Serological Evidence

In 1998, Pekka Saikku and his associates of the University of Helsinki made the first suggestion of an association between C. pneumoniae and coronary artery disease (CAD) (6). They had described an epidemic of mild pneumonia caused by what was then considered to be an unusual strain of Chlamydia psittaci. Following up on earlier reports linking myocarditis and arterial emboli with chlamydial infection, they measured titers of antibody to C. pneumoniae. They discovered that men experiencing acute myocardial infarction (AMI) or with significant CAD were more likely to be seropositive for C. pneumoniae than age- and sex-matched control subjects (Fig. 2).

This serological evidence was strengthened later when Saikku et al. (7) evaluated patients in the Helsinki Heart Study, in which hyperlipidemic patients with no previously documented heart disease were randomized to receive gemfibrozil or placebo and followed for the development of MI or cardiovascular death. Patients who were seropositive for C. pneumoniae at baseline were 2.6 times more likely to experience CVD during the study than those who were seronegative. Since these initial reports, a large number of serological studies have been performed (Table 1). Based on the largest of these studies, as well as systematic overviews, the association between C. pneumoniae seropositivity and CAD appears to be independent but weak. However, a few caveats should be kept in mind when considering the seroepidemiological evidence.

First, in control populations who are similar in age to most patients with CAD (©60 yr), the incidence of seropositivity to C. pneumoniae is often nearly 70% (8). This high incidence of seropositivity in the control population, therefore, makes it difficult to document a significant difference in incidence between the control and the diseased population. One must remember, however, that atherosclerosis, especially when asymptomatic atherosclerosis is included, is nearly ubiquitous in this age population and, therefore, a

Fig. 2. Graph showing results of MIF (microimmunofluorescence test for antibodies specifically targeted against C. pneumoniae) and LPS (enzyme-linked immunoassay for antibodies against the chlamydial group antigen) assays in patients experiencing AMI in patients with known CAD, and in control subjects (6).

Fig. 2. Graph showing results of MIF (microimmunofluorescence test for antibodies specifically targeted against C. pneumoniae) and LPS (enzyme-linked immunoassay for antibodies against the chlamydial group antigen) assays in patients experiencing AMI in patients with known CAD, and in control subjects (6).

high incidence of seropositivity to C. pneumoniae in the control population does not necessarily indicate an absence of an association between atherosclerosis and C. pneumoniae.

Second, serological titers of IgG or IgA to C. pneumoniae merely reflect having been exposed to the infectious agent sometime in the past. They do not necessarily represent an ongoing chronic infection. Therefore, the presence of patients both in the case and in the control series in which a previous infection occurred but the immune system was capable of complete eradication could contaminate serological results.

Third, the serological techniques used in the various studies have not been well standardized. In an expert panel consensus conference sponsored by the Centers for Disease Control (CDC), Dowell et al. (9) reported that diagnostic testing for C. pneumoniae from different laboratories is highly variable and "gold standards" are lacking, leading to calls for more standardized approaches. In addition, the expert panel reviewed the available approaches to serological testing and recommended that only microimmunofluorescence be used. Even though a variety of enzyme-linked immunosorbent assay (ELISAs) were evaluated, none were felt to be adequate. The use of single IgG titers for determining acute infection and IgA for determining chronic infection was also discouraged.

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