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Emergency Health and Nutrition Training Epidemiology, Prevention, Treatment, History, & Current Threat Pandemic Influenza Last Updated June 18, 2007

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Three Different Kinds of Influenza Seasonal Influenza The Flu Seasonal Influenza The Flu Avian Influenza Bird Flu Avian Influenza Bird Flu Pandemic Influenza A Pandemic Pandemic Influenza A Pandemic Related to each other, but public health implications of each is very different

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Influenza Type A Virus The Cause of All Avian & Pandemic Flu & Much of the Seasonal Flu Neuraminidase (N) protein facilitates virus detachment Hemagglutinin (H) protein facilitates viral attachment onto our cells for invasion & replication

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H16 XXXXXX (type A)

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Origin of Pandemic Influenza Migratory water birds H 1-16 N 1-9 Domestic pig Domestic birds (All human flu pandemics come from bird flu by 1 of 2 mechanisms)

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Circulating Seasonal Influenza A Sub-Types from Pandemics of the 20 th Century 19201940196019802000 H1N1 Seasonal Flu H2N2 H3N2 Seasonal Flu 1918/191957/581968/69 40-100 million deaths ~2 million deaths~1 million deaths 4 pandemics since 1889, with 11 to 39 years (average ~30 years) between each = ~3.3% annual risk of pandemic onset (but likely higher now)

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Camp Funston, Kansas, March 1918: Sadly, the comparatively benign first wave was not at all predictive of what was to come

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(John Barry. The Great Influenza.)

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In Philadelphia the number of dead quickly overwhelmed the citys ability to handle bodies. It was forced to bury people, without coffins, in mass graves and soon began using steam shovels to dig the graves. (John Barry, The Great Influenza)

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Published Pandemic Mortality Estimates for Selected Countries (Johnson NPAS & Mueller J. Bulletin of the History of Medicine (2002) 76:105-15) (1918: 28% of current global population. http://birdfluexposed.com/resources/NIALL105.pdf ) http://birdfluexposed.com/resources/NIALL105.pdf USA: 675,000 Bangl./ India/ Pak.: 18.5 million Nigeria: 455,000 Egypt: 139,000 Guatemala: 49,000 Afghan.: 320,000 Indonesia: 1.5 million Philip.: 94,000 Japan: 388,000 Brazil: 180,000 South Africa: 300,000 Kenya: 150,000 Global Total: 50 100 million (WHO: 40 million +) Russia/USSR: 450,000 Spain: 257,000 Canada: 50,000 Chile: 35,000 Australia: 15,000, in 1919 only British isles: 249,000

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(Also had some shift in deaths to younger adults in 1957 & 1968) typical for seasonal flu U.S. life expectancy dropped by 12 years

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Modes of Person-to-Person Transmission: 1.Large droplets from coughing, sneezing, & talking, to others eyes, nose, or mouth; 2.Contact: direct (hand-to-hand) & indirect (hand-to-surface-to-hand less common?); 3.? Airborne / aerosol / droplet Courtesy of CDC

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Decent Understanding of Modes of Transmission Led to Non-Pharmaceutical Interventions But Guidance in the US was Inconsistent & Communities Made Very Different Decisions

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Gunnison, Colorado 1 of 7 U.S. towns & residential institutions to escape the 2 nd wave Flu Cases: 0 in town; 2 in county Flu Deaths: 0 in town; 1 in county Non-Pharmaceutical Interventions Barricades on roads for 4 months; Rail travel restricted; Quarantine of arrivals to county, & jailing of those in violation; Isolation of suspected cases; Schools & all institutions closed; No public gatherings, per state law

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(For SARS, R o = 3, v = 9 days: From 1 to 4 cases in 9 days, & 40 by Day 30) Flu: From 1 to a cluster of 15 cases in 9 days, & 2,047 by Day 30! (Reproductive Number: R 0 for flu = 1.5 3.0, but higher in closed settings & among children.) Explosive flu outbreaks are due to this short generation time (due to short incubation period & peak infectivity early in illness.)

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Expect human cases in all areas with substantial human exposure to HPAI H5N1+ birds 313 lab.-confirmed cases with 191 deaths (61%) in 12 countries Expect human cases in all areas with substantial human exposure to H5N1 HPAI + birds (So far, limited serological surveys suggest that sub- clinical infection & mild illness remain rare.)

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Tamiflu! (oral) Ralenza (inhaled) (Older drugs) (Viral resistance to these is more common) (Injectable Peramivir has completed phase-1 trials)

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WHO, May 2006: In patients with confirmed or strongly suspected H5N1 infection, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence). (Evidence = seasonal flu clinical trials in humans & H5N1 animal data). clinicians might administer a combination of neuraminidase inhibitor & M2 inhibitor (weak recommendation, very low quality evidence). (Resistance to Tamiflu is a concern.)

