high and it is therefore possible that the antibodies used were cross-reacting with a component of atherosclerosis rather than C. pneumoniae.

Community acquired pneumonia and respiratory infections. Numerous serological studies have confirmed that C. pneumoniae is a cause of community acquired pneumonia throughout the world. In most instances, the diagnosis has been based on a significant increase in specific IgG titres. In a prospective study from a general population in Seattle where serum specimens were collected twice a year and also at times of illness, specific IgG titre rises were not seen in children under the age of 5. The incidence was at its highest with an annual rate of 9.2% in those aged between 5 to 10 and it dropped to 1.5% in those over 20 [29]. It was not reported how many of the seroconversion episodes were associated with illness except that in children, one third of episodes were asymptomatic [30]. In fact, it is unlikely that all seroconversion episodes were associated with community acquired pneumonia. For instance, the incidence of community acquired pneumonia in the United Kingdom is approximately 0.1% per year. In studies which have looked specifically at adults with community acquired pneumonia, C. pneumoniae was the causative agent in 3.4% to 43% of cases [31-34]. It was never the most common aetiological agent and co-infection with a second organism was often present [31,33]. If it is assumed in adults, that the annual incidence of community acquired pneumonia is 0.1%, that C. pneumoniae is responsible for 10% of these and that the annual seroconversion rate is 1.5%, then only 1 in 150 C. pneumoniae infections will result in pneumonia. Apart from pneumonia, there is limited evidence that C. pneumoniae can also cause upper respiratory tract infections [35] but it has been suggested that 90% or more of C. pneumoniae infections are asymptomatic [36]. It is possible that the incidence of asymptomatic acute infection is even higher than the Seattle data suggests. This is because seroconversion may not always be present. In one study, only 3 of 8 culture positive patients had serologic evidence of acute infection [37].

Apart from acute respiratory infections, C. pneumoniae has also been implicated in chronic respiratory carriage and culture studies have shown that asymptomatic infection may persist for at least a year [37-39]. The seroprevalence of C. pneumoniae IgG antibodies in adults is 50% or more [11] but as there is no evidence to suggest that any particular IgG titre can distinguish between current infection and past exposure, it cannot be assumed that half the adult population is chronically infected. Studies have shown that C. pneumoniae can be isolated from the nasopharynx of up to 4.7% of subjectively healthy subjects [40-42]. Hypothetically, if chronic C. pneumoniae infection were highly endemic, then large epidemics would not be expected because of herd immunity. However, both local and generalised outbreaks of C. pneumoniae infection have been described. Reports of localised outbreaks concern mainly young subjects in institutional surroundings such as students at a boy’s school [43] and conscripts at military garrisons [36,44]. In one study, 43 of 86 conscripts with respiratory symptoms from a garrison of 1200 were diagnosed as having C. pneumoniae infection on the basis of culture or paired serology [44]. Ten of these 43 subjects had pneumonia and the incidence of C. pneumoniae pneumonia was therefore 0.83%, a sizeable epidemic. It is possible that a significant proportion of these subjects had not previously been exposed to C. pneumoniae and this, together with their close proximity may have resulted in the high attack rate. Rates twice as high as this were found for students in another serological study although their living conditions were not described [45]. Reports of generalised outbreaks of C. pneumoniae infection have been retrospective, based on serology and emanate from Scandinavia. In two studies, an increase in the incidence of ornithosis, a notifiable disease, was investigated for the possibility that these had been caused by C. pneumoniae rather than by C. psittaci [46,47]. In one of these studies [47], the incidence of C. pneumoniae pneumonia for Denmark in 1981 can be calculated to be 0.00084% and this increased to 0.0047% in the epidemic year of 1982. Therefore, although there was an approximate six fold increase in incidence, the absolute number of infections was small even allowing for under reporting and whether this can be termed an epidemic is debatable. Nevertheless, a population based seroprevalence study has implied that C. pneumoniae epidemics are frequent and affect significant numbers of the population [48]. It was found that periods of low and high prevalence (IgG titre ≥ 16), ranging from 44 to 67%, alternated in an epidemic cycle of approximately 10 years. It is difficult to reconcile these figures which suggest that 20% of the population are involved with the much smaller figures found in the other studies. As this study did not attempt to measure seroconversion, it does not provide definitive evidence that large scale epidemics occur.

