Avian Influenza Shoreland, Inc.

April 2006

Taipei ‘Wet Market’

China--Backyard Farms

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– Similar mortality possible if no effective intervention

H5N1: Confirmed Cases in Humans, Wild Birds, & Poultry

(April 4, 2006)

H5N1: Confirmed Cases in Humans 192 cases / 109 deaths

WHO counts only lab-confirmed cases

The 2 Mechanisms Whereby Pandemic Influenza Originates

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

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)

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

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

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.

† H5 confirmed in poultry with further tests pending; however 1 human case has been confirmed as H5N1.‡ Affected birds exclusively wild/migratory species to date.

Countries with outbreaks in 2003 and/or 2004 but not in 2005-06: Japan, Korea, Laos

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

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 higher

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)

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

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

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)– Consider po/IV ribavirin

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

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

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

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)

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

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

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

30% Attack Rate; 10% of Workforce

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

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”

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

Avian Vaccines - HumanHuman 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

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

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