Avian influenza, and the medical emergencies it brings' - PowerPoint PPT Presentation

1 / 69
About This Presentation

Avian influenza, and the medical emergencies it brings'


Ducks in USA markets are currently harboring many influenza A viruses ... The local newspaper, 'Santa Fe Monitor' reported on it as follows. ... – PowerPoint PPT presentation

Number of Views:98
Avg rating:3.0/5.0
Slides: 70
Provided by: danhin


Transcript and Presenter's Notes

Title: Avian influenza, and the medical emergencies it brings'

Avian influenza, and the medical emergencies it
  • Daniel R. Hinthorn, MD, FACP
  • Division of Infectious Diseases
  • University of Kansas Medical Center

Influenza virion structure
Tamiflu works here
9 types, N1-9
N gene 6
16 types, H1-16
H gene 4
Amantadine works here

Internal gene virulence factor

8 RNA genes

Allows escape from host cell response
Kilbourne, Influenza, 1987. Pringle, IDN, 2004
Incidental hosts
Incidental hosts
Fecal spreaders
Virus mixers With both human And bird virus
Large numbers Assist in spread To humans
  • Swine receptors are both 2,3 and 2,6 receptors
  • Avian receptor is a 2,3 sialic acid receptor.
  • Human receptor is a 2,6 sialic acid receptor.

Incidental hosts
Can emergence of pandemic strains of
influenza viruses be prevented?
  • A classic mistake made by chicken turkey
    farmers is
  • To raise a few domestic ducks on a pond near
    poultry barns
  • These birds attract wild ducks.
  • Solution Raise domestic poultry in ecologically
    controlled houses with a high standard of
    security limited access.
  • Humans, pigs aquatic birds are the principal
    variables associated with the emergence of new
    human pandemic influenza viruses.
  • Pigs are probably the major mixing vessel for
    influenza viruses because the respiratory
    epithelial cells in pigs have receptors for both
    human avian influenza viruses.
  • Solution Separate pigs from people ducks. In
    live bird markets, separate chickens from other
    species, especially from aquatic birds.

Transmission of human influenza
  • Influenza is highly infectious, easily and
    rapidly transmitted by
  • Droplets with sneezing, coughing, talking
    especially among people in close proximity
  • Incubation period is 1-2 days
  • The virus grows quickly in the new cells over 4-6
    hours releasing new virons to infect nearby cells
  • When is someone contagious?
  • From 1-2 days before onset of symptoms until 5-7
    days after start of symptoms.
  • High viral concentrations in the throat allows
    for rapid spread of influenza for 2 days before

Courtesy of Chien Liu, MD
(No Transcript)
Length of illness before resuming normal
activities after influenza
  • 0-24 hrs 14.5
  • 25-48 hrs 26
  • 49-72 hrs 24
  • gt72 hrs 31
  • 60 return 72 hours

Clin Drug Invest 2000 19111-121
Complications of influenza
  • Exacerbation of COPD
  • Prolonged cough even without COPD
  • Pneumonia
  • Primary viral
  • Secondary bacterial pneumonia
  • Newer concerns CA-MRSA
  • Increased mortality rates from pneumonia
  • Reyes syndrome
  • CNS and fatty liver
  • Other myocarditis, neurologic syndrome

Clinical avian influenza Index case of H5N1 in
humans in Hong Kong 1997
  • May 21, 1997 a 3 y/o boy died in ICU on day 5
    after admission with Reye syndrome,
  • Acute influenza pneumonia ARDS.
  • Tracheal aspirate yielded influenza virus, no
  • The childs illness death was complicated by
    the use of aspirin causing Reye syndrome.
  • The virus was H5N1 avian influenza.
  • Each of the 8 RNA segments was of avian origin
  • The virus was highly pathogenic for chickens.

