3. Pandemic Influenza
Next pandemic inevitable in the near term
Wide agreement by WHO, CDC, others
Current H5N1 “bird flu” or another strain
Worldwide spread within 2-3 months possible
Initial quarantine may close borders for weeks to months
Highly contagious
Humans have no immunity to new strains
Vaccine availability will lag by months
Insufficient anti-viral drugs currently available
Significant mortality
1% of world’s population (30 million) died in 1918
pandemic
1-2 million died in 1957 & 1968 pandemics
9. WHO Pandemic Phases
Inter-Pandemic Period
Phase 1: Animal virus present; no human transmission
Phase 2: Animal virus with features posing risk of human
transmission
Pandemic Alert Period
Phase 3: Human infection through animal contact but no
human-to-human spread (rarely, spread to a close contact)
Phase 4: Small clusters of limited human-to-human
transmission; highly localized
Phase 5: Larger clusters of human-to-human transmission
but still localized
Pandemic Period
Phase 6: Worldwide human-to-human infection; increased
and sustained transmission in general population
10. Terminology: Pathogenic Avian
Serotypes
(defined according to disease caused in birds)
Influenza A has many subtypes, classified
according to 16 “H” and 9 “N” proteins
Poultry cases
H5 (generally highly pathogenic)
H7 (high or low pathogenic varies by strain)
H9 (always low pathogenic)
Human cases
H5 (generally severe)
H7 (mild disease even if highly pathogenic in
birds)
H9 (mild disease; only 3 cases documented)
11. Avian Influenza A (H5N1)
Occurs primarily in poultry, waterfowl, or other birds
Mammals are susceptible to infection--ingested chicken
Become ill and die
Thus far don’t serve as natural carriers
2004: pigs (China); tigers & domestic cats (Thailand)
2006: domestic cat, stone marten (Germany)
Emerged in Asia sometime before 1997 in poultry
1997 - Mutated into highly pathogenic form
Infected 18 humans (6 deaths) in Hong Kong
2003 - Re-emerged in poultry
Mutated slightly to “Z” strain
Current wave of bird to human cases since Dec. ‘03
12. Reasons for Concern for
Pandemic H5N1
H5N1 can infect many avian and animal species
Facilitates geographic spread
Recombination event is not necessary for a
pandemic
1918 strain pure avian virus that underwent ~10 spontaneous
mutations, became infective for humans, and was exceptionally
virulent
Several similar mutations present in currently circulating H5N1 virus
NS1 gene possible virulence factor:
one variant of a specific NS1 gene present in all AI isolates
(plus 1918 strain), but no human influenza A
13.
14.
15.
16. H5N1 Outbreaks in Birds
Countries with H5N1 Outbreaks in 2005-06
Asia Africa Europe
Cambodia Cameroon Albania Serbia & Montenegro
China * Egypt Austria ** Slovakia
Hong Kong Niger Bosnia & Herzegovina ** Slovenia **
Indonesia Nigeria Bulgaria ** Sweden
India Burkina Faso Croatia Switzerland**
Kazakhstan Denmark Ukraine
Malaysia France United Kingdom**
Mongolia Mid-East Germany
Pakistan (H5) Azerbaijan Greece**
Russia Iran** Hungary
Thailand Iraq Italy**
Viet Nam Israel Poland**
Georgia** Jordan Romania
Burma (Myanmar) Turkey
* Cases were reported in birds in the following provinces or autonomous regions during 2005 and/or 2006: Anhui, Guizhou, Hubei, Hunan, Inner Mongolia,
Jiangxi, Liaoning, Ningxia, Qinghai, Shanxi, Sichuan, Xinjiang, Xizang (Tibet), and Yunnan.
17. Transmission
Spread by domestic ducks, poultry, wild
migratory birds
Transmitted bird to human through:
Direct contact with sick / infected birds
Surfaces contaminated with droppings,
respiratory secretions, ocular secretions
Possibly: eating under-cooked eggs & poultry,
duck blood
Human-to-human transmission non-existent
or rare with existing H5N1 strain
Incubation period unknown -- 2-8 days
Pandemic virus (after human adaptation) likely 1-
4 days
18. Transmission (cont’d)
Mainly large droplet spread
3 feet
Emphasis on social distancing
Environmental contact (H5N1 viruses can
survive for up to 6 days)
Airborne transmission possible?
Isolate first cases with airborne precautions
Infectious period
1 day before onset of symptoms to 5 days after in adults and
3 weeks in young children
Big contrast to SARS
Seasonally unclear; winter may be still be
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30. H5N1 Clinical -- Symptoms
Initially cannot differentiate from other cases of
severe influenza
Presents with fever and influenza-like symptoms,
cough, sore throat, rhinitis, muscle aches, headache
Conjunctivitis
Rapid onset of viral pneumonia, ARDS
H5N1 mouse studies indicate diffuse extrapulmonary
involvement, macrophage activation, cytokine storm effect
Severest mortality in young adults
Other symptoms, e.g., severe diarrhea, encephalitis,
etc. (see notes)
31. Use of Antivirals
Stand-by treatment
For use (after medical consultation) after becoming ill in an
outbreak situation
Dosing as per treatment regimen on “Treatment
of Avian Influenza” slide
Prophylaxis
In an outbreak situation, antivirals to be taken as instructed
before becoming ill
32. Types of Antivirals
Oseltamivir (Tamiflu) -- recommended
Active against H5N1 in vitro and likely effective in vivo (mice)
Shelf life: at least 5 years
Supplies limited; not currently in retail stores
Until this year 2 million doses per year
U.S. current stockpile of antiviral drugs: 5.5 million treatment
courses
an additional 12.4 million treatment courses of Tamiflu and 1.75
million treatment courses of Relenza due by Sept 2006
? production issues
Zanamivir (Relenza) -- may also be effective
Taken via inhalation - less convenient to use
Amantadine, rimantadine: H5N1 is resistant to these drugs
33. Treatment of Avian Influenza
Need to start antiviral treatment in first 48 hours
Reduce mortality / complications
Non-severe cases
75 mg oseltamivir (Tamiflu) po bid for 5 days
2 Vietnamese cases with oseltamivir-resistant mutation
developing during therapy with death.
