Avian influenza, and the medical emergencies it brings'

1
Avian influenza, and the medical emergencies it
brings.

• Daniel R. Hinthorn, MD, FACP
• Division of Infectious Diseases
• University of Kansas Medical Center

2
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
3
Incidental hosts
Incidental hosts
Fecal spreaders
Virus mixers With both human And bird virus
receptors
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
4
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.

5
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
  illness.

Courtesy of Chien Liu, MD
6
(No Transcript)
7
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
8
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

9
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
  bacteria.
• 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.

10
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
11
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
  platelets.
• Condition worsened.
• Transferred to a tertiary hospital with Dx viral
  pneumonitis or dengue.
• Despite ventilation, broad-spectrum antibiotics
  fluids
• Died on 9/8/04 17 hours after onset of clinical
  influenza pneumonia.

12
Mother of the girl

• 26 y/o woman lived 4 h away by car
• Worked in a garment factory with no contact to
  chickens.
• 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

13
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
  hemagglutinin
• Serum day 8 was negative for antibody (Sept 23)
• Serum day 21 was positive for H5 antibody (Oct 7)

14
Chest radiographs from the three patients with
avian influenza A (H5N1)
Ungchusak, K. et al. N Engl J Med 2005352333-340
15
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
16
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

17
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
18
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.

19
(No Transcript)
20
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
  freezers
• 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
• 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
21
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
  flu!
• 1918 H1N1 Spanish influenza
• 1957 H2N2 Asian influenza reassortment
• 1968 H3N2 Hong Kong influenza reassortment

Belshe NEJM 3532209, 2005
22
All 3 previous pandemics were caused by avian
influenza!

23
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
24
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
  transplants.
• We immunize for all sorts of previously lethal
  diseases.
• 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
  levees
• 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.

25
Seasonal and pandemic influenza preparedness a
global threat

• 1918 pandemic was the worst plague of the past
  century.
• 50-100 million deaths, mostly under age 65 y.
• Extraordinarily high replication of virus in
  lungs.
• 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?

26
Pandemic influenza occurs when 3 factors occur at
once.

• When 3 things come together for a pandemic
• Antigenic shift or a substantial change in viral
  antigens
• 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
27
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

28
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
  symptoms.
• 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.

29
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.

30
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
  hours.
• 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.

31
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
32
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
33
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.

34
The epidemic spread in 1918 pandemic influenza

• U.S. soldiers were sent overseas causing spread
  to
• 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.

35
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
  curve).
• Deaths worldwide 20,000,000
• (Revised upwards to 50 M)
• USA 500,000 or more

36
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
37
H5N1 deaths
38
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
  were
• 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
39
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
40
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

www.pandemicflu.gov
41
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
  facilities.
• 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
  virus.

www.pandemicflu.gov
42
Strategies to contain the spread of contagious
illnesses

• 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
  sites

43
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
  quarantine

44
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.

45
What we can help the media emphasize during an
outbreak

• 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.

46
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.

47
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,
  fever
• Worse underlying illnesses as heart, lungs, or
  diabetes

48
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
  diabetes

49
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
  2X)
• 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
  influenza.

50
April 2007
51
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.

www.pandemicflu.gov
52
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.

53
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
  (China)
• 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.

54
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
  nationally.

55
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
  show.
• 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
56
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
  deaths.
• 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
  afterwards.

Hayden and Pavia, JID 2006194S120
57
Oseltamavir

• Aoki studied time between onset of symptoms and
  treatment.
• 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
  adherence.

Hayden and Pavia, JID 2006194S120
58
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
59
Oseltamavir in the treatment of H5N1 influenza
patients

• 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
  pneumonia
• 4 had prompt decrease in the levels of pharyngeal
  virus
• 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
  loads.
• Death followed several days after oseltamavir was
  stopped.
• Implication is that development of resistance
  promotes treatment failure.

Hayden and Pavia, JID 2006194S120
60
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
  resistance.

Hayden and Pavia, JID 2006194S120
61
Antiviral resistance mechanism neuraminidase
inhibitors

• 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
  ferrets.
• Japanese Rx 6 million courses, 5 population
• Isolates collected from across Japan, 1180
  isolates
• 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
62
Antiviral resistance mechanism neuraminidase
inhibitors

• Not all neuraminidase inhibitors are alike
• Resistant mutants to osel still suscept to
  zanamivir, to A-315675, and partially to
  peramavir
• 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
63
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.

64
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
  concentrations
• Dual therapy would be expected to reduce
  selection of resistant mutants
• Untried but worth doing.

NEJM 3541423, 2006
65
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
66
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
  each.
• 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
  preparation?
• Need potential is to produce 300 million doses of
  vaccines
• Time needed would be within 3-6 months
• The vaccine must match the pandemic or epidemic
  strain.

JID 1942006S74
67
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
68
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
  mcg.
• No travelers cant get it now. It all goes into
  the stockpile.
• It does contain thiomerosol.

69
Influenza pandemic preparations.Who would get a
ventilator?

• 1918 bird flu, 1000s died in a few weeks.
• Current populations are much greater.
• During a typical yr, 50,000 people die of
  influenza.
• 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