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Influenza in the 21st Century and the Risk of a
Pandemic

• Michelle A. Barron, M.D.
• Assistant Professor of Medicine
• Division of Infectious Diseases
• UCHSC, Denver, CO

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Influenza virus

• Family Orthomyxoviridae.
• Single stranded RNA virus.
• Zoonosis of swine, birds, horses, and humans.
• 3 Distinct types
• Influenza A virus
• Influenza B virus
• Influenza C virus

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History of Influenza

• Estimated 51,000 excess deaths annually in the US
  from influenza.
• Thought to have appeared in the first half of the
  16th century.
• ex influentia colesti Italian expression
  which alluded to the thought that the epidemic
  was due to celestial influence.
• The 1510 pandemic began in Sicily, spread to
  Italy and to the rest of Europe.
• Hundreds of thousands of individuals affected.

Cunha, B.A. Infect Dis Clin N Am 18 (2004)
141-155.
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Influenza pandemic of 1918-1919 Spanish flu

• Spanish flu A (H1N1) originated in the U.S. and
  was transported to Europe by American troops
  fighting in World War I.
• More than half a million deaths in the US alone.
• 20-50 million people may have died worldwide.

Cunha, B.A. Infect Dis Clin N Am 18 (2004)
141-155.
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Spanish Flu 1918-1919

• Unusually high mortality in healthy young adults.
• Single most lethal infectious outbreak to occur
  worldwide over a 1-year period.
• Small pox took half a century to move across
  Europe.

Cunha, B.A. Infect Dis Clin N Am 18 (2004)
141-155.
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History of Influenza

• 1933 Influenza A is isolated.
• 1936 Influenza is grown in embryonated eggs.
• 1939 Influenza B is isolated.
• 1941 Hemagglutination reactions discovered.
• 1950 Influenza C virus isolated.

Cunha, B.A. Infect Dis Clin N Am 18 (2004)
141-155.
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History of Influenza

• 1957-58 Asian flu A (H2N2)
• 70,000 deaths in the US.
• First to be studied using modern scientific
  techniques.
• 1968-69 Hong Kong flu A (H3N2)
• Approximately 34,000 deaths in the U.S.
• Both 1957 and 1968 pandemics due to reassortment
  of a human virus with an avian influenza virus.

Cunha, B.A. Infect Dis Clin N Am 18 (2004)
141-155.
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Epidemiology of Influenza

• Hemagglutinin (HA)
• 15 distinct HAs (numbered 1-15).
• Important in attaching and infecting respiratory
  epithelial cells by cell fusion.
• Neuraminidase (NA)
• 9 distinct NAs (numbered 1-9).
• Important in the release of influenza viruses
  from the apices of infected cells facilitating
  cell-to-cell spread of the virus.
• Only 3 HA subtypes (H1, H2, H3) and two NA
  subtypes (N1, N2) have caused influenza epidemics.

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Epidemiology of Influenza

• Antigenic Shift
• Seen only with Influenza A viruses.
• Results from replacement of HA and sometimes NA
  with novel subtypes not present in human viruses.
• Source of new genes is large reservoir of
  influenza viruses in waterfowl.

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Epidemiology of Influenza

• Antigenic Drift
• Occurs in both influenza A and B.
• Pattern observed is somewhat different for each
  virus.
• Involves the accumulation of mutations within the
  antibody-binding sites in HA, the NA, or both.

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Adapted from NEJM. 2004. 350(3)219.
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Clinical Features - Adults

• Incubation period of 1-5 days.
• Abrupt onset of severe headache, chills, and
  non-productive cough.
• Also prominent muscle aches accompanied by high
  fevers.
• Fever peaks on the first day and may decrease
  over the next 72 hours.
• Decreased energy and appetite are universal.
• Mild-moderate cases usually resolve in 7 days.
• Weakness, cough, and lack of energy may persist
  for weeks after clinical resolution.

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Clinical Features - Children

• Similar syndrome in children, except croup is
  common in kids lt1 year old.
• Nausea, vomiting, and abdominal pain more common
  complaints in children lt 3 years of age.
• Inflammation in the muscles of the calf are
  common.
• Febrile seizures may occur.
• Encephalitis may accompany illness.

