(Stroke. 2000;31:2517-b.)
© 2000 American Heart Association, Inc.
Letters to the Editor |
Chlamydia pneumoniae Infection and PFO-Associated Ischemic Stroke
Department of Neurological Sciences
Department of Tropical and Infectious Diseases, University of Rome "La Sapienza", Rome, Italy
To the Editor:
Ischemic stroke in young adults is a topic that has received increasing attention in recent years and has been accompanied by descriptions of case series in which the relative frequencies of risk factors and presumed etiology are assessed.1 A number of epidemiological and pathogenic studies have been published on the association between Chlamydia pneumoniae infection and ischemic stroke. The results are, however, controversial. These studies show a high degree of heterogeneity in the selection of patients and controls and in the interpretation of serological results.2 3 Wimmer et al4 studied a series of stroke patients aged <50 years. They concluded that chronic C pneumoniae infection is associated with an increased risk of stroke and TIA but were unable to detect any correlation between antibody titers and etiologic stroke subtypes.
Our study was designed to evaluate the potential role of C
pneumoniae infection in specific etiologic subtypes of stroke in
young patients. In our consecutive series of 101 patients with
ischemic stroke, aged <46 completed years, and 101 matched
controls, we evaluated C pneumoniae IgG and IgM antibodies
by means of the microimmunofluorescence method. When the study
was planned, the detection of IgA was not yet available. There was a
statistically significant difference between the 2 groups with regard
to the frequency of active chronic C pneumoniae infection
(IgG 
1:512) (25.7% versus 7.8%, P<0.05). After
adjustment for cerebrovascular risk factors, the OR for inactive
chronic infection (IgG 
1:256) was 1.3 (95% CI 0.6 to 3.2), whereas
that for active chronic infection was 2.7 (95% CI 1.0 to 7.3).
Furthermore, we considered serological patterns for the following etiologic subtypes: (1) atherosclerosis, (2) cardioembolism (80% of patients had a "high-risk" patent foramen ovale [PFO; eg, width >2 mm] and larger amounts of interatrial shunting, or PFO in association with atrial septal aneurysm),5 (3) nonatherosclerotic vasculopathy (arterial dissection, arteritis), (4) procoagulant conditions, and (5) undetermined cause. Although we did not find any significant difference between stroke etiologic subtypes, a positive trend toward an increased prevalence of active chronic C pneumoniae infection was found in the cohort of 35 patients with PFO (13 of 35; 7 of these 13 had IgG titers equal to 1:1024). In the remaining 66 stroke patients, only 5 had the higher IgG titers. Considering these data, what pathogenetic mechanisms might link active chronic C pneumoniae infection and PFO as a cause of stroke? Might C pneumoniae reinfection induce a transient procoagulant state and be an additional risk factor for symptomatic emboli, when a potential route for paradoxical emboli is patent? Because the lungs are the usual site of C pneumoniae infection, is the spreading of the pathogen from the lungs to the endothelium of the heart pathogenically plausible from an anatomic and physiopathological point of view?
Our preliminary study has certain limitations, such as the relatively small sample size, if compared with the 5 etiologic categories we considered, which may have limited the power of the statistical analysis performed to detect possible correlations. This correlations would require a larger study, perhaps including PCR and culture techniques to test whether C pneumoniae infection, besides being associated with activation of the atherosclerotic plaque6 at later age, might indeed explain the occurrence of ischemic events associated with PFO in the young. Nevertheless, we wish to suggest the hypothesis of a possible role of C pneumoniae infection in ischemic stroke for preventive purposes in the young, since the microorganism is susceptible to antibiotic therapy.
References
1. Fieschi C, Rasura M, Anzini A, De Castro S, Di Gianfilippo G, Valesini G, Violi F, Zanette EM. A diagnostic approach to ischemic stroke in young and middle-aged adults. Eur J Neurol.. 1996;3:325–330.
2. Syrjanen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding infection as an important risk factor for ischemic brain infarction in young and middle aged patients. BMJ.. 1988;296:1156–1160.
3. Cook PJ, Honeybourne D, Lip GY, Beevers DG, Wise R, Davies P. Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke.. 1998;29:404–410.
4. Wimmer MLJ, Sandmann-Strupp R, Saikku P, Haberl RL. Association of chlamydial infection with cerebrovascular disease. Stroke.. 1996;27:2207–2210.
5. Di Pasquale G, Pozzati A. Heart disease and stroke. In: Fieschi C, Fisher M, eds. Prevention of Ischemic Stroke. 1999:27–50.