Criteria needed for influenza to become pandemic
  • Characteristics needed for influenza virus to
    become pandemic
  • Highly pathogenic to humans
  • Readily transmissible between humans
  • Global population with no immunity to the virus

Mayo Clinic Proc 801552, 2005
Person to person spread of bird flu began in a
family in 2004
  • 11 y/o Thai girl lived with her aunt, had contact
    with sick chickens
  • Ill with fever, cough sore throat on September
    2, 2004.
  • Admitted to hospital on 9-7-04 with temp of 38.5
    C dyspnea
  • Findings were pneumonia, lymphopenia low
  • Condition worsened.
  • Transferred to a tertiary hospital with Dx viral
    pneumonitis or dengue.
  • Despite ventilation, broad-spectrum antibiotics
  • Died on 9/8/04 17 hours after onset of clinical
    influenza pneumonia.

Mother of the girl
  • 26 y/o woman lived 4 h away by car
  • Worked in a garment factory with no contact to
  • She came to see the daughter
  • Provided unprotected bedside care of her daughter
    for 16-18 hrs on September 7 and 8.
  • Mother developed fever on Sept 11
  • Returned to Bangkok after the funeral.
  • She was admitted to a hospital on Sept 17
  • Had pneumonia
  • Died on Sept 20

Aunt of the little girl
  • 32 y/o woman had sick chickens with deaths.
  • Buried 5 dead chickens on Aug 29 30
  • Used plastic bags on her hands no more contact
    with chickens.
  • The aunt provided 13 hrs of care for the girl on
    Sept 7.
  • Aunt attended the childs funeral - Sept 9.
  • Aunt developed fever - Sept 16
  • Admitted to a hospital - Sept 23.
  • Treated with oseltamivir (Tamiflu) recovered.
  • RT PCR - Sept 23 was positive for H5
  • Serum day 8 was negative for antibody (Sept 23)
  • Serum day 21 was positive for H5 antibody (Oct 7)

Chest radiographs from the three patients with
avian influenza A (H5N1)
Ungchusak, K. et al. N Engl J Med 2005352333-340
Live bird markets spread avian influenza
  • Live birds promote the spread of avian viruses.
  • H5N2 H5N1 viruses
  • Isolated from live birds until in Hong Kong.
  • Ducks in USA markets are currently harboring many
    influenza A viruses
  • These include H2N2 viruses
  • Related to the Asian/57 (H2N2) viruses that have
    disappeared from transmission among humans.

Emerg Infect Dis 4436, 1998
Reported exposures and OR likelihood of getting
avian influenza
  • Visiting a live poultry market 0
  • Touching an unexpectedly dead bird 29
  • Having such a bird around the house 6
  • Dressing a dead bird, plucking a bird 17
  • Being lt3 feet away from a dead bird 13
  • Storing products of a sick or dead bird in 9
  • house
  • Touching a sick bird or being lt3 feet 4
  • from it
  • Contact with someone with suspected 1
  • H5N illness

Avian influenza shows species spread
  • 1997, H5N1 poultry sold live animal markets in
    Hong Kong
  • 2003, poultry in 8 Asian countries contracted it.
  • Human disease as poultry contacts increased
  • Species transmission steadily increases
  • Bengal Tigers
  • Domestic cats affected
  • 2004, Mongolia, Siberia, Croatia
  • 2005, Europe poultry affected
  • 2006, Africa poultry affected
  • gt30 countries worldwide now harbor H5N1.

Mayo Clinic Proc 801552, 2005
Global bird flu has spread to gt30 countries.
  • To Africa where veterinary medicine is sparse
  • To Europe France, Romania, Germany
  • To Asia India, Iran
  • Recent acquisitions Greece, Italy, Turkey,
    Croatia, Russia, Azerbaijan and Romania in
    Europe, Iraq and Iran in the Middle East and in
    Nigeria, Africa.
  • April 15, 2006 surveillance shows 59 birds now
    positive for N5H1 in Germany.
  • Increased from 1 bird two weeks ago.

