Update On Avian Influenza Wallace Greene, PhD, ABMM Director, Diagnostic Virology Laboratory Department of Pathology M. S. Hershey Medical Center Hershey, Pennsylvania

Were 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 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

Ive 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 Universitys 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, ) 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, ) 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 % 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/Rimantadine Not 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 American January, 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 H3N2 virus. Both H2N2 and H3N2 strains likely due to exchange of genes between avian and human flu viruses May 21, 1997 Bird flu virus H5N1 is isolated for the first time in a human in Hong Kong. The virus infects 18 people after close contact with poultry, with six deaths. Within three days, Hong Kongs entire 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 industry in Thailand, Vietnam, Japan, and South Korea and is found in 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 flocks in Asia, has caused 34 human cases, with 23 deaths July 2004 – Several countries, including Thailand, Vietnam, China and 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 million chickens May 2005 – Reports of human deaths reported in China, and over 1,000 dead 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 – 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 World Population1.8 Billion5.9 Billion Primary Mode ofTroopshipsJet Aircraft TransportationRailroadautomobile Time for Virus to4 months4 days Circle the Globe Estimated Dead50 Million????? Worldwide

Death toll in 20th century pandemics and projections for the next pandemic Population Death Toll per 100,000 people billion 50 million 2, billion 1 million billion 1 million 27 Next 6.5 billion 1.7 million 26 Next 6.5 billion 180 million 2,777 According to data from Population/Population_Growth/Population_Growth.htm

1918 The 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.

1918 Half 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.