6. Rothwell PM, Villagra R, Gibson R, Donders RCJM, Warlow CP. Evidence of a chronic systemic cause of atherosclerotic plaques. Lancet.. 2000;355:19–24.
Response
Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, England
We thank Rasura et al for sharing with us their interesting data, which suggests a possible role of Chlamydia pneumoniae infection in ischemic strokes among young patients with patent foramen ovale. As the authors rightly point out, their cross-sectional study, as previous similar studies, does not prove a causative role of the agent but gives new insights into the association and raises more questions, especially into plausible mechanism(s) of association between C pneumoniae and stroke.
A number of infectious agents have generated considerable research interest as possible causative agents in vascular disorders, with the greatest interest in C pneumoniae and Helicobacter pylori.R1 Indeed, many patients with chronic coronary heart disease and carotid artery disease appear to have a chronic C pneumoniae infection,R2 R3 and C pneumoniae antigen has been detected in fatty streaks and atheromatous plaques.R4 Our cross-sectional study from the West Birmingham Stroke Project also found an independent relationship between positive C pneumoniae serology and acute stroke, even after correcting for possible confounders, such as ethnic origin, age, sex, smoking habit, diabetes mellitus, steroid medication, and social deprivation.R5 Nevertheless, it has never been entirely clear whether it is the organism itself or the virulence of the antibodies raised against it that is associated with atherosclerotic disorders. Indeed, elevated antibody titers or immune complexes containing Chlamydia lipopolysaccharide are an independent significant risk factor for acute myocardial infarction.R6 R7
Plausible mechanisms linking C pneumoniae and vascular disease may be an adverse influence on markers of inflammation and interaction with other vascular risk factors. For example, C pneumoniae infection is more common among smokers than nonsmokers, perhaps due to a decrease in cell-mediated immunity among smokers.R7 R8 Both acute and chronic infection with C pneumoniae are associated with an adverse lipid profile, including higher triglyceride and lower high density lipoprotein concentrations.R9 R10 R11 In the West Birmingham Stroke Project, we found no apparent association between C pneumoniae antibody titers and the serum cholesterol, triglyceride, fibrinogen, and von Willebrand factor concentrations, which suggests that the prothrombotic state or endothelial dysfunction may not be the principal mechanisms of association between C pneumoniae and cerebrovascular disease.R5 Indeed, each of the above vascular risk factors is independently related to atherosclerotic disease and a potential increase in the risk of stroke.
Perhaps another way to ascertain the causative link between C pneumoniae infection and vascular disease is by conducting interventional trials aiming to look at the effect of antibiotics that eradicate C pneumoniae. For example, Gupta et alR12 reported that among patients after myocardial infarction, those with high titers of C pneumoniae antibodies had a significantly higher number of cardiovascular events, which was reduced with azithromycin treatment. The ROXIS studyR13 showed a significant reduction of the composite triple end point (cardiac ischemic death, myocardial infarction and severe recurrent ischemia) at 30 days after unstable angina/non–Q-wave myocardial infarction, among patients treated with roxithromycin, another macrolide antibiotic against C pneumoniae. However, 6 months after the study treatment termination, there was no longer any significant difference between the treatment and placebo groups.R14 In contrast to Gupta et al,R12 the ROXIS study did not find any difference in the outcome related to the baseline IgG antibody titers or to decreases in titers with antibiotic treatment. In the ACADEMIC study,R15 probably the largest of the published interventional study of antibiotics in coronary artery disease, there was no significant difference in antibody titers or clinical events at the 6-month follow-up among coronary artery disease patients treated with azithromycin. We are not aware of any randomized, double-blind, placebo-controlled study of the effect of antibiotics against C pneumoniae among patients with cerebrovascular disease per se.
Thus, the question of a clinically significant relationship between C pneumoniae infection or antibodies against C pneumoniae and atherosclerotic vascular disorders, including stroke, remains largely unanswered. One cannot help but wonder whether any (possibly unknown) confounding factor has been missing in the analysis of these data.
Perhaps the story of C pneumoniae in the context of cardiovascular or cerebrovascular diseases is somewhat similar to that seen with H pylori. Indeed, there was tremendous initial enthusiasm for attempting to establish a causative link between H pylori and ischemic heart disease after initial studies demonstrated a possible association.R16 R17 However, this enthusiasm has suffered a setback after a few recent studies have demonstrated a lack of a significant association between H pylori and ischemic heart disease (as reviewed by Edmunds and LipR18 ).
