GIDSAS
JIT:
The Impact of Pandemic
Influenza on Public Health
Rashid A. Chotani, MD, MPH
Director, Global Infectious Disease Surveillance & Alert System
Johns Hopkins Bloomberg School of Public Health
410-502-3116/410-322-7469
rchotani@jhsph.edu
Chotani, GIDSAS-JHU, 2006
Part I : Basics
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Influenza Virus
RNA, enveloped
Viral family:
Orthomyxoviridae
Size:
80-200nm or .08 – 0.12 μm
(micron) in diameter
Three types
A, B, C
Credit: L. Stammard, 1995
Surface antigens
H (haemaglutinin)
N (neuraminidase)
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Influenza Virion
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Natural hosts of influenza viruses
Haemagglutinin subtype
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15
Neuraminidase subtype
N1
N2
N3
N4
N5
N6
N7
N8
N9
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The Burden of Influenza
Seasonal Influenza
Globally: 250,000 to 500,000 deaths per year
In the US (per year)
• ~35,000 deaths
• >200,000 Hospitalizations
• $37.5 billion in economic cost (influenza &
pneumonia)
Pandemic Influenza
An ever present threat
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Contagiousness
 Influenza is a highly contagious disease
 Typical incubation 2 days (range 1-4 days)
 Individuals are contagious for 1 to 4 days before
the onset of symptoms and about 5 days after the
first symptoms

Peak viral shedding - first 3 days of illness
Subsides usually by 5-7th day in adults

can be 10+ days in children
 Approximately 50% of infected people do not
present any symptoms but are still contagious
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Spread of Influenza
Most human influenza infections are spread by virusladen respiratory droplets that are expelled during
coughing and sneezing.
Influenza viruses range in size from 0.08 to 0.12 μm.
They are carried in respiratory
secretions as small-particle
aerosols (particle sized <10μm).
Sneezing generates particles
of varying sizes
10-100 μm
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Modes of Transmission
The 3 modes of transmission include:
Droplet transmission
Airborne transmission, and
Contact transmission
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Droplet Transmission
Droplet transmission occurs when contagious
droplets produced by the infected host through
coughing or sneezing are propelled a short
distance and come into contact with another
person’s
conjunctiva,
mouth, or
nasal mucosa.
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Airborne Transmission
Airborne transmission occurs when viruses
travel on dust particles or on small respiratory
droplets that may become aerosolized when
people sneeze, cough, laugh, or exhale.
They can be suspended in the air much like invisible
smoke.
They can travel on air currents over considerable
distances.
With airborne transmission, direct contact with
someone who is infected is not necessary to become
ill.
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Contact Transmission
Two Types
Direct: involves body-to-body surface contact
Indirect: occurs via contact with contaminated
intermediate objects, such as contaminated hands, or
inanimate objects (fomites), such as countertops, door
knobs, telephones, towels, money, clothing, dishes,
books, needles etc.
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Survival of Influenza Virus on Surfaces*
Hard non-porous surfaces 24-48 hours
Plastic, stainless steel
• Recoverable for > 24 hours
• Transferable to hands up to 24 hours
Cloth, paper & tissue
Recoverable for 8-12 hours
Transferable to hands 15 minutes
Viable on hands <5 minutes only at high viral
titers
Potential for indirect contact transmission
*Humidity 35-40%, temperature 28C (82F)
Source: Bean B, et al. JID 1982;146:47-51
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Affects of humidity on infectivity influenza,
Loosli et al, 1943
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Definitions
Epidemic – a located cluster of cases
Pandemic – worldwide epidemic
Antigenic drift
Changes in proteins by genetic point
mutation & selection
Ongoing and basis for change in vaccine
each year
Antigenic shift
Changes in proteins through genetic
reassortment
Produces different viruses not covered
by annual vaccine
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Reassortment (in humans)
Migratory
water birds
Source: WHO/WPRO
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Reassortment (in pigs)
Migratory
water birds
Source: WHO/WPRO
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Mutation (in humans)
Migratory
water birds
Source: WHO/WPRO
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From birds to humans
Migratory
water birds
Domestic birds
• Hong Kong,
SAR China 1997,
H5N1
• Hong Kong,
SAR China 1999,
H9N2
• The
Netherlands
2003, H7N7
• Hong Kong,
SAR China 2003,
H5N1
Source: WHO/WPRO
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Part II : History
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“Spanish Flu” A(H1N1): 1918-19
Approximately 20-40 million people died
worldwide, and over 500,000 in US.
