Influenza: Preparing to Prevent

a Pandemic Disaster
Alan M. Ducatman, MD, MSc
Professor and Chair, Department of
Community Medicine
West Virginia University School of
Medicine

Annual Toll of Influenza

Place/Time

Annual Deaths

US Annual Average

30,000-50,000

Global Annual Estimate

600,000-1,500,000

Global 1918-19 Pandemic

> 20,000,000 (some

estimates up to 100,000,000)

Causes of Death

Fever
Pneumonia
ARDS

Pandemic Influenza

The Three Types of Influenza

Hemagglutinin subtypes (15)
Type A

Surface proteins
Neuraminidase subtypes (9)
(Tamiflu, an effective drug,
is a neuraminidase inhibitor)

Pandemic
Type

Can infect animals

and humans

B, C

Smaller, localized
outbreaks
Affects humans
only

Shifting Nature of Influenza

Antigenic drift small, ceaseless
changes in the genetic structure. New
strains continually replace old strains.
Antigenic shift major change, usually
occurs when species hosting virus
trade viral genes. Novel strain appears
without natural immunity in host
population.

Pandemic Threshold

Source: Centers for Disease Control,

http://www.cdc.gov/flu/weekly/fluactivity.htm

Recent Virus Hitchhikers

(Zoonoses)
HIV
Hantavirus
Monkeypox
Several viral hemorrhagic fevers
Avian influenza
West Nile
Nonviral
Variant CJD (mad cow)

Environmental Health and

Infectious Disease
The toll can be substantial.
HIV is estimated to have caused 20 million
deaths, so far.

There is very little international

investment in wild (or even domestic)
animal pathogen surveillance.

H5N1 Timeline
Date

Animal

1996

Pathogenic H5N1 isolated in a

domestic goose from Guangdong,
China

1997

Human

18 Hong Kong cases, 6

fatal

2003

Tigers and leopards fed chicken

carcasses die of avian type (felines
previously thought immune)

Family cases in Fujtun,

China

2004

Outbreaks in poultry in SE Asia,

China, and Japan. Japan eradicates
its poultry epidemic

Sporadic reports of
H5N1 throughout SE
Asia, high fatality rates

2005

Poultry and wild bird outbreaks

spread
From WHO website
http://www.who.int/csr/disease/avian_influenza/Timeline_28_10a.pdf

Avian Influenza in Asia

(22 August, 2005)

Why H5N1?
1. It is endemic, now found in domestic fowl,
pigs, and even tigers. There is no way to
eradicate it.
2. Porcine hosts can replicate both avian and
human influenza viruses. It is inevitable
that recombination will occur, and humanhuman transmission capability may
increase.
3. World poultry population has grown tenfold
since the last (1968) pandemic (750,000
deaths), from 1.3 billion birds to 13 billion
birds.

Reengineered Virulence:
1918 vs. Modern (Texas) Strains
Viral particle release in human lung cell
culture: 50 times
Viral particle replication in mouse lung
tissue at 4 days: 39,000
Mortality in mice: all vs. none

1918 Hemagglutinin Causes Severe

Lung Damage

M88/Hsp

M88

Kobasa et al. Nature 2004;431:703

H5N1 Toll
Fall 2005: > 100 reported infections, >
60 deaths, millions of birds culled.
Vietnam has culled millions of
chickens, accounting for 0.5% of its
GNP.
In addition, the virus is gaining the
ability to infect its natural host,
waterfowl.

Cumulative Number of Confirmed Human Cases of

Avian Influenza A/(H5N1) since 26 December 2003
to 10 October 2005

Species Surveillance
In the US, poultry surveillance is in
place (required reporting by farmers).
In addition, ornithologists,
veterinarians, park rangers, and
amateur bird watchers have been
recruited to trap sentinel bird species,
test, and release, or else test hunted
game birds.
Estimated investment: $10 million/yr.

Overcoming Barriers: Surveillance

for Avian Influenza (H5N1)
1. Countries affected may be reluctant to
share specimens. This limits ability to
track mutations.
2. The PCR tests may be out of date,
providing false negative results.
3. The ability to find the virus and track
genetic changes is essential to
vaccine preparation.

Barriers to Surveillance
Inadequate human surveillance
Grossly inadequate domestic and wild
animal surveillance
Political barriers to cooperation
Lack of reimbursement for economic
losses

Barriers to Surveillance
Overcoming anarchy in animal and
human surveillance
Lab restrictions
Data management
Communication restrictions

Distribution and cost of validated

diagnostic tests

Human View of Path of Spread

Wild Fowl

Domestic Birds
Humans
Domestic Livestock

Mode of Spread
Birds shed virus for about 10 days.
Initial transmission mode is bird feces,
feathers, tissue, or saliva to humans
(oral).
Virus is hardy in cool weather, so
surface contact may intervene.
The fear is direct human-to-human
droplet transmission.