Asthma. Asthma is a chronic inflammatory condition characterised by reversible narrowing of the bronchial airways. It is diagnosed by the response to bronchodilators and the measurement of the forced expiratory volume in one second and the peak expiratory flow rate, both of which show reductions and a marked diurnal variation. The cause is unknown but asthma attacks can be precipitated by a number of factors including allergens, exertion, excitement, cold air and respiratory infections.

Wheezing is a symptom of asthma and as it is also a feature of C. pneumoniae infection, it was wondered whether the two were linked. The first report of an association was published in 1991 [49]. In this study, 365 subjects presenting with respiratory illness had throat swab samples taken for C. pneumoniae culture and blood for paired serology. The organism was isolated from only one subject but acute infection was diagnosed in 19 on the basis of serology. It was not reported whether these 19 patients were more or less likely to develop wheezing and asthma compared with other subjects. However, it was found that subjects with an IgG titre of ≥ 64 were more likely to have a wheeze on presentation than subjects who had titres of < 64. In a subset analysis, 71 subjects with an IgG titre of ≥ 64 were compared with 71 matched controls with titres of < 16. A high proportion (29.6%) of high titre patients were diagnosed as having asthma in the subsequent 6 months compared with only 7% of low titre patients (odds ratio 7.2, 95% confidence interval 2.2 to 23.4). Unfortunately, it cannot be certain that these diagnoses were accurate because pulmonary function tests were not obtained. Moreover, rather than asthma, it is likely that some of these patients had post infective bronchial hyper-reactivity, a well known clinical syndrome which usually improves by 6 months. One other longitudinal study followed up 198 subjects between the ages of 11 and 21. It was found that subjects with high IgG titres were significantly less likely to have asthma [50]. Unfortunately, results from cross sectional studies fail to clarify the situation. Studies are just as likely to report no association [51-54] as to support one [55-58].

Although it is controversial as to whether or not C. pneumoniae causes asthma, it seems reasonable to believe that like other acute infections, it can precipitate asthmatic attacks. Studies have shown that between 9.5 to 45% of subjects presenting with acute asthma attacks demonstrate an increase in C. pneumoniae antibody titres [59-62]. Furthermore, some [63,64] but not all controlled studies [53] have shown that seroconversion or culture confirmed infection is more frequent in cases than controls.

Chronic obstructive pulmonary disease (COPD). COPD is a condition where there is airflow obstruction secondary to chronic bronchitis or emphysema. Unlike asthma, there is always some degree of obstruction but acute infections can cause exacerbations. A limited number of studies have investigated the role of C. pneumoniae as a cause of COPD and only recently, has there been a prospective study [65]. This showed that in men who already had COPD, disease progression was not associated with C. pneumoniae seropositivity. Cross sectional studies have also failed to provide convincing evidence for an association. Although 2 studies reported an association [66,67], others have shown no clear link [68,69]. In acute COPD exacerbations, an increase in C. pneumoniae antibody titre has been seen in between 7 to 18% of cases [66,68-72].

Coronary heart disease. Lymphogranuloma venereum (LGV) occurs mainly in tropical and subtropical countries and is caused by C. trachomatis serotypes L1-3. It is acquired by coitus and can result in fibrosis and destruction of the inguinal lymph nodes with subsequent genital elephantiasis. In the 1940’s, South American researchers thought that there were similarities between the pathological processes of atherosclerosis and the lymphatic destruction of LGV. It was subsequently reported that subjects with atherosclerosis were more likely to have a positive result with the intra-dermal skin test using Frei’s LGV antigen [73-75]. In the 1980’s, it was found that 68% of Finnish subjects presenting with myocardial infarction (MI) had at least a three-fold rise in antibody titres against genus specific chlamydial lipopolysaccharide compared with only 2.4% of controls. The only known chlamydial species common enough to be the candidate was the then recently described C. pneumoniae [76,77]. MI is an acute event, which in most cases, is due to rupture of atherosclerotic plaques [78]. However, the causes of plaque rupture are unknown. One interpretation of the Finnish data then, is that acute C. pneumoniae infection is a cause of plaque rupture. Thus, this may be another example of acute C. pneumoniae infection causing an exacerbation of a chronic disease. Despite this impressive result, only a few inconclusive studies have looked at acute C. pneumoniae infection as a cause of MI [79,80]. Instead, the main question of interest has been whether chronic C. pneumoniae infection is a cause of the atherosclerotic process itself. In fact, the Finnish researchers played down the high seroconversion rate. Apart from genus specific antibodies, they also measured specific antibodies to C. pneumoniae. It was found that specific antibodies were also more likely to be found in cases (85 vs. 61% for IgG titre ≥ 32) but because seroconversion of specific antibodies was not seen, this was interpreted as showing that chronic, rather than acute infection was associated with coronary heart disease. The significance as to why such a high seroconversion rate was seen with genus specific but not with species-specific antibody was not addressed.

