Skip to main content

Advertisement

SpringerLink
Log in

Infection and Stroke: an Update on Recent Progress

  • Infection (J Halperin, Section Editor)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

The role of infection in cerebrovascular disease is complex and remains incompletely understood. Over the last 5 years, investigators have made notable inroads in untangling this thorny topic. In this review, we examine these recent developments, concentrating on four aspects of the relationship between infection and stroke. We first discuss specific infectious agents as direct causes of stroke, focusing on recent work implicating herpesviruses and HIV in cerebral vasculopathy. We then discuss systemic infection of any type as a stroke trigger, focusing on the relationship of infection to timing of acute stroke, both in children and adults, as well as the role of vaccination in stroke prevention. We examine the evidence for chronic infection or “infectious burden” as a stroke risk factor. Finally, we discuss recent work on infection as a risk factor for increased morbidity after stroke, possible mechanisms mediating this effect, and the evidence for prophylactic antibiotics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Karenberg A, Hort I. Medieval descriptions and doctrines of stroke: preliminary analysis of select sources. Part I: the struggle for terms and theories—late antiquity and early middle ages. J Hist Neurosci. 1998;7:162–73.

    Article  PubMed  CAS  Google Scholar 

  2. Marie P. Hémiplégie cérébrale infantile et maladies infectieuses. Prog Med Paris. 1885;13:167–9.

    Google Scholar 

  3. Freud S. Die infantile Cerebrallähmung. Nothnagel H, editor. Specielle Pathologie 9, Teil 3 (I. Hälfte). Vienna, Austria: Holder; 1897. pp. 1–327.

  4. Osler W. The principles and practice of medicine, designed for the use of practitioners and students of medicine. 7th ed. New York: D. Appleton and company; 1910.

    Google Scholar 

  5. Frothingham C. The relation between acute infectious diseases and arterial lesions. Arch Intern Med. 1911;8:153–62.

    Article  Google Scholar 

  6. Ophüls W. Arteriosclerosis and cardiovascular disease: their relation to infectious diseases. JAMA. 1921;76:700–1.

    Article  Google Scholar 

  7. Fabricant CG, Fabricant J, Litrenta MM, Minick CR. Virus-induced atherosclerosis. J Exp Med. 1978;148:335–40.

    Article  PubMed  CAS  Google Scholar 

  8. Hindfelt B, Nilsson O. Brain infarction in young adults (with particular reference to pathogenesis). Acta Neurol Scand. 1977;55:145–57.

    Article  PubMed  CAS  Google Scholar 

  9. Grindal AB, Cohen RJ, Saul RF, Taylor JR. Cerebral infarction in young adults. Stroke. 1978;9:39–42.

    Article  PubMed  CAS  Google Scholar 

  10. Chopra JS, Prabhakar S. Clinical features and risk factors in stroke in young. Acta Neurol Scand. 1979;60:289–300.

    Article  PubMed  CAS  Google Scholar 

  11. Syrjanen J, Valtonen VV, Iivanainen M, Kaste M, Huttunen JK. Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients. Br Med J (Clin Res Ed). 1988;296:1156–60.

    Article  CAS  Google Scholar 

  12. Finsterer J, Auer H. Parasitoses of the human central nervous system. J Helminthol. 2013;87:257–70.

    Article  PubMed  CAS  Google Scholar 

  13. Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW, et al. Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation. 1996;94:922–7.

    Article  PubMed  CAS  Google Scholar 

  14. Zhu J, Quyyumi AA, Norman JE, Csako G, Epstein SE. Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation as reflected by elevated C-reactive protein levels. J Am Coll Cardiol. 1999;34:1738–43.

    Article  PubMed  CAS  Google Scholar 

  15. Sorlie PD, Nieto FJ, Adam E, Folsom AR, Shahar E, Massing M. A prospective study of cytomegalovirus, herpes simplex virus 1, and coronary heart disease: the atherosclerosis risk in communities (ARIC) study. Arch Intern Med. 2000;160:2027–32.

