H1N1 Influenza Outbreak: Modeling for a Major Global Pandemic

1. H1N1 Influenza Outbreak: Modeling for a Major Global Pandemic Shelley Salpeter, MD, FACP Stanford University School of Medicine Santa Clara Valley Medical Center

2. H1N1 Influenza Outbreak:Outline • Major global pandemic case scenario • Basics of the influenza virus • Molecular origins • Definitions • Outbreak, epidemic, pandemic • Historical clues • Previous outbreaks, pandemics • H1N1 outbreak, 2009 • Chance of major pandemic • In near future • In far future

4. Major Global Pandemic:Outbreak Scenario • A major pandemic, estimates: • Clinical attack rate: 25-35% • Case fatality rate: 0.1% - 1% • 1-2 million deaths in US • 20-80 million deaths worldwide • Present H1N1: • Clinical attack rate: <1% • 7 million presumed affected • Case fatality rate: 0.1% • 7,000 deaths worldwide in 2009

5. Influenza: Molecular origins Influenza A & B Pandemic potential 2 major surface glycoproteins Hemagglutinin (HA) Neuraminidase (NA) -Subtypes - H1, H2, H3: -Site of attachment to host cells -Antibody confers protection against disease -Subtypes – N1, N2, N3: -Aids in release of virions from cells -Antibody can help modify disease severity Influenza: Infects multiple species: Humans, birds, pigs

6. Influenza: Molecular origins Antigenic drift • - Continuous evolving process modifications in viral HA or NA  new strains reinfect people throughout life yearly updated flu vaccine • Small drift: outbreaks (yearly) • Large drift: epidemics (every few years) Antigenic shift • Sudden, major change in HA and/or NA proteins on virus surface  new influenza A virus to which there is no pre-existing immunity • - Small shift: minor pandemic (every 30-50 years) • - Large shift: major pandemic (every 100 years)

7. Influenza: Molecular Origins • Wild waterfowl: natural reservoir of influenza A • Migratory birds: carry viruses todomesticated fowl • Responsible for flu seasons in Northern and Southern Hemisphere • Two ways to get a novel human strain • Genetic reassortment of two viruses new hybrid • Infection and human transmission (Rare) • Genetic mutation in avian or swine virus: • Infection and transmission in humans (Extremely rare)

8. Influenza: Potential Reassortment

9. Influenza Outbreaks: Definitions • Outbreak: seasonal transmission • 3-10% population affected (0.1% mortality) • 20,000 deaths US: 2-7% of all deaths caused by influenza • Epidemic: larger than expected outbreak • 10-20% population affected (0.1% mortality) • 50,000 deaths US: >8% of all deaths caused by influenza • Pandemic: widespread, efficient transmission • >20% population affected (0.1-1% mortality) • >80,000 deaths US: >15% of deaths caused by influenza

10. Seasonal Epidemic Threshold, 1972-1997 Number of influenza and pneumonia deaths per 100,000 population,1972 through 1997 (black lines). Red lines represent the epidemic threshold defined by a seasonal regression. Emerg Inf Dis 2004;10:32-39

11. Seasonal Epidemic Threshold, 2003-2009

12. WHO Pandemic Phases: Standard Definition

13. WHO Pandemic Phases: 2009 Definition

14. Major Pandemic: Historical Clues 1918 Pandemic -20-40 million deaths worldwide - Several waves Targeted young, healthy adults Next older patients -Clinical attack rate: 25-40% -Case fatality rate: 1-2% NEWSBREAK:   Science 10/05: Characterization of the reconstructed 1918 pandemic virus  H1N1 strain Nature 10/05: 1918 strain likely due to human-adapted mutation in a swine virus

15. Minor Pandemic: Historical Clues 1957: Asian Flu February: New strain H2N2 Reassortment (avian/human) May: Vaccine production begins • September: “Back to school” outbreak, highest mortality • February 1958: Second wave: elderly • Clinical attack rate: 25% • Case fatality rate: 0.1% • Total mortality: 70,000 in US, 1 million worldwide

