Influenza Virus

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Influenza Virus

  1. 1. INFLUENZA VIRUS INFLUENZA VIRUS www.freelivedoctor.com
  2. 2. ‘ FLU’ <ul><li>True influenza </li></ul><ul><ul><li>influenza virus A or influenza virus B </li></ul></ul><ul><ul><li>(or influenza virus C infections - much milder) </li></ul></ul><ul><li>Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often inaccurately called ‘flu’ </li></ul>www.freelivedoctor.com
  3. 3. South Carolina 1996-1997 DHEC bulletin http://www.state.sc.us/dhec/LAB/labbu017.htm no virus influenza A influenza B CULTURE RESULTS malathia influenzae per le stelle www.freelivedoctor.com
  4. 4. THE IMPACT OF INFLUENZA PANDEMICS Deaths: www.freelivedoctor.com
  5. 5. THE IMPACT OF INFLUENZA <ul><li>In the US, 1979-2001, on average: </li></ul><ul><li>41,000 deaths per year </li></ul><ul><li>290,000 hospitalizations per year </li></ul><ul><li>Dushoff et al, Am J Epidemiol. (2006)163:181 </li></ul><ul><li>Nichol et al, J Infect. Diseases (2006)194:S111 </li></ul>www.freelivedoctor.com
  6. 6. THE IMPACT OF INFLUENZA <ul><li>recently some increase in morbidity and mortality - possible factors? </li></ul><ul><ul><li>more elderly people </li></ul></ul><ul><ul><li>CF patients live longer </li></ul></ul><ul><ul><li>more high risk neonates </li></ul></ul><ul><ul><li>more immunosuppressed patients </li></ul></ul>www.freelivedoctor.com
  7. 7. ORTHOMYXOVIRUSES http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html <ul><li>pleomorphic </li></ul><ul><li>influenza types A,B,C </li></ul><ul><li>febrile, respiratory illness with systemic symptoms </li></ul>www.freelivedoctor.com
  8. 8. ORTHOMYXOVIRUSES type A, B, C : NP , M1 protein sub-types: HA or NA protein www.freelivedoctor.com M1 protein helical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complex lipid bilayer membrane NA - neuraminidase
  9. 9. TRANSMISSION <ul><li>AEROSOL </li></ul><ul><ul><li>100,000 TO 1,000,000 VIRIONS PER DROPLET </li></ul></ul><ul><li>18-72 HR INCUBATION </li></ul><ul><li>SHEDDING </li></ul>www.freelivedoctor.com
  10. 10. NORMAL TRACHEAL MUCOSA 3 DAYS POST-INFECTION 7 DAYS POST-INFECTION Lycke and Norrby Textbook of Medical Virology 1983 www.freelivedoctor.com
  11. 11. <ul><li>DECREASED CLEARANCE </li></ul><ul><li>RISK BACTERIAL INFECTION </li></ul><ul><li>VIREMIA RARE </li></ul>Lycke and Norrby Textbook of Medical Virology 1983 www.freelivedoctor.com
  12. 12. RECOVERY <ul><li>INTERFERON - SIDE EFFECTS INCLUDE: </li></ul><ul><ul><li>FEVER, MYALGIA, FATIGUE, MALAISE </li></ul></ul><ul><li>CELL-MEDIATED IMMUNE RESPONSE </li></ul><ul><li>TISSUE REPAIR </li></ul><ul><ul><li>CAN TAKE SOME TIME </li></ul></ul>www.freelivedoctor.com
  13. 13. An immunological diversion INTERFERON www.freelivedoctor.com
  14. 14. INTERFERON time course of virus production will vary from virus to virus www.freelivedoctor.com
  15. 15. INTERFERON www.freelivedoctor.com
  16. 16. INTERFERON www.freelivedoctor.com antiviral state antiviral state antiviral state antiviral state
  17. 17. INTERFERON www.freelivedoctor.com antiviral state antiviral state antiviral state antiviral state
  18. 18. INTERFERON www.freelivedoctor.com antiviral state antiviral state antiviral state antiviral state
  19. 19. INTERFERON THE VIRUSES ARE COMING! http://www.paulreverehouse.org/midnight.html PAUL REVERE http://www.mfa.org/collections/one_hour/6.htm www.freelivedoctor.com
