Objectives
INFLUENZAS
old and new
Jeremy Schafer, PharmD
Infectious Diseases Research Fellow
Experimental and Clinical Pharmacology
University of Minnesota College of Pharmacy
Influenza: still a heavy hitter
• About 36,000 deaths per year in the U.S.
• Influenza associated hospitalizations range
from 54,000-430,000 per epidemic
• 63% of these were for people > 65 years of
age
• Incidence of influenza associated pulmonary
or circulatory death ranges from 0.4-
98.3/100000
• Influenza associated deaths are rising
Pathophysiology of influenza
• Two types: A and B
• Type A is further categorized into subtypes
• Different types are more than just names
– Some drugs ineffective against type B
– Epidemics more serious with type A
– Wrong strain selection for vaccine = big trouble
– Antigenic drift
– Antigenic shift
• Be able to discuss the epidemiology and
pathophysiology of influenza
• Compare and contrast influenza vaccines
• Discuss differences in influenza medications
• Identify groups at risk for serious influenza
complications
• Describe avian influenza and the potential
problems
• Identify possible therapies for avian influenza
No one is safe!
• Hospitalization rates for children < 5 yrs old
are between 100-500/100,000
• Deaths among children and healthy adults
are rare
• Lost work days and decreased productivity
substantial
• And a lot of this is preventable!
Pathophysiology of influenza
• Transmitted via respiratory droplets
• Incubation period is 1-4 days
• Adults are infectious for about 5 days from
when symptoms start
• Children for >10 days
• Immunosuppressed may shed virus for
extended periods
• Illness usually lasts 3-7 days
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 Which of the following is NOT true
Signs and symptoms
regarding Influenza?

• The usual suspects • A. Influenza B causes more severe

• N/V and otitis media may occur in children
• Frying pan into fire….
– Can exacerbate underlying conditions
– May lay groundwork for subsequent bacterial
pneumonia
– Has been associated with encephalopathy,
myocarditis, Reye syndrome, and ARDS
epidemics than influenza A
• B. Influenza only kills people who are 65
years of age or older
• C. Immunity to one type of influenza does
not confer immunity to other types.
• D. A and B
• E. None of the above are true

Challenges of influenza MMWR

• Different strains every year means a new
vaccine
• Vaccination rates are still too low
• Changing resistance picture
• Still causes considerable morbidity/mortality
• Where do you go for the latest information?
• New guidelines published every year
• Provided by the CDC
• Latest information for up coming influenza
season
• Outlines criteria for at risk groups
• Vaccines, drugs, prevention, and much,
much more!

Treatment/Prevention options Inactivated influenza vaccine

• Vaccine • Contains killed viruses

– Inactivated • Given intramuscularly by injection
– Live
• Inexpensive
• Neuraminidase inhibitors • Approved for ages 6 months and up
– Zanamivir
• Two shots for kids 6 months-<9 years if no
– Oseltamivir
previous influenza vaccination
• Adamantanes
• One shot for everyone else
– Amantadine
– Rimantadine
• Infection control

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 MMWR recommendations for
MMWR recommendations continued
inactivated vaccine 2006-2007
• Children aged 6-23 months
• Children and adolescents on long-term • Children aged 24-59 months
aspirin therapy • Persons aged 50-64 years
• Pregnant women • Healthy contacts or caregivers of at risk
• People with chronic CV or pulmonary people
conditions • Health care workers
• People with chronic metabolic, blood, or renal • People interested in avoiding influenza
diseases who required medical intervention in
preceding year
• Immunodeficient
• People with conditions that may compromise
respiratory function
• Residents of nursing homes or chronic care
facilities
• Persons aged > 65 years

So who should get the Efficacy of inactivated vaccine

vaccine….. • Multiple studies show an advantage for 2

EVERYBODY! doses of vaccine vs. 1 for children less than 9
years old
• Vaccination prevents 70-90% of influenza
cases in healthy adults aged < 65 years
• In persons aged > 65 years, the inactivated
vaccine is 50-60% effective in preventing
influenza-related hospitalization and 80%
effective in preventing influenza-related death
• Efficacy has been shown in preventing
influenza in HIV patients

Which statement is true regarding the

Safety of inactivated vaccine
inactivated influenza vaccine?

