1. Influenza: Virus and Disease Kenneth H. Fife, MD, PhD Indiana University School of Medicine

2. Centers for Disease Control and Prevention. Influenza Prevention and Control. Influenza. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm. Clinically Relevant Influenza Viruses Type APotentially severe illness Epidemics and pandemics Rapidly changing Type BUsually less severe illness Epidemics Genetically more stable

3. Neuraminidase Hemagglutinin RNA Influenza Surface Proteins M 2 protein (only on type A)

4. H = Hemagglutinin and N = Neuraminidase Hemagglutinin allows the virus to bind to host cells Neuraminidase helps the virus to release itself from the highjacked cells in which it has reproduced ROLE OF H AND N PROTEINS

5. SubtypeHumanSwineHorseBird H1H2H3H4H5H6H7H8H9H10H11H12H13H14H15 Hemagglutinin Subtypes of Influenza A Virus Adapted from Levine AJ. Viruses. 1992;165, with permission.

6. SubtypeHumanSwineHorseBird N1N2N3N4N5N6N7N8N9 Neuraminidase Subtypes of Influenza A Virus Adapted from Levine AJ. Viruses. 1992;165, with permission.

7. Influenza A Virus Constantly Changes  Antigenic drift  Small changes in H or N proteins that occur from year to year  Population is partially immune, but may be re- infected over time (periodic epidemics)  Antigenic shift  Acquisition of new H or N protein, possibly from an animal virus  Population is not immune, everyone is susceptible (pandemics)

8. YearsFluVirusMortality 1918-19“Spanish”Type A (H1N1) 20 million worldwide 550,000 US 1957-58“Asian”Type A (H2N2)70,000 US 1968-69“Hong Kong”Type A (H3N2)34,000 US Glezen WP. Epidemiol Rev. 1996;18:65. Centers for Disease Control and Prevention. Influenza Prevention and Control. Influenza. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm. Influenza Pandemics in the 20th Century

9. 1918 “Spanish Flu” Pandemic l Type A virus (H1N1) l 20-50 million deaths worldwide l 550,000 deaths in the United States l 21,000 Flu-Orphans in NYC

10. 1918 Pandemic It killed more people in 25 weeks than AIDS has killed in 25 years It killed more people in a year than the plagues of the Middle Ages killed in a century Seven times as many people died of influenza than in the First World War

11. 1957 Pandemic  1957-1958 Asian Flu  Type A virus (H2N2)  First identified in China February 1957  Spread to U.S. by June 1957  70,000 deaths in the United States

12. 1968 Pandemic  1968-1969 Hong Kong Flu l Type A virus (H3N2) l First detected in Hong Kong early 1968 l Spread to U.S. later that year l Approx 34,000 deaths in the United States Our seasonal flu kills 36,000Our seasonal flu kills 36,000 l Virus still circulating today

13. 1977 Pandemic  H1N1 reintroduced in 1977 “Russian Flu”  Affected mostly young adults not exposed to influenza before 1957  Still circulating

14. Natural History of Influenza Viruses Topley and Wilson’s Microbiology and Microbial Infections. 9th ed, Vol 1, Virology. Mahy and Collier, eds, 1998, Arnold, page 387, with permission. 1880189019001910192019301940195019601970198019902000 H3N2 H1N1 H2N2 H3N8 H2N? H1N1 Serum antibody prevalence Virus isolation

15. Influenza Type A (H5N1)  First appeared in humans in Hong Kong, 1997  Primarily associated with avian species  Fatal epidemic among Hong Kong poultry in 1997  Continuing avian epidemics through 2006  To date, 225 human cases with 128 deaths  No sustained human-to-human transmission

16. Human Cases of H5N1 Avian Flu: 2003-2006 Country Total Cases Deaths Azerbaijan85 Cambodia66 China1912 Djibuoti10 Egypt146 Indonesia4937 Iraq22 Thailand2214 Turkey124 Vietnam9342 Total227129 As of 06/16/06 Source: World Health Organization (laboratory confirmed cases)

17. Distribution of H5N1 Infection – 2006

18. Epizootiology - Birds  Natural Hosts  Domestic fowl, ducks, geese, turkeys, guinea fowl, quail, and pheasants  Source of Infection  Domestic flocks felt to be primary source  Migratory waterfowl may spread over wide areas  Spread  Rapid in flocks by direct contact  Viral shed in feces and nasal and ocular discharges

19. Implications of H5N1 Infection  Potential for pandemic infection by little-known pathogen  Morbidity and mortality in both young and old  No previous human exposure; no vaccine  Signals need for  Pandemic readiness plan  Rapid detection and diagnosis of new viral strains  Veterinary surveillance  Continuing research for new antiviral agents Lee, Mak, Saw. Public Health and Epidemiology Bulletin. 1999;8:1-7.

20. Pandemic Response  Many communities throughout the U.S. will be affected at the same time, others will be at risk  Each community will have to deal with the pandemic mostly on their own  Society as a whole will have to work together to minimize the impact of the pandemic

21. Influenza Illness (Typical Case)  Incubation period (time between exposure and symptoms) short – 1-3 days  Infected person may shed virus for 12-24 hours before onset of symptoms  Viral shedding peaks on day 2 or 3 then declines  Virus may be present as long as there are symptoms (usually 5-10 days)

22. Influenza Spread  Nearly all spread is person-to-person  Spread is by small droplets (as from a cough or sneeze) inhaled by a susceptible person  Inanimate object (doorknobs, towels) and physical contact (handshaking) may contribute to spread, but their role is minor

23. Signs and Symptoms  Abrupt onset of symptoms  Fever, usually over 100°F  Cough with little or no sputum  Chills and/or sweats  Headache  Muscle aches  Sore throat  Potentially severe, persistent malaise  Chest soreness, light sensitivity, and eye pain

24. Differences Between H5N1 and Current Strains  Typical influenza involves only the upper respiratory tract  Persons with underlying medical problems (lung disease, heart disease, cancer) or the elderly are at increased risk of secondary bacterial pneumonia  Influenza viral pneumonia is rare  H5N1 has the ability to infect the upper and lower respiratory tract (including the lung)  Anyone who is susceptible to H5N1 can get pneumonia caused by the influenza virus  The resulting influenza virus pneumonia is severe and may be fatal

25. Economic Costs of Influenza Outbreak  Total annual costs of influenza are estimated at $14.6 billion in the US  10%: Direct costs of increased medical care  90%: Indirect costs (lost productivity, employee absenteeism) American Lung Association. Fact Sheet – Influenza, at http://www.lungusa.org/diseases/influenza_factsheet.html. Accessed 3/25/99.

26. Inactivated Influenza Virus Vaccine HistoryFirst developed in 1940s ContentUpdated yearly to protect against anticipated strains, consists of type A (2) and type B (1) ProcessGrown in embryonated chicken eggs and formalin inactivated MMWR. 1999;48:4-5.

27. Influenza Virus Vaccine  Most effective in young, healthy people  Often prevents infection, usually prevents serious disease  Less effective in the elderly  Many develop infection, but vaccine reduces the frequency of serious disease and death  Response directly related to overall state of health

28. ZanamivirOseltamivir (Relenza ® )(Tamiflu ® ) IndicationTreatment Treatment, Prophylaxis SpectrumType A, type BType A, type B AdministrationInhaled Oral 2 puffs bid 1 tablet bid for 5 days for 5 days Selective Neuraminidase Inhibitors Currently Available