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Prevention and Good Health Habits

• Vaccination is the key prevention strategy.
• Stay home when you are sick.
• Avoid direct contact with people that are
  coughing or sneezing.
• Cover your mouth when you cough or sneeze.
• Wash your hands frequently or use antibacterial
  gels frequently.

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Antiviral Drugs Amantadine Rimantadine

• Effective against influenza A only.
• Both inhibit viral replication.
• Prophylaxis is preventative in about 50 of
  infections and 70-90 of illnesses.
• Must be given daily throughout the period of
  exposure.
• Effective for the treatment of influenza A if
  given during the first 2 days of illness.
• Resistance can develop rapidly during treatment.
• Has been recognized in 25-35 of treated
  patients.

Couch, R.B. NEJM. 2000. 343(24)1778-87.
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Antiviral Drugs Zanamivir and Oseltamivir

• Neuraminidase inhibitors.
• Effective against both influenza A and B viruses.
• Approved for treatment of influenza only in
  person with symptoms lt2 days.
• Reduces symptoms by 1-1.5 days.
• Both have been shown to prevent influenza if
  given before exposure during a community epidemic.

Couch, R.B. NEJM. 2000. 343(24)1778-87.
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Pandemic Influenza Strains

• Sources
• Avian influenza viruses thought to be likely
  source of reassortment.
• Pigs have receptors for avian and human influenza
  viruses and are susceptible to both.
• Possible intermediary for viral reassortment.
• Features
• Highly pathogenic for humans.
• Easily transmitted between humans.
• Genetically unique (lack of preexisting immunity
  in the human population.)

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Seasonal versus Pandemic Influenza

• Seasonal Flu
• Outbreaks follow predictable seasonal patterns
• Usually some immunity built up from previous
  exposure
• Healthy adults usually not at risk for serious
  complications
• Health systems can usually meet public and
  patient needs

• Pandemic Flu
• Occurs rarely (three times in 20th century - last
  in 1968)
• No previous exposure little or
• no pre-existing immunity
• Healthy people may be at increased risk for
  serious complications
• Health systems may be overwhelmed

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Seasonal versus Pandemic Influenza

• Vaccine developed based on known flu strains and
  available for annual flu season
• Adequate supplies of antivirals are usually
  available
• Average U.S. deaths approximately 36,000/yr
• Symptoms fever, cough, runny nose, muscle pain.
  Deaths often caused by complications, such as
  pneumonia
• Generally causes modest impact on society (e.g.,
  some school closing, encouragement of people who
  are sick to stay home)
• Manageable impact on domestic and world economy

• Vaccine probably would not be available in the
  early stages of a pandemic
• Effective antivirals may be in limited supply
• Number of deaths could be quite high (e.g., U.S.
  1918 death toll approximately 500,000)
• Symptoms may be more severe and complications
  more frequent
• May cause major impact on society (e.g.
  widespread restrictions on travel, closings of
  schools and businesses, cancellation of large
  public gatherings)
• Potential for severe impact on domestic and world
  economy

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Moderate and Severe Influenza Scenarios
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Current H5N1 Threat

• Virus has spread rapidly throughout poultry
  flocks in Asia in past 2 years.
• The subtype mutates rapidly.
• Has shown a propensity to acquire genes from
  viruses infecting other species.
• Causes severe disease in humans with high
  case-fatality rate.
• Notable that sustained human-to-human
  transmission has not occurred.
• Potential of exposure and infection in humans is
  likely ongoing in rural Asia.

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Avian influenza A (H5N1)

• December 2003
• 19,000 of 24,000 chickens on a farm in Korea die
  in a week.
• Epidemic of the highly pathogenic avian influenza
  H5N1 strain found as the cause of the poultry
  deaths.
• More than 1.3 million chickens and ducks have
  died or been destroyed.
• January 2004
• Outbreak of severe respiratory illness in 12
  previously healthy children and 1 adult
  hospitalized in Viet Nam reported to WHO 8
  cases are fatal.
• Test on samples from two of the fatal cases
  confirm infection with H5N1 avian influenza virus
  strain.