  20. 20. TYPES OF INTERFERON <ul><li>TYPE I </li></ul><ul><ul><li>Interferon-alpha (leukocyte interferon, about 20 related proteins) </li></ul></ul><ul><ul><ul><ul><li>- leukocytes, etc </li></ul></ul></ul></ul><ul><ul><li>Interferon-beta (fibroblast interferon) </li></ul></ul><ul><ul><ul><ul><li>- fibroblasts, epithelial cells, etc </li></ul></ul></ul></ul><ul><li>TYPE II </li></ul><ul><ul><li>Interferon-gamma (immune interferon) </li></ul></ul><ul><ul><ul><ul><li>- certain activated T-cells, NK cells </li></ul></ul></ul></ul>www.freelivedoctor.com
  21. 21. INDUCTION OF INTERFERON <ul><li>interferon-alpha and interferon-beta </li></ul><ul><ul><li>induced by </li></ul></ul><ul><ul><ul><li>viral infection (especially RNA viruses) </li></ul></ul></ul><ul><ul><ul><li>double stranded RNA </li></ul></ul></ul><ul><ul><ul><li>certain bacterial components </li></ul></ul></ul><ul><ul><li>- strong anti-viral properties </li></ul></ul><ul><li>interferon-gamma </li></ul><ul><ul><li>- antigens, mitogenic stimulation of lymphocytes </li></ul></ul>www.freelivedoctor.com
  22. 22. INTERFERON <ul><li>induces variety of proteins in target cells </li></ul><ul><li>many consequences, not all fully understood </li></ul>www.freelivedoctor.com
  23. 23. INTERFERON-ALPHA AND INTERFERON-BETA www.freelivedoctor.com
  24. 24. interferon-alpha, interferon-beta interferon receptor induction of 2’5’oligo A synthase induction of protein kinase R (PKR) 2’5’oligo A induction of ribonuclease L activated ribonuclease L ATP activated protein kinase R activated 2’5’oligo A synthase ATP 2’5’oligo A mRNA degraded phosphorylated initiation factor (eIF-2) inhibition of protein synthesis www.freelivedoctor.com
  25. 25. interferon-alpha, interferon-beta interferon receptor induction of 2’5’oligo A synthase induction of protein kinase R (PKR) 2’5’oligo A induction of ribonuclease L activated ribonuclease L ATP ds RNA ds RNA activated protein kinase R activated 2’5’oligo A synthase ATP 2’5’oligo A mRNA degraded phosphorylated initiation factor (eIF-2) inhibition of protein synthesis www.freelivedoctor.com
  26. 26. interferons <ul><li>only made when needed </li></ul>www.freelivedoctor.com
  27. 27. OTHER EFFECTS OF INTERFERONS <ul><li>ALL TYPES </li></ul><ul><ul><li>INCREASE MHC I EXPRESSION </li></ul></ul><ul><ul><ul><li>CYTOTOXIC T-CELLS </li></ul></ul></ul><ul><ul><li>ACTIVATE NK CELLS </li></ul></ul><ul><ul><ul><li>CAN KILL VIRALLY INFECTED CELLS </li></ul></ul></ul>www.freelivedoctor.com
  28. 28. OTHER EFFECTS OF INTERFERONS <ul><li>INTERFERON-GAMMA </li></ul><ul><ul><li>INCREASES MHC II EXPRESSION ON APC </li></ul></ul><ul><ul><ul><li>HELPER T-CELLS </li></ul></ul></ul><ul><ul><li>INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES </li></ul></ul><ul><ul><ul><li>INTRINSIC </li></ul></ul></ul><ul><ul><ul><li>EXTRINSIC </li></ul></ul></ul>www.freelivedoctor.com
  29. 29. THERAPEUTIC USES OF INTERFERONS <ul><li>ANTI-VIRAL </li></ul><ul><ul><li>e.g. interferon-alpha is currently approved for certain cases of acute and chronic HCV and chronic HBV </li></ul></ul><ul><li>MACROPHAGE ACTIVATION </li></ul><ul><ul><li>interferon-gamma has been tried for e.g. lepromatous leprosy, leishmaniasis, toxoplasmosis </li></ul></ul><ul><li>ANTI-TUMOR </li></ul><ul><ul><li>have been used in e.g. melanoma, Kaposi’s sarcoma, CML </li></ul></ul><ul><li>MULTIPLE SCLEROSIS </li></ul><ul><ul><li>interferon-beta </li></ul></ul>www.freelivedoctor.com
