Influenza and the Threat of Pandemic

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Influenza and the Threat of Pandemic

• Gregory D Harrington, D.O.
• Center for Infectious Diseases and Pulmonary
  Medicine

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Definitions

• Endemic persistent low to moderate
  level of disease occurrences
• Epidemic occurrence of disease in
  excess of expected levels
• Pandemic epidemic spreads over
  several countries or continents

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More Definitions

• Colonization presence of organism
  without evidence of disease
• Infectivity proportion of exposed who
  become colonized
• Pathogenicity proportion of colonized
  who develop disease
• Virulence proportion with disease who
  become severely ill

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Epidemic Triangle
Mode Transmission
Agent
Host
(Reservoir)
Environment
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Structure of Influenza
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History of Influenza

• 1580 pandemic is first described outbreak
• 1729-1730 pandemic
• 1732-1733 epidemic
• 1761-62 epidemic
• 1781-82 pandemic
• 1788-89 epidemic
• 1847-48 pandemic
• 1889-90 pandemic
• 1918-19 Spanish Influenza - gt40 million dead
• 1957-58 Asian Flu pandemic 1- 4 million
• 1968-69 Hong Kong Flu pandemic 1 million

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Recent History of Viral Types
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Ecology of Influenza

• Primarily a viral infection of birds
• Multiple virus combinations are circulating
• Mutates to infect mammals and humans
• Prior herd immunity limits disease
• Unique balance between mutation frequency, animal
  and humans

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Influenza Outbreaks and Movement

• Massive Frontal Movement
• Single wave in one or more areas with rapid
  diffusion
• Multiple Sequestered Movement
• Multiple epicenters at once
• Slow to diffuse and low mortality
• Seasonal Epicenter Relocation
• Move from one geographic area to another
• Herald Explosion
• Starts remote areas in spring with low mortality
• Diffuses widely and develops second wave in fall

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Virus TypesHemagglutinin and Neuramidase

• Two important proteins
• Hemagglutinin viral attachment to host cells
• Neuraminidase cleans newly formed HA on budding
  viruses
• Antibody response is primarily directed at HA

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Types of HA and NA

• Hemagglutinin
• H1-human pathogen
• H2-human pathogen
• H3-human pathogen
• H4-bird
• H5-bird
• H6-bird
• H7-15-bird

• Neuraminidase
• N1-human pathogen
• N2-human pathogen
• N3-9

Highly Pathogenic Avian Influenza H5-7
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Antigenic Variation

• Antigenic drift
• Minor genetic (amino acid) changes in HA/NA
• Antibody response not as effective
• Occurs yearly to every-other year
• Antigenic Shift
• Major genetic changes produce new virus
• No herd immunity
• Results in pandemic influenza

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Viral Dynamics Pandemic and Epidemic Influenza
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Mechanisms of Pandemic Influenza

• Reassortment of virus
• Mixing of genes from animal and human influenza
  virus yielding new virus
• Adaptation of virus
• Genetic mutations lead to direct infection from
  bird to humans

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Relationship of Influenza to Absenteeism E.R.
visits Pneumonia Mortality Positive cases
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2004 Influenza Season
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Influenza Mortality
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Influenza Activity Last 3 Years
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Uncomplicated Influenza

• Influenza-like illness fever (gt100.4) with
  either sore throat or cough
• Acute onset after 2 day incubation
• Headache, myalgias, prostration
• Severe symptoms last 3-4 days
• Malaise and fatigue can last days to weeks

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Response to Infection
Days
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Complicated Influenza

• Primary viral pneumonia
• Secondary bacterial pneumonia
• Bacterial sinusitis
• Myositis
• Myocarditis / pericarditis
• Guillian-Barre syndrome
• Reyes Syndrome

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Diagnosis of Influenza

• Viral culture
• Rapid antigen detection

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Treatment of Influenza

• MUST initiate within 48 hours to impact on
  symptoms of uncomplicated influenza
• M2 inhibitors
• Amantadine, rimantadine
• Neuraminidase inhibitors
• Oseltamivir, zanamivir

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Influenza Virus
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Prevention of Infection
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Prevention

• Hand washing
• Cover mouth when sneezing and coughing
• Avoiding work and school when sick
• Use crook of elbow not hands
• Immunization
• Chemoprophylaxis