(No Transcript)
Smuggling predominant mechanism of transmission
of bird flu today?
  • 3 million packages of chicken smuggled from China
    to Milan
  • 260 tons of chicken meat shipped illegally into
    Italy just last year.
  • Bags of duck feet found stacked on pizza in
  • Trafficking in illegal animals is a close second
    behind illegal drug trafficking
  • Live poultry and prepared foods are believed to
    be the new mechanism of transmission worldwide of
  • H5N1 survives on meat, feathers, bones, and cages
    but dies with cooking
  • Nigeria, Viet Nam chicken cases but no wild birds

NYT April 15, 2006
How the 1918 pandemic flu is relevant to the
current bird flu
  • Virus gene sequence from tissue blocks kept at
    AFIP, studied by Taubenberger
  • Influenza was recovered from a body frozen in the
    tundra in 1918 never thawed. (Tumpey)
  • All 3 pandemics of 20th century started from bird
  • 1918 H1N1 Spanish influenza
  • 1957 H2N2 Asian influenza reassortment
  • 1968 H3N2 Hong Kong influenza reassortment

Belshe NEJM 3532209, 2005
All 3 previous pandemics were caused by avian

1918 influenza virus has unique qualities vs
usual human influenza
  • It does not need protease to activate H but it
    can activate H by neuraminidase
  • It grows faster, reaches higher titers.
  • It is 100 times more lethal in mice than any
    other human influenza virus.
  • It replicates rapidly to high titers in lungs of
    mice quickly killing.
  • Kills ALL mice in 3 days with 39,000X more virus
    in lungs vs usual influenza that kills NO mice.
  • It quickly kills developing egg embryos in which
    it is grown. (Difficult to make vaccines!)
  • NB H5N1 gives higher lung concentrations of
    virus may be receptor based.
  • Did 1918 cause more pneumonia for same reason?

Belshe NEJM 3532209, 2005
Our attitudes and public health infrastructures.
  • More people are alive today because of health
    care public health measures.
  • We treat diabetics, AIDS, neoplasms, do organ
  • We immunize for all sorts of previously lethal
  • In the 2/3 world, people are now surviving
    because of better nutrition and infrastructure
    though they have a long way to go.
  • Influenza preparedness is like the New Orleans
  • Are we doing all the right things or just doing a
    partial job?
  • The levees may be there but will not protect as
    needed in a real pandemic.
  • To support that concept, look at the large
    numbers of influenza deaths each yr.
  • Have we accepted 36,000 flu deaths each year as
    just the way things are.
  • If our influenza Katrina comes in the future,
    well be glad we prepared.

Seasonal and pandemic influenza preparedness a
global threat
  • 1918 pandemic was the worst plague of the past
  • 50-100 million deaths, mostly under age 65 y.
  • Extraordinarily high replication of virus in
  • Vigorous cytokine cascade caused ARDS.
  • World population now 3X more than in 1918.
  • Estimated deaths now 180-360 million if
    lethality then.
  • The US has 36,000 deaths every year from
    influenza, and 200,000 hospitalizations.
  • Globally, there are 500,000 deaths every year
    from influenza
  • Again if we can learn to control seasonal
    influenza, not accepting it as the inevitable, we
    may be able to make progress toward controlling a
    future influenza pandemic.
  • If we cant control the annual flu, why do we
    think we can control a pandemic?

Pandemic influenza occurs when 3 factors occur at
  • When 3 things come together for a pandemic
  • Antigenic shift or a substantial change in viral
  • Human population is immunologically naïve to the
    new virus. We dont have antibody so the new
    strain of virus.
  • Highly pathogenic organism for humans doing lots
    of damage.
  • This has occurred 3 times in the past century
  • H1N1 in 1918, H2N2 in 1957, H3N2 in 1968
  • H5N1 concerns are via migratory birds in
    traditional flyways
  • Legal and illegal transport of live birds and
    bird meats.

Fauci, JID 2006194S74
The Great Pandemic of 1918
  • By the Honorable Mike Leavitt, Secretary of
    Health and Human Services
  • That great pandemic touched Kansas. In fact, it
    is likely to have begun here.
  • In January to February, 1918, a physician in
    Haskell County noticed an outbreak of severe
    influenza. The local newspaper, Santa Fe
    Monitor reported on it as follows.
  • Mrs. Eva Van Alstine is sick with pneumonia. Her
    little son, Roy, is now able to get up. . . .
  • Ralph Linderman is still quite sick. . . .
  • Goldie Wolgehagen is working at the Beeman store
    during her sister Eva's sickness.
  • An infected soldier from Haskell County is
    thought to have carried the influenza with him to
    Camp Funston, now Fort Riley

Historical details of the great influenza of 1918
  • March 11, 1918 - Albert Gitchell, an army cook
  • Became ill with high fever, headache, myalgia,
    sore throat cough.
  • By noon, 107 persons in the Camp had similar
  • By the end of the first week, 500 soldiers were
    ill, and many had died.
  • Mr Gitchell survived.
  • In mid-March the outbreak affected more than
    1,100 soldiers, killing 38.
  • The disease disappeared, then returned with a
    vengeance in the fall.
  • The first official report of the disease came on
    September 27th.

