The document discusses influenza virus and the flu. It describes how influenza A and B cause seasonal flu epidemics through antigenic drift, and occasionally pandemic outbreaks through antigenic shift when a new virus emerges. It notes that influenza A infects multiple species including birds, pigs, and humans, and this interspecies transmission enables antigenic shift and the emergence of new pandemic strains. It also summarizes symptoms, transmission, treatment, prevention, and vaccination recommendations for influenza.

1. INFLUENZA VIRUS INFLUENZA VIRUS www.freelivedoctor.com

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 inaccurately called ‘flu’ www.freelivedoctor.com

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. THE IMPACT OF INFLUENZA PANDEMICS Deaths: www.freelivedoctor.com

5. THE IMPACT OF INFLUENZA In the US, 1979-2001, on average: 41,000 deaths per year 290,000 hospitalizations per year Dushoff et al, Am J Epidemiol. (2006)163:181 Nichol et al, J Infect. Diseases (2006)194:S111 www.freelivedoctor.com

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 www.freelivedoctor.com

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

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. TRANSMISSION AEROSOL 100,000 TO 1,000,000 VIRIONS PER DROPLET 18-72 HR INCUBATION SHEDDING www.freelivedoctor.com

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

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

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

13. An immunological diversion INTERFERON www.freelivedoctor.com

14. INTERFERON time course of virus production will vary from virus to virus www.freelivedoctor.com

15. INTERFERON www.freelivedoctor.com

16. INTERFERON www.freelivedoctor.com antiviral state antiviral state antiviral state antiviral state

17. INTERFERON www.freelivedoctor.com antiviral state antiviral state antiviral state antiviral state

18. INTERFERON www.freelivedoctor.com antiviral state antiviral state antiviral state antiviral state

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. 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 www.freelivedoctor.com

21. 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 www.freelivedoctor.com

22. INTERFERON induces variety of proteins in target cells many consequences, not all fully understood www.freelivedoctor.com

23. INTERFERON-ALPHA AND INTERFERON-BETA www.freelivedoctor.com

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. 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. interferons only made when needed www.freelivedoctor.com

27. OTHER EFFECTS OF INTERFERONS ALL TYPES INCREASE MHC I EXPRESSION CYTOTOXIC T-CELLS ACTIVATE NK CELLS CAN KILL VIRALLY INFECTED CELLS www.freelivedoctor.com

28. OTHER EFFECTS OF INTERFERONS INTERFERON-GAMMA INCREASES MHC II EXPRESSION ON APC HELPER T-CELLS INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES INTRINSIC EXTRINSIC www.freelivedoctor.com

29. 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 www.freelivedoctor.com

30. 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! www.freelivedoctor.com

31. SIDE EFFECTS OF INTERFERONS FEVER MALAISE FATIGUE MUSCLE PAINS www.freelivedoctor.com

32. BACK TO INFLUENZA www.freelivedoctor.com

33. SYMPTOMS FEVER HEADACHE MYALGIA COUGH RHINITIS OCULAR SYMPTOMS www.freelivedoctor.com

34. INTERFERON time course of virus production will vary from virus to virus www.freelivedoctor.com

35. 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) www.freelivedoctor.com

36. CLINICAL FINDINGS SEVERITY VERY YOUNG ELDERLY IMMUNO-COMPROMISED HEART OR LUNG DISEASE www.freelivedoctor.com

37. PULMONARY COMPLICATIONS CROUP (YOUNG CHILDREN) PRIMARY INFLUENZA VIRUS PNEUMONIA SECONDARY BACTERIAL INFECTION Streptococcus pneumoniae Staphlyococcus aureus Hemophilus influenzae www.freelivedoctor.com

38. NON-PULMONARY COMPLICATIONS myositis (rare, > in children, > with type B) cardiac complications recent studies report 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 www.freelivedoctor.com

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

40. Guillian-Barré syndrome peripheral nervous system involved 1976/77 swine flu vaccine 35,000,000 doses 354 cases of GBS 28 GBS-associated deaths recent vaccines much lower risk www.freelivedoctor.com

41. MORTALITY MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH BACTERIAL PNEUMONIA CARDIAC FAILURE 90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE www.freelivedoctor.com

42. DIAGNOSIS ISOLATION NOSE, THROAT SWAB GROW IN TISSUE CULTURE OR EGGS SEROLOGY PCR RAPID TESTS provisional - clinical picture + outbreak www.freelivedoctor.com

43. HA protein - attachment, fusion inside of virion membrane www.freelivedoctor.com S S S S S S host enzymes acid pH

44. NA protein - neuraminidase inside of virion membrane www.freelivedoctor.com

45. ANTIGENIC DRIFT HA and NA accumulate mutations RNA virus immune response no longer protects fully sporadic outbreaks, limited epidemics www.freelivedoctor.com

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

47. INFLUENZA A PANDEMICS Ryan et al., in Sherris Medical Microbiology www.freelivedoctor.com

48. 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 www.freelivedoctor.com

49. Where do “new” HA and NA come from? www.freelivedoctor.com

50. H5N1 – in birds Avian H5N1 has spread to humans So far human cases in Asia and Africa 331 cases (12-1-03 through 10-17-07) 203 (61%) fatal Have been a few instances where may have spread human-to-human So far no sustained spread in humans Surveillance continues www.freelivedoctor.com

51. VACCINE ‘ BEST GUESS’ OF MAIN ANTIGENIC TYPES CURRENTLY TRIVALENT type A - H1N1 type A - H3N2 type B each year choose which strain of each subtype is the best to use for optimal protection www.freelivedoctor.com

52. VACCINE inactivated (trivalent inactivated influenza vaccine, TIV) egg grown some formulations licensed for children reassortant, trivalent live vaccine approved 2003 (live attenuated vaccine, LAIV) for healthy persons (those not at risk for complications from influenza infection) ages 5-49 years September 2007 also approved for healthy children 24-59 months old without a history of recurrent wheezing www.freelivedoctor.com

53. RECOMMENDATIONS Annual vaccine is recommended for persons at increased risk for influenza-related complications, including Persons aged 50 years and older from public health point of view, easier to target by age than by high-risk condition (which may not have been discovered) Children aged 6-59 months Women who will be pregnant during the influenza season Adults and children with chronic medical conditions (e.g., asthma, diabetes, heart disease, kidney failure, hemoglobinopathies or weakened immune system) 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. Residents of nursing homes and other chronic care facilities Children and adolescents on long-term aspirin therapy adults and children who have immunosuppression (including immunosuppression caused by medications or by HIV) www.freelivedoctor.com

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. RECOMMENDATIONS Annual vaccine is recommended for contacts of persons at increased risk for influenza-related complications, including 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) Health-care workers Employees of assisted living or other types of residences for persons in groups at high risk 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. www.freelivedoctor.com

56. RECOMMENDATIONS others, including travellers and the general population may wish to be vaccinated www.freelivedoctor.com

57. PREVENTION - DRUGS RIMANTADINE (M2) type A only AMANTADINE (M2) type A only 2005-6 season H3N2 virus - 92% isolates resistant to rimantadine and amantadine in US, so these drugs not recommended until % resistance in major circulating type(s) drops ZANAMIVIR (NA) types A and B OSELTAMIVIR (NA) types A and B www.freelivedoctor.com

58. 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 www.freelivedoctor.com

59. NA protein - neuraminidase . . . . . . . . . . . . . . . . . . . www.freelivedoctor.com

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

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