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Trivalent Inactivated Vaccine

• Subunit vaccines (HA, NA)
• One injection, lasts 6 months
• Side effects
• Local soreness
• Fever within 24 hours
• Flu-like illness
• Reduces risk of influenza, pneumonia, death

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Current Influenza Activity
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Images of the 1918-19 Spanish Influenza
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1918-1919 Spanish Flu 1st wave

• Started in Haskell, Ks. Jan-Feb 1918
• First outbreak at Camp Funston, Ka, March 1918,
  then Ft Riley Ks
• Rapidly spreads to East coast and carried to
  Europe in April 1918
• Low mortality and slows down by end of June 1918

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1918-1919 Spanish Flu 2nd wave

• August 1918, reports of illness in US and Europe
• Higher mortality in young, healthy soldiers
• Death occurs in 2 to 5 days
• Those exposed in first wave dont get as sick
• Cases and deaths sky-rocket Sept-Oct 1918
• Second wave covered the globe by November
• Slows down by Wars end..

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The 2nd Wave of Spanish Flu
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Deaths from Spanish Flu
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1918-1919 Spanish Flu 3rd wave

• By November 1918, the cases and mortality were
  dropping.
• But, in December 1918 a third wave hit
• End of WW1 contributed to the third wave
• Those who survived previous waves are less ill
• The spread continued thru Spring 1919
• Slowly declined by December 1919
• Next three years saw smaller epidemics

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New Data on H1N1 Spanish Flu

• Did not originate as reassortment
• All 8 genes are most closely related to avian
  origin than other sources
• Able to kill cells in culture without trypsin
• 100 times more lethal in mice than other known
  human influenza viruses

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The Toll of the Great Influenza

• One fifth of the worlds population was infected
• gt 40 50 million died world-wide in two years
• Primarily killed 20 - 40 year olds
• Infected 28-30 of Americans
• Estimated mortality rate 2.5
• 675,000 Americans died..10x the loss in the War
• Half of US casualties were from influenza (43K)
• Average life-span in US dropped 10 years

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Asian Flu 1957-58

• H2N2
• Started in China 2/57
• Spread to U.S. in June 1957
• 70,000 U.S. deaths
• Dual infection of mammal with reassortment H2N2
  and H1N1

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Hong Kong Flu 1968-69

• H3N2
• Started in Hong Kong spring 1968
• Detected in U.S. fall 1968
• 38,000 U.S. deaths
• Dual mammal reassortment of H2N2 with H3N2
• Virus still in circulation

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Avian Influenza
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Epidemiology of Avian Influenza

• Natural reservoir
• Wild migratory fowl, quails and pheasants
• Other potential reservoirs
• Domestic fowl, ? Swine, ? Felines
• Low-level endemicity
• Transmission
• Nasal, occular discharges, feces
• Incubation is 24-48 hours

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WHO Pandemic Phases
Phase 1 No new type A influenza subtypes
Phase 2 New subtype in animals pose risk to humans
Phase 3 Human infection with new type No human-to-human transmission
Phase 4 Small clusters of human-to-human transmission localized
Phase 5 Large clusters of human-to-human transmission geographically limited
Phase 6 Increased and sustained transmission in general population
Interpandemic period
Pandemic Alert
Pandemic period
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Poultry Outbreaks 2004
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Infected Chicken

• Signs and
• Symptoms
• Soft-shell eggs
• Cyanotic combs
• and wattles
• Loss of appetite
• Diarrhea
• Respiratory
• distress

Comb
Wattles
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Avian Influenza Transmission

• Direct exposure to infected poultry
• Plucking and preparing
• Handling live birds
• Consuming blood or under cooked poultry
• Transmission to felines
• Feeding raw infected chickens to tigers and
  leopards in Thailand
• Experimental transmission in cats

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Human-to-Human Transmission

• No clear documentation but
• Suggested by case studies
• Case patient may have transmitted to mother
  without contact with birds or other cases
• Family clusters
• Genetic analysis suggests progressive human
  adaptation