Influenza and how a recruit wrote about it
  • A soldier from Camp Funston followed the effects
    of the pandemic in his letters sent home.
  • On September 29, he wrote we are held up because
    "influenza," or some such a name, is in the camp.
  • It is some such a thing as pneumonia, and they
    seem to think it is pretty bad. It is at least
    bad enough to beat us out of our passes.
  • A week later, on October 6th, he wrote, Lots of
    them go to the base hospital every day and quite
    a number of them are 'checking in.'
  • There are between 6 and 7,000 cases in the camp.

Two days later he wrote I am still playing the
part of a "dry nurse," ha-ha.
  • This is the name us boys have invented for a
    gentleman nurse.
  • The roof of our hospital has been leaking in
    several places and we have been having some time
    keeping the poor devils dry.
  • They are keeping our beds all filled with new
    patients as fast as we send the old ones "home
    well" or to the hospital, half-dead.
  • There haven't been so many cases the last 48
  • I sure hope that they all get well soon, for I am
    sure getting tired of the job.
  • I don't like to stay up every night in the world.
  • We put six more of our boys in bed today.
  • We are getting real short-handed.

A physician wrote about the 1918 influenza
  • It starts with what appears to be an attack of
    ordinary influenza.
  • When brought to the hospital, they very rapidly
    develop the most vicious type of pneumonia that
    has ever been seen.
  • Two hours after admission they have mahogany
    spots over the cheek bones.
  • A few hours later you can begin to see cyanosis
    extend from the ears all over the face.
  • It is hard to distinguish the colored man from
    the white.
  • It is only a matter of a few hours then until
    death comes, and it is simply a struggle for air
    until they suffocate.
  • It is horrible.
  • We have an average of 100 deaths per day.

Kilbourne, Influenza 1987
A nurse wrote about the 1918 influenza
  • It happened so suddenly.
  • In the morning we received an order to open a
    unit for flu.
  • By night wed moved into a converted convent.
  • Almost before the desks were out, the stretchers
    were in, 60 to 80 to a classroom.
  • We could hardly squeeze between the cots and oh,
    they were so sick.
  • They all had pneumonia.
  • We knew those whose feet were black wouldnt live.

Kilbourne, Influenza 1987
The epidemic raged
  • In Topeka, the hospitals overflowed.
  • Emergency hospitals were opened at the Garfield
    School and the Reid Hotel.
  • Two infirmaries connected to Washburn College
    were opened.
  • The college gym was transformed into an
    observation hospital.
  • The Secretary of the State Board of Health did
    all he could to contain the disease
  • He closed schools, churches and theaters.
  • He quarantined homes with ill patients.
  • He limited the numbers of people in stores and
    passengers on streetcars.
  • Yet, the pandemic still took a terrible toll.
  • The final cost will never be known.

The epidemic spread in 1918 pandemic influenza
  • U.S. soldiers were sent overseas causing spread
  • England, France, Russia and Germany.
  • In May, an estimated 8 million people died of it
    in Spain.
  • The virus was brought back to the US and as the
    Spanish flu.

The Spanish flu was devastating back in the US
  • Initially confined to military installations.
  • First civilian case was in Boston, September
    1918, and spread throughout the country.
  • 33,387 died in New York
  • 15,785 died in Philadelphia
  • 14,014 died in Chicago
  • 6,225 died in Boston
  • 2,302 died in Kansas City
  • Mortality was high in young people (W shape
  • Deaths worldwide 20,000,000
  • (Revised upwards to 50 M)
  • USA 500,000 or more

Pneumonia and influenza mortality curves of 1892,
1918, 1957 pandemics
  • Note the W shaped curves for 1918 compared with
    the U or J shaped curves of other pandemics.
  • Mortality was far lower during pandemics of 1957,
    1968 vs 1918. Possible reasons
  • Lower virulence of viral strains
  • New medical interventions
  • Vaccine, antibiotics

