1. 1 INFLUENZA VIRUS CDC WEBSITE http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm 2002

2. 2 ‘FLU’ True influenza –influenza virus A or influenza virus B (or influenza virus C infections - much milder) Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often called ‘flu’

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

4. 4 THE IMPACT OF INFLUENZA PANDEMICS Deaths:

5. 5 THE IMPACT OF INFLUENZA 1972-1994 (19 influenza seasons) –>20,000 US deaths in 11 seasons –>40,000 US deaths in 6 of these –many more hospitalizations (~110,000 per year)

6. 6 THE IMPACT OF INFLUENZA recently some increase in morbidity and mortality - possible factors? –more elderly people –CF patients live longer –more high risk neonates –more immunosuppressed patients

7. 7 ORTHOMYXOVIRUSES http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html pleomorphic influenza types A,B,C febrile, respiratory illness with systemic symptoms

8. 8 ORTHOMYXOVIRUSES M1 protein helical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complex lipid bilayer membrane NA - neuraminidase type A, B, C : NP, M1 protein sub-types: HA or NA protein

9. 9 TRANSMISSION AEROSOL –100,000 TO 1,000,000 VIRIONS PER DROPLET 18-72 HR INCUBATION SHEDDING

10. 10 NORMAL TRACHEAL MUCOSA 3 DAYS POST-INFECTION 7 DAYS POST-INFECTION Lycke and Norrby Textbook of Medical Virology 1983

11. 11 DECREASED CLEARANCE RISK BACTERIAL INFECTION VIREMIA RARE Lycke and Norrby Textbook of Medical Virology 1983

12. 12 RECOVERY INTERFERON - SIDE EFFECTS INCLUDE: –FEVER, MYALGIA, FATIGUE, MALAISE CELL-MEDIATED IMMUNE RESPONSE TISSUE REPAIR –CAN TAKE SOME TIME

13. 13 An immunological diversion INTERFERON

14. 14 INTERFERON timecourse of virus production will vary from virus to virus

15. 15 INTERFERON

16. 16 INTERFERON antiviral state

17. 17 INTERFERON antiviral state

18. 18 INTERFERON 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

20. 20 TYPES OF INTERFERON TYPE I Interferon-alpha (leukocyte interferon, about 20 related proteins) - leukocytes, etc Interferon-beta (fibroblast interferon) - fibroblasts, epithelial cells, etc TYPE II Interferon-gamma (immune interferon) - certain activated T-cells, NK cells

21. 21 INDUCTION OF INTERFERON interferon-alpha and interferon-beta - viral infection (especially RNA viruses), double stranded RNA, certain bacterial components - strong anti-viral properties interferon-gamma - antigens, mitogenic stimulation lymphocytes

22. 22 INTERFERON induce various proteins in target cells many consequences, not all fully understood

23. 23 INTERFERON-ALPHA AND INTERFERON-BETA

24. 24 interferon-alpha, interferon-beta interferon receptor induction of 2’5’oligo A synthase induction of a protein kinase 2’5’oligo A induction of ribonuclease L activated ribonuclease L ATP ds RNA activated protein kinase activated 2’5’oligo A synthase ATP 2’5’oligo A mRNA degraded phosphorylated initiation factor (eIF-2) inhibition of protein synthesis

25. 25 interferons only made when needed

26. 26 OTHER EFFECTS OF INTERFERONS ALL TYPES –INCREASE MHC I EXPRESSION CYTOTOXIC T-CELLS –ACTIVATE NK CELLS CAN KILL VIRALLY INFECTED CELLS

27. 27 OTHER EFFECTS OF INTERFERONS INTERFERON-GAMMA –INCREASES MHC II EXPRESSION ON APC HELPER T-CELLS –INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES INTRINSIC EXTRINSIC

28. 28 THERAPEUTIC USES OF INTERFERONS ANTI-VIRAL –e.g. interferon-alpha is currently approved for certain cases of acute and chronic HCV and chronic HBV MACROPHAGE ACTIVATION –interferon-gamma has been tried for e.g. lepromatous leprosy, leishmaniasis, toxoplasmosis ANTI-TUMOR –have been used in e.g. melanoma, Kaposi’s sarcoma, CML MULTIPLE SCLEROSIS –interferon-beta

29. 29 Viral response to host immune system Viruses may : block interferon binding inhibit function of interferon-induced proteins inhibit NK function interfere with MHC I or MHC II expression block complement activation inhibit apoptosis etc!

30. 30 SIDE EFFECTS OF INTERFERONS FEVER MALAISE FATIGUE MUSCLE PAINS

31. 31 BACK TO INFLUENZA

32. 32 PROTECTION AGAINST RE-INFECTION IgG and IgA –IgG less efficient but lasts longer antibodies to both HA and NA important –antibody to HA more important (can neutralize)

33. 33 SYMPTOMS FEVER HEADACHE MYALGIA COUGH RHINITIS OCULAR SYMPTOMS

34. 34 CLINICAL FINDINGS SEVERITY –VERY YOUNG –ELDERLY –IMMUNO- COMPROMISED –HEART OR LUNG DISEASE

35. 35 PULMONARY COMPLICATIONS CROUP (YOUNG CHILDREN) PRIMARY INFLUENZA VIRUS PNEUMONIA SECONDARY BACTERIAL INFECTION –Streptococcus pneumoniae –Staphlyococcus aureus –Hemophilus influenzae

