Pandemic Flu

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					Pandemic: 1918

Pandemic flu, 1918-1919
• • • • 20% of world population infected 21 million – 100 million deaths Killed up to 8-10% of young adults 2/3 of fatalities occurred over a period of 24 weeks
Photo: Princeton Alumni Weekly

Photo: Dartmouth College Archives

War, Pestilence and Death

100 90 80
Deaths (millions)

70 60 50 40 30 20 10 0
WWI (military dead) WWII (military dead) Black Death Influenza (lower bound) Influenza (upper bound)

How it began
• Jan-Feb 1918: First influenza outbreak in rural Haskell County, KS • Feb: Several soldiers went to Camp Funston, 237 men infected • April-July: Soldiers shipping out spread to other bases in America and France, then to German troops and rest of Europe and Asia • Unusually mild, relatively few casualties. “Three day fever”

Ft. Riley, KS

Photo: US Naval Center

The Second Wave
• In August 1918, ships with virulent influenza • Simultaneous appearance of epidemic worldwide. • Camp Devins (outside Boston) infected, hundreds of casualties. Tried quarantine but too late. • Steamers and troop transports spread to New Orleans, Philadelphia, Rhode Island.

Plague in the cities
• In US, influenza spread along railways from coast to coast. • Philadelphia: hundreds of thousands ill, hundreds died each day. • Hospitals overcrowded, city opened 12 ad hoc hospitals manned by medical students, volunteer nurses, nuns. • Public gatherings forbidden, closed churches, school, theater, public funerals

• Most victims still recovered.
– Headache, fever, chills, muscle pain, cough

• But 10-20% had virulent form
– Pneumonia – Confusing symptoms: extreme fever and chills (malarial) joint pain (dengue-like) – Cyanosis from lung damage – Some symptoms caused by cytokine storm – Death often came within 12 hours

Origin of the virus
• Sequencing of RNA fragments from lung tissue samples • Probably originated as avian virus • H1 N1 antigens, unlike modern bird flu (H5 N1)

• First wave virus likely related to second wave virus – infection conferred resistance. • First wave virus not very deadly; may have adapted to better infect humans producing second wave

Mortality mysteries
• Normal influenza pandemics hardest on young and elderly, but in 1918 young people hit hard. • In past 20 years only pandemic was H3 strain (1889). • So, elderly may be more immune because of earlier epidemics. • Or, young adults’ strong immune systems Reid, AH et al. The 1918 Spanish influenza: integrating triggered cytokine storms, history and biology. Microbes and Infection 3, 81-87 (2001) leading to tissue damage.

Fighting the Pandemic
• Army quarantined soldiers, but inevitable cramming • Surgeon General didn’t act until Sept. 22. • Suppression of information (wartime), newspapers unreliable and people cynical.
– Tried to boost morale, did not report early cases. – LA public health director: “If ordinary precautions are observed, there is no cause for alarm.” – Literary Digest “Fear is our first enemy.” – Albuquerque Morning Journal: “Don’t Get Scared.”

Photo: US Naval Center

Fighting the Pandemic
• Public health service appropriated $1M to hire non-drafted doctors and nurses. • Philadelphia hired street cleaners, but few signed on. • Public gatherings forbidden, many stayed home • Placards on houses with sicknesses • Social and family ties broken, uninfected afraid to care for sick. • Shipyards reported >50% absenteeism • Widespread use of gauze masks

Patrolmen in masks

Photo: US Naval Center

Australian Red Cross nurses suited up
We have lost an outrageous number of Nurses and Drs. -Camp Devins physician
Photo: Australian War Memorial

Photo: US Naval Center

Source: Trench and Camp Newspaper, 2 October 1918

Fighting the Pandemic
• Western world suffered least; urbanization exposed people to previous influenza viruses
– Medical intervention of dubious value – Only in 1943 was influenza recognized as a viral disease

• Less developed countries harder hit
– US deaths 0.65% of population – Mexico deaths 2.3% of population – Pacific islands hard hit: Western Samoa lost 90% of population – Japan and American Samoa blockaded, prevented widespread infection

What worked?
• Quarantines, isolation, close churches and schools • Measures should be early and sustained.
– St. Louis closed schools and canceled public gatherings early, maintained >10 weeks – New York isolated sick in hospitals or makeshift wards, quarantined homes, >10 weeks – But median only 4 weeks

Scatterplot of Public Health Response Time for 43 US Cities From September 8, 1918, Through February 22, 1919

Markel, H et al. Nonpharmaceutical Interventions Implemented by US Cities During the 1918-1919 Influenza Pandemic. JAMA 298, 644-654 (2007)

Later epidemics
• Asian flu (H2N2), 1956-8
– Avian flu outbreak originating in China, spread to southeast Asia and US – Death toll 1-4 million

• Hong Kong flu (H3N2), 1968-9
– – – – Descendant of Asian flu, arose in swine Originated in Hong Kong, spread to southeast Asia and US Death toll 0.75-1 million Same neuraminidase as previous outbreak, maybe lower death toll from partial

• Bird flu (H5N1), 2003 - ?
– Endemic in domestic and wild birds – Humans infected from birds, little human-human spread

Source: WHO

Source: WHO

Biology of the Influenza Virus
Denrick C.