Monto et al, JID 2006194S92
H5N1 deaths
CDC on pandemic deaths
  • Little is known about clinical events that
    contributed to deaths in pandemic influenza
  • Review of 1918-1919 clinical data shows that
    bacterial superinfection was NOT the cause of
    death for most people.
  • It is not clear what the most likely mechanisms
  • If we knew these, could some provide opportunity
    for future interventions in a pandemic.
  • Even a moderate pandemic would exceed the surge
    capacity of US hospitals, ICUs, supply chains,
    domestic production systems.
  • Thus stockpiling of antivirals and vaccines and
    to address the whole production cycle.
  • CDC questions would washing masks for reuse
    provide protection?

Gerberding, JID 2006194S77
What may we learn from the 1918 bird flu pandemic
for today?
  • Nothing elseno infection, no war, no faminehas
    ever killed so many in so short a period.
  • (CFR in 1918 was 10. SARS CFR was 8.)
  • Single handedly, flu thrust the year of the 1918
    back into the previous century.
  • Not since the 1890s had the mortality rate in New
    Orleans, Chicago, and San Francisco been as high.
  • The 1918 death rate in Philadelphia was higher
    than at any time since the typhoid and smallpox
    epidemics of 1876.

Kilbourne, Influenza 1987
Potential for impact in Kansas of a future
pandemic of influenza
  • The USA estimates
  • 89,000 to 207,000 dead
  • 314,000 - 734,000 hosp
  • 18 to 42 million OP visits
  • 20 to 47 million ill
  • The economic impact 71.3 to 166.5 billion
  • Kansas estimates
  • 2,500 deaths
  • 5,000 hospitalizations
  • 500,000 outpatient visits
  • 1 million ill

How to control the pandemic in Kansas,
non-hospital isolation quaratine
  • Influenza is now among the list of communicable
    diseases with federal authorization for isolation
    and quarantine (Amendment to EO 13295)
  • State have the authority to declare and enforce
    quarantine in their borders.
  • Quarantine is very effective in protecting the
    public from disease.
  • People in isolation may be cared for in their
    homes, in hospitals, or in designated healthcare
  • The Governor of Kansas may choose to use snow
    days as a means of disease prevention.
  • Non-hospital isolation and quarantine is a
    non-issue in pandemic influenza due to a novel

Strategies to contain the spread of contagious
  • Control of infected or potentially infected.
  • These may be voluntary or controlled by public
    health authorities
  • Isolation refers to people who have an illness
  • Separation of people
  • Restriction of movement
  • Now common for tuberculosis
  • Federal, state, and local authorities all have
    this power to isolate the ill
  • Quarantine refers to people exposed but who may
    or may not become ill.
  • Focused delivery of specialized health care
  • Protects health people from exposure
  • May be in homes, hospitals, or other designated

Special powers at the federal level
  • The CDC has powers that states do not have
  • Community Containment measures
  • Applies to groups or communities where there is
    extensive transmission
  • Designation is to reduce social interactions,
    prevent inadvertent exposures.
  • Increase social distance between people
  • Community wide quarantine
  • The snow day to stay at home.
  • Schools, work place, public gatherings, and
    transportations are halted or scaled back.
  • Requires fewer resources than community wide

Community wide quarantine
  • Quarantine is resource intensive
  • Requires mechanism to enforce it
  • Requires provision for necessities
  • Snow days are preferred
  • Quarantine is reserved for times when drastic
    measures are a must and when snow days have not
    contained an outbreak.

What we can help the media emphasize during an
  • Simple steps to reduce transmission of
    respiratory viruses like influenza
  • Avoid close contact with people who are sick.
  • Wash hands hourly.
  • If staying at home, keep gt3 feet away from others
    (ill or not).
  • Cover mouth and nose when coughing or sneezing
    and wash hands after each time.

How to care for someone at home during a
respiratory pandemic
  • Get plenty of rest.
  • Drink lots of fluids.
  • Avoid using alcohol or tobacco
  • Use OTC medications to treat symptoms
  • But NEVER give aspirin to children or teenagers
    with possible flu.
  • Reyes syndrome.
  • Cover nose and mouth with a tissue when coughing
    or sneezing.
  • Dont touch eyes, nose or mouth without washing
    hands before and after.