36. 36 NON-PULMONARY COMPLICATIONS myositis (rare, > in children, > with type B) cardiac complications recent studies report encephalopathy –studies of patients <21 yrs in Michigan - 8 cases seen last season liver and CNS –Reye syndrome peripheral nervous system –Guillian-Barré syndrome

37. 37 Reye’s syndrome liver - fatty deposits brain - edema vomiting, lethargy, coma risk factors –youth –certain viral infections (influenza, chicken pox) –aspirin

38. 38 NON-PULMONARY COMPLICATIONS myositis (rare, > in children, > in type B) cardiac complications encephalopathy liver and CNS –Reye’s syndrome peripheral nervous system –Guillian-Barré syndrome

39. 39 Guillian-Barré syndrome 1976/77 swine flu vaccine –35,000,000 doses 354 cases of GBS 28 GBS-associated deaths recent vaccines much lower risk

40. 40 MORTALITY MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH –BACTERIAL PNEUMONIA –CARDIAC FAILURE 90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE

41. 41 DIAGNOSIS ISOLATION –NOSE, THROAT SWAB –TISSUE CULTURE OR EGGS SEROLOGY RAPID TESTS provisional - clinical picture + outbreak

42. 42 SS SS SS cell enzymes acid pH HA protein - attachment, fusion

43. 43 NA protein - neuraminidase

44. 44 ANTIGENIC DRIFT HA and NA accumulate mutations –RNA virus immune response no longer protects fully sporadic outbreaks, limited epidemics

45. 45 ANTIGENIC SHIFT “new” HA or NA proteins pre-existing antibodies do not protect may get pandemics

46. 46 INFLUENZA A PANDEMICS Ryan et al., in Sherris Medical Microbiology

47. 47 where do “new” HA and NA come from? 13 types HA 9 types NA –all circulate in birds pigs –avian and human

48. 48 where do “new” HA and NA come from?

49. 49 why do we not have influenza B pandemics? so far no shifts have been recorded no animal reservoir known

50. 50 SURVEILLANCE CDC/Katherine Lord

51. 51 actual percentage of deaths (CDC MMWR 2003 / Vol. 52 / No. RR-8)

52. 52

53. 53 VACCINE ‘BEST GUESS’ OF MAIN ANTIGENIC TYPES –CURRENTLY type A - H1N1 type A - H3N2 type B each year choose which variant of each subtype is the best to use for optimal protection

54. 54 VACCINE inactivated egg grown sub-unit vaccine for children reassortant live vaccine approved 2003 –for healthy persons (those not at risk for complications from influenza infection) ages 5-49 years

55. 55 CDC

56. 56 RECOMMENDATIONS Persons at High Risk for Influenza-Related Complications · $ 65 years · residents of nursing homes and other chronic-care facilities · adults/children who have chronic pulmonary or cardiovascular disorders, including asthma · adults/children who have required regular medical follow-up or hospitalization during the last year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications)

57. 57 RECOMMENDATIONS Persons at High Risk for Influenza-Related Complications · children and teenagers (6 mths to 18 yrs) receiving long-term aspirin therapy - might be at risk for developing Reye syndrome after influenza · women who will be in the 2nd or 3rd trimester of pregnancy during the influenza season.

58. 58 RECOMMENDATIONS Persons aged 50-64 years increased prevalence of high-risk conditions from public health point of view, easier to target by age than by high-risk condition (which may not have been discovered)

59. 59 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.

60. 60 RECOMMENDATIONS · physicians, nurses, and other personnel in both hospital and outpatient-care settings · employees of nursing homes and chronic-care facilities who have contact with patients or residents · employees of assisted living and other residences for persons in high-risk groups · persons who provide home care to persons in high-risk groups · household members (including children) of persons in high-risk groups.

61. 61 RECOMMENDATIONS Children from 0-23 mths are at increased risk for hospitalization from influenza, vaccination is encouraged for their household contacts and out-of-home caretakers, particularly for contacts of children aged 0–5 months because influenza vaccines have not been approved for use among children aged <6 months.

62. 62 RECOMMENDATIONS others, including travellers and the general population may wish to be vaccinated

63. 63 PREVENTION - DRUGS RIMANTADINE (M2) type A only AMANTADINE (M2) type A only ZANAMIVIR (NA) types A and B, not yet approved for prevention OSELTAMIVIR (NA) types A and B

64. 64 TREATMENT - DRUGS RIMANTADINE (M2) type A only, needs to be given early AMANTADINE (M2) type A only, needs to be given early ZANAMIVIR (NA) types A and B, needs to be given early OSELTAMIVIR (NA) types A and B, needs to be given early

65. 65 NA protein - neuraminidase...................

66. 66 OTHER TREATMENT REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS) BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

67. 67 TYPE A ++++ yes shift, drift yes sensitive 2 severity of illness animal reservoir human pandemics human epidemics antigenic changes segmented genome amantadine, rimantidine zanamivir surface glycoproteins TYPE B ++ no yes drift yes no effect sensitive 2 TYPE C + no no (sporadic) drift yes no effect (1)

68. 68 END

69. 69 live vaccine development adapted from Treanor JJ Infect. Med. 15:714

70. 70