    Article  PubMed  CAS  Google Scholar 

  16. Grahame-Clarke C, Chan NN, Andrew D, Ridgway GL, Betteridge DJ, Emery V, et al. Human cytomegalovirus seropositivity is associated with impaired vascular function. Circulation. 2003;108:678–83.

    Article  PubMed  Google Scholar 

  17. Sun Y, Pei W, Welte T, Wu Y, Ye S, Yang Y. Cytomegalovirus infection is associated with elevated interleukin-10 in coronary artery disease. Atherosclerosis. 2005;179:133–7.

    Article  PubMed  CAS  Google Scholar 

  18. Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS. 2006;20:2275–83.

    Article  PubMed  Google Scholar 

  19. Nerheim PL, Meier JL, Vasef MA, Li W-G, Hu L, Rice JB, et al. Enhanced cytomegalovirus infection in atherosclerotic human blood vessels. Am J Pathol. 2004;164:589–600.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ridker PM, Hennekens CH, Stampfer MJ, Wang F. Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke. Circulation. 1998;98:2796–9.

    Article  PubMed  CAS  Google Scholar 

  21. Fagerberg B, Gnarpe J, Gnarpe H, Agewall S, Wikstrand J. Chlamydia pneumoniae but not cytomegalovirus antibodies are associated with future risk of stroke and cardiovascular disease: a prospective study in middle-aged to elderly men with treated hypertension. Stroke. 1999;30:299–305.

    Article  PubMed  CAS  Google Scholar 

  22. Borgia MC, Mandolini C, Barresi C, Battisti G, Carletti F, Capobianchi MR. Further evidence against the implication of active cytomegalovirus infection in vascular atherosclerotic diseases. Atherosclerosis. 2001;157:457–62.

    Article  PubMed  CAS  Google Scholar 

  23. Betjes MGH, Litjens NHR, Zietse R. Seropositivity for cytomegalovirus in patients with end-stage renal disease is strongly associated with atherosclerotic disease. Nephrol Dial Transplant. 2007;22:3298–303.

    Article  PubMed  Google Scholar 

  24. Ozdemir FN, Akgul A, Altunoglu A, Bilgic A, Arat Z, Haberal M. The association between cytomegalovirus infection and atherosclerotic events in renal transplant recipients. Transplant Proc. 2007;39:990–2.

    Article  PubMed  CAS  Google Scholar 

  25. Wolf SC, Brehm BR, Mayer O, Jurgens S, Schultze G, Risler T. Infectious risk factors for atherosclerotic vascular disease in hemodialysis patients--Chlamydia pneumoniae but not Helicobacter pylori or cytomegalovirus is associated with increased C-reactive protein. Ren Fail. 2004;26:279–87.

    Article  PubMed  CAS  Google Scholar 

  26. Ji Y-N, An L, Zhan P, Chen X-H. Cytomegalovirus infection and coronary heart disease risk: a meta-analysis. Mol Biol Rep. 2012;39:6537–46. This systematic review and meta-analysis examined the association of CMV and coronary artery atherosclerosis, looking at 55 case–control studies (6 prospective, 49 retrospective) involving 9000 cases and 8608 controls. CMV was a clear risk factor for coronary disease; the association was even stronger (OR 8.21) in studies where PCR was used as the detection method.

    Article  PubMed  CAS  Google Scholar 

  27. Tracy RP, Doyle MF, Olson NC, Huber SA, Jenny NS, Sallam R, et al. T-helper type 1 bias in healthy people is associated with cytomegalovirus serology and atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc. 2013;2:e000117.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sacre K, Hunt PW, Hsue PY, Maidji E, Martin JN, Deeks SG, et al. A role for cytomegalovirus-specific CD4+CX3CR1+ T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis. AIDS. 2012;26:805–14.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Assinger A, Kral JB, Yaiw KC, Schrottmaier WC, Kurzejamska E, Wang Y, et al. Human cytomegalovirus-platelet interaction triggers toll-like receptor 2-dependent proinflammatory and proangiogenic responses. Arterioscler Thromb Vasc Biol. 2014;34:801–9.