At home, persons may develop problems what to
look for in children
  • Take the person to the ED, or call physician.
  • Tell the receptionist or nurse about symptoms
  • This will allow triage, and monitoring in a
    separate area.
  • Signs to seek medical care in children
  • High or prolonged fever
  • Rapid breathing or trouble breathing
  • Bluish skin color
  • Not drinking enough fluids
  • Changes in somnolence, irritability
  • Seizure
  • Influenza symptoms that improve then worse cough,
  • Worse underlying illnesses as heart, lungs, or

At home, persons may develop complications look
for these in adults
  • High or prolonged fever
  • Difficulty in breathing, rapid breathing or
    trouble breathing
  • Pain or pressure in chest
  • Not drinking enough fluids
  • Near fainting or actual passing out
  • Confusion
  • Persistent or severe vomiting, or passing blood
  • Worse underlying illnesses as heart, lungs, or

What to tell students staff in schools. Include
teachers, janitors.
  • Frequently cleanse hands and be sure there are
    supplies to do so.
  • Wash hands 15 sec, (time to sing birthday song
  • Alcohol based is OK but rub hands until dry.
  • Cover mouth and noses when coughing or sneezing
    and be sure there are tissues available.
  • Discard in containers and cleanse hands.
  • Be sure supplies are everywhere, lunchroom,
    library, playgrounds.
  • Encourage sick students to stay at home until
    afebrile 24 hrs
  • Work closely with local health department if
    there are plans to close the school.
  • It is unknown if school closure helps control

April 2007
Areas of planning for a pandemic in Kansas (see
also the handouts)
  • Plan for an impact on businesses
  • How it will impact travelers
  • Establish policies and procedures to implement
    during a pandemic
  • Include how to keep the business running
  • How to prevent employees from getting the illness
  • Allocate resources to make the above happen
  • Educate and communicate with your employees,
    suppliers, and customers
  • Coordinate with people external to your
    organization to learn from and mutually support
    your community during such events.

Epidemics and pandemics in the 21st century
  • The history of humanity is replete with deaths
    due to epidemics and pandemics.
  • But we are so advanced, we are tempted to believe
    that we can now control epidemics so that we have
    nothing to worry about today.
  • Is this assumption correct?
  • A resounding no.
  • Plagues can and will strike humanity again.
  • Could we really be at risk for an influenza
    pandemic? Most scientists believe we have great
    potential risk.

Anti-influenza viral studies
  • Two major targets for antiviral drugs
  • M2 inhibitors
  • Amantadine, Rimantadine
  • Neuraminadase inhibitors
  • Oseltamavir, Zanamavir
  • Clade 1 (Vietnam Thailand) versus Clade 2
  • Clade 2, unlike clade 1, appears to be
    susceptible to both classes
  • Shows differences in antigenic shift and drift in
    clades, and the need to do susceptibility studies
    on isolates to properly treat pts.
  • Unlikely antivirals will contain a pandemic, but
    could help in local areas.

What current influenza research is focused on
  • New drugs and new classes
  • Peramivir, neuraminidase inhibitor
  • Use of oseltamivir in children under age 1
  • Dose ranging studies
  • Screening for other new antivirals
  • Looking for new influenza targets for drugs
  • Viral entry, replication, and HA maturation.
  • Current goal of national stockpile is to have 81
    million doses of drugs available for use

Pandemic preparedness antivirals
  • Major targets for influenza viruses 2 now
  • Neuraminidase (zanamavir, oseltamivir)
  • M2 inhibitors (amantadine, rifantadine)
  • Clade 1 SE Asia (Vietnam, Thailand) 2004, some R
    to M2
  • Clade 2 China susceptible to both classes
  • Susceptibility studies are needed as these data
  • Planned studies
  • Use in ages lt1yr
  • Varying dose regimens
  • Combination regimens of the two targets
  • New neuraminidase inhibitors (eg. peramivir)
  • Screening new antiviral drugs
  • Evaluating novel drug targets (entry,
    replication, HA maturation)
  • Attempt to have 81 million doses for initial
    containment then use in 25 population.

