Pandemic Influenza: A Zoonotic Infection Kathleen M. Neuzil, MD, MPH PATH University of Washington School of Medicine April 27, 2009

Questions  What is the epidemiology of human influenza?  What is the role of animals in influenza epidemiology?  When do we worry about a pandemic?

Excess mortality: Hallmark of epidemic influenza  1837: Robert Graves, Dublin.  1847: William Farr, London.  : Selwyn Collins, USA.

Influenza: An epidemic respiratory disease associated with “excess” deaths

“Conductor turns away man because he is not wearing his anti-flu mask.”

“Hunt up your wood-workers and cabinet-makers and set them to making coffins. Then take your street laborers and set them to digging graves. If you do this you will not have your dead accumulating faster than you can dispose of them.” Amer J Public Health 1918; 8: 787.

20th Century Influenza Pandemics 20th Century Influenza Pandemics

Influenza pandemics: Mutations of animal viruses, or viral reassortants 1918Spanish (H1N1) Avian mutated H1N million deaths 1957Asian flu (H2N2) Human H1N1 Avian H2N2 H1N1 disappeared 1968Hong Kong (H3N2) Human H2N2, avian H3Nx H2N2 disappeared 1977Russian (H1N1) Virus identical to human strains Benign — H1N1, H3N2 circulate

Surface antigens of the Influenza A virus Hemagglutinin Neuraminidase M2

HA NA M NS PA HA NA M NS PB2 PB1 PB2 NS PA PB1 HA M NS NA PA NS PB1 Epidemic human virus A(H2N2) Avian virus A(H3N?) New epidemic virus A(H3N2) 1968 Pandemic Steinhoff MC. Epid and Prev of Influenza. In: Infectious Dis Epidemiology. Nelson et al.

Incidents with limited spread before Swine flu H1N1 NJ: Enzootic in swine herds. One death in military camp. 1986H1N1Netherlands: Swine virus from avian source. One adult with severe pneumonia. 1988Swine flu H1N1 Wisconsin: Swine virus. Pregnant woman died. 1993H3N2Netherlands: Swine — human H3N2, avian H1N2. Two children; mild disease. 1995H7N7UK: Duck virus.One adult — conjunctivitis.

What is the role of pigs?

H5N1 – Where did it start?  1996: First detected in geese in Guangdong Province, China.  1997: First recognized in humans: Hong Kong,18 human cases, 6 fatal.  H5N1 viruses isolated from birds at wholesale and retail markets in Hong Kong.  No further cases following widespread culling of chickens.

Avian Influenza A (H5N1) outbreak in humans  Vietnam, Thailand, Cambodia  55 cases, 42 deaths  Predominantly children and young adults.  Rural Asia: Households maintain free-ranging poultry for income, food.  Children play near poultry; families slaughter birds for food.  Pathogenesis: high and disseminated viral replication and intense inflammatory response. N Engl J Med 2005: 353; 25 N Engl J Med 2004; 350: 1179

H5N1: How did it spread?  1997-May 2005: largely confined to SE Asia.  Infected wild birds in Qinghai Lake, China; rapidly spread westward.  Death of swans and geese marked spread into Europe, India and Africa.  Ducks may be “stealth carriers.”  Wild mallard ducks do not always show signs of disease when infected with highly pathogenic H5N1 viruses. N Engl J Med 2006; 355: 2174

Number of confirmed human H5N1 cases by month as of Source: World Health Organization

H5N1: Human-to-human transmission?  Infection after close contact with infected child leading to illness and death.  Evidence of antibodies to H5 in health care workers who cared for patients in Hong Kong in  Intensified surveillance (PCR) with contacts has led to detection of mild cases, more infections in older adults, and increased numbers of family clusters in Vietnam.  Family clusters in Indonesia. NEJM 2005; 353;13. NEJM 2006; 355: 2186.

So…  H5N1 is a novel virus with ability to infect and cause disease in humans  Limited human to human transmission at present  Total number of cases small; case fatality rate high  Exposure and risk of future cases increasing with increasing spread of virus among birds  Is avian influenza worth the investment of resources, and if so, what can/should be done?

WHO: Pandemic alert  Influenza A virus with a novel HA or novel HA and NA — substantial proportion of the population has little or no antibody to the novel virus.  Novel virus demonstrates ability to cause disease in humans.  Novel virus demonstrates ability to spread easily among humans.

Updated WHO guidance will be available in 2009 Revised Pandemic Phases Source: World Health Organization

WHO Strategic Actions  The objectives of the strategic actions correspond to the principal opportunities to intervene and are likewise phase-wise.  Phase: pre-pandemic  1. Reduce opportunities for human infection  2. Strengthen the early warning system  Phase: emergence of a pandemic virus  3. Contain or delay spread at the source  Phase: pandemic declared and spreading internationally  4. Reduce morbidity, mortality, and social disruption  5. Conduct research to guide response measures

So what should be done, pre-pandemic (now!)?  Improve surveillance worldwide. –All types of influenza. –All types of respiratory disease. –Easier, more reliable, less expensive diagnostics. –Year-round surveillance. –Clinical research on human cases/ populations.

Reduce opportunities for human infection  Education about human behaviors.  Control spread in birds/animals (collaboration between animal and public health sectors).  Improve approaches to environmental detection of virus.

General emergency preparedness  Clearly-defined plans, leadership structure.  Responsibility/accountability.  Communications.  Surge capacity — Mass delivery mechanisms for drugs/vaccines/health services.  Stockpiles of essential medical supplies.  Table-top exercises.

Preventing/minimizing morbidity and mortality  Pandemic vaccines – Supplies, equitable access, developing country manufacturers, novel ways to use less antigen (make limited supply go further).  Antivirals – International stockpiles, supplies, equitable access, developing country manufacturers, international clinical trials networks.  Community mitigation strategies – Quarantines/border or school closures.

Flu vaccine supply: Inadequate, inequitable  >95% of world flu vaccine comes from 9 countries  4 European companies produce 65% of world supply Fedson DS. Vaccine Development for an Imminent Pandemic. Human Vaccines 2006: 2(1) Dennis C. Flu-vaccine makers toil to boost supply. Nature 440:1099. Apr 2006.

Near term strategy: Is real-time response viable? Real time response is not a viable solution in the near-term since existing infrastructure would only serve a small portion of the world’s population within 6 months of outbreak. Real-time Global Pandemic Capacity – “Best Case” Global Demand = 6.8B Availability Timeframe for Global Need Pandemic Courses Filled in 6 Month Timeframe ~2yrs~1.4yrs~1.3yrs ~1yr~2yr