Influenza Virus Infection, Infectious Burden, and Atherosclerosis
To the Editor:
We read with great interest the study by Philippa Lavallée et al1 in a recent issue of Stroke. The authors found in a case-control study of 450 subjects that the risk of stroke was significantly reduced in the subjects vaccinated against influenza during the last 5 years. The authors conclude that influenza vaccination may protect against brain infarction by reducing infections.
A possible relationship between influenza and atherosclerosis, in particular myocardial infarction, was first suggested after epidemics of influenza struck Europe and the United States in the early 1900s.2 Increasing evidence exists indicating that inflammation and possibly infections play an important role in atherogenesis.3,4⇓ The hypothesis of infectious agents that may play an important role in the atherogenesis is supported by the results of several epidemiologic studies, suggesting a possible atherogenic potential from particular pathogens, like Helicobacter pylori, cytomegalovirus (CMV), herpes simplex virus (HSV), and Chlamydia pneumoniae. However, existing epidemiologic data about the association of some of these pathogens and atherosclerosis are conflicting, and although attractive, the microbial pathogenesis theory for atherosclerosis remains unproven.5 Clinical data about the association of influenza virus seropositivity (in unvaccinated subjects) and atherosclerosis are lacking. We tested the possible association between influenza type A and B infection and presence of atherosclerosis of coronary arteries (defined as >50% diameter stenosis of at least 1 coronary artery assessed angiographically) in a study of 218 consecutive patients (not previously vaccinated against influenza) undergoing coronary angiography.
Blood of all subjects was tested for serum IgG antibodies to influenza A and B and for seromarkers of 4 other pathogens (C pneumoniae, hepatitis A virus [HAV], H pylori, and CMV). Of the 218 patients (54.6% men, mean age 64.6 years), 95 (43.6%) had anti-influenza A IgG antibodies and 141 (64.7%) had anti-influenza B IgG antibodies. Coronary artery disease (CAD) prevalence was 69.5% in anti-influenza A seropositive patients and 61% in anti-influenza A seronegative patients (P=0.25). CAD was found in 66% of anti-influenza B seropositive subjects and 62.3% of anti-influenza B seronegative patients (P=0.69). This analysis demonstrates that influenza (A and B) seropositivity represents no predictor of risk for CAD. Moreover, seropositivity for each other pathogen (tested in our study) was not associated with CAD. In contrast, the number of infectious pathogens to which an individual has been exposed (“infectious burden”6) correlated with prevalence of CAD. Four or more of the 6 seromarkers tested for particular infections were positive in 48.8% of patients with CAD and in 31.2% of patients in patients without CAD (P=0.02). Five or 6 seromarkers were positive in 21.3% of patients with CAD and in 9% of patients without CAD (P=0.03).
Therefore, we support the interpretation of the results by Philippa Lavallée et al1 that infections subsequent to influenza may play a role in promoting the complications of atherosclerotic disease (in particular, brain and myocardial infarction) and may also induce hypercoagulation, rather than influenza virus infection playing a causal role in atherogenesis. However, some triggers like additional exposure to other pathogens or nonspecific stimulation of the immune system7 could influence the susceptibility to the atherogenic effects of infection with a particular pathogen agent.
- ↵Lavallée P, Perchaud V, Gautier-Bertrand M, Grabli D, Amarenco P. Association between influenza vaccination and reduced risk of brain infarction. Stroke. 2002; 33: 513–518.
- ↵Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Rippin G, Victor A, Hafner G, Schlumberger W, Meyer J. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation. 2002; 105: 15–21.
- ↵Shor A. A pathologist’s view of organisms and human atherosclerosis. J Infect Dis. 2001; 183: 1428–1429.
- ↵Rupprecht HJ, Blankenberg S, Bickel C, Rippin G, Hafner G, Prellwitz W, Schlumberger W, Meyer J. Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. Circulation. 2001; 104: 25–31.
- ↵Lehr HA, Sagban TA, Ihling C, Zahringer U, Hungerer KD, Blumrich M, Reifenberg K, Bhakdi S. Immunopathogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet. Circulation. 2001; 104: 914–920.