    Article  PubMed  CAS  Google Scholar 

  30. Ponroy N, Taveira A, Mueller NJ, Millard A-L. Statins demonstrate a broad anti-cytomegalovirus activity in vitro in ganciclovir-susceptible and resistant strains. J Med Virol. 2015;87:141–53. This bench study examined the effect of statins on CMV-infected human aortic endothelial cells and fibroblasts in vitro. Atorva-, fluva-, and pravastatin, but not simvastatin, reduced CMV titers in both cell types with an efficacy comparable to ganciclovir. The effect was retained in ganciclovir-resistant strains.

    Article  PubMed  CAS  Google Scholar 

  31. Rosenblum WI, Hadfield MG, Young HF. Granulomatous angiitis with preceding varicella zoster. Ann Neurol. 1978;3:374–5.

    Article  PubMed  CAS  Google Scholar 

  32. Gilden DH, Kleinschmidt-DeMasters BK, Wellish M, Hedley-Whyte ET, Rentier B, Mahalingam R. Varicella zoster virus, a cause of waxing and waning vasculitis: the New England Journal of Medicine case 5–1995 revisited. Neurology. 1996;47:1441–6.

    Article  PubMed  CAS  Google Scholar 

  33. Nagel MA, Gilden D. Update on varicella zoster virus vasculopathy. Curr Infect Dis Rep. 2014;16:407.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nagel MA, Traktinskiy I, Azarkh Y, Kleinschmidt-DeMasters B, Hedley-Whyte T, Russman A, et al. Varicella zoster virus vasculopathy: analysis of virus-infected arteries. Neurology. 2011;77:364–70.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Nagel MA, Traktinskiy I, Stenmark KR, Frid MG, Choe A, Gilden D. Varicella-zoster virus vasculopathy: immune characteristics of virus-infected arteries. Neurology. 2013;80:62–8. This study examined pathological changes in VZV-infected cerebral and temporal arteries at various stages of infection, and compared with control normal arteries. Inflammatory cells and viral antigen were found in abundance in the adventitia of VZV-infected arteries only, along with thickened intima, supporting a role for viral-induced inflammation in arterial wall remodeling.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Nagel MA, Forghani B, Mahalingam R, Wellish MC, Cohrs RJ, Russman AN, et al. The value of detecting anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology. 2007;68:1069–73.

    Article  PubMed  CAS  Google Scholar 

  37. Nagel MA, Khmeleva N, Choe A, Gutierrez J, Gilden D. Varicella zoster virus (VZV) in cerebral arteries of subjects at high risk for VZV reactivation. J Neurol Sci. 2014;339:32–4.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Nagel MA, Choe A, Khmeleva N, Overton L, Rempel A, Wyborny A, et al. Search for varicella zoster virus and herpes simplex virus-1 in normal human cerebral arteries. J Neurovirol. 2013;19:181–5.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Gilden D, White T, Khmeleva N, Heintzman A, Choe A, Boyer PJ, et al. Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology. 2015;84:1948–55. This pathological study looked for VZV antigen, virions and DNA in 82 temporal arteries from patients with biopsy-proven giant cell arteries, compared with 13 normal temporal arteries. VZV antigen was found in 74% of GCA-positive TAs, compared with 1/13 normal TAs (p < 0.0001, RR 9.67, 95%CI 1.46-63.69). The VZV was found mostly in skip areas adjacent to regions with GCA pathology.

    Article  PubMed  Google Scholar 

  40. Langan SM, Minassian C, Smeeth L, Thomas SL. Risk of stroke following herpes zoster: a self-controlled case-series study. Clin Infect Dis. 2014;58:1497–503.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kang J-H, Ho J-D, Chen Y-H, Lin H-C. Increased risk of stroke after a herpes zoster attack: a population-based follow-up study. Stroke. 2009;40:3443–8.