16. Minor Pandemic: Historical Clues 1968: Hong Kong Flu -H3N2 strain: thought reassortment -Clinical attack rate: 20-25% -Case fatality rate: 0.1% -Mortality: 45,000 US, < 1 million in world Mildest 20th century pandemic • Immunity from Asian Flu • Vaccine production • Better medical care, antibiotics • - Similar to large epidemic

17. Avian Influenza Outbreaks Southeast Asia: Prime influenza media -Agricultural practices -Proximity: Human, bird, swine Chance for reassortment “We know the recipe, and all the ingredients are there" WHO - flu surveillance

18. Novel Avian Influenza in Humans 1997-2006

19. H1N1 Influenza Outbreak:Outline • Major global pandemic case scenario • Basics of the influenza virus • Molecular origins • Definitions • Outbreak, epidemic, pandemic • Historical clues • Previous outbreaks, pandemics • H1N1 outbreak, 2009 • Chance of major pandemic • In near future • In far future

20. Origins of the 2009 H1N1 Virus • Swine influenza: • Regularly causes respiratory outbreaks in pigs • High clinical attack rate, low case fatality rate • Novel H1N1 influenza A virus: • Human, avian and swine • reassortment. • Segments have coexisted in • swine strains for > 10 years • Recent introduction of • Eurasian swine strain • Mixing vessel for current • reassortment likely swine host N Engl J Med 2009; 360(28)

21. Swine Influenza A H1N1: 2009 • Mexico Outbreak: Late March to Mid-April • 3-fold spike in standard flu-like illnesses • Mainly affecting healthy young adults • Deaths from pneumonia: most with underlying illness • Mexico estimates: 250,000 cases, 250 deaths • Clinical attack rate: <1% • Case fatality: 0.1% - Confirmed cases: H1N1, Mexico March – May - Outbreak: Peaked at 6 weeks

22. H1N1 Outbreak: Southern Hemisphere Influenza strains, New Zealand, April - Aug ICU stays, Australia, June - Sept Flu-like illness, New Zealand, 2008- 2009 H1N1 cases, Peru, May - July

23. H1N1 Outbreak: United States • United States H1N1 • Outbreaks: • May, October • Children, young adults • Pediatric deaths : • Similar to seasonal epidemics • Yearly vaccination, older age: • Partial immunity from similar strains • Below peak epidemic threshold • Exceeded threshold: • Measured between seasons

24. H1N1 Outbreak: United States • Present wave: peaked at week 43 (6 weeks) • Seasonal outbreak: yet to come • US estimate: 1,000,000 cases, 1000 deaths • Clinical attack: <1%, case fatality: ~ 0.1%

25. Chance of Major Pandemic:Swine Influenza? 2003: Experts predict the next “big one” is H5N1, it is inevitable…. 2009: Experts predict global disaster is imminent with H1N1, we are at the “brink of a major pandemic”… Other experts: It may come now, or over the next several years….

26. Chance of Pandemic Influenza • Novel Avian/Swine outbreaks • 10 major outbreaks in 50 years • One every 5 years • With each major novel outbreak: • 5% chance of major pandemic • 10% chance minor pandemic • H1N1: Will not make pandemic • Followed its course over several waves • Similar to seasonal flu • Low transmission rate, low mortality • Chance of new mutation in each strain • Negligible, as with all seasonal strains • Small drifts do occur

27. H1N1 Influenza Outbreak: Summary • Novel H1N1 influenza outbreak: • In between seasons in Northern Hemisphere • Clinical attack rate <1%, case fatality 0.1% • May reach peak seasonal epidemic threshold • Influenza clinical attack rates: • Seasonal: 3-10% • Epidemic: 10-20% • Pandemic: >20% • Case fatality: generally 0.1% • Surveillance: track mortality • Put into perspective