Coronary heart disease is a common manifestation of atherosclerosis and it appears to be a multifactorial disease. Genetic [81] as well as environmental factors have been implicated and smoking, hypertension and hypercholesterolaemia are major risk factors but others are likely to be important. The World Health Organisation MONICA (monitoring of trends and determinants in cardiovascular disease) project found that these three factors accounted for less than 25% of the variance in cardiovascular mortality in men from 35 populations [82]. At first sight, the epidemiology of C. pneumoniae does not suggest that it is an important risk factor for coronary heart disease. There seems to be no correlation between its prevalence and coronary death rates. For instance, the coronary death rate for men throughout the world varies between 50 per 100000 in Japan to rates that are ten times higher in Scotland [83]. In contrast, the seroprevalence of C. pneumoniae is uniformly high throughout the world [84,85]. Nevertheless, there is indirect evidence to suggest that infections may be important in coronary heart disease. Some have speculated that the decline in coronary mortality seen recently in developed countries is due to the use of tetracycline [86] and we ourselves have found that death rates for MI are associated with household size, a factor likely to be important in the transmission of infection [87].

To test the hypothesis that chronic C. pneumoniae infection is a cause of coronary artery disease, the presence of specific IgG has often been taken to be a marker of chronic infection. To date, numerous such cross sectional [77,79,80,84,88-117]and prospective [118-134] studies have been reported and their results have been extensively reviewed [11,132,135,136]. In summary, there is general agreement that whereas cross sectional studies have suggested some sort of association, prospective studies have not [137]. It has been argued that the prospective studies have been negative because serology was only tested at one time point several years before the development of disease. Therefore, controls may have developed chronic infection in the intervening years so masking any association. However, annual infection rates in adults are low and that there is no convincing evidence that widespread epidemics occur. Also, studies with relatively short follow up periods of 1.5 to 5 years [124,127,129]were just as likely to be negative as those with longer follow up. It is known that negative studies are less likely to be published and in reviewing the literature, one way of detecting such publication bias is to construct funnel plots [138]. These are plots of the studies’ effect estimates against sample size (or study precision). Generally, the precision in estimating the underlying association will increase as the sample size increases. Results from small studies will scatter widely at the bottom of the graph with the spread narrowing among larger studies. In the absence of bias, the plot resembles a symmetrical inverted funnel but otherwise, the plot will often be skewed and asymmetrical. The Figure shows the funnel plot for 33 cross sectional studies of which 17 found no significant association (some of these 17 were reported as positive because apart from IgG, other markers of infection such as IgA were used). It can be seen that the plot is asymmetrical. In fact, it is almost half of a funnel plot and one interpretation is that the majority of negative studies have not been published. It can also be seen that the studies with the greatest precision show no or only small associations.

Since chronic infection cannot be diagnosed on the basis of serology, more specific diagnostic methods are required. We used the PCR reaction to detect for C. pneumoniae DNA in the mononuclear cell layer of blood and found an association with coronary heart disease in men but not in women [109]. Such a test is likely to be specific and a positive result to indicate current infection. However, whereas we found the prevalence to be 2.9% in control males, 10.8% in control females and 8.8% in male cases, a Swedish study reported that 46% of healthy blood donors had circulating C. pneumoniae DNA [139]. This discrepancy may be due to population or methodological differences and subsequent studies have also shown wide variations. One study reported that in British men with coronary heart disease, circulating C. pneumoniae DNA could not be detected [140] while others have found prevalence rates of between 11.5 to 28% [141-145]. The Swedish group also found rates of 50% in Italian men [146] and similar figures were seen in two other studies [147,148]. It is unlikely that population differences can solely be responsible for these variations. We think that the true prevalence is probably less than 50% in subjects with or without coronary heart disease. For instance, such high rates have not been seen in PCR and culture studies of respiratory specimens while in pathological studies of blood vessels, the detection rate of C. pneumoniae by PCR is generally much less than 50% [11]. In those studies with a control group [139,145,147], none has found a significant association with coronary artery disease apart from ours although an association was seen for abdominal aortic aneurysms [142].