    Article  PubMed  CAS  Google Scholar 

  42. Lin H-C, Chien C-W, Ho J-D. Herpes zoster ophthalmicus and the risk of stroke: a population-based follow-up study. Neurology. 2010;74:792–7.

    Article  PubMed  Google Scholar 

  43. Zepper P, Wunderlich S, Forschler A, Nadas K, Hemmer B, Sellner J. Pearls & Oy-sters: cerebral HSV-2 vasculitis presenting as hemorrhagic stroke followed by multifocal ischemia. Neurology. 2012;78:e12–5.

    Article  PubMed  CAS  Google Scholar 

  44. Guerrero WR, Dababneh H, Hedna S, Johnson JA, Peters K, Waters MF. Vessel wall enhancement in herpes simplex virus central nervous system vasculitis. J Clin Neurosci. 2013;20:1318–9.

    Article  PubMed  Google Scholar 

  45. Snider SB, Jacobs CS, Scripko PS, Klein JP, Lyons JL. Hemorrhagic and ischemic stroke secondary to herpes simplex virus type 2 meningitis and vasculopathy. J Neurovirol. 2014;20:419–22.

    Article  PubMed  CAS  Google Scholar 

  46. Terlizzi V, Improta F, Di Fraia T, Sanguigno E, D’Amico A, Buono S, et al. Primary herpes virus infection and ischemic stroke in childhood: a new association? J Clin Neurosci. 2014;21:1656–8.

    Article  PubMed  Google Scholar 

  47. Fullerton HJ, Elkind MSV, Glaser CA, Hills NK, Luna JM, Sear K, et al. Herpes viruses in childhood arterial ischemic stroke: interim results of the VIPS Study. Stroke. 2014;45:A38.

    Article  Google Scholar 

  48. Mizusawa H, Hirano A, Llena JF, Shintaku M. Cerebrovascular lesions in acquired immune deficiency syndrome (AIDS). Acta Neuropathol. 1988;76:451–7.

    Article  PubMed  CAS  Google Scholar 

  49. Kieburtz KD, Eskin TA, Ketonen L, Tuite MJ. Opportunistic cerebral vasculopathy and stroke in patients with the acquired immunodeficiency syndrome. Arch Neurol. 1993;50:430–2.

    Article  PubMed  CAS  Google Scholar 

  50. Benjamin LA, Bryer A, Emsley HCA, Khoo S, Solomon T, Connor MD. HIV infection and stroke: current perspectives and future directions. The Lancet Neurology. 2012;11:878–90.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Ovbiagele B, Nath A. Increasing incidence of ischemic stroke in patients with HIV infection. Neurology. 2011;76:444–50.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Gutierrez J, Elkind MSV, Marshall RS. Cardiovascular profile and events of US adults 20–49 years with HIV: results from the NHANES 1999–2008. AIDS Care. 2013;25:1385–91.

    Article  PubMed  Google Scholar 

  53. Vinikoor MJ, Napravnik S, Floris-Moore M, Wilson S, Huang DY, Eron JJ. Incidence and clinical features of cerebrovascular disease among HIV-infected adults in the Southeastern United States. AIDS Res Hum Retroviruses. 2013;29:1068–74.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Mateen FJ, Post WS, Sacktor N, Abraham AG, Becker JT, Smith BR, et al. Long-term predictive value of the Framingham Risk Score for Stroke in HIV-positive vs HIV-negative men. Neurology. 2013;81:2094–102.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Krsak M, Kent DM, Terrin N, Holcroft C, Skinner SC, Wanke C. Myocardial infarction, stroke, and mortality in cART-treated HIV patients on statins. AIDS Patient Care STDS. 2015;29:307–13.