  30. 30. Viral response to host immune system <ul><li>Viruses may : </li></ul><ul><li>block interferon binding </li></ul><ul><li>inhibit function of interferon-induced proteins </li></ul><ul><li>inhibit NK function </li></ul><ul><li>interfere with MHC I or MHC II expression </li></ul><ul><li>block complement activation </li></ul><ul><li>inhibit apoptosis </li></ul><ul><li>etc! </li></ul>www.freelivedoctor.com
  31. 31. SIDE EFFECTS OF INTERFERONS <ul><li>FEVER </li></ul><ul><li>MALAISE </li></ul><ul><li>FATIGUE </li></ul><ul><li>MUSCLE PAINS </li></ul>www.freelivedoctor.com
  32. 32. BACK TO INFLUENZA www.freelivedoctor.com
  33. 33. SYMPTOMS <ul><li>FEVER </li></ul><ul><li>HEADACHE </li></ul><ul><li>MYALGIA </li></ul><ul><li>COUGH </li></ul><ul><li>RHINITIS </li></ul><ul><li>OCULAR SYMPTOMS </li></ul>www.freelivedoctor.com
  34. 34. INTERFERON time course of virus production will vary from virus to virus www.freelivedoctor.com
  35. 35. PROTECTION AGAINST RE-INFECTION <ul><li>IgG and IgA </li></ul><ul><ul><li>IgG less efficient but lasts longer </li></ul></ul><ul><li>antibodies to both HA and NA important </li></ul><ul><ul><li>antibody to HA more important (can neutralize) </li></ul></ul>www.freelivedoctor.com
  36. 36. CLINICAL FINDINGS <ul><li>SEVERITY </li></ul><ul><ul><li>VERY YOUNG </li></ul></ul><ul><ul><li>ELDERLY </li></ul></ul><ul><ul><li>IMMUNO-COMPROMISED </li></ul></ul><ul><ul><li>HEART OR LUNG DISEASE </li></ul></ul>www.freelivedoctor.com
  37. 37. PULMONARY COMPLICATIONS <ul><li>CROUP (YOUNG CHILDREN) </li></ul><ul><li>PRIMARY INFLUENZA VIRUS PNEUMONIA </li></ul><ul><li>SECONDARY BACTERIAL INFECTION </li></ul><ul><ul><li>Streptococcus pneumoniae </li></ul></ul><ul><ul><li>Staphlyococcus aureus </li></ul></ul><ul><ul><li>Hemophilus influenzae </li></ul></ul>www.freelivedoctor.com
  38. 38. NON-PULMONARY COMPLICATIONS <ul><li>myositis (rare, > in children, > with type B) </li></ul><ul><li>cardiac complications </li></ul><ul><li>recent studies report encephalopathy </li></ul><ul><ul><li>2002/2003 season studies of patients younger than 21 yrs in Michigan - 8 cases (2 deaths) </li></ul></ul><ul><li>liver and CNS </li></ul><ul><ul><li>Reye’s syndrome </li></ul></ul><ul><li>peripheral nervous system </li></ul><ul><ul><li>Guillian-Barré syndrome </li></ul></ul>www.freelivedoctor.com
  39. 39. Reye’s syndrome <ul><li>liver - fatty deposits </li></ul><ul><li>brain - edema </li></ul><ul><li>vomiting, lethargy, coma </li></ul><ul><li>risk factors </li></ul><ul><ul><li>youth </li></ul></ul><ul><ul><li>certain viral infections (influenza, chicken pox) </li></ul></ul><ul><ul><li>aspirin </li></ul></ul>www.freelivedoctor.com
  40. 40. Guillian-Barré syndrome <ul><li>peripheral nervous system involved </li></ul><ul><li>1976/77 swine flu vaccine </li></ul><ul><ul><li>35,000,000 doses </li></ul></ul><ul><ul><ul><li>354 cases of GBS </li></ul></ul></ul><ul><ul><ul><li>28 GBS-associated deaths </li></ul></ul></ul><ul><ul><ul><li>recent vaccines much lower risk </li></ul></ul></ul>www.freelivedoctor.com
  41. 41. MORTALITY <ul><li>MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH </li></ul><ul><ul><li>BACTERIAL PNEUMONIA </li></ul></ul><ul><ul><li>CARDIAC FAILURE </li></ul></ul><ul><li>90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE </li></ul>www.freelivedoctor.com