JID 1942006S74
Benefits of oseltamavir in 2004 insurance records
  • Influenza like illness, treated with oseltamavir
    in outpatient offices
  • Total of 39,202 pts were treated
  • Less likely to develop pneumonia
  • Less required hospitalization
  • Fewer died in the 30 days after
  • 32 fewer CAP, 67 fewer MI, 91 fewer all cause
  • Control group not prescribed the drug
  • Total of 136,799 pts.
  • Canadian study compared osel vs either (aman or
    no therapy)
  • Osel Rx needed fewer Rx antibiotics afterward,
  • Osel Rx were less likely to be hospitalized soon

Hayden and Pavia, JID 2006194S120
  • Aoki studied time between onset of symptoms and
  • Controls started therapy 48h after onset
  • Started in 6 h dec impaired activity by 6 days
  • Duration of impaired health by 3.5 days
  • Duration of fever reduced by 2.5 days
  • The benefits of treatment are maximized when
    early treatment is provided.
  • But no data on treatment infancts lt1 y,
    compromised hosts, effect on encephalopathy,
    myositis, cardiomyopathy, myocarditis and risk
    for bacterial complications.
  • In murine model, osel dec extent of pneumonia,
    prevents death, and decreases pneumococcal

Hayden and Pavia, JID 2006194S120
Oseltamavir in a murine model vs avian influenza
isolates from different years
  • But murine models showed difference in the
    current H5N1 vs the 1997 H5N1 there were major
    differences in responses
  • 1997 strain, oseltamavir given 36 hr after the
    virus was protective from death.
  • 2004 strain, osel given even 4 hrs before flu
    inoculation and given at the highest doses was
    only partly protective.
  • Treatment had to be extended to 8 days from 5
    days for 75 to survive.
  • There was no difference in susceptibility and no
    emergence of resistance.

Hayden and Pavia, JID 2006194S120
Oseltamavir in the treatment of H5N1 influenza
  • Development of resistance during therapy has been
    reported in Vietnam
  • Level of pharyngeal virus were followed daily in
    influenza patients
  • Oseltamavir 75 mg BID for 5 days after onset of
  • 4 had prompt decrease in the levels of pharyngeal
  • All survived!
  • In contrast, 4 that did not clear pharyngeal
    influenza virus by the end of the 5 day course
    did not survive
  • One pt developed resistance after receiving
    treatment 4 days
  • This patient had increased influenza throat viral
  • Death followed several days after oseltamavir was
  • Implication is that development of resistance
    promotes treatment failure.

Hayden and Pavia, JID 2006194S120
Antiviral resistance
  • Amantadine res viruses are infectious, virulent,
    fit and transmit.
  • Rapid resistance has just occurred from 1-14 in
    2003 to 92 in 2004.
  • Mechanism is single serine to asparagine
    substitution in amino acid 31 (S31N).
  • All were susceptible to neuraminidase inhibitors
  • So we cant depend on M2 ion channel inhibitors
    this year.
  • Oseltamavir, resistance dev in clinical trials
  • Adults 1, children 5.
  • In Japan where lower doses used, 16-18 dev

Hayden and Pavia, JID 2006194S120
Antiviral resistance mechanism neuraminidase
  • Mutations emerge during treatment at
    predominantly 3 amino acid sites in NA
  • Arginine for lysine at 292 (R292K)
  • Glutamate for valine at 119 (E119V)
  • Histidine for tyrosine at 274 (H274Y)
  • Leads to high level resistance gt400 fold
  • Also dec replication, and dec pathogenicity in
  • Japanese Rx 6 million courses, 5 population
  • Isolates collected from across Japan, 1180
  • Only 3, 0.3 were resistant, 2 E119V and 1 R292K.
  • Reassuring that only low level of resistance is
    seen clinically when these drugs are used widely.

Hayden and Pavia, JID 2006194S120
Antiviral resistance mechanism neuraminidase
  • Not all neuraminidase inhibitors are alike
  • Resistant mutants to osel still suscept to
    zanamivir, to A-315675, and partially to
  • Combinations
  • H9N2, rimantadine and osel improved survival in
    mice challenged vs either drug alone.
  • Dual NA need to be tried
  • Ribavirin with NA look good in animal studies
  • New mechanisms being investigated
  • Transcriptase inhibitors (ribavirin), long acting
    NA, conjugated sialidase, hemagglutinin
    inhibitors, small interfering RNA, polymerase
    inhibitors, protease inhibitors.