    Article  PubMed  Google Scholar 

  56. Sico JJ, Chang C-CH, So-Armah K, Justice AC, Hylek E, Skanderson M, et al. HIV status and the risk of ischemic stroke among men. Neurology. 2015;84:1933–40. This study examined the incidence of ischemic stroke in a cohort of 76,835 male veterans free of baseline cardiovascular disease. Over a median follow-up period of 5.9 years, HIV-infected veterans had a higher stroke rate than matched uninfected veterans (incidence rate ratio 1.25, p < 0.01). The rate remained higher even after adjusting for comorbidities.

    Article  PubMed  Google Scholar 

  57. Chow FC, He W, Bacchetti P, Regan S, Feske SK, Meigs JB, et al. Elevated rates of intracerebral hemorrhage in individuals from a US clinical care HIV cohort. Neurology. 2014;83:1705–11. This retrospective cohort study used billing data to compare rates of ICH in HIV-infected and uninfected patients. The incidence of ICH was higher in the HIV-infected patients (unadjusted incidence rate ratio of 1.85, 95%CI 1.37-2.47, p < 0.001). In the multivariable model, the effect was more pronounced in young patients and in women.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Womack JA, Chang C-CH, So-Armah KA, Alcorn C, Baker JV, Brown ST, et al. HIV infection and cardiovascular disease in women. J Am Heart Assoc. 2014;3:e001035.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Thakur KT, Lyons JL, Smith BR, Shinohara RT, Mateen FJ. Stroke in HIV-infected African Americans: a retrospective cohort study. J Neurovirol. 2015.

  60. Sweeney EM, Thakur KT, Lyons JL, Smith BR, Willey JZ, Cervantes-Arslanian AM, et al. Outcomes of intravenous tissue plasminogen activator for acute ischaemic stroke in HIV-infected adults. Eur J Neurol. 2014;21:1394–9.

    Article  PubMed  CAS  Google Scholar 

  61. Chow FC, Bacchetti P, Kim AS, Price RW, Hsue PY. Effect of CD4+ cell count and viral suppression on risk of ischemic stroke in HIV infection. AIDS. 2014;28:2573–7.

    Article  PubMed  Google Scholar 

  62. Marcus JL, Leyden WA, Chao CR, Chow FC, Horberg MA, Hurley LB, et al. HIV infection and incidence of ischemic stroke. AIDS. 2014;28:1911–9.

    Article  PubMed  CAS  Google Scholar 

  63. Goldstein DA, Timpone J, Cupps TR. HIV-associated intracranial aneurysmal vasculopathy in adults. J Rheumatol. 2010;37:226–33.

    Article  PubMed  Google Scholar 

  64. Gutierrez J, Glenn M, Isaacson RS, Marr AD, Mash D, Petito C. Thinning of the arterial media layer as a possible preclinical stage in HIV vasculopathy: a pilot study. Stroke. 2012;43:1156–8.

    Article  PubMed  Google Scholar 

  65. Gutierrez J, Elkind MSV, Petito C, Chung DY, Dwork AJ, Marshall RS. The contribution of HIV infection to intracranial arterial remodeling: a pilot study. Neuropathology. 2013;33:256–63. This pathological study examined a measure of arterial remodeling by comparing the ratio of arterial lumen diameter to wall thickness in 51 cerebral arteries from 5 HIV-infected and 13 uninfected brain donors. Arteries from HIV-infected donors had significantly higher ratios, suggesting an association of HIV infection with brain outward arterial remodeling.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Gutierrez J, Rosoklija G, Murray J, Chon C, Elkind MSV, Goldman J, et al. A quantitative perspective to the study of brain arterial remodeling of donors with and without HIV in the Brain Arterial Remodeling Study (BARS). Front Physiol. 2014;5:56.