• Local site irritation • A. The vaccine is most often given IV

• Systemic symptoms rare • B. Two doses should be given to children
• Allergic reactions less than 9 years of age who are vaccine
• GBS naïve
• Thimerosal • C. Through antigenic changes, the vaccine
can cause influenza
• Chicken egg allergy
• D. The vaccine contains live, attenuated
viruses
• E. None of the above are true

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LAIV-Live attenuated influenza vaccine MMWR recommendations for LAIV
2006-2007

• Contains live viruses • Healthy, non-pregnant persons aged 5-49

• Administered intranasally years
• Approved for healthy persons aged 5-49 • Caretakers of high risk individuals
years • Health care workers
• More expensive than inactivated
• Dosing
– 5-<9 years old, no previous vaccine: 2 doses 6-10
weeks apart
– 5-<9 years old, previous vaccination: one dose
– 9-49 years: one dose
– Do not administer until 48 hours after cessation of
antivirals
– Do not give antivirals until 2 weeks after LAIV

Efficacy of LAIV Safety of LAIV

• A two season study showed efficacy of 93%
for year one and 86% for year two
• In adults aged 18-49 years, advantages were
found in fewer lost work days, fewer health
care visits, and reduced antibiotic use
• A study comparing inactivated vaccine and
LAIV found similar efficacy
• Adverse events include: runny nose,
congestion, headache, and sore throat
• LAIV should be avoided in non-indicated
groups
• LAIV should be avoided by caregivers of
severely immunosuppressed individuals
• Chicken egg allergy

Advantages of LAIV to inactivated

Vaccine comparison
vaccine include….

• Similarities • A. Expanded indications

– Similar efficacy • B. May produce a stronger immune
– Well tolerated response
– Virus types
• C. Less invasive administration
– Both produced from chicken eggs
• D. Not derived from chicken eggs
• Differences
• E. B and C
– Live vs. killed
– Eligible patient groups • F. B, C, and D
– Route of administration
– Price