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The big pandemic of 1918
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Images from the 1918 Influenza Epidemic
National Museum of Heath and Medicine
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The big pandemic of 1918
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Images from the 1918 Influenza Epidemic
National Museum of Heath and Medicine
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“Asian Flu” A(H2N2) 1957-58
During the 1957-58
Asian flu epidemic, a
school child in
Islington, London,
gargles to keep the
virus at bay.
More than a million
people died worldwide
and about 70,000 in
US.
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Spread of H2N2 Influenza in 1957
“Asian Influenza”
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“Hong Kong Flu” A(H3N2)
1968-69
Members of the Red
Guard in China
covered their
mouths against flu
germs in 1968 on
the orders of
Chairman Mao.
The Hong Kong flu
of 1968-69 killed
more than 1 million
people worldwide,
and 34,000 in US.
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Timeline of Emergence of
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Influenza A Viruses in Humans
Avian
Influenza
Russian
Influenza
H9
H5
H7
H5
H1
H3
H1
1918
Spanish
Influenza
H1N1
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H2
1957 1968 1977
Asian
Hong
Influenza Kong
H2N2 Influenza
H3N2
1997 2003
1998/9
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Recorded Influenza Pandemics
37
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Part III: H5N1 Avian
Outbreaks
from July 2004
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Current Pandemic Concerns
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Countries Reporting Confirmed Occurrence of H5N1 Influenza
in Poultry and Wild Birds Since 2003
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As of May 30, 2006. Source: WHO/WPRO
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Countries Reporting Confirmed Occurrence of H5N1 Influenza
in Poultry and Wild Birds Since 2006
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As of May 30, 2006. Source: WHO/WPRO
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In Cats???
7 March 2006, Rome Following the finding of the
H5N1 avian influenza virus in a dead cat on the
island of Rügen in Germany, the European
Commission has advised its member states to
take specific measures regarding cats and dogs
in the infected areas. The general public and cat
owners especially have increasingly shown
concern and are consulting veterinarians for
advise.
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Dept of Health and Human Services: www.pandemicflu.gov
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Current Pandemic Concerns
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Current Pandemic Concerns
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Part IV: H5N1 Human
Outbreaks
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Avian Influenza A(H5N1), 1997
Avian Influenza A(H5N1) caused
18 cases of influenza with 6 deaths
in the Hong Kong area. Experts are
concerned that the virus may
acquire a mutation encouraging
human-to-human transmission.
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The H5N1 Influenza Pandemic Threat
• Avian infection in 9
countries
• 34 human cases and
23 deaths (68%)
• Culled >100 m
chickens
• Avian infection in
Hong Kong
• 18 human cases and
6 deaths (33%)
• Culled poultry
• Avian infection in 4
countries
• 7 human cases and
6 deaths (86%)
• Person-to-person?
• Ongoing avian H5N1 infections
1997
1998
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1999
2000
2001
2002
2003
2004
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Affected Countries with Confirmed Human
Cases of H5N1 Influenza since 2003
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As of May 24, 2006. Source: WHO/WPRO
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Affected Countries with Confirmed Human
Cases of H5N1 Influenza since 2006
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As of May 24, 2006. Source: WHO/WPRO
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Geographic Location of the North Sumatra Cluster
and cases Confirmed on May 29, Indonesia, 2006
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Cumulative Number of Confirmed Human Cases of Avian
Influenza A/(H5N1) since 26 December 2003 to 24 May 2006
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124 Deaths
93
100
75
42
33
50
18
12
25
8 5
6 6
42
22
14
14
6
1 0
12
2 2
4
am
N
Vi
et
Tu
rk
ey
d
Th
ai
la
n
Ira
q
on
es
ia
t
ut
i
Eg
yp
C
jib
o
D
In
d
A
hi
na
0
ze
rb
ai
ja
n
C
am
bo
di
a
No. of Reported Cases
218 Cases
Countries
Source: WHO
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As of May 24, 2006.