    PubMed  PubMed Central  Google Scholar 

  67. Gutierrez J, Goldman J, Dwork AJ, Elkind MSV, Marshall RS, Morgello S. Brain arterial remodeling contribution to nonembolic brain infarcts in patients with HIV. Neurology. 2015;85:1–8. Expanding on prior work (see ref 65), this study examined 1,878 cerebral artery segments from 284 HIV-infected and uninfected brain donors. HIV infection was associated with two extremes of arterial remodeling: inward remodeling with accelerated cerebral atherosclerosis causing ischemic infarcts, and outward remodeling causing dolichoectasia and otherwise unexplained infarcts. The dolichoectatic subtype predominated in more immunosuppressed patients.

    Article  Google Scholar 

  68. Douvoyiannis M, Litman N, Goldman DL. Neurologic manifestations associated with parvovirus B19 infection. Clin Infect Dis. 2009;48:1713–23.

    Article  PubMed  Google Scholar 

  69. Mandrioli J, Portolani M, Cortelli P, Sola P. Middle cerebral artery thrombosis in course of parvovirus B19 infection in a young adult: a new risk factor for stroke? J Neurovirol. 2004;10:71–4.

    Article  PubMed  Google Scholar 

  70. Isumi H, Nunoue T, Nishida A, Takashima S. Fetal brain infection with human parvovirus B19. Pediatr Neurol. 21:661–3.

  71. Luna JM, Fullerton HJ, Wintermark M, deVeber GA, Hills NK, Muhammad K, et al. Parvovirus B19 DNA prevalence is increased in pediatric stroke patients compared to controls: pilot findings from the Vascular Effects of Infection in Pediatric Stroke (VIPS) study. Stroke. 2014;45:A36.

    Article  Google Scholar 

  72. Elkind MSV. Why now? Moving from stroke risk factors to stroke triggers. Curr Opin Neurol. 2007;20:51–7.

    Article  PubMed  Google Scholar 

  73. 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;351:2611–8.

    Article  PubMed  CAS  Google Scholar 

  74. Elkind MSV, Carty CL, O’Meara ES, Lumley T, Lefkowitz D, Kronmal RA, et al. Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. Stroke. 2011;42:1851–6.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Gurfinkel EP, de la Fuente RL. Two-year follow-up of the FLU Vaccination Acute Coronary Syndromes (FLUVACS) Registry. Tex Heart Inst J. 2004;31:28–32.

    PubMed  PubMed Central  Google Scholar 

  76. Grau AJ, Fischer B, Barth C, Ling P, Lichy C, Buggle F. Influenza vaccination is associated with a reduced risk of stroke. Stroke. 2005;36:1501–6.

    Article  PubMed  Google Scholar 

  77. Davis MM, Taubert K, Benin AL, Brown DW, Mensah GA, Baddour LM, et al. Influenza vaccination as secondary prevention for cardiovascular disease: a science advisory from the American Heart Association/American College of Cardiology. J Am Coll Cardiol. 2006;48:1498–502.

    Article  PubMed  Google Scholar 

  78. Lin H-C, Chiu H-F, Ho S-C, Yang C-Y. Association of influenza vaccination and reduced risk of stroke hospitalization among the elderly: a population-based case–control study. Int J Environ Res Public Health. 2014;11:3639–49.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Lavallee PC, Labreuche J, Fox KM, Lavados P, Mattle H, Steg PG, et al. Influenza vaccination and cardiovascular risk in patients with recent TIA and stroke. Neurology. 2014;82:1905–13. This meta-analysis pooled data from 2 prospective cohort studies and one randomized trial (total 23,110 patients) to examine whether influenza vaccination was associated with reduced risk of major vascular events in patients with recent TIA or ischemic stroke. After adjusting for baseline characteristics, influenza vaccination was not associated with a reduction in vascular event rate. Subgroup analysis similarly showed no reduction in stroke or MI separately.

    Article  PubMed  CAS  Google Scholar 

  80. Rahman B, Heywood A, Moa A, MacIntyre CR. Influenza vaccination and cardiovascular risk in patients with recent TIA and stroke. Neurology. 2015;84:105.