C. pneumoniae was first detected in vascular tissue in 1992 [149] and since then, it has frequently been found in diseased blood vessels. It has been observed that based on published reports, C. pneumoniae is twenty times more likely to be found in atherosclerotic compared with normal vascular tissue [132]. However, atherosclerosis is ubiquitous and truly normal vascular tissue is difficult to find. This is compounded by the fact that vascular samples are generally not available from live subjects unless obtained during interventions such as coronary atherectomy or bypass surgery and even then, normal tissue is usually not obtainable. In fact, we found that just under half of all published studies reviewed up to September 1998 [11] did not use control tissue [97,150-158] and in only three studies were case and control tissues matched for age, source of tissue and method of detection [159-161]. To date, this situation remains unchanged and no subsequent study has had control tissues fulfilling these criteria [111,162-173]. Nevertheless, it is possible to assess the role of C. pneumoniae by examining its prevalence amongst populations at differing risk for vascular disease. In making such comparisons, it is important to take into account the investigators involved and the methods used. This is because examination of the same tissue by different groups and methods can result in widely varying results [22]. The Seattle group has examined the prevalence of the organism in coronary arteries from Eskimos dying mainly from non cardiovascular causes (mean age 34.1 years, range 15 to 57 years) [155], young Americans (age 15 to 34 years) who also did not die from coronary disease [159] and Americans who had coronary atherectomy (median age 55, range 35 to 81) [151]. The reported prevalence for these 3 groups using PCR were 23.3%, 0 to 17% and 32% respectively. It can be seen that there appears to be a gradient with respect to age but the prevalence in the Eskimos, a low risk group for coronary heart disease, was not much lower than that of the older Americans with coronary disease. However, the young Americans study was amongst those with adequate control tissue and all three such studies did find an association with atherosclerosis.

Another way of assessing the role of C. pneumoniae in atherosclerosis is to correlate its presence with the extent or severity of disease. The results are conflicting. We found that the presence of the organism was focal and not associated with either severity or extent of disease [20]. Similar results were found by others [155,174] but associations have been reported [111,166,175] and the organism was said to be more prevalent in unstable compared with stable plaques [164,173]. What is clear from these studies is that in any individual, C. pneumoniae has never been found at all atherosclerotic sites. This suggests that infection occurs after the development of atherosclerosis and if anything, it is an exacerbating rather than a causal factor.

Despite these numerous studies, the prevalence of C. pneumoniae in blood vessels and therefore, the size of any potential public health problem remains in doubt. In the blinded, multicentre PCR comparison study, 15 atheroma specimens were tested by nine centres. Three centres using a total of seven different PCR protocols failed to detect the organism at all while one centre using four protocols found it inconsistently in two samples and the remaining centres found C. pneumoniae in between one to nine samples. Results were still inconsistent when centres using the same PCR protocol were compared. The reasons for these varying results could not be determined but since only a few studies prior to this study had failed to find C. pneumoniae in atherosclerotic tissue [97,171,176,177], it is possible that there are other negative studies which have not been published due to publication bias. Furthermore, if powerful molecular techniques have such difficulty in confirming the presence of the organism, it must be questioned whether C. pneumoniae is present in any great number and therefore, whether it is of pathogenic importance.

