Pandemic Influenza: A Zoonotic InfectionKathleen M. Neuzil, MD, MPH

PATHUniversity of Washington

School of MedicineApril 17, 2007

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.

• 1887-1956: Selwyn Collins, USA.

Influenza 1918: The route of Victoria

• Story begins in Seattle, October 1918.

• Passengers and mail aboard Victoria for distribution to Alaskan camps and villages via dog team.

• Three passengers removed from the ship in Seattle due to influenza.

• Victoria was 9 days en route to Nome; arrived October 20, 1918.

• Crew was quarantined upon arrival; but mail dispersed to outlying communities 12 hours after the ship’s arrival.

The Victoria pulls away from the slip between Pier 2 and Colman Dock, Seattle, WA. (Courtesy of Seattle Times, March 18, 2007.)

Ganley. Circumpolar Health 1996; 247.

Reconstructed routes of virus dispersal, Seward Peninsula, Alaska

By January 1, 1919, 35 to 40% of the native population along Seward peninsula had died

Teller Mission, Alaska: 1918

• Influenza spread through the village in 5 days.

• Killed 72 people (85% of the adult population).

• Victims buried in mass grave in permafrost.

Teller Mission, Alaska: 1997

• Four victims exhumed; in situ lung biopsy.

• Tissue: massive pulmonary hemorrhage (bleeding into lung) and edema (swelling of lung).

• Influenza RNA isolated and sequenced (A/Brevig Mission/1/18/H1N1).

Reid et al. Proc Natal Acad Sci 1999; 96: 1651.Taubenberger JK et al. Science 1997; 275: 1793.

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 Pandemics20th Century Influenza Pandemics

Influenza pandemics: Mutations of animal viruses, or viral reassortants

1918 Spanish (H1N1)

Avian mutated H1N1

>20 million deaths

1957 Asian flu(H2N2)

Human H1N1Avian H2N2

H1N1 disappeared

1968 Hong Kong (H3N2)

Human H2N2, avian H3Nx

H2N2 disappeared

1977 Russian(H1N1)

Virus identical to human strains

Benign —H1N1, H3N2circulate

HANAM

NS

NSPAHANAMNS

PB2PB1

PB2

PB2

NSPA

PB1

HA

MNS

NA

PANS

PB1

Epidemic human virus A(H2N2)

Avian virus A(H3N?)

New epidemic virusNew epidemic virusA(A(H3H3N2N2))

1968 Pandemic1968 Pandemic

Steinhoff MC. Epid and Prevof Influenza. In: Infectious DisEpidemiology. Nelson et al.

Avian Influenza VirusesAvian Influenza Viruses

• 15 hemagglutinins and 9 neuraminidases

• Widespread in migratory birds and waterfowl: natural reservoir

• Domestic poultry susceptible

Incidents with limited spread before 1997

1976 Swine flu H1N1

NJ: Enzootic in swine herds.

One death in military camp.

1986 H1N1 Netherlands: Swine virus from avian source.

One adult with severe pneumonia.

1988 Swine flu H1N1

Wisconsin: Swine virus.

Pregnant woman died.

1993 H3N2 Netherlands: Swine — human H3N2, avian H1N2.

Two children; mild disease.

1995 H7N7 UK: Duck virus. One adult —conjunctivitis.

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.

2003-2005 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

Avian Influenza A (H5N1) human infections: 2003-2007

Who is not on this list?

Country Cases Deaths

Azerbaijan 8 5Cambodia 7 7China 24 15

Egypt 34 14

Nigeria 1 1

Djibouti 1 0

Indonesia 81 63Iraq 3 2Lao 2 2

Thailand 25 17Turkey 12 4Vietnam 93 42TOTAL 291 172

As of April 16, 2007 www.who.int

Why is H5N1 of particular concern?

• Mutates rapidly, acquires genes from viruses infecting other species.

• H5N1 clades and subclades differ in antigenic structure.

• Direct transmission from birds to humans.

• Causes severe disease in humans.

• Acquisition of drug resistance on therapy.

• Increasing numbers of human clusters.

• Environmental resistance.

Risk ractors for Avian Influenza

• Exposure to live poultry.• Exposure to ill poultry and butchering of birds

(NOT culling).• Direct contact with poultry (plucking, preparing

diseased birds; handling fighting cocks; playing with poultry; consumption of duck’s blood; possibly undercooked poultry).

WHO. NEJM 2005; 353;13.

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 1997.

• 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.

Environment-to-human transmission?

• Theoretical given survival of H5N1 in environment.

• Oral ingestion of contaminated water during swimming?

• Contamination of hands from infected fomites and subsequent self-inoculation?

• Poultry feces used as fertilizer?

WHO. NEJM 2005; 353;13.

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.

Controlling H5N1 infection: Hong KongControlling H5N1 infection: Hong Kong

• Banned ducks, geese, quail from live market

• 2 “clean” days per month in market

• Use of “good” vaccines – vaccines that can reduce viral load below level of transmission

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?

How do we determine the burden of illness during How do we determine the burden of illness during annual influenza epidemics?annual influenza epidemics?

“…probably the most under-rated major pathogen in the developed world…one of the major infectious causes of death from a single microorganism.”

John Bartlett Update in Infectious Diseases

Annals of Internal Medicine August 1999

Impact of Influenza, U.S.Impact of Influenza, U.S.

• More than 20,000 excess deaths per typical epidemic

• >90% of deaths in persons >65 years

• 110,000 or more excess hospitalizations ($600 million direct costs)

• Severe epidemic costs $12 billion

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.

February 8, 2007

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 countries4 European companies produce 65% of world supply450 million people immunized at best

Fedson DS. Vaccine Development for an Imminent Pandemic. Human Vaccines 2006: 2(1)38-42.Dennis C. Flu-vaccine makers toil to boost supply. Nature 440:1099. Apr 2006.

Summary

• H5N1 is highly pathogenic and has crossed the species barrier to cause many human fatalities and pose an increasing pandemic threat.

• Yearly influenza epidemics are associated with substantial morbidity and mortality; impact in developing countries uncertain, but likely substantial.

• Investment in pandemic preparedness can yield more immediate health gains.