Chronic diseases & C. pneumoniae
Cerebrovascular incident / stroke
Given the suspected association of C. pneumoniae with coronary artery disease and atherosclerosis, it is logical to determine whether there might be an association with cerebrovascular incidents (stroke), which share many of the same pathological features. Investigation of this topic in many ways parallels investigation of C. pneumoniae and coronary artery disease generally, but with much less data. Here again, serological studies do not provide a definitive answer.
The initial serological studies showed a strong association between the presence of C. pneumoniae antibody and stroke. The initial study by Wimmer et al., 1996 compared 58 consecutive patients with ischaemic infarction (39 persons) or transient ischaemic attacks (n = 19) with 52 hospital control subjects without known vascular disease. Specific IgG antibodies in circulating immune complexes were significantly elevated in 24.1% of the patients versus 7.7% of control subjects (P= .047). After adjustment for the vascular risk factors hypertension, age, sex, and migraine, the odds ratios were 1.71 (95% CI, 1.08 to 2.70) of elevated IgA antibody, 2.00 (95% CI, 1.07 to 3.76) for circulating IgG immune complexes and 2.20 (95% CI, 1.09 to 4.41) for both factors together leading to the conclusion that chronic infection with C. pneumoniae was associated with an increased risk of stroke and transient ischaemic events [Wimmer et al., 1996].
Cook et al., 1998 compared C. pneumoniae IgG, IgM and IgA antibodies in176 patients with stroke or transient cerebral ischemia versus 1518 control subjects with noncardiovascular, nonpulmonary disorders. They reported an even stronger association of cerebral vascular disease with previous C. pneumoniae infection and the association of stroke and transient cerebral ischemia with recrudescence of infection. [MEW Comment: This study presupposed that one can tell the difference between previous C. pneumoniae infection or recrudescent infection from antibody determination, which I do not believe]. Tarnacka et al., 2002 from Poland reported an association between circulating immune complexes incorporating chlamydial lipopolysaccharide or cytomegalovirus with stroke. By contrast a population-based study of Helicobacter pylori and C. pneumoniae antibody in stroke did not find evidence of any strong association between the antibody response to C pneumoniae as a marker of prior infection and ischaemic stroke, although there was evidence of a possible weak association for H. pylori antibody as an independent risk factor for small-artery occlusion patients [Heuschmann et al., 2001].
Bucurescu & Stieritz, 2003 reported an association between IgG and IgA antibodies to C. pneumoniae and stroke and noted that this association was independent of other risk factors such as diabetes and hypercholesterolaemia. In contrast a prospective study from Israel by Tanne et al., 2003 found that antibody to C. pneumoniae was not an independent risk factor for stroke while the major prospective HOPE study from Canada found that antibody to cytomegalovirus, but not to C. pneumoniae, Helicobacter pylori or Hepatitis A virus was associated with vascular disease including stroke [Smieja et al., 2003]. In a case control study Ngeh et al., 2003 also failed to find an association of C. pneumoniae antibody with stroke. Thus the association is unclear.
In a more direct and elegant approach, Gibbs et al., 2000 used transcranial doppler ultrasonography of cerebral artery to determine the presence of preoperative cerebral embolization or infarcts in relationship to the presence of C. pneumoniae DNA by PCR. C. pneumoniae DNA was detected in 25.5% of 98 symptomatic patients but appeared to make no difference to cerebral plaque stability as measured by the embolization rates between chlamydial-positive or chlamydial-negative specimens. Furthermore, there was no correlation between the number of ipsilateral hemispheric infarcts in the territory of the middle cerebral artery and the patient chlamydial status. Their study showed and confirmed that C. pneumoniae is a common finding in atherosclerotic plaques of the carotid artery but indicates that the presence of the infectious organism had little detectable impact on plaque instability. By analogy with coronary artery disease and the key question of whether chlamydiae trigger plaque instability, thrombosis and myocardial infarct, these results suggest that they do not raising questions concerning the rationale of antibiotic therapy in atherosclerosis [Gibbs et al., 2000], presently under large scale clinical trials. Neureiter et al., 2003 reported a slightly increased rate of Apoptosis in C. pneumoniae (but not H. pylori) - infected carotid atherosclerotic plaque, presumably because of T cell infiltration. However it seems unlikely that this would be sufficient to trigger plaque rupture. The presence of C. pneumoniae DNA in atherosclerotic middle cerebral arteries was confirmed in a small scale post-mortem study by Virok et al., 2001. [MEW comment: This study involved only 15 test and 4 control subjects].
LaBiche et al., 2001 in a PCR-based study of endarterectomy material from the carotid artery of 37 symptomatic and 57 asymptomatic patients found that the proportion of plaques positive for C. pneumoniae DNA was around 15% in both groups. The low sensitivity of seropositivity for IgG, IgA, or IgM antibody to C. pneumoniae associated with the presence of C. pneumoniae DNA in the plaque made antibody unlikely to be valuable as a predictor for actively infected plaque.