  42. 42. DIAGNOSIS <ul><li>ISOLATION </li></ul><ul><ul><li>NOSE, THROAT SWAB </li></ul></ul><ul><ul><li>GROW IN TISSUE CULTURE OR EGGS </li></ul></ul><ul><li>SEROLOGY </li></ul><ul><li>PCR </li></ul><ul><li>RAPID TESTS </li></ul><ul><li>provisional - clinical picture + outbreak </li></ul>www.freelivedoctor.com
  43. 43. HA protein - attachment, fusion inside of virion membrane www.freelivedoctor.com S S S S S S host enzymes acid pH
  44. 44. NA protein - neuraminidase inside of virion membrane www.freelivedoctor.com
  45. 45. ANTIGENIC DRIFT <ul><li>HA and NA accumulate mutations </li></ul><ul><ul><li>RNA virus </li></ul></ul><ul><li>immune response no longer protects fully </li></ul><ul><li>sporadic outbreaks, limited epidemics </li></ul>www.freelivedoctor.com
  46. 46. ANTIGENIC SHIFT <ul><li>“ new” HA or NA proteins </li></ul><ul><li>pre-existing antibodies do not protect </li></ul><ul><li>may get pandemics </li></ul>www.freelivedoctor.com
  47. 47. INFLUENZA A PANDEMICS Ryan et al., in Sherris Medical Microbiology www.freelivedoctor.com
  48. 48. where do “new” HA and NA come from? <ul><li>~16 types HA </li></ul><ul><li>~9 types NA </li></ul><ul><ul><li>all circulate in birds </li></ul></ul><ul><li>pigs </li></ul><ul><ul><li>can be infected by avian and human influenza viruses </li></ul></ul>www.freelivedoctor.com
  49. 49. Where do “new” HA and NA come from? www.freelivedoctor.com
  50. 50. H5N1 – in birds <ul><li>Avian H5N1 has spread to humans </li></ul><ul><li>So far human cases in Asia and Africa </li></ul><ul><ul><li>331 cases (12-1-03 through 10-17-07) </li></ul></ul><ul><ul><li>203 (61%) fatal </li></ul></ul><ul><li>Have been a few instances where may have spread human-to-human </li></ul><ul><li>So far no sustained spread in humans </li></ul><ul><li>Surveillance continues </li></ul>www.freelivedoctor.com
  51. 51. VACCINE <ul><li>‘ BEST GUESS’ OF MAIN ANTIGENIC TYPES </li></ul><ul><ul><li>CURRENTLY TRIVALENT </li></ul></ul><ul><ul><ul><li>type A - H1N1 </li></ul></ul></ul><ul><ul><ul><li>type A - H3N2 </li></ul></ul></ul><ul><ul><ul><li>type B </li></ul></ul></ul><ul><ul><ul><li>each year choose which strain of each subtype is the best to use for optimal protection </li></ul></ul></ul>www.freelivedoctor.com
  52. 52. VACCINE <ul><li>inactivated (trivalent inactivated influenza vaccine, TIV) </li></ul><ul><li>egg grown </li></ul><ul><li>some formulations licensed for children </li></ul><ul><li>reassortant, trivalent live vaccine approved 2003 (live attenuated vaccine, LAIV) </li></ul><ul><ul><li>for healthy persons (those not at risk for complications from influenza infection) ages 5-49 years </li></ul></ul><ul><ul><li>September 2007 also approved for healthy children 24-59 months old without a history of recurrent wheezing </li></ul></ul>www.freelivedoctor.com
  53. 53. RECOMMENDATIONS <ul><li>Annual vaccine is recommended for persons at increased risk for influenza-related complications, including </li></ul><ul><ul><li>Persons aged 50 years and older </li></ul></ul><ul><ul><ul><li>from public health point of view, easier to target by age than by high-risk condition (which may not have been discovered) </li></ul></ul></ul><ul><ul><li>Children aged 6-59 months </li></ul></ul><ul><ul><li>Women who will be pregnant during the influenza season </li></ul></ul><ul><ul><li>Adults and children with chronic medical conditions (e.g., asthma, diabetes, heart disease, kidney failure, hemoglobinopathies or weakened immune system) </li></ul></ul><ul><ul><li>Adults and children who have any condition which can compromise respiratory function or the handling of respiratory secretions than can increase the risk for aspiration. </li></ul></ul><ul><ul><li>Residents of nursing homes and other chronic care facilities </li></ul></ul><ul><ul><li>Children and adolescents on long-term aspirin therapy </li></ul></ul><ul><ul><li>adults and children who have immunosuppression (including immunosuppression caused by medications or by HIV) </li></ul></ul>www.freelivedoctor.com