Cumulative Number of Confirmed Human Cases of

Avian Influenza A/(H5N1) since 26 December 2003
to 10 October 2005

Transmission
Intensified surveillance in Vietnam by
reverse transcriptase polymerase chain
reaction testing of patient contacts
suggests the evidence of mild cases
and clusters. The concern is that the
Vietnamese H5N1 is adapting to
residence in human hosts.

Incubation Period
Probably 2 to 5 days, possibly as long
as 8 days
Reports of 17 days suggest
intermediate hosts

Most Common Symptoms and

Findings in H5N1 Patients

Fever > 38 C
Cough
Dyspnea
Pulmonary infiltrates (can progress to
ARDS)

Detection
Diagnostic yields of different
approaches to detection are
problematic.
Viral RNA can be detected in throat
swabs; sensitivity and specificity are
both lower than desired.

Household Contact Treatment

Frequent handwashing
N95 masks/eye protection (feasible?)
Monitor temperature twice daily for 7 days
No Fever

Fever

Prophylaxis

Treatment

Quarantine
Public health concept of ring treatment

Quarantine
In the US, community-level quarantine
experience essentially ended in . . . .
1954.

Quarantine Compliance Issues

Contact tracing is not a HIPAA problem.
Enforcement measures are unprecedented in
US living memory; education is essential to
public and professional enforcement.
Those ordered into quarantine will have
concerns about vacation, sick leave, and
wages (as will employers). No funds or laws
address this issue for nonmilitary personnel.
Differential health services and policies may
have border effects (traffic flow, preferential
seeking of or fleeing from services).

Quarantine Needs
Public health access to airline and
other passenger lists
Quarantine infrastructure
Support for contact tracing
Speedy appeals process
Legal authority to immunize or treat
prophylactically

Health Care Facility Precautions

Patient precautions: standard, contact,
droplet, airborne
Protective equipment: N95 mask, cuffed
gowns, face shields or goggles, gloves
Room: negative pressure.
Alternative 1: Isolation with door closed
Alternative 2: Multibed wards one meter apart
with physical barriers.

Minimize:
visitors
attending personnel

Local Resources and Public

Health
Reality Check: most Vietnamese
hospitals do not have designated
isolation wards.

Health Care Worker Surveillance

Record temperature twice daily
Prophylaxis

Normal

Abnormal
Symptoms

Remove from
workplace

Evaluate for
influenza

Treatment

More Reality: Surge Capacity in a

Just-in-Time Economy
Average Number of people on respirators, daily 75,000
Average Number of people on respirators, flu
surge

100,000

Number of respirators in USA

105,000

Source: Osterholm MT. Preparing for the next epidemic. N Engl

J Med 2005; 352: 1839-42.

Travelers Precautions
Immunization > 2 weeks before travel
Avoid chickens, ducks, geese, wild
birds, open markets, fecally
contaminated surfaces
Wash hands frequently
Consult health care provider for fever
or symptoms
Avoid raw eggs, mayonnaise,
hollandaise sauce, and ice cream in
endemic areas

Influenza: An International
Problem
Up to 20% of the worlds population may
become ill.
Our point of reference for pandemic flu may
be something that comes from elsewhere
and affects us.
For Asian nations such as China, pandemic
flu is a threat to civil order as well as health.
Vaccination capability is much lower in the
countries likely to be most affected.

What Predicts Community

Cohesiveness vs. Divisiveness?
1.
2.
3.
4.

Infrastructure in place
Opinion leaders
Communications without politics
Policy makers accustomed to public
health input

Influenza: The International

Response
There are important differences in national
capabilities to prevent, detect, and respond
to an influenza pandemic.
Geographic differences in production of host
species, including
mixing domestic and wild species
proximity to populations
measures to protect workers

Virologic, serologic, clinical, and public

health capabilities vary greatly.

Influenza and the Global

Economy
An influenza pandemic will cause national
leaders to suppress foreign travel and trade.
Vastly disruptive, this action is unlikely to
achieve the goal.
Domestic economic investment in many
nations will be directed toward surge
capacity and possibly national defense
against civil unrest.
Unequal distribution of inadequate health care
resources, including immunizations, will create
tensions within and across borders.

What about state lines?

Threats to Health
Consequences of infection
Uncoordinated efforts of individuals to
avoid infection

Local Economies and Public

Health
In Vietnam, large commercial poultry
farms cull infected birds successfully.
But local households with small flocks
have no resources and only negative
incentives for participating.
Poultry vaccination may address the
problem, but it is so far mandated only
for flocks of > 200 birds.
A number of European countries have
banned the outdoor penning of poultry.