• • • • Structure Replication Cycle Infection Biology of Influenza virus A in 1918 • Biology of Current Influenza virus A (H5H1) • Anti-Virals

Virion Structure
• 80- 120 nanometers • Spherical • Negative-sense RNA

• • • • HA –Hemagglutanin NA –Neuraminidase NP – Nucleoprotein Polymerase complex proteins • Matrix proteins • Non- structural proteins

Three types of Influenza virus
• Influenza virus A - birds and humans - high mutation rate • Influenza virus B - humans and seals - one serotype • Influenza virus C - less common - humans

Influenza Strains
H1N1 – Spanish flu 1918 H2N2 – Asian in 1957 H3N2 – Hong Kong Flu in 1968 H5N1- pandemic threat ?

Replication Cycle
• Stage 1Hemagglutinin binding to sialic acid sugar • Stage 2- Opening of the viral coat • Stage 3 – vRNA and proteins transported to nucleus • HA and NA Bulge
The M2 Ion Channel Protein of Influenza A Virus- Northwestern

Antigenic shift/drift
• Lack of proofreading capability in RNA polymerase • Mixing of vRNA in co-infection

The Infection
• Respiratory system infection • 2-5 day incubation • Lower lung hemorrhaging • Pneumonia

How does Influenza cause Pneumonia? • Decreased immune function? - lymphopenia induced in mice • Favorable environment? - alveoli hemorrhaging - NO and O radicals • Streptococcus pneumoniae bacteria stability

Biology in 1918
• Spring - Novel Hemagglutanin surface protein • Fall – Mutation in HA = anitgenic shift epidemic • Single Amino Acid Change E190D • Glycosylation sites • Intact NA

Damaging the immune system (H5N1) • Dysregulation of chemokines and cytokines • Up-regulation of TRAIL • Reduced cytotoxicity of lymphocytes • Antigenic drift • HA1-HA2 polybasic amino acid motif

• Neuramindase inhibitors -Oseltamivir = Tamiflu -Zanamivir • M2 inhibitors - Amantadines = Symmetrel

• Lindstrom S. E. et al. Comparative Analysis of Evolutionary Mechanisms of the Hemagglutinin and Three Internal Protein Genes of Influenza B Virus: Multiple Cocirculating Lineages and Frequent Reassortment of the NP, M, and NS Genes. American Society for Microbiology. (1999) 73. 4413-4426 Hay, A.J., Gregory, V., Douglas A.R., Lin, Y.P. The evolution of human influenza viruses. (2001). 356, 1861-1870. Weinstock, D.M., Zuccotti, G. The Evolution of Influenza Resistance and Treatment. (2009) 301, 1066-1069. WHO. Update on Avian Influenza A (H5N1) Virus Infection in Humans. (2008). 358. 261- 273. Korteweg, Christine., Gu, Jiang. Pathology, Molecular Biology, and Pathogenesis of Avian Influenza A (H5N1) Infection in Humans. (2008) 172. 1155-1169. Reid, A.H., Taubenberger, A.K., Fanning, T. G. The 1918 Spanish Influenza; integrating history and biology. (2001) 81-87. Nobusawa, E., Sato, K. Comparison of the Mutation Rates of Human Infleunza A and B Viruses. (2006). 80. 3675-3678. Matsuzaki, Y. et al. Genetic Diversity of influenza B Virus; The Frequent Reassortment and Cocirculation of the Genetically Distinct Reassortant Viruses in a Community. (2004) 74. 132-140.