Thus, in providing an answer to the question, "Is there a link between C pneumoniae and stroke?" the answer may well be a resounding "maybe." If we were dealing with the Scottish legal system, perhaps the verdict of "not proven" (rather than the "guilty" or "not guilty" verdicts of the English legal system) would be more appropriate, which probably infers that some blame may be implied but the more serious offenders (eg, hypertension, smoking, hyperlipidemia) are more likely to be in possession of the smoking gun. Indeed, the case for a clinically significant causal relationship between C pneumoniae and atherosclerotic vascular disease (whether cerebrovascular or cardiovascular) has not yet been proved beyond reasonable doubt to justify "prosecution" with routine antibiotic therapy to eradicate C pneumoniae.
References
1. Cook PJ, Lip GYH. Chlamydia pneumoniae and atherosclerotic vascular disease. Q J Med.. 1996;89:727–735.
2. Linnanmaki E, Leinonen M, Mattila K, Nieminen MS, Valtonen V, Saikku P. Chlamydia pneumoniae–specific circulating immune complexes in patients with chronic coronary heart disease. Circulation.. 1993;87:1130–1134.
3. Melnick SL, Shahar E, Folsom AR, Grayston JT, Sorlie PD, Wang SP, Szklo M. Past infection by Chlamydia pneumoniae strain TWAR and asymptomatic carotid atherosclerosis. Am J Med.. 1993;95:499–504.
4. Shor A, Kuo CC, Patton DL. Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques. S Afr Med J.. 1992;82:158–161.
5. Cook PJ, Honeybourne D, Lip GY, Beevers DG, Wise R, Davies P. Chlamydia pneumoniae antibody titers are significantly associated with acute stroke and transient cerebral ischemia: the West Birmingham Stroke Project. Stroke.. 1998;29:404–410.
6. Saikku P. Epidemiologic association of Chlamydia pneumoniae and atherosclerosis: the initial serologic observation and more. J Infect Dis. 2000;181(Suppl 3):S411–S413.
7. Strachan DP, Carrington D, Mendall MA, Ballam L, Morris J, Butland BK, Sweetnam PM, Elwood PC. Relation of Chlamydia pneumoniae serology to mortality and incidence of ischaemic heart disease over 13 years in the Caerphilly prospective heart disease study. BMJ.. 1999;318:1035–1039.
8. Hahn DL, Golubjatnikov R. Smoking is a potential confounder of the Chlamydia pneumoniae–coronary artery disease association. Arterioscler Thromb.. 1992;12:945–947.
9. Karvonen M, Tuomilehto J, Pitkaniemi J, Naukkarinen A, Saikku P. Importance of smoking for Chlamydia pneumoniae seropositivity. Int J Epidemiol.. 1994;23:1315–1321.
10. Laurila A, Bloigu A, Nayha S, Hassi J, Leinonen M, Saikku P. Chronic Chlamydia pneumoniae infection is associated with a serum lipid profile known to be a risk factor for atherosclerosis. Arterioscler Thromb Vasc Biol.. 1997;17:2910–2913.
11. Leinonen M, Saikku P. Interaction of Chlamydia pneumoniae infection with other risk factors of atherosclerosis. Am Heart J.. 1999;138:S504–S506.
12. Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation.. 1997;96:404–407.
13. Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B, and the ROXIS Study Group. Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study. Lancet.. 1997;350:404–407.
14. Gurfinkel E, Bozovich G, Beck E, Testa E, Livellara B, Mautner B. Treatment with the antibiotic roxithromycin in patients with acute non-Q-wave coronary syndromes: the final report of the ROXIS Study. Eur Heart J.. 1999;20:121–127.
15. Anderson JL, Muhlestein JB, Carlquist J, Allen A, Trehan S, Nielson C, Hall S, Brady J, Eggar M, Horne B, Lim T. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for Chlamydia pneumoniae infection: the Azithromycin in Coronary Artery Disease: Elimination of Myocardial Infection with Chlamydia (ACADEMIC) study. Circulation.. 1999;99:1540–1547.
16. Mendall M, Goggin P, Levy J, Molineaux N, Strachan D, Camm A, Northfield T. Relation of Helicobacter pylori infection and coronary heart disease. Br Heart J.. 1994;71:437–449.
17. Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: Is there a link? Lancet.. 1997;350:430–436.
18. Edmunds E, Lip GYH. An independent verdict: does infection with Helicobacter pylori cause ischaemic heart disease? Dig Liver Dis. 2000;32;69–70.
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