Hayden and Pavia, JID 2006194S120
Neuraminidase inhibitors Tamiflu (oseltamavir)
Relenza (zanamivir)
  • Tamiflu given orally.
  • ADE HA, Mild nausea. 75 mg BID for 5 days.
  • For avian flu, 2X75mg for 2X5 days may be needed?
  • Spectrum and potency similar to that of zanamivir
    against influenza A B.
  • Zanamivir (Relenza) is used by inhalation
  • Relieves influenza (beware asthma)
  • Hayden, JAMA 2821240, 1999.

Neuraminidase inhibitors may be used together
  • Oseltamivir resistance is due to H274Y mutation.
  • Zanamivir is active against such resistant
    isolates with this mutation.
  • Reason is differences in binding sites
  • Systemic effect vs respiratory tract
  • Dual therapy would be expected to reduce
    selection of resistant mutants
  • Untried but worth doing.

NEJM 3541423, 2006
Pandemic preparedness vaccines
  • Significant component of the 3.8 billion
    approved by Congress used to
  • Vaccine development
  • Creating surge capacity of vaccines
  • Alternative vaccine methods
  • Development of cell based system alternative
    influenza cultures
  • Working with Sanofi Pasteur Novartis
  • Prepandemic strain vaccine based on H5N1 virus
    from Vietnam in 2004. (Report in NEJM 2006)

JID 1942006S74
Pandemic preparedness vaccines
  • N5N1 vaccine, 451 adults given the vaccine.
  • Instead of 7.5 or 15 mcg, two doses of 90 mcg
    required for great antibody response predictive
    of immunity.
  • Alum adjuvant vaccine allowed 2 doses of 30 mcg
  • H9N2 vaccine, another study of an avian vaccine
    included the new adjuvant MF59.
  • Two doses of 3.75 mcg gave good immune responses.
  • Can this or other methods reduce the dose needed
    allowing more surge capacity for vaccine
  • Need potential is to produce 300 million doses of
  • Time needed would be within 3-6 months
  • The vaccine must match the pandemic or epidemic

JID 1942006S74
Avian influenza vaccine from strain 1203, a
Vietnam isolate
  • H5N1 vaccine made just as for usual influenza
  • Each dose of vaccine requires one egg.
  • H5N1 vaccine antigenically poor (Clade 1).
  • Only when given 90 mcg of antigen did 50 of
    vaccinees develop 140 antibody titer.
  • If 15 mcg, 900 million doses per year potential
  • At 90 mcg, 75 million doses
  • Need MF59 or an alum adjuvant to use lower doses.
  • Indonesian Clade 2 is antigenically distinct from
    Clade 1 used to make current vaccine.

NEJM 3541412, 2006
FDA has approved the Sanofi Pasteur H5N1 vaccine
  • A/Vietnam/1203/2004. This is a Clade 1 viral
    vaccine. This means it might not work for a
    Chinese strain of Clade 2 H5N1.
  • This goes directly into the National Stockpile.
  • 291 cases, 172 deaths. None in this hemisphere.
  • 90 mcg doses gave antibody potentially protective
    for 45 of recipients.
  • Requires two doses 28 days apart each with 90
  • No travelers cant get it now. It all goes into
    the stockpile.
  • It does contain thiomerosol.

Influenza pandemic preparations.Who would get a
  • 1918 bird flu, 1000s died in a few weeks.
  • Current populations are much greater.
  • During a typical yr, 50,000 people die of
  • US has 105,000 ventilators functioning.
  • 75,000 to 80,000 are in use on any given day.
  • During an ordinary flu outbreak, gt100,000
    ventilators are in use. Are we ready?
  • Pandemic needs 425,000 ventilators needed
    costing 30,000 each. (13 billion needed just to
    purchase new ventilators).

Osterholm, NEJM 3521839, 2005
Write a Comment
User Comments (0)
About PowerShow.com