Update On Avian Influenza

Wallace Greene, PhD, ABMM

Director, Diagnostic Virology Laboratory

Department of Pathology

M. S. Hershey Medical Center

Hershey, Pennsylvania

“We’re all holding our breaths. H5N1 is the most important threat the world is facing.”

“People who fail to prepare for a flu pandemic are going to be tragically mistaken.”

Julie Gerberding, Head of the CDC

“Get rid of ‘if’. This is going to occur.”

–Anthony Fauci, NIH Director

“The world is now in the gravest danger of a pandemic. It is coming.” “There is no disagreement that this is just a matter of time”

Director-General of the World Health Organization

“There is a credible risk that the spread of avian influenza and resulting disease in the future constitute a public health emergency.”

Official declaration of a potential pandemic emergency by the federal government.

Mike Leavitt - U.S. Secretary of Health and Human Services

February 1, 2007

“More deaths occurred in 2006 than in previous years combined. The fatality rate for H5N1 rose to 70% last year, 10 points higher than the average since the current series of outbreaks began in 2003. The message is straight forward: we must not let down our guard.”

Margaret Chan, Head of the World Health Organization

January 22, 2007

“This virus is particularly nasty. We have never seen any influenza virus like it before”

Nancy Cox, Chief Influenza Scientist at the CDC

“I’ve never experienced anything like it in terms of its destructive power. It is staggering in terms of how much lung tissue is destroyed.”

Director of Oxford University’s Clinical Research Unit”

•The Virus

•The Disease

•Diagnosis

•Treatment

•Management

INFLUENZA

Influenza A Viruses

Subtyped based on surface glycoproteins:

16 hemagglutinins (HA) and

9 neuraminidases (NA)

Current human subtypes - H1N1, H3N2, H1N2

CURRENTLY CIRCULATING AVIAN INFLUENZA VIRUSES

THE NEXT PANDEMIC COULD COME FROM ANY OF THESE

Viral evolution can not be predicted.

Reassortment - rapid development of a new variant explosive spread

Adaptive mutations - more gradual development, limited transmission

in the beginning

•Acute febrile illness

•Usually self-limiting

•Can be problematic in children and elderly

•Characterized by:

–“Generic” symptoms

–Fever, Chills, Myalgia, Cough, Headache, Malaise

–Symptoms typically last 3 days, up to 8 days

–Complications – secondary pneumonia

SEASONAL FLU

• H5N1 is the only avian flu virus to repeatedly cause severe disease in humans

• Initial symptoms same as seasonal influenza

• Watery diarrhea may proceed respiratory symptoms

• Abnormal chest radiographs include interstitial infiltration, patchy lobar infiltrates in a variety of patterns progressing to diffuse bilateral ground-glass appearance with clinical features of ARDS

• Median time from fever to ARDS is 6 days (range of 4-13 days)

• Multi-organ failure occurs with liver, kidneys and brain all affected.

• Bacterial secondary infections not seen

• “Cytokine storm” Nature (January 18, 2007, 319-323) “Aberrant innate immune response in lethal infection of macaques with 1918 influenza virus”

“AVIAN FLU”

Multi-organ failure occurs with liver, kidneys and brain all affected.

Bacterial secondary infections not seen

“Cytokine storm” Nature (January 18, 2007, 319-323) “Aberrant innate immune response in lethal infection of macaques with 1918 influenza virus”

•WHO recommends that infection control precautions for adults remain in place for 7 days after resolution of fever, 21 days for children

• “Family members should be educated in personal hygiene and infection control measures.”

“AVIAN FLU”

Public Health Importance of Influenza

Approximately 40,000 deaths yearly

Over 85% mortality is in persons 65 and older

Attack rates of 5 - 20% in general populations (normal flu)

Nursing home attack rates of 60%

Transmission

Typical incubation - 2 days, range 1-4 days

Viral shedding - can begin one day before onset of symptoms

peak shedding first 3 days of illness

subsides by days 5-7 in adults, >10 days in children

Treatment

• Supportive

• Antiviral Therapy

– Amatidine/RimantadineNot recommended due to resistance

– Neuraminidase Inhibitors

Neuraminidase Inhibitors

• Relenza ® (Zanamivir)– Glaxo Wellcome– Inhaled

• Tamiflu™ (Oseltamivir phosphate)– Roche– Oral

• Mode of action - inhibition of replication by interference with neuraminidase activity

Viral Inhibitors

Scientific AmericanJanuary, 1999

INFLUENZA TIMELINE

1890 – first recorded influenza pandemic

1918 – “Spanish flu pandemic, caused by an H1N1 strain kills more than 40 million people.” Recently shown to be due to a bird-human jump

1957 – Asian flu pandemic kills 100,000 people, due to H2N2 virus

1968 – Hong Kong flu pandemic kills 700,000 people, due to H3N2virus. Both H2N2 and H3N2 strains likely due to exchangeof genes between avian and human flu viruses

May 21, 1997 Bird flu virus H5N1 is isolated for the first time in a humanin Hong Kong. The virus infects 18 people after close contact with poultry, with six deaths. Within three days, Hong Kong’sentire chicken population is slaughtered.