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Pandemic Flu Prevention & Treatment Challenge ~2 day incubation period for seasonal flu is expected for pandemic flu also High levels of virus, & some person-to-person transmission, 1 day before symptoms! Transmission up to 7 days after fever ends longer in kids & immune suppressed Peak transmission

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Oseltamivir Therapy in H5N1 Thailand and Vietnam, 2004-2005 Oseltamivir Treatment Number Patients Number (%) Survivors Yes256 (24%) No123 (25%) Writing Committee. N Engl J Med. 2005;353:1374-1385. Tamiflu treatment often started late Dosage too low? Poor absorption of oral Tamiflu? Course of treatment too short? Some H5N1 resistance to Tamiflu

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Case-Fatality by Age WHO Data on 256 Confirmed Cases, 11/03 - 11/06 This case-fatality distribution among H5N1 cases is reminiscent of those observed during previous pandemics, particularly in 1918 (WHO, June 2006, re. a similar distribution)

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H5N1 in Humans Remains Rare: Currently Implicated Exposures (Source of infection is unknown in many cases. Very few cases are in presumed high-risk groups: Commercial poultry workers, workers at live poultry markets, cullers, veterinarians, & health staff caring for patients without using protective equipment) Some cases are in family clusters, some due to person-to-person transmission (genetics?) Preparing or disposing of diseased birds Handling fighting cocks Handling poultry, esp. asymptomatic ducks Consuming uncooked duck blood (& undercooked poultry?)

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established in 1812 January 27, 2005 vol. 352 no. 4 Probable Person-to-Person Transmission of Avian Influenza A (H5N1) Kumnuan Ungchusak, M.D., M.P.H., Prasert Auewarakul, M.D., Scott F. Dowell, M.D., M.P.H., Rungrueng Kitphati, M.D., Wattana Auwanit, Ph.D., Pilaipan Puthavathana, Ph.D., Mongkol Uiprasertkul, M.D., Kobporn Boonnak, M.Sc., Chakrarat Pittayawonganon, M.D., Nancy J. Cox, Ph.D., Sherif R. Zaki, M.D., Ph.D., Pranee Thawatsupha, M.S., Malinee Chittaganpitch, B.Sc., Rotjana Khontong, M.D., James M. Simmerman, R.N., M.S., and Supamit Chunsutthiwat, M.D., M.P.H. (http://birdflubook.com/resources/Ungchusak333.pdf)http://birdflubook.com/resources/Ungchusak333.pdf Thailand, Sep. 2004: A.11 year old girl died in Kamphaeng Phet province without H5N1 test. B.Mother visited daughter in hospital from BKK, H5N1+ without poultry exposure, & died. C.Aunt H5N1+, recovered

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April /May 2006 Karo, N. Sumatra cluster Limited WHO/MOH containment activities No transmission beyond this family Local people resist chicken culling & demand departure of WHO team Viet Nam: No human cases, 2006

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Three Requirements for a Flu Pandemic: 1.Novel flu virus for humans Yes 2.Ability to replicate in humans Yes & cause illness 3.Ability to pass easily Not Yet from person to person (signaled by growing clusters / outbreaks of human cases) H5N1 in 1997 & Since 2003:

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* Key to Phases 3 - 6: The size & growth of clusters of human cases (WHO phases apply to the whole world. Phases 4 & 5 may be skipped altogether - they assume gradual evolution of the virus & an R 0 < 1.0.) (See notes below)

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Current (~1950s!) flu vaccine technology requires slow production in eggs * * Recent progress in growth of virus in cell cultures instead of in eggs

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(for USA) (In millions of courses for the US market) Global flu vaccine production capacity can meet only a small fraction of global need. The US goal is to be able to immunize the entire US population within 6 months of pandemic onset by 2011

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Medical masks (surgical / procedure) help protect against droplets N95 masks (should be fit- tested) Neither protect eyes or prevent contact transmission Neither tested for influenza Must discard after dirty or moist Will likely be in short supply Woven cloth masks: Little data 1918 (& 21 st Century?)

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Analysis of 1918 data: early & sustained use of multiple partially effective non- pharmaceutical interventions (NPIs), can: Delay the outbreak peak; Reduce peak burden on hospitals & infrastructure; & Modestly reduce total # of cases & deaths. (US CDC, Feb., 2007: http://www.pandemicflu.g ov/plan/community/mitigat ion.html) http://www.pandemicflu.g ov/plan/community/mitigat ion.html (* see photos in Barry, The Great Influenza) Excess pneumonia & flu mortality over 19131917 baseline in Philadelphia & St. Louis, Sep. 8Dec. 28, 1918 NPIs 16 days after 1 st case NPIs 2 days after 1 st case

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Community Strategies by Pandemic Flu Severity (1) From U.S. CDC (& 15 Other Federal Agencies!) Feb. 1, 2007 Pandemic Severity (Based Mostly on Case Fatality Ratio) Interventions by SettingSeasonal Flu1957 / 19681918 or Worse Workplace/Community Adult social distancing decrease number of social contacts (e.g., encourage teleconferences, alternatives to face-to-face meetings) Generally not recommended ConsiderRecommend increase distance between persons (e.g., reduce density in public transit, workplace) Generally not recommended ConsiderRecommend modify, postpone, or cancel selected public gatherings to promote social distance (e.g., stadium events, theater performances) Generally not recommended ConsiderRecommend modify workplace schedules and practices (e.g., telework, staggered shifts) Generally not recommended ConsiderRecommend

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Community Strategies by Pandemic Flu Severity (2) (http://www.pandemicflu.gov/plan/community/mitigation.html)http://www.pandemicflu.gov/plan/community/mitigation.html Pandemic Severity (Based Mostly on Case Fatality Ratio) Interventions by SettingCFR < 0.1%0.1% -