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Summary of Human-to-Human Contacts
Contacts Locale year s Positives
household Vietnam 2004 51 0
HCW Vietnam 2004 143 0
Thailand 2004 89 0
Family Vietnam 2004 20 1
Clusters Thailand 2004 17 1
Cambodia 2005 4 1
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Epidemiology of H5N1
Thailand n17 Vietnam n10 Ho Chi Minh n10 Cambodia n4
Median age 14(2-58) 14(5-24) 19(6-35) 22(8-28)
Family Cluster 1 2 1 1
Median onset 4(2-8) 3(2-4) __ __
Poultry Exposure 14/17 8/9 6/6 3/4
Deaths 12(71) 8(80) 8(80) 4(100)
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Species Interaction
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Highly Pathogenic Avian Flu
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Current Extent of H5N1
Human and Poultry
Poultry only

• South Korea
• Japan
• Vietnam
• China
• Cambodia
• Thailand
• Indonesia
• Loas

• Russia
• Kazakhstan
• Romania
• Mongolia
• Greece
• Macedonia
• Ethiopia

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Prevention of Avian Influenza
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Burning Birds
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Close Proximity to Fowl
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Human Avian Influenza Cases

• 1997 Hong Kong H5N1
• Thought to be 1st case of bird-to-human trans.
• 18 cases, 6 deaths
• 1.5 million chickens killed in 3 days
• 1999 Hong Kong H9N2
• 2 cases, no deaths
• Currently found in mainland China
• Low level activity

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Human Avian Influenza Cases

• 2003 Hong Kong H5N1
• 2 related cases acquired from China, 1 death
• 2003 Netherlands H7N7
• 84 cases in poultry workers and families
• 1 death
• Conjunctivitis primarily
• Evidence of person-to-person transmission
• 2003 Hong Kong H9N2
• 1 case, survived

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U.S. Experience with Avian Influenza

• 2003 Delaware H7N2
• 12,000 chickens infected and destroyed
• Low pathogenic strain
• 2004 Texas H5N2
• 7,000 chickens infected and destroyed
• Highly pathogenic strain

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Reported Symptoms
Presentation Thailand-17 Vietnam-10 HoChiMinh-10
Fever 100 100 100
Myalgias 53 0 20
Diarrhea 41 70 0
Cough 94 100 100
SOB 76 100 100
CXR 100 100 100
LFTs 67 83 70
ARF 76 90 70
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Summary of Symptoms

• Incubation 2-5 days (lt 17 days)
• Clinical Coarse influenza-like illness
• Early respiratory distress
• ARDS, MOSF
• Mortality
• 50 average
• 80 lt 15 yo
• Death averages 10 days (6-30 days)

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Management Options

• Airborne precautions
• Supplemental O2
• Avoid high-flow 02 mask
• Ventilator support
• Neuramidase inhibitors Osteltamivir
• Adults75 mg po bid x 5 days within 48 hrs
• Children 2 mg/kg po bid x 5 days

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CDC Interim RecommendationsInfection Control
H5N1

• All patients with febrile respiratory illness
• Review recent travel history
• Respiratory/cough etiquette in health care
  setting
• Hospitalized patient who are evaluated for H5N1
• Isolation precautions same as SARS
• Outpatient or hospital D/C within 14 days
• Same principles as home isolation with SARS
• Continue precautions for 14 days after onset
• Abort if alternate diagnosis

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Precautions for Travelers

• Immunize with available trivalent vaccine
• Avoid contact with poultry
• Avoid contact with farms and live animal markets
• Practice good hand hygiene
• Become ill with fever and respiratory symptoms
  within 10 days of return

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Precautions for Household / Close Contacts

• Use good hand hygiene
• Do not share utensils
• Avoid face-to-face encounters or HEPA mask
• Post exposure prophylaxis
• Follow for temps and resp. symptoms x 7 d

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HCW Exposure

• Monitor for temps bid and report fever
• If ill-avoid patient care
• Diagnostic testing
• Treat if no alternative dx
• Post-exposure prophylaxis for exposure to bodily
  fluids
• Pre-exposure prophylaxis for high-risk procedures

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Isolation Precautions in Health Care Facilities

• Combine contact, droplet and airborne precautions
• Place in negative-pressure rooms
• NIOSH N-95 masks
• Long-sleeved gowns
• Face/eye shields
• Limit of HCW with contact with patients

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Pan-Pacific Avian Flyways
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Avian Influenza in Humans
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Avian Flu by Country 10/05