In an elegant study, Johnston et al., 2001 studied the association between serum C-reactive protein levels as a known risk factor for stroke and the presence of labile C. pneumoniae mRNA transcripts, as well as DNA, in carotid artery atherosclerotic plaque. Of 48 samples, mRNA transcripts were present in 18 samples and were significantly associated with the presence in serum of the inflammatory acute phase C-reactive protein. It was suggested these findings perhaps explained the link between C-reactive protein levels and risk of cardiovascular disease or stroke. However the authors wisely concluded further investigations were required on a larger group [Johnston et al., 2001].
Luchsinger et al., 2001 analyzed data on health and antibiotic usage for 199,553 subjects age 65 years or older in a health care claims database. Using a proportional hazards models with time-dependent covariates for prior antibiotic prescription, adjusting for cardiovascular risk factors, they sought evidence of any association between antibiotic use and first health care claim for ischaemic stroke in a total of 7,335 individuals. The rates of stroke per 1,000 person-years were 6.64 for macrolides, 9.27 for quinolones, 7.49 for tetracyclines, 6.88 for penicillins, 7.97 for cephalosporins, 8.58 for trimethoprim-sulfamethoxazole, and 7.29 for subjects with no antibiotic claims. It was concluded that exposures to short courses of antibiotics were not associated with a lower risk of ischaemic stroke in this population-based study [Luchsinger et al., 2001].
[MEW comment: The evidence that C. pneumoniae is associated with cerebrovascular stroke is uncertain while any causal link is completely unproven ].
[MEW] August 2003
NEXT: C. pneumoniae and multiple sclerosis
Bucurescu, G. & Stiertiz, D. D. (2003). Evidence of an association between Chlamydia pneumoniae and cerebrovascular accidents. European Journal of Neurology 10, 449 - 452.
Cook, P. J., Honeybourne, D., Lip, G. Y., Beevers, D. G., Wise, R. & Davies, P. (1998). Chlamydia pneumoniae_ antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke 29, 404 - 410.
Gibbs, R. G., Sian, M., Mitchell, A. W., Greenhalgh, R. M., Davies, A. H. Carey, N. (2000). Chlamydia pneumoniae_ does not influence atherosclerotic plaque behavior in patients with established carotid artery stenosis. Stroke 31, 2930 - 2935.
Heuschmann, P. U., Neureiter, D., Gesslein, M. et al., (2001). Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: Results from a population-based case-control study. Stroke 32, 2253 - 2258.
Johnston, S. C., Messina, L. M., Browner, W. S., Lawton, M. T., Morris, C. & Dean, D. (2001). C-reactive protein levels and viable Chlamydia pneumoniae in carotid artery atherosclerosis. Stroke 32, 2748 - 2752.
LaBiche, R., Koziol, D., Quinn, T. C., Gaydos, C., Azhar, S., Ketron, G., Sood, S. & DeGraba, T. J. (2001). Presence of Chlamydia pneumoniae in human symptomatic and asymptomatic carotid atherosclerotic plaque. Stroke 32, 855 - 860.
Luchsinger, J. A., Pablos-Mendez, A., Knirsch, C., Rabinowitz, D. & Shea, S. (2001). Antibiotic use and risk of ischemic stroke in the elderly. American Journal of Medicine 111, 361 - 366.
Neureiter, D., Heuschmann, P., Stintzing, S., Kolominsky-Rabas, P., Barbera, L., Jung, A., Ocker, M., Maass, M., Faller, G. & Kirchner, T. (2003). Detection of Chlamydia pneumoniae but not of Helicobacter pylori in symptomatic atherosclerotic carotids associated with enhanced serum antibodies, inflammation and apoptosis rate. Atherosclerosis 168, 153 - 162.
Ngeh, J., Gupta, S., Goodbourn, C., Panayiotou, B. & McElligott, G. (2003). Chlamydia pneumoniae in elderly patients with stroke (C-PEPS): a case-control study on the seroprevalence of Chlamydia pneumoniae in elderly patients with acute cerebrovascular disease. Cerebrovascular Disease 15, 11 - 16.
Smieja, M., Gnarpe, J., Lonn, E., Gnarpe, H., Olsson, G., Yi Q, et al., (2003). Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation 107, 251 - 257.
Tanne D, Haim M, Boyko V, Goldbourt U, Reshef T, Adler Y, Brunner D, Mekori YA, Behar S. (2003). Prospective study of Chlamydia pneumoniae IgG and IgA seropositivity and risk of incident ischemic stroke. Cerebrovascular Disease 16, 166 - 170.
Tarnacka, B., Gromadzka, G. & Czlonkowska, A. (2003). Increased circulating immune complexes in acute stroke: the triggering role of Chlamydia pneumoniae and cytomegalovirus. Stroke 33, 936 - 940.
Virok, D., Kis, Z., Karai, L., Intzedy, L., Burian, K., Szabo, A., Ivanyi, B. & Gonczol, E. (2001). Chlamydia pneumoniae in atherosclerotic middle cerebral artery. Stroke 32, 1973 - 1976.
Wimmer, M. L., Sandmann-Strupp, R., Saikku, P. & Haberl, R. L. (1996). Association of chlamydial infection with cerebrovascular disease. Stroke 27, 2207 - 2210.