Cumulative Number of Confirmed Human Cases of Avian
Influenza A/(H5N1) since 26 December 2003 to 24 May 2006
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No. of Reported Cases
Cases
100
90
80
70
60
50
40
30
20
10
0
Deaths
Linear (Cases)
Mortality: 43%
95
Mortality: 65%
74
Mortality: 70%
46
Mortality: 100%
3
41
48
32
3
2003
2004
2005
2006
Countries
Source: WHO
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As of May 24, 2006.
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Cumulative Number of Confirmed Human Cases of Avian
Influenza A/(H5N1) since 26 December 2003 to 24 May 2006
Survived, 95,
43%
Deaths, 124,
57%
Source: WHO
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As of May 24, 2006.
Avian & Human H5N1 Identified in No. of Countries
(Since 26 December 2003 to 24 May 2006)
No. of Reported Cases
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50
45
40
35
30
25
20
15
10
5
0
Cases in Birds
Cases in Humans
46
18
11
1
1
2003
10
5
2
2004
2005
2006
Countries
Source: WHO
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As of April 24, 2006.
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Nations With Confirmed Cases
H5N1 Avian Influenza (May 19, 2006)
Dept of Health and Human Services: www.pandemicflu.gov
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Part V: Interventions
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WHO Global Influenza Surveillance
Network
Makes recommendations on influenza vaccine
formulation
Antigenic &
Genetic
Analysis
WHO CC
Serologic Studies
National
Licensing
Agencies
Diagnostic Reagents
Vaccine Strains
Potency Testing Reagents
Isolation of Representative Strain from Clinical Sample
National Influenza Centers
Disease & Epidemiology Data
Source: WHO Global Influenza
Program
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Influenza Vaccine Development
Source: WHO Global Influenza
Program
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Influenza Pandemic Vaccine
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Lag between pandemic strain detection
and full scale vaccine production
Optimistic Projection
Today
Clinical batch production &
Testing
1-2 months????
Vaccine Prototype
Development
1-2 months
0
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2
4
Months Source: WHO Global Influenza
Program
6
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Key “bottlenecks”
1. “Purity” of strain
2. Production requirements
Production system “EGG”
Biosecurity
Reverse genetics
3. Clinical
Clinical
data
allowing
increase
in
data
allowing
increase
in vaccine
vaccine availability
availability
…
…
Clinical Trials
Source: WHO Global Influenza
Program
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Vaccine Production Capacity
Source: WHO Global Influenza
Program
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Vaccine Consumption - 2000
Source: WHO Global Influenza
Program
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Vaccine
Challenges:
H5 HA is poorly immunogenic as compared
to H3N2 or H1N1 viruses
• To date vaccines against H5 have required 2
doses or an adjuvant to induce necessary
level of neutralizing antibodies
Influenza virus has a high error rate
making it evolve continuously
There are already two clades of HPAI H5N1
virus circulating
Manufacturing capacity is limited and
licensing requirements are stringent
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Vaccine
September 16, 2005 – HHS
News Headlines
US DHHS buying $100 million of
avian vaccine
Vaccine has not been approved
by FDA
Proper dosage being determined
• Protection for 2 to 20 million
Americans
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Vaccine
Inactivated vaccine candidate:
Sanofi Pasture has developed an unadjuvanted,
inactivated H5N1 vaccine candidate
Prospective, randomized, double-blind trials
(~450 adults, 18-64 years) established the need
for two doses (neutralizing titer 1:40)
Now being tested in children and elderly
Live, attenuated vaccine candidate:
MedImmune will develop (under US contract)
will develop at least one vaccine for each of the
16 HA
Candidate vaccine has been developed for H5 &
H9 (phase 1 clinical trials)
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Vaccine
Sanofi Pasture has developed an unadjuvanted, inactivated H5N1
(virus isolated in Southeast Asia in 2004) vaccine candidate. Reported
in NEJM
The higher the dosage of vaccine, the greater the antibody response
produced.