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Vaccine timing
• September: underlying risk factors and
caregivers
• October-November: Optimal time for
vaccination
• December: booster shots for patients who
need two doses, other people who missed
out
• January-end of season: Still useful
Adamantanes
• Includes amantadine and rimantadine
• Only active against type A
• Decrease duration of illness by 1 day
• Simple, 5 day regimen
• However, not recommended this year
because…
Neuraminidase inhibitors
• Includes zanamivir and oseltamivir
• Both approved for treatment and
chemoprophylaxis
• Resistance is infrequent
• Reduce duration of illness by one day
• May reduce risk of influenza related
complications
• Treatment course is 5 days
Antivirals
• Adamantanes
• Neuraminidase inhibitors
• Prophylaxis vs. treatment
• Place in therapy
Resistance!
• CDC reported 193/209 influenza A (H3N2)
strains were resistant
• Resistance conferred by change at amino
acid 31 in M2 gene
• 25% of H1N1 strains were resistant
• Canada found similar results
• Resistance develops rapidly during treatment
• Adamantanes are no longer recommended
Indications for chemoprophylaxis
• In high risk individuals who receive vaccine
after the influenza season has begun
• Unvaccinated caregivers of high risk
individuals
• Persons with severe immunodeficiency
• High risk persons who can not receive the
vaccine
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Adverse effects/safety
• Zanamivir is not recommended for patients
with underlying airway disease
• Oseltamivir may cause N/V
• Drug interactions are rare
• Both drugs are pregnancy category C
Regarding antiviral therapy for
influenza…
• A. Adamantanes are useful antivirals due to
few side effects and low resistance
• B. Neuraminidase inhibitors reduce duration
of illness by more days than adamantanes
• C. Oseltamivir is approved for children
greater than 1 year of age
• D. Resistance to adamantanes is via a
mutation in the M5 gene
• E. None of the above are true
Avian influenza
Dosing
• Zanamivir
– Treatment: 10 mg (two inhalations) twice daily x
5d
– Chemoprophylaxis: 10 mg (two inhalations) once
daily
• Oseltamivir
– Treatment: 75 mg bid for ages 13 and up
– Chemoprophylaxis: 75 mg once daily for ages 13
and up
• Hepatic dysfunction
– no adjustment necessary
• Renal dysfunction
– If Crcl is 10-30 ml/min reduce oseltamivir dose
Influenza: important points
• Still a significant cause of morbidity and
mortality
• Vaccine compliance still too low
• Both vaccines effective in preventing disease
• Adamantanes are no longer recommended
due to resistance
• Antivirals can be useful but do not take the
place of vaccination
Background of avian influenza
• Outbreaks in humans in Hong Kong in 1997
and 2003
• First cases of current epidemic appeared in
December 2003
• Cases confirmed in Azerbaijan, Cambodia,
China, Djibouti, Egypt, Indonesia, Iraq,
Thailand, Turkey, Vietnam, and elsewhere
• Half those infected with H5N1 virus have died
• Most cases occurred in children and young
adults
• No sustained human-human transmission,
yet…..
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 Nations with confirmed cases of avian
influenza H5N1
Which is true regarding avian
influenza?
• A. Pandemic potential is limited by lack of
human to human spread
• B. Cases have been limited to the Asian
continent only
• C. Human cases mortality is 30%
• D. Pneumonia is rarely seen in human cases
• E. H5N1 is an influenza B virus
Avian influenza pathophysiology
• Caused by influenza A virus
• H5N1 subtype is most concerning
• Normally carried in bird intestines
• One of the few strains to cross species
barrier
• Most human cases result from poultry contact
Avian influenza clinical features
• Incubation is 2-8 days
• Initial symptoms include: high fever,
influenza-like symptoms
• Other early symptoms: diarrhea, vomiting,
abdominal and chest pain, bleeding from
nose and gums
• Nearly all patients will develop pneumonia
• Clinical deterioration is rapid
• Multi-organ dysfunction
The Hong Kong experience-1997
• In 1997 there were 200 active chicken farms
in Hong Kong
• 120,000 live poultry sold each day in markets
• Local farms supplied about 22% of live
chickens to market
• Outbreak began in March and spread to two
more farms in vicinity
• First virus isolated in April
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The Hong Kong experience - 1997
• 100% mortality on first farm, 75% on other
two
• First human case occurs in May
• Atypical influenza virus isolated from 3 year
old boy
• Patient expired
• Source of infection not established
Current state of affairs
• Vietnam hardest hit
• Human cases detected from Turkey to
Indonesia
• Virus in poultry detected in Sudan, Pakistan,
Russia, and Romania
• Virus detected in wild animals in Germany,
UK, Denmark, and Sweden
• Still limited evidence of human to human
transmission
Drug therapy options
• Neuraminidase inhibitors are frontline choice
• Oseltamivir is most studied
• Administration within 48 h of symptom onset
is necessary
• WHO reserve is at 3 million courses
• Conditions for successful prophylaxis
– Non urban setting
– Early intervention
– Virus of low to moderate transmissibility
– Prophylaxis of 80-90% of population
– High compliance
– Movement restrictions, social distancing
The Hong Kong experience - 1997
• Additional human cases occur in November
• By end of December a total of 17 human
cases have occurred
• Infection in main wholesale market occurs
shortly after
• Additional outbreaks occur in markets and
farms in late December
• Decision made to depopulate all Hong Kong
poultry markets and farms
Vaccine status
• Vaccine development is underway
• Multiple types, multiple routes
• Pandemic vaccine should:
– Stimulate immunity quickly
– Preferably active after only one dose
– Able to produce in massive quantities
– Effective despite differences to pandemic strain
• Current vaccine candidates may require 2
doses
NEJM 353;25 December 2005
• Previously healthy 13 year old Vietnamese
girl
• Presents with one day history of fever and
cough
• Mother recently deceased from H5N1
infection
• H5N1 suspected in young girl, oseltamivir
given, patient referred
• On admission: temp 40.3 C, pulse 106 bpm,
RR 36 breaths per minute, WBC 4800
cells/mm3 , platelet count 183,000 cells/mm3
• X-ray reveals small focal infiltrate in right
middle lobe
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NEJM 353;25 December 2005
• Patient receives second dose 6h after first
• Third dose 24 hours after admission
• Treatment continued for 4 more days
• Patient stable 3 days post admission
NEJM 353;25 December 2005
Pharyngeal viral loads during Oseltamivir treatment for
H5N1
NEJM 353;25 December 2005
• On fourth day, condition worsens
• O2 given by nasal cannula, then continuous
positive pressure
• Pneumonia now involves most of right middle
lobe
• Condition continues to worsen by day 5
• Placed on ventilator on day 6
• Radiograph on day 7 showed pneumonia of
entire right lung with extension to the left lung
• Patient expires on day 7
• Resistant virus isolated post therapy
NEJM 353;25 December 2005
• Six of 8 patients given oseltamivir within 48
hours survived
• Drug-resistant variants isolated from two
patients
• Extended use or higher doses may be
beneficial
• Data on chemoprophylaxis is absent
Conclusions
• H5N1 is unable to cause a pandemic in
current form
• Disease is characterized by rapid
deterioration, multi-organ failure, and death
• Over 50% of known human cases have
expired
• Vaccine is still a ways off
• Oseltamivir may be effective if given within 48
hours
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H5N1 has become transmittable from human
to human. Outbreaks have occurred in major
cities around the world. The vaccine
developed is a poor match and is ineffective.
What do you do now?

• A. Begin fast-track development of a new

vaccine
• B. Mass produce oseltamivir and distribute to
as many people as you can
• C. PANIC! The apocalypse is upon you!
• D. A and B
• E. all of the above

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