    Article  PubMed  Google Scholar 

  81. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, Gutierrez-Perez A, Vila-Rovira A, Gomez F, et al. Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up. BMC Public Health. 2012;12:222.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, de Diego C, Satue E. Ineffectiveness of pneumococcal vaccination in cardiovascular prevention: the CAPAMIS study. JAMA Intern Med. 2013;173:1918–20. This prospective cohort study followed 27,204 patients over age 60 in primary care practices in Spain, to assess the effect of pneumococcal vaccination on hospitalization for stroke, MI and community acquired pneumonia. At 3 year follow-up, there was no protective effect of vaccination on any of these measures, in contrast to interim analysis that had shown such an effect.

    PubMed  Google Scholar 

  83. Tseng HF, Slezak JM, Quinn VP, Sy LS, Van den Eeden SK, Jacobsen SJ. Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men. JAMA. 2010;303:1699–706.

    Article  PubMed  CAS  Google Scholar 

  84. Huss A, Scott P, Stuck AE, Trotter C, Egger M. Efficacy of pneumococcal vaccination in adults: a meta-analysis. CMAJ. 2009;180:48–58.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Moberley S, Holden J, Tatham DP, Andrews RM. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev. 2013;1:CD000422.

    PubMed  Google Scholar 

  86. Bloemenkamp DGM, Mali WPTM, Tanis BC, Rosendaal FR, van den Bosch MAAJ, Kemmeren JM, et al. Chlamydia pneumoniae, Helicobacter pylori and cytomegalovirus infections and the risk of peripheral arterial disease in young women. Atherosclerosis. 2002;163:149–56.

    Article  PubMed  CAS  Google Scholar 

  87. Haider AW, Wilson PWF, Larson MG, Evans JC, Michelson EL, Wolf PA, et al. The association of seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus with risk of cardiovascular disease: a prospective study. J Am Coll Cardiol. 2002;40:1408–13.

    Article  PubMed  Google Scholar 

  88. Smieja M, Gnarpe J, Lonn E, Gnarpe H, Olsson G, Yi Q, et al. Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003;107:251–7.

    Article  PubMed  Google Scholar 

  89. Khairy P, Rinfret S, Tardif J-C, Marchand R, Shapiro S, Brophy J, et al. Absence of association between infectious agents and endothelial function in healthy young men. Circulation. 2003;107:1966–71.

    Article  PubMed  Google Scholar 

  90. Muller BT, Huber R, Henrich B, Adams O, Berns G, Siebler M, et al. Chlamydia pneumoniae, herpes simplex virus and cytomegalovirus in symptomatic and asymptomatic high-grade internal carotid artery stenosis. Does infection influence plaque stability? Vasa. 2005;34:163–9.

    Article  PubMed  CAS  Google Scholar 

  91. Hagiwara N, Toyoda K, Inoue T, Shimada H, Ibayashi S, Iida M, et al. Lack of association between infectious burden and carotid atherosclerosis in Japanese patients. J Stroke Cerebrovasc Dis. 2007;16:145–52.

    Article  PubMed  Google Scholar 

  92. Rupprecht HJ, Blankenberg S, Bickel C, Rippin G, Hafner G, Prellwitz W, et al. Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. Circulation. 2001;104:25–31.

    Article  PubMed  CAS  Google Scholar 

  93. Espinola-Klein C, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Victor A, et al. Impact of infectious burden on progression of carotid atherosclerosis. Stroke. 2002;33:2581–6.

    Article  PubMed  CAS  Google Scholar 

  94. Elkind MSV, Ramakrishnan P, Moon YP, Boden-Albala B, Liu KM, Spitalnik SL, et al. Infectious burden and risk of stroke: the northern Manhattan study. Arch. Neurol. [Internet]. 2009;67:33–8. Available from: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=19901154&retmode=ref&cmd=prlinks.