• • • • • •

The Pandemic Threat
Public Health: Preparedness and Prevention

Potential Pandemic
• An influenza pandemic occurs when a new influenza virus appears, and the human population has no immunity against it. • Would an influenza pandemic today be more or less severe than the 1918 pandemic?
– More severe: dense population, global transportation, proportion of elderly, pre-existing immunocompromised – Less severe: advanced medicine, tools for surveillance

• Estimates
– WHO: 2-7 M deaths – Others have predicted up to 60 M deaths

H5N1 - “Avian Influenza”
• H5N1
– Influenza virus commonly found in birds – Very severe in humans – Thought to be the candidate for the next pandemic influenza in humans

• First identified in 1997
– 2003 epizootic in Hong Kong – Since: 400 cases, 60% mortality

• Symptoms
– Fever, cough, muscle aching, Pink Eye – Can lead to pneumonia and cause death

• Treatment

CDC: Three Conditions for Pandemic

1. 2. 3.
• •
– –

A new influenza virus subtype must emerge It must infect humans and cause serious illness It must spread easily and sustainably (continue without interruption) among humans
H5N1 satisfies the 1st and 2nd condition It can achieve the 3rd condition by
Reassortment Adaptive Mutation


Possible cases of human-to-human transmission

WHO: Six Phases of Pandemic Alert

International & National Preparedness
• WHO Pandemic Preparedness Plan

– Goals, Objectives, Actions for: Planning and Coordination, Situation monitoring and assessment, Prevention and Containment, Health System Response, Communications

• HHS Pandemic Influenza Plan
– Strategic Plan, Public Health Guidance for State and Local Partners, HHS Agencies’ Operational Plan

PU Emergency Preparedness

• WHO Global Influenza Surveillance Network (GISN)
– National Influenza Centers (NICs) – WHO Collaboration Centers (WHO CCs)

Surveillance (continued)
• Google Flu Trends – even earlier detection?
( – Flu-related queries, correlation with CDC

• Animal Health

– OFFLU: OIE/FAO Network of Expertise on Avian Influenza – Other susceptible mammals – Migratory patterns

• Making influenza vaccines are uniquely complicated and difficult
– Constantly evolving, spreads rapidly

Vaccine Recommendations
• Since 1971, WHO has made recommendations for the composition of the seasonal flu vaccine based on information from the GISN

• GISN also serves as a global alert mechanism for emergence of viruses with pandemic potential

Pandemic Influenza Vaccine
• Pandemic Influenza Vaccine
– Considered most effective to limit spread/damage – Complications

• H5N1 Vaccine
– Relatively new

• FDA approved first US vaccine for humans, 2007
– Two intramuscular injections, 28 days apart – National Stockpile – $127M (2007), $192M (2008)

Sanofi Pasteur
• Donate 60M doses to WHO (2008)
– Influenza vaccine global stockpile for vulnerable populations

• Emerflu® in Australia (2009) • Sanofi’s commitment
– Seasonal influenza vaccine facilities to switch to pandemic vaccine manufacturing – New facilities in US and China

Vaccine Development Methods
• Standard
– Killed flu virus – Grown from chicken eggs

• Live-attenuated
– Weakened, live flu virus – Grown from chicken eggs

1 dose = 1 chicken egg

• Cell Culture
– Produced in living cells

– Injecting engineered DNA of the influenza virus instead of virus itself

Still undergoing clinical trials and FDA approval

Universal Vaccine?
• Universal vaccine to protect against all strains
– Only needs to be given once (seasonal and avian) – Still a concept rather than a product

• Current seasonal flu vaccines
– Target outer surface of virus that differ between strains

• Attempts
– Dr. Wayne Marasco (2009) – Japan, Oxford – Still undergoing clinical trials and not yet approved by FDA

Problems with Vaccines
• Time needed for vaccine manufacturing • Priority
– Reasons to shift priority from the elderly (65+ yrs) YLLs, vaccine efficacy, mortality patterns, herd immunity

• Swine Flu Affair of 1976
– Mass vaccination program after H1N1 outbreak in Fort Dix – After 10 months: no epidemic, association with GB

• What if the pandemic strain is not H5N1?

Community-based Prevention
• Hygiene • Education and Planning • Social distancing (all age groups) • Avoid sick poultry (dead or alive)

• Antiviral treatment for cases, prophylaxis for household members

Manhattan Project of 21st Century
• Senator Bill Frist calls for a Manhattan Project of 21st century
– – – – – – Communication to the public Surveillance Antivirals Vaccines Research and Development Stockpile and Surge Capacity

“A pandemic influenza is no longer a question of if, but a question of when. While there is absolutely no way to know when an avian pandemic will occur, we can predict and we do know the cost of being underprepared.”

• Would we better or worse off today than we were in 1918? • Should we focus funds on virus control in birds or humans? • How much money/effort should we be investing in pre-pandemic vaccines – are we currently spending too much, or too little? • Should we be putting more priority in vaccines, surveillance, or basic community-based prevention?

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