  54. 54. RECOMMENDATIONS Persons Who Can Transmit Influenza to Those at High Risk Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. www.freelivedoctor.com
  55. 55. RECOMMENDATIONS <ul><li>Annual vaccine is recommended for contacts of persons at increased risk for influenza-related complications, including </li></ul><ul><ul><li>Household contacts of persons at high risk, including children aged less than 5 years, particularly contacts of children aged 0–5 mths (no approved vaccine for this age group) </li></ul></ul><ul><ul><li>Health-care workers </li></ul></ul><ul><ul><li>Employees of assisted living or other types of residences for persons in groups at high risk </li></ul></ul><ul><li>for the above groups, LAIV can be used to vaccinate healthy persons aged 5-49 years (and healthy children ages 24-59 months old without a history of recurrent wheezing) who are not contacts of severely immunosuppressed persons. </li></ul>www.freelivedoctor.com
  56. 56. RECOMMENDATIONS <ul><li>others, including travellers and the general population may wish to be vaccinated </li></ul>www.freelivedoctor.com
  57. 57. PREVENTION - DRUGS <ul><li>RIMANTADINE (M2) </li></ul><ul><ul><ul><li>type A only </li></ul></ul></ul><ul><li>AMANTADINE (M2) </li></ul><ul><ul><ul><li>type A only </li></ul></ul></ul><ul><li>2005-6 season </li></ul><ul><ul><ul><li>H3N2 virus - 92% isolates resistant to rimantadine and amantadine in US, so these drugs not recommended until % resistance in major circulating type(s) drops </li></ul></ul></ul><ul><li>ZANAMIVIR (NA) </li></ul><ul><ul><ul><li>types A and B </li></ul></ul></ul><ul><li>OSELTAMIVIR (NA) </li></ul><ul><ul><ul><li>types A and B </li></ul></ul></ul>www.freelivedoctor.com
  58. 58. TREATMENT - DRUGS <ul><li>RIMANTADINE (M2) </li></ul><ul><ul><ul><li>type A only, needs to be given early </li></ul></ul></ul><ul><li>AMANTADINE (M2) </li></ul><ul><ul><ul><li>type A only, needs to be given early </li></ul></ul></ul><ul><li>ZANAMIVIR (NA) </li></ul><ul><ul><ul><li>types A and B, needs to be given early </li></ul></ul></ul><ul><li>OSELTAMIVIR (NA) </li></ul><ul><ul><ul><li>types A and B, needs to be given early </li></ul></ul></ul>www.freelivedoctor.com
  59. 59. NA protein - neuraminidase . . . . . . . . . . . . . . . . . . . www.freelivedoctor.com
  60. 60. OTHER TREATMENT <ul><li>REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS) </li></ul><ul><li>BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY </li></ul>www.freelivedoctor.com
  61. 61. TYPE A ++++ yes yes yes shift, drift yes (sensitive) sensitive 2 severity of illness animal reservoir human pandemics human epidemics antigenic changes segmented genome amantadine, rimantidine zanamivir,oseltamivir surface glycoproteins TYPE B ++ no no yes drift yes no effect sensitive 2 TYPE C + no no no (sporadic) drift yes no effect (1) www.freelivedoctor.com

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