**4.** *Chlamydia pneumoniae* **and stroke**

Despite the presence of serologic and biologic evidences, and the information from *in vitro* and animal studies which demonstrated the possible mechanism of the CP role in atherosclerosis development, definite human atherosclerosis evidences are not present yet. Solely, from the human atherosclerosis studies we have the information of serological traces and the PCR and IHC evidences of CP. Despite their biological evidences in human atherosclerotic plaques, the definitive role in the human atherosclerotic disease is not clear. We derive the information in which the possible role of CP in atherosclerosis development from animal and *in vitro* studies. Moreover, the in-human trials with the antibiotic treatment were failed to demonstrate any atherosclerosis protective result [92, 93].

Serologic traces and PCR/IHC evidences of CP are demonstrated in stroke patients. Many studies demonstrated the increased IgG and IgA antibody titers in stroke patients. In one meta-analysis of these studies demonstrated, CP infection was significantly associated with increased risk of cerebral infarctions and the immunoglobulin A was more effective to predict the risk of stroke. However, the value of these serological studies is limited due to uncertainty in the titers of CP antibodies to diagnose acute, chronic, and chronic active infection. There are also discrepancies

between the serological tests and the PCR tests, and also the inconsistency among the PCR studies [94–97].

The detection of circulating CP DNA from peripheral blood monocytes is more reliable tool to diagnose an active infection; however, this method should be performed cautiously to prevent false-positive and false-negative results. One study demonstrated the higher prevalence of CP DNA in peripheral blood monocytes in symptomatic patients with carotid artery disease. Despite controversy between similar studies, one meta-analysis demonstrated an increased risk for cerebrovascular disease. These finding of evidences of an active infection might lead a speculation of the CP inflammation-associated atherosclerotic plaque vulnerability and resulting stroke [98–100].

Controversy exits between the PCR studies from atheromatous plaques in patients with carotid artery disease. There can be problems with sensitivity and specify due to PCR testing resulting with discrepant results [101, 102].

Previous studies mainly focused on the large artery atherosclerosis etiology comprising for the stroke. In all these studies, the exact etiological evaluation is not clearly defined. Cardioembolic stroke especially due to atrial fibrillation could also be a possible cause of the stroke in these patients. Animal studies demonstrated the involvement of cardiac muscle involvement by the CP infection. Either by direct atrial tissue involvement and/or *via* the increased cytokine levels atrial fibrillation could be triggered by the CP infection. The thrombophilic milieu propensity *via* the increased cytokine levels due to infection could be another potential contributory factor for the development of stroke. Moreover, most of the patients with atrial fibrillation have also coincident widespread atherosclerosis development, which could mean the possible high burden of chronic CP infection. Further well-designed studies with a clear definition of stroke etiology might answer this question [103, 104].

There are two problems arising with the studies, which investigate the possible role of CP infection in stroke patients: First, there is not any clear diagnostic criteria in the serological evaluation of a CP infection and there are controversies between PCR tests and serology; second problem is the etiologic diagnosis of the stroke; the etiology is a vulnerable plaque complication result or a cardioembolism, should be clearly defined [102, 104].

The studies that investigate the CP role in stroke that clearly defined the clinical presentation and etiology (symptomatic carotid artery stenosis and/or stroke) have conflicting results. The PCR studies could not demonstrate the CP presence in the carotid plaques of symptomatic patients. However in a study that used the IHC method, it is demonstrated that the CP in carotid plaques is significantly associated with the cerebrovascular events [102, 105, 106].

Another interesting common finding of these studies is that of similar to finding by Elkind et al., the high serum anti chlamydial Ig-A presence in symptomatic patients. This finding could indicate the possible role of the acute and/or chronic infections of CP anywhere in the body could play a role in atherosclerotic plaque activation and plaque vulnerability [98, 102, 106].

However, it is unclear whether the possible pathophysiologic chain of the events ongoing with increased cytokine levels result in the plaque vulnerability and stroke is unique to CP infection. The epidemiological studies demonstrated the increased risk of stroke after certain infections. The pathophysiological scenario ongoing with increased cytokine levels which ends with the plaque vulnerability related events may not unique to infection by CP. Increased risk of stroke was also demonstrated after certain upper respiratory tract infections. Also, the etiology could also be an atrial

*The Probable Role of* Chlamydia pneumoniae *Infection in Acute Stroke DOI: http://dx.doi.org/10.5772/intechopen.109582*

fibrillation-related cardioembolism, which also shares similar pathophysiological basis due to increased cytokines. However, there is necessity for large-scale epidemiological studies in which the etiology of stroke is well defined [107–109].

The levels of proinflammatory cytokines, and the inflammatory markers such as the CRP and ESR (erythrocyte sedimentation rate) are found to be increased in symptomatic carotid stenosis patients. The cerebral ischemia/infarct, and/or the inflammation of the plaque itself could be either an explanation for the increased cytokine levels and inflammatory markers. Also, the possible aggravating etiologies which triggered this chain of events might have a role in this finding [110, 111].
