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Prof. Michael Bohm
Dr. Nicolas Werner
Influenza infection has been associated with increased rates of cardiovascular events. Various studies have demonstrated the important role of vaccination with a concomitant decrease in all-cause mortality and cardiovascular mortality and morbidity. The arrival of the avian influenza A (H5N1) virus among poultry in Europe, underlines the importance of a consequent vaccination of patients and health care providers according to current guidelines.
The recent detection of the influenza virus subtype H5N1 in Europe has focused public attention on influenza and its prevention and treatment. In contrast to the H5N1 virus which is primarily pathogenic for poultry and can only rarely cause human infections and deaths, the human influenza A virus infection (subtypes H1N1, H1N2, and H3N2) leads to thousands of deaths each year. Several studies have underlined the importance of influenza vaccination, especially in patients with cardiovascular disease. In expectation of the next influenza season 2005/2006, the evidence for the need of consequent immunization particularly in high-risk patients and in patients with cardiovascular disease is reviewed.
Iapolipoprotein E (ApoE)-deficient mice infections with influenza A lead to a marked increase in inflammation, plaque thrombosis, smooth muscle cell proliferation, and fibrin deposition1. Interestingly, in this model only plaque regions are inflamed but not normal aortic segments. It is postulated that the consequences of systemic inflammation including the release of inflammatory cytokines, the development of endothelial dysfunction, changes in plasma viscosity as well as endogenous catecholamines, dehydration, and induction of pro-coagulative activity of infected endothelial cells contribute to the development of instable plaques and plaque rupture2. The infection of monocytes with influenza especially has been associated with the release of IL-6 and IL-8, both interleukins, which are known to trigger plaque rupture and atherosclerosis2.
Influenza infections have been suggested as an explanation for the peak of acute myocardial infarction (AMI) during the winter season 3;4. Death rates due to cardiovascular causes were similar to the rates of death due to influenza and pneumonia - with a two week delay for the subsequent cardiovascular events. In a recently published study by Smeeth et al. in 20,486 persons with a first AMI and 19,063 patients with a first stroke, no increase in the risk of AMI and stroke was noted after influenza, tetanus, or pneumococcal vaccination5. However, the risk for both events was significantly higher after a systemic respiratory tract infection with a peak during the first 3 days. This observation supports the concept that systemic inflammatory diseases may be associated with increased cardiovascular event rates.
All-cause Mortality Influenza vaccination has been associated with a 50% reduction in all-cause mortality in healthy elderly persons6. In a Swedish sample of 260,000 individuals >65 years of age, a combined influenza/pneumococcal vaccination resulted in a 57% decrease in all-cause mortality7. A meta-analysis of 20 cohort studies confirmed a reduction in death rates of 68%8. Recently, these results were extended to persons younger than 65 years with high risk medical conditions. In this study, vaccination prevented 78% of deaths (95%CI, 39%-92%)9.
Cardiovascular Mortality and Morbidity
Naghavi and colleagues demonstrated that in patients with manifest cardiovascular disease, vaccination against influenza was associated with a decreased rate in new onset AMI within the influenza season 1997/199810. In two cohorts with a total of 280,000 patients, Nichol et al. showed that vaccination against influenza was associated with a risk reduction for hospitalization due to cardiovascular disease, cerebrovascular disease, and all-cause mortality11. Interestingly, the FLUVACS study revealed that vaccination against influenza is associated with a significant reduction in the incidence of a single and composite endpoint of death, myocardial infarction or recurrent ischemia in patients with myocardial infarction and planned percutanous coronary intervention12;13. Surprisingly, the incidence for the primary endpoint cardiovascular death was at 1 year still significantly lower among vaccinated patients compared to controls13. Similar results for the 1 year follow-up were obtained for the combined endpoint (death, AMI, recurrent ischemia) which was mainly driven by a reduction in myocardial infarction.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
There is convincing evidence that vaccination against influenza can significantly reduce all-cause mortality and cardiovascular mortality and morbidity in patients >65 years as well as in patients with high-risk medical conditions - including patients with atherosclerotic disease. The importance of influenza as a systemic inflammatory disease in triggering cardiovascular events has been demonstrated in various studies. However, the underlying molecular mechanisms are still poorly understood. We are currently facing a new situation in infectious disease in Europe: The worst scenario, a genetic mixture of the H5N1 virus with the common human influenza virus may allow the infection from person to person. Although there is no evidence for the occurrence of this scenario at present, it is most important that health care providers stick to the current guidelines: All patients with severe medical conditions - including patients with chronic heart or lung disease, patients in nursing homes as well as all patients>65 years of age (high risk group) should be immunized until October 24th according to the guidelines of the CDC (http://www.cdc.gov/flu/protect/keyfacts.htm). Finally, as a reminder: Health care providers themselves should receive influenza vaccination each year!
1. Naghavi M, Wyde P, Litovsky S, Madjid M, Akhtar A, Naguib S, Siadaty MS, Sanati S, Casscells W. Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation. 2003;107:762-768. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12578882&query_hl=1 2. Madjid M, Naghavi M, Litovsky S, Casscells SW. Influenza and cardiovascular disease: a new opportunity for prevention and the need for further studies. Circulation. 2003;108:2730-2736. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14610013&query_hl=3 3. Cold exposure and winter mortality from ischaemic heart disease, cerebrovascular disease, respiratory disease, and all causes in warm and cold regions of Europe. The Eurowinter Group. Lancet. 1997;349:1341-1346. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9149695&query_hl=5 4. Gordon T, Thom T. The recent decrease in CHD mortality. Prev Med. 1975;4:115-125. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1153392&query_hl=7 5. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004;351:2611-2618. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15602021&query_hl=10 6. Nichol KL, Wuorenma J, von Sternberg T. Benefits of influenza vaccination for low-, intermediate-, and high-risk senior citizens. Arch Intern Med. 1998;158:1769-1776. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9738606&query_hl=12 7. Christenson B, Lundbergh P, Hedlund J, Ortqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in adults aged 65 years or older: a prospective study. Lancet. 2001;357:1008-1011. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11293594&query_hl=14 8. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Ann Intern Med. 1995;123:518-527. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=7661497&query_hl=16 9. Hak E, Buskens E, van Essen GA, de Bakker DH, Grobbee DE, Tacken MA, van Hout BA, Verheij TJ. Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: the PRISMA study. Arch Intern Med. 2005;165:274-280. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15710789&query_hl=18 10. Naghavi M, Barlas Z, Siadaty S, Naguib S, Madjid M, Casscells W. Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation. 2000;102:3039-3045. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11120692&query_hl=20 11. Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med. 2003;348:1322-1332. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12672859&query_hl=22 12. Gurfinkel EP, de la Fuente RL, Mendiz O, Mautner B. Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation. 2002;105:2143-2147. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11994246&query_hl=24 13. Gurfinkel EP, Leon dlF, Mendiz O, Mautner B. Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) Study. Eur Heart J. 2004;25:25-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14683739&query_hl=26
N. Werner1,2 and M. Böhm2 1 Medizinische Klinik und Poliklinik Klinik für Innere Medizin II Universitätsklinikum Bonn 53105 Bonn
2 Klinik für Innere Medizin III Universitätsklinikum des Saarlandes 66421 Homburg-SaarCorrespondence: Nikos Werner, MD Medizinische Klinik und Poliklinik Innere Medizin II Universitätsklinikum Bonn Sigmund-Freud-Str. 25 53105 Bonn phone +49-228-287-5217/5218 fax +49-228-287-6423 Email: firstname.lastname@example.org
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