  95. Katan M, Moon YP, Paik MC, Sacco RL, Wright CB, Elkind MSV. Infectious burden and cognitive function: the Northern Manhattan Study. Neurology. 2013;80:1209–15. A composite index of infectious burden was previously shown to be associated with stroke risk and atherosclerosis in this multi-ethnic urban cohort. In this study, the same measure was found to be associated with worse performance on cognitive assessments, even after adjusting for vascular risk factors. The measure was not associated with cognitive decline over time.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wright CB, Gardener H, Dong C, Yoshita M, DeCarli C, Sacco RL, et al. Infectious burden and cognitive decline in the northern Manhattan study. J Am Geriatr Soc. 2015;63:1540–5.

    Article  PubMed  Google Scholar 

  97. Bu X-L, Yao X-Q, Jiao S-S, Zeng F, Liu Y-H, Xiang Y, et al. A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol. 2014.

  98. O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, et al. Azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290:1459–66.

    Article  PubMed  Google Scholar 

  99. Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352:1637–45.

    Article  PubMed  CAS  Google Scholar 

  100. Westendorp WF, Nederkoorn PJ, Vermeij J-D, Dijkgraaf MG, van de Beek D. Post-stroke infection: a systematic review and meta-analysis. BMC Neurol. 2011;11:110.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Lord AS, Langefeld CD, Sekar P, Moomaw CJ, Badjatia N, Vashkevich A, et al. Infection after intracerebral hemorrhage: risk factors and association with outcomes in the ethnic/racial variations of intracerebral hemorrhage study. Stroke. 2014;45:3535–42. This retrospective study of 800 patients with ICH found that post-ICH infections were more likely to occur in patients with larger and deeper hemorrhages, and in black patients. Patients with infections had higher discharge mortality (16% vs 8%, p=0.001) and worse 3-month functional outcomes.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Emsley HCA, Smith CJ, Gavin CM, Georgiou RF, Vail A, Barberan EM, et al. Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production. BMC Neurol. 2007;7:5.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Chamorro A, Urra X, Planas AM. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke. 2007;38:1097–103.

    Article  PubMed  Google Scholar 

  104. Westendorp WF, Vermeij J-D, Zock E, Hooijenga IJ, Kruyt ND, Bosboom HJLW, et al. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet. 2015;385:1519–26. This PROBE-design trial randomly assigned 2550 patients in the first 24 hours after acute stroke admitted to stroke units to IV ceftriaxone for 4 days vs usual care. In the intention-to-treat analysis, antibiotic treatment did not improve functional outcomes at three months.

    Article  PubMed  CAS  Google Scholar 

  105. Zierath D, Kunze A, Fecteau L, Becker K. Effect of antibiotic class on stroke outcome. Stroke. 2015;46:2287–92.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. José Gutierrez for his assistance with the figure on HIV vasculopathy.

Author information

Authors and Affiliations

  1. The Neurological Institute of New York, 710 W. 168th St., 14th floor, New York, NY, 10032, USA

    Eliza C. Miller

  2. The Neurological Institute of New York, 710W. 168th St., Room 642, New York, NY, 10032, USA

    Mitchell S. V. Elkind

Authors
  1. Eliza C. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitchell S. V. Elkind
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eliza C. Miller.

Ethics declarations

Conflict of Interest

Eliza C. Miller declares no conflict of interest.

Mitchell S.V. Elkind has received personal fees from UpToDate, Boehringer-Ingelheim, Inc., BMS-Pfizer, Daiichi-Sankyo, Janssen Pharmaceuticals, and BioTelemetry/Cardionet. He also has received grants from Diadexus, Inc. and BMS-Pfizer.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Infection

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miller, E.C., Elkind, M.S.V. Infection and Stroke: an Update on Recent Progress. Curr Neurol Neurosci Rep 16, 2 (2016). https://doi.org/10.1007/s11910-015-0602-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11910-015-0602-9

Keywords

Search

Navigation