WHO. 2004
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Avian influenza A (H5N1)

• H5N1 outbreaks poultry in Cambodia, China,
  Indonesia, China, Japan, Laos, South Korea,
  Thailand and Vietnam reported.
• Millions of birds either died from the disease or
  were culled in efforts to contain the outbreaks.
• February 2004
• 34 human cases with 23 deaths reported in
  Thailand and Vietnam.
• August/September/October 2004
• 4 human deaths from avian influenza H5 infection
  reported in Vietnam 4 fatal cases in Thailand..
• 1 case of possible human-to-human transmission
  reported.

WHO. 2004
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Avian influenza A (H5N1)

• December 2004
• Resurgence of poultry outbreaks and human cases
  reported in Vietnam.
• Suggested transmission to at least two persons
  through consumption of uncooked duck blood.
• February 2, 2005
• The first of 4 human cases of H5N1 infection from
  Cambodia was reported.
• July 21, 2005
• First human case of H5N1 in Indonesia was
  reported.
• Indonesia has continued to report human cases in
  August, September, and October 2005.

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Avian influenza A (H5N1)

• January 2006
• Two cases of avian influenza in Turkey and 1st
  case detected in Iraq.
• February 2006
• China reports its 12 case and 8th fatality.
  Indonesia reports its 25th case and 18th
  fatality. Iraq reports its 2nd case.
• March 2006
• Azerbaijan and Egypt report their 1st human
  cases.
• August 2006
• 60 cases confirmed to date in Indonesia, 46 have
  been fatal .

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Cumulative Number of Confirmed Human Cases of
Avian Influenza A/(H5N1) Reported to WHO
Total number of cases includes number of
deaths.WHO reports only laboratory-confirmed
cases. Adapted from CDC (August 23, 2006)
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Nations With Confirmed Cases H5N1 Avian
Influenza (July 7, 2006)
Adapted from CDC
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Symptoms of Avian flu in Humans

• Range of symptoms.
• Typical flu-like symptoms (fever, cough, sore
  throat and muscle aches),
• Eye infections,
• Pneumonia,
• Severe respiratory diseases (such as acute
  respiratory distress),
• and other severe and life-threatening
  complications such as encephalitis.
• The symptoms may depend on which virus caused the
  infection.

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Advice to Travelers

• Avoid all direct contact with poultry, including
  touching well-appearing, sick, or dead chickens
  and ducks.
• Avoid places such as poultry farms and bird
  markets where live poultry are raised or kept,
  and avoid handling surfaces contaminated with
  poultry feces or secretions.
• Cleaning hands often with soap and water.
• Waterless alcohol-based hand gels may be used
  when soap is not available and hands are not
  visibly soiled.
• All foods from poultry, including eggs and
  poultry blood, should be thoroughly cooked.

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Treatment Options and Prevention

• The current H5N1 virus infecting birds in Asia
  that has caused human illness and death is
  resistant to amantadine and rimantadine.
• Oseltamavir and zanamavir would probably work to
  treat flu caused by the H5N1 virus, but
  additional studies still need to be done.
• No commercially available vaccine to protect
  humans against the H5N1 virus that is being seen
  in Asia and Europe .

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Ten Things You Need to Know About Pandemic
Influenza

• 1. Pandemic influenza is different from avian
  influenza.
• 2. Influenza pandemics are recurring events.
• 3. The world may be on the brink of another
  pandemic.
• 4. All countries will be affected.
• 5. Widespread illness will occur.
• 6. Medical supplies will be inadequate.
• 7. Large numbers of deaths will occur.
• 8. Economic and social disruption will be great.
• 9. Every country must be prepared.
• 10. WHO will alert the world when the pandemic
  threat increases.

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What Does the Future Hold?

• It is unclear whether additional global outbreaks
  of influenza or some other emerging infectious
  disease will occur.
• If outbreaks occur, it is unclear whether it will
  be localized zoonoses or wider epidemics.
• We must remain alert and prepared.

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• Chance Favors the Prepared Mind.
• Louis Pasteur

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Questions?