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

2. Swine Influenza A (H1N1) Infection in Two Children --- Southern California, March--April 2009 OnApril 17, 2009, CDC determined that two cases of febrile respiratory illness occurring in children who resided in adjacent counties in southern California were caused by infection with a swine influenza A (H1N1) virus.The viruses from the two cases are closely related genetically, resistant to amantadine and rimantadine, and contain a unique combination of gene segments that previously has not been reported among swine or human influenza viruses in the United States or elsewhere. Neither child had contact with pigs; the source of the infection is unknown.Investigations to identify the source of infection and to determine whether additional persons have been ill from infection with similar swine influenza viruses are ongoing. Although this is not a new subtype of influenza A in humans,concern exists that this new strain of swine influenza A (H1N1) is substantially different from human influenza A (H1N1) viruses, that a large proportion of the population might be susceptible to infection, and that the seasonal influenza vaccine H1N1 strain might not provide protection. The lack of known exposure to pigs in the two cases increases the possibility that human-to-human transmission of this new influenza virus has occurred.Clinicians should consider animal as well as seasonal influenza virus infections in their differential diagnosis of patients who have febrile respiratory illness and who 1) live in San Diego and Imperial counties or 2) traveled to these counties or were in contact with ill persons from these counties in the 7 days preceding their illness onset, or 3) had recent exposure to pigs. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm

3. ‘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 inaccurately called ‘flu’

4. South Carolina 1996-1997 DHEC bulletin malathia influenzae per le stelle no virus CULTURE RESULTS influenza A influenzaB SEASONAL INFLUENZA http://www.state.sc.us/dhec/LAB/labbu017.htm

5. THE IMPACT OF INFLUENZAPANDEMICS Deaths:

6. THE IMPACT OF INFLUENZA • In the US, 1990-1999, on average: • 36,000 deaths per year • 226,000 hospitalizations per year http://www.cdc.gov/flu/professionals/acip/clinical.htm

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

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

9. TRANSMISSION • AEROSOL • 100,000 TO 1,000,000 VIRIONS PER DROPLET • SURFACES - VIRUS CAN SURVIVE APPROX 2 TO 8 HRS • 18-72 HR INCUBATION • SHEDDING

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

11. An immunological diversion INTERFERON

12. INTERFERON time course of virus production will vary from virus to virus

13. INTERFERON

14. antiviral state antiviral state antiviral state antiviral state INTERFERON

15. antiviral state antiviral state antiviral state antiviral state INTERFERON

16. antiviral state antiviral state antiviral state antiviral state INTERFERON

17. 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

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

19. INTERFERON • induces variety of proteins in target cells • many consequences, not all fully understood

20. INTERFERON-ALPHA AND INTERFERON-BETA

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

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

23. interferons • only made when needed

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

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

26. 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

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

28. SIDE EFFECTS OF INTERFERONS • FEVER • MALAISE • FATIGUE • MUSCLE PAINS

29. BACK TO INFLUENZA

30. SYMPTOMS • FEVER • HEADACHE • MYALGIA • COUGH • RHINITIS • OCULAR SYMPTOMS • GI tract symptoms not typically seen • but common with 2009 H1N1 influenza (‘swine flu’) • vomiting, diarrhea

31. INTERFERON time course of virus production will vary from virus to virus

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

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

35. NON-PULMONARY COMPLICATIONS • myositis (rare, > in children, > with type B) • cardiac complications • encephalopathy • 2002/2003 season studies of patients younger than 21 yrs in Michigan - 8 cases (2 deaths) • liver and CNS • Reye’s syndrome • peripheral nervous system • Guillian-Barré syndrome

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

37. Guillian-Barré syndrome • peripheral nervous system involved • autoimmune • 3000-6000 cases per year US • most recover fully • may follow infectious disease • Campylobacter jejuni one of most common risk factors • may be associated with some viral infections • 1976/77 swine flu vaccine • 35,000,000 doses • 354 cases of GBS (approx 1-2 additional cases per 100,000 vaccinated) • 28 GBS-associated deaths • recent infuenza vaccines much lower risk • risk from vaccination much lower than risk from infection

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

39. DIAGNOSIS • ISOLATION • NOSE, THROAT SWAB • GROW IN TISSUE CULTURE OR EGGS • SEROLOGY • PCR • RAPID TESTS • provisional - clinical picture + outbreak

40. S S host enzymes S S HA protein - attachment, fusion membrane inside of virion =antibody

41. NA protein - neuraminidase membrane inside of virion =antibody

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

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

44. where do “new” HA and NA come from? • ~16 types HA • ~9 types NA • all circulate in birds • pigs • can be infected by avian and human influenza viruses

45. Where do “new” HA and NA come from?

46. Where do “new” HA and NA come from2009 PANDEMIC H1N1?

47. Where do “new” HA and NA come from- can ‘new’ bird flu directly infect humans? Current “Bird flu” H5N1? 1918 influenza

48. H5N1 – in birds • Avian H5N1 has spread to humans • So far human cases in Asia and Africa • 442 cases (12-1-03 through 09-24-09) • 262 (59%) fatal • Have been a few instances where may have spread human-to-human • So far no sustained spread in humans • Surveillance continues

49. 2009 NOVEL H1N1 PANDEMIC • first novel H1N1 patient in the United States confirmed by laboratory testing at CDC on April 15, 2009. • Quickly determined that the virus was spreading from person-to-person. • By June 3, 2009, all 50 states in the United States and the District of Columbia and Puerto Rico were reporting cases of novel H1N1 infection. http://www.cdc.gov/h1n1flu/update.htm

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