INFLUENZA TIMELINE

Sept 1998 – Two new influenza drugs are announced

Feb 2003 – H5N1 infects two people in Hong Kong, one dies

Dec 2003 – South Korea has first outbreak of H5N1 virus

Jan 2004 – Japan has first outbreak on H5N1 since 1925

WHO confirms H5N1 infection in 11 people, eight fatal, in Thailand and Vietnam. Virus wrecks havoc in poultry industryin Thailand, Vietnam, Japan, and South Korea and is foundin China

WHO begins work on developing H5N1 vaccines in U.S. and U.K.

INFLUENZA TIMELINE

March 2004 – H5N1 flu virus becomes more widespread among flocksin Asia, has caused 34 human cases, with 23 deaths

July 2004 – Several countries, including Thailand, Vietnam, Chinaand Indonesia report new infections in poultry with H5N1

August 2004 – H5N1 is reported to have killed 5 more people in Vietnam

Chinese scientists report H5N1 infections in pigs

H5N1 has spread throughout most of SE Asia, resulting in the culling of over 100 million chickens. In Vietnam and Thailand, 37 people have been infected, with 26 deaths

October 2004 – UK authorities suspend manufacturing of flu vaccine

November 2004 – WHO ramps up activities, urges focus on vaccine development

INFLUENZA TIMELINE

Jan/Feb 2005 – 13 additional human cases in Vietnam, 12 fatal

Feb 2005 – First report on H5N1 in Cambodia

Probable person-to-person transmission reported in Vietnam

First vaccines begin clinical trials

March 2005 – 15 additional cases in Vietnam and one in Cambodia

Bird flu has spread to 10 countries and killed around 50 millionchickens

May 2005 – Reports of human deaths reported in China, and over 1,000dead migratory birds have been identified.

July 2005 – Philippines report their first case

INFLUENZA TIMELINE

2005 – Vietnam – Transmission through consumption of uncooked duck blood

2006 – Azerbaijan – children were found to be infected through collecting feathers from dead swans.

2006 – Indonesia - WHO reported evidence of human-to-human spread. In this situation, 8 people in one family were infected. The first family member is thought to have become ill through contact with infected poultry. This person then infected six family members. One of those six people (a child) then infected another family member (his father). No further spread outside of the exposed family was documented or suspected.

Flu Pandemics – A Comparison

Year 1918 2000

World Population 1.8 Billion 5.9 Billion

Primary Mode of Troopships Jet AircraftTransportation Railroad automobile

Time for Virus to 4 months 4 daysCircle the Globe

Estimated Dead 50 Million ?????Worldwide

Death toll in 20th century pandemics and projections for the next pandemic

Population Death Toll per 100,000 people

1918 1.8 billion 50 million 2,777

1957 3.8 billion 1 million 26

1968 4.5 billion 1 million 27

Next 6.5 billion 1.7 million 26

Next 6.5 billion 180 million 2,777

According to data from http://www.census.gov/ipc/www/world.html +http://www.prb.org/Content/NavigationMenu/PRB/Educators/Human_Population/Population_Growth/Population_Growth.htm

1918The virus first appeared March 4, 1918 in soldiers at Camp Funston, Kansas and spread rapidly to most American cities and was relatively mild.

In June, the Spanish news reported “A strange form of disease of epidemic character has appeared in Madrid…. The epidemic is of a mild nature, no deaths having been reported.

In late August, a deadly variant exploded simultaneously in the French port city of Brest (a major disembarkation of American soldiers), Boston (where troops returned from the battlefield), and Freetown, Sierra Leone (where British navy vessels were docked.

1918Half of the world became infected

25% of Americans were ill

99% of excess deaths were among those under 65 years old

Mortality peaked in 20 to 34 year olds

Women under 35 accounted for 70% of all female flu deaths

In 1918, more people died from influenza than the bubonic plague killed in a century

This virus killed more people in 25 weeks than HIV has killed in 25 years

An Emergency Hospital for US Influenza Patients The influenza virus had a profound virulence, with a mortality rate at 2.5% compared to the previous influenza epidemics, which were less than 0.1%. The death rate for 15 to 34-year-olds of influenza and pneumonia were 20 times higher in 1918 than in previous years (Taubenberger). People were struck with illness on the street and died rapid deaths.