In contrast to the serological and pathological studies, there is more definite evidence from animal trials that C. pneumoniae has a role in atherosclerosis. The evidence that C. pneumoniae can cause atherosclerosis is not convincing since studies have either reported no effect [178,179] or only inflammatory or early atherosclerotic changes were seen [180-184]. However, there is evidence that infection can exacerbate atherosclerosis [185,186] although the presence of hypercholesterolaemia may be required [187,188]. It has also been reported that antibiotics can prevent the effects of infection [182,187]. The effects of antibiotics in humans are more controversial. As yet, there has been no primary prevention study but a number of small secondary prevention trials have been reported. The first two studies generated a lot of enthusiasm. In the first, 213 male patients from London were recruited after being admitted with MI [189]. It was found that the future risk of cardiac events was associated with IgG antibody levels against C. pneumoniae and that this excess risk could be abolished by a three or six day course of azithromycin. The event rate in untreated subjects with IgG titres ³ 64 was 28% compared with 8% in similar subjects given antibiotics. A similar sized, Argentinian study had smaller event rates but the reduction after a one month course of antibiotics was just as dramatic (9.8 vs. 1.1%). Disappointingly, these results referred only to follow up after 30 days [190] and no significant difference was seen at the end of the study at 6 months [191]. Even more disappointingly, an American study failed to find any beneficial effect with a three month course of antibiotic even though inflammatory markers were reduced in the treated group [192]. Nevertheless, another study from the London group and recently published in abstract form [193], found that treatment directed against C. pneumoniae and Helicobacter pylori reduced the incidence of coronary events by 40%. The largest study to date was also a secondary prevention trial but rather than recruiting patients following MI, patients were recruited following coronary stenting and the outcome measure was the occurrence of restenosis [194]. From this point of view, its results should not be generalised. This is because the mechanism of restenosis, although incompletely understood, is distinct from progression of atherosclerosis or plaque rupture [195]. In fact, contributory factors to restenosis such as elastic recoil are very unlikely to be related to infection. Essentially, the study found no effect on the restenosis rate after a 28 day course of roxithromycin. However, it found that subjects with IgG titres ≥ 512 were likely to benefit from antibiotics while subjects with low titres actually did worse. It is difficult to explain these results. As antibody levels do not correlate with chronic infection, subjects with low titres should be just as likely to be infected as those with high titres. Furthermore, there appears to be no obvious reason why roxithromycin should increase the restenosis rate in subjects with low titres. It is possible that this is a chance finding and the results of several large studies are awaited.

Multiple sclerosis. Multiple sclerosis (MS) is a chronic inflammatory condition characterised by demyelination of the central nervous system. Classically, demyelinated plaques are disseminated in time and space. The aetiology is unknown but one theory is that disease is produced by the host immune response to an infectious agent or autoantigen. Viruses are the microorganisms which have most often been implicated but a case report in 1998 described the detection of C. pneumoniae by culture and PCR from the cerebrospinal fluid (CSF) of a patient with MS whose condition improved with antibiotics [196]. Subsequently, the same group found that C. pneumoniae could be cultured from the CSF in 64% of 37 patients with MS and C. pneumoniae DNA was detected by PCR in an astonishingly 97% [197]. The corresponding figures for a control group comprising of patients with other neurological conditions were 11% and 18%. Immunoelectrophoresis of the CSF in MS often shows oligoclonal bands and in a third study, this group demonstrated that in 16 of 17 MS patients, the oligoclonal bands reacted against C. pneumoniae elementary body antigens compared with none of 14 control patients [198]. Unfortunately, further studies by other groups have brought conflicting results. A German study confirmed that C. pneumoniae was found preferentially in the CSF of MS patients [199] but another reported that although C. pneumoniae DNA could indeed be detected, it was more frequent in other neurological conditions although absent in neurologically healthy controls [200]. Two experienced groups though, failed to detect the organism in studies of brain tissue and CSF [201,202].

C. pneumoniae causes a significant proportion of community acquired pneumonias and there is evidence that it exacerbates asthma. In teenagers and young adults, epidemics may occur although the data for older persons is less convincing. Even more controversial is whether C. pneumoniae is a cause of chronic diseases such as asthma, coronary heart disease and multiple sclerosis. C. pneumoniae has also been associated with Alzheimer’s disease [203-206] and bronchial carcinoma [207-209] but the literature is sparse. Studies of these chronic diseases are characterised by conflicting results which may partly be due to different methodology. Efforts to standardise methods are commendable [22,27] but the real problem is that there is no simple method to detect chronic infection. The diagnosis of acute infection is relatively easy if paired sera are available for serology. We propose that this should be taken advantage of in antibiotic trials of myocardial infarction. This is because studies have suggested that MI is frequently associated with acute C. pneumoniae infection. As some of these infections are likely to become chronic, then the effect of antibodies on future cardiac events in MI patients with seroconversion should be informative.

Table 1. Phenotypic characteristics of the four chlamydial species.

*The genome of C. psittaci is extremely diverse and intra-species homology varies from 14 to 95% indicating that new species will be eventually derived from C. psittaci.

Table 2. Epidemiology of diseases associated with Chlamydia pneumoniae.

*Male Prevalence.

Figure. Funnel plot for 33 cross sectional studies investigating the association between coronary heart disease and IgG seropositivity for C. pneumoniae.

* The Estimates precision is the reciprocal of the standard error (the standard error can be calculated from the 95% confidence interval limits).

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