Higher dosing may be necessary
Resistant virus not necessarily infectious
OR
10 mg zanamivir (Relenza) inhaled bid for 5 days
Almost none currently available
Severe cases
150 mg oseltamivir po bid for 7-10 days
Consider adding inhaled zanamivir (Relenza)
34. Prophylaxis of Avian Influenza
Oseltamivir 75 mg po once daily
during period of exposure and for 7-
10 days after last exposure
If staying in an area of on-going
epidemic with no vaccine available, this
could mean taking prophylaxis for 2
months or longer.
Prophylaxis of general public not in
current HHS plan
35. Prevention for the Traveler:
Pre-travel
Check for any travel restrictions
Prohibit travel with a fever to/from H5N1 areas
Educate & provide handout on avian influenza
Provide travel health kit
Supply antivirals (e.g., oseltamivir) if traveling to
H5N1-affected area (Freedman DO, Leder K. J Trav Med 2005; 12: 36-44)
Vaccinate with conventional influenza vaccine
Does not protect against H5N1 but may decrease
chance of confusing human influenza with H5N1
Identify in-country health care resources
36. Education: Preventive Measures
During Travel
Avoid contact with birds, animal markets / farms, bird
droppings or secretions, and potentially
contaminated surfaces
Frequent thorough hand washing
Carry and use alcohol hand sanitizer / wipes
Need for paper towels in washrooms
After shaking hands
Ingestion of eggs and poultry that are well cooked
Good respiratory hygiene
When possible, change of airplane seats to avoid travelers
with respiratory symptoms; masks when appropriate
Seek early medical consultation for any fever or
influenza-like symptoms during or after travel to
H5N1 areas
37. Travel Kit for H5N1 Areas
First aid and medical supplies
Oral thermometer and probe covers
Household disinfectant
Disposable gloves and plastic storage bags
Alcohol-based wipes / hand sanitizer
Masks (2- or 3-ply surgical, N95, others)
Consider antivirals (e.g., oseltamivir)
38. Masks
Surgical masks 2- or 3-ply
Benefit controversial but may be cultural mandate
N-95 masks
Fit testing required; some limitations but may be good
stand-by protection and useful on airplanes
N-95 or N-100 with exhalation valve
Alternative to N-95
Exhalation valve increases comfort, temperature, and
“wetness” of mask
May be difficult to ensure compliance unless high risk
exists
39. Employees/Visitors After
Return from H5N1 Areas
Employees/visitors with fever or respiratory illness < 10
days from H5N1-affected area should inform appropriate
contact point by telephone and have their illness
assessed by the corporate or other health care provider
before going into the workplace
40. Pandemic Planning
Assumptions
Two or more waves in same year or in successive flu seasons
Second wave may occur 3-9 months later; may be more serious than first (seen
in 1918)
Each wave lasts about 6 weeks in a given community
42. Community-based Containment
Measures
Slow spread locally; allow for preparation
Slow spread to other communities
Local containment plan
Care, food, services to the isolated or quarantined
Legal preparedness
Flu/fever clinics hotlines
Community communication & cooperation
Voluntary quarantine can work
43. Pandemic Public Health Measures
Respiratory etiquette
Cover mouth/nose with sneeze/cough
Use tissues
Dispose of tissues
Immediate hand hygiene
Avoid large gatherings
Surgical masks in public controversial
Social distancing (3 feet) more effective
Symptomatic individuals to wear masks
Snow days; Closure of public places
“Cordon sanitaire”
44. Avian Vaccines - Poultry
Avian vaccines used in poultry
Used extensively in several locales,
including China
Feb 2004 to Jan 2005: China inoculated
2.68 billion birds
Not currently thought to be an
effective control measure
45. Avian Vaccines - Human
Human monovalent H5N1-only vaccines undergoing trials in
U.S. and elsewhere
Sanofi: 2 doses were needed at 90 µg given 1 month apart--only 50% of
subjects protected (seasonal flu vaccine contains 15 µg)
GSK: Human trials have begun in Europe with low antigen content
vaccines with adjuvants
8 million H5N1 doses on hand by 2/06 (4 million people)
NIH long-term project (MedImmune) to develop seed virus strains against
all known H types, including H5N1
Egg technology: Long time-line (3-6 months) for additional doses
once decision made, current capacity 5 million doses / month
Cell culture techniques; new investment, several years off
Priority plans: HCWs at top
50% of the population that are healthy and 2-64 years at bottom
Current flu vaccines do NOT include avian strains and offer no partial
or cross-protection
46. Eliminate pandemic virus
strain at source?
Recent mathematical models of
massive antiviral administration in a
localized epidemic situation
“Ring eradication” feasible if:
Low to moderate transmissibility (R0 <
1.8)
Chemoprophylaxis of 90% of
population within 1-3 weeks
1-3 million courses of oseltamivir needed
Movement restrictions; high compliance
47. Recombined pandemic H5N1 strain
vs. SARS
Much more explosively contagious than SARS
Airborne spread
Easy in-flight spread compared to SARS
More difficult to contain with simple
quarantine measures than SARS
Will still more rapidly lead to definitive
international travel prohibition
May not be seasonal