Of the 99 people evaluated in the 90-mcg, high-dose group, 54 percent
achieved a neutralizing antibody response to the vaccine at serum
dilutions of 1:40 or greater
Only 22 percent of the 100 people evaluated who received the 15-mcg
dose developed a similar response to the vaccine.
Generally, all dosages of the vaccine appeared to be well tolerated:
Almost all reported side effects were mild
The second dose of vaccine did not cause more local or systemic
symptoms than the first
Systemic complaints of fever, malaise, muscle aches, headaches and
nausea occurred with the same frequency in all dosage groups as in
the placebo group
Lab tests did not reveal any clinically significant abnormalities
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Vaccine
A new genetically engineered vaccine created by
scientists at the CDC, is egg-independent and
adjuvant-independent.
Hoelscher MA at al. Lancet. 2006 Feb 11;367(9509):475-81.
A similar vaccine, adenovirus-based influenza A
virus vaccine directed against the hemagglutinin
(HA) protein of the A/Vietnam/1203/2004 (H5N1)
(VN/1203/04) strain isolated during the lethal
human outbreak in Vietnam from 2003 to 2005.
Gao W et al. Protection of mice and poultry from lethal H5N1
avian influenza virus through adenovirus-based immunization.
J Virol. 2006 Feb;80(4):1959-64.
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Chemotherapy
Prevent membrane fusion (M2
Inhibitors)
Amantidine (Symmetrel)
Remantidine (Flumadine)
Neuraminidase inhibitors
Zanamivir (Relenza)
• US buying $2.8 million (could treat 84,300 people)
Oseltamivir (Tamiflu)
Peramivir (more potent in vitro)???
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Chemotherapy
Relenza:
Reduced the incidence of the disease in both
young and older populations
First Study: In participants 18 years of age or
older, the proportion of people who
developed symptoms confirmed to be flu was
6.1% for the placebo group and 2.0% for the
Relenza group.
The second community study: enrolled
people 12 to 94 years of age (56% of whom
were older than 65 years).
• In this trial, the percent of people who developed
symptoms confirmed to be flu were reduced from
1.4% of the participants on placebo to 0.2% for
those who used Relenza.
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Types of protective masks
Surgical masks
Easily available and commonly used for routine
surgical and examination procedures
High-filtration respiratory mask
Special microstructure filter disc to flush out
particles bigger than 0.3 micron. These masks are
further classified:
• oil proof
• oil resistant
• not resistant to oil
The more a mask is resistant to oil, the better it is
The masks have numbers beside them that indicate
their filtration efficiency. For example, a N95 mask
has 95% efficiency in filtering out particles greater
than 0.3 micron under normal rate of respiration.
The next generation of masks are called
Nanomasks. These boast of latest technologies like
2H filtration and nanotechnology, which are
capable of blocking particles as small as 0.027
micron.
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Food Safety
Conventional cooking (temperatures at or above 70°C in all parts
of a food item) will inactivate the H5N1 virus.
Properly cooked poultry meat is therefore safe to consume.
The H5N1 virus, if present in poultry meat, is not killed by
refrigeration or freezing.
Home slaughtering and preparation of sick or dead poultry for
food is hazardous: this practice must be stopped.
Eggs can contain H5N1 virus both on the outside (shell) and the
inside (whites and yolk). Eggs from areas with H5N1 outbreaks in
poultry should not be consumed raw or partially cooked (runny
yolk); uncooked eggs should not be used in foods that will not be
cooked, baked or heat-treated in other ways.
There is no epidemiological evidence to indicate that
people have been infected with the H5N1 virus following
consumption of properly cooked poultry or eggs.
The greatest risk of exposure to the virus is through the handling
and slaughter of live infected poultry.
Good hygiene practices are essential during slaughter and postslaughter handling to prevent exposure via raw poultry meat or
cross contamination from poultry to other foods, food preparation
surfaces or equipment
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Survival of Influenza Virus on Surfaces*
(WHO) recommends that environmental surfaces
be cleaned by :
disinfectants such as Sodium hypochloride 1% in-use
dilution, 5% solution to be diluted 1:5 in clean water for
materials contaminated with blood and body fluids;
bleaching powder 7 gram/liter with 70% available
chlorine for toilets and bathrooms; and
70% alcohol for smooth surfaces, tabletops and other
surfaces where bleach cannot be used.
Environmental cleaning must be done on a daily basis.
Source: World Health Organization. Highly pathogenic avian influenza
(HPAI) Interim infection control guidelines for health care facilities.
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New laboratory test
The FDA has approved a new laboratory test developed by
the CDC to diagnose H5 strains of influenza in patients
suspected to be infected with the virus.
The product – the Influenza A/H5 (Asian lineage) Virus Realtime RT-PCR Primer and Probe Set – provides preliminary
results on suspected H5 influenza samples within four
hours once a sample is tested.
If the presence of the H5 strain is identified, then further
testing is conducted to identify the subtype.
If clinicians suspect a patient may be infected with an avian
influenza virus, they should contact their state or local
health department.
For more information:
CDC. New laboratory assay for diagnostic testing of avian
influenza A/H5 (Asian lineage). MMWR. 2006;55(RR5):127.
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Part VI: Where are we …..
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CURRENT WHO PHASE of PANDEMIC ALERT
Inter-Pandemic Phase
New Virus in Animals,
NO Human Cases
Pandemic ALERT
New Virus Causes
Human Cases
PANDEMIC
Low Risk of Human Cases
1
High Risk of Human Cases
2
No or Very Limited Human-to-Human
Transmission
3
WHO: May 23 reported a cluster of 8 individuals (Sumatra is ) of one extended
family – raising questions of potential Human-to-Human transmission
Evidence of Increased Human-to-Human
Transmission
4
Evidence of Significant Human-to-Human
Transmission
5
Efficient & Sustained Human-to-Human
Transmission
6
Source: WHO Global Influenza
Program
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THE NEXT PANDEMIC?
Potential impact of next pandemic
(CDC)
2-7.4 million deaths globally
In high income countries:
• 134-233 million outpatient visits
• 1.5-5.2 million hospitalizations
• ~25% increase demand for ICU
beds, ventilators, etc.
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Planning Assumptions:
US Healthcare
50% or more of those who become sick will
seek medical care
Number of hospitalization and deaths will
depend upon the virulence of the pandemic
virus
Moderate (1957-like)
Severe (1918-like)
Illness
90 million (30%)
90 million (30%)
Outpatient medical care
45 million (50%)
45 million (50%)
Hospitalization
865,000
9,900,000
ICU care
128,750
1,485,000
Mechanical ventilation
64,875
745,500
Deaths
209,000
1,903,000
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What Needs to be Done?
Surveillance
Culling
Domestic poultry vaccine issues
Quarantine
Ring??
Vaccination against circulating flu
H5N1 vaccine development
Stockpiling of antivirals
Quicker laboratory testing
Stringent infection control practices
Handwashing Disinfection, Masks etc
Masks
Education
Vaccination, antivirals, masks, food safety,
handwashing, disinfection, etc
Coordination
Through planning & preparedness
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US Pandemic Influenza Plan Funding 2006
Appropriations: HHS Allocations ($3.3B)
Dollars in Millions
Dept of Health and Human Services: www.pandemicflu.gov
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Take-home messages
The threat to public health will remain so
long as the virus continues to cause
disease in domestic poultry
The outbreaks in poultry are likely to take
a very long time to control
Should the final prerequisite for a
pandemic be met, the consequences for
human health around the world could be
devastating
Regardless of how the present situation
evolves, the world needs to be better
prepared to respond to the next influenza
pandemic
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Timing has a lot to do with
the outcome of a rain dance
“The only thing more
difficult than planning for
an emergency is having to
explain why you didn’t.”
Be Proactive NOT Reactive!!!!
We have to prepare
for the next pandemic!!!
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