Antiviral Treatment
Chinese farmers have been using
Amantadine (the least expensive
antiviral agent) to treat chicken flocks
and prevent the spread of H9 viruses.
H5N1 strain of avian influenza has been
resistant to Amantadine since 2003.
More expensive antivirals such as
Oseltamivir (Tamiflu) and Zanamivir
(Relenza) may still work.

Tamiflu
Tamiflu is an neuraminidase inhibitor that
can be taken as a pill or dissolved powder.
The inhibitor diminishes release of virus from
infected cells if taken within 48 hours of
infection.
Cost per treatment: $10 (less for stockpile)
Availability % population: Britain, 25%;
Canada, 5%; US, 1%
As with immunization, health care workers
will be treated first.

Can Statins and Pneumovac Fill

the Tamiflu Shortage Gap?
In previous influenza epidemics from
1996-2003, statin users experienced
26% less incidence of pneumonia.
Pneumovac (pneumococcal pneumonia
vaccine) may also help.
Cabbage and untested hypotheses.

Long-Term Planning
NIH is developing three attenuated
vaccines for each of the known avian
flu subtypes. In theory, this will allow
speedy scale-up of vaccine production
in the event of a pandemic. In addition,
NIH researchers are looking for
antigens that are conserved across
several strains.

Vaccine Development
The US president has made vaccine
industry development and liability
protection a cornerstone of his $1.7
billion program to safeguard America
against pandemic influenza.
Media accounts suggest cell-based
vaccines will cut production time.
They are more likely to increase
production quality (surge capacity).

Scrambling for An Egg Alternative

Source: Centers for Disease Control,

http://www3.niaid.nih.gov/news/focuson/flu/research/prevention/hillegas_
egg.htm

General Conditions
for Vaccine Success
1. Immunogenic (achieved!)
2. Effective against rapidly mutating
pandemic strain
3. Produced in sufficient quantities
4. Administered at sufficient dose
5. Administered in time to achieve
protection in population at risk

Immunization Quantities
In a typical year, hundreds of millions
of flu vaccine doses are available. In an
epidemic, billions of doses are needed.
Bridging this gap requires planning
and investment.

Immunization and Adjuvant

Immunizations work better (and require
much less material) if boosted with
adjuvant, a chemical additive that
stimulates the immune system.
This is hopeful news, but it requires
more complex clinical trials which
include adjuvant.

Bird Immunization
Benefits

Problems

Decrease infection rates

Aymptomatic infections

Decrease virus shed through

nasal secretions and feces

Possibly harder to identify virus

Should decrease transmission

May not completely eliminate

virus
Barrier to international
transportation

US Leadership in a Pandemic
In an influenza pandemic, leadership would
be split between the Department of
Homeland Security and DHHS. Immediate
declarations:
preparedness plan implementation
travel and trade

Problems:
internal migrations (much worse in other
countries)
workforce
multiple moves

Pandemics and US Public Health

Ethics
The realization of autonomy is a strong
health trend, nurtured even during the
AIDS epidemic.
The role of informed consent is central
to autonomy.
The absence of a public health view
that accounts for rapidly spreading
infection has been noted by
international observers.

Clinicians Uneasy Role in Public

Health Emergencies
Normal Conditions:
The clinician is accustomed to acting as a
patient advocate, for reasonable, requested
interventions.
Emergency Conditions:
The clinician must refuse reasonable but
not recommended requests for scarce
resources.
The clinician may report families or
populations for quarantine, and patients may
object to intrusions initiated by their doctors.

Can a Pandemic Be Contained?

1. Will it occur this year, or in 5 years?
2. The basic reproductive number (Ro)
is crucial. If Ro is < 2, public health
models (isolation, immunization, and
early antibiotics) have more chance to
minimize spread.
3. Tamiflu resistance (already found in a
Vietnamese patient) would further
compromise ability to contain spread.

Is Pandemic Flu Containable?

In a preimmunized population, rapid
recognition, followed by isolation,
combined with social distance
strategies (reducing places for masses
of people to meet), and augmented by
wide-scale antiviral treatment and
prophylaxis (i.e., treat the 20,000
people nearest the outbreak), can be
modeled to contain a local outbreak.

Education: Thai Children at Risk for

H5N1 Infection
Knowledge, attitudes, and practices*

Before

After

pvalue

Thought it was safe to touch sick or

dead poultry with bare hands

78 (40)

27 (14)

<0.01

Thought it was safe for children to touch

sick or dead poultry with bare hands

45 (23)

9 (5)

<0.01

Children in your household touched sick

or dead poultry with bare hands

12 (6)

7 (4)

0.4

17 (9)

0.3

Took dead chicken or poultry from your

yard and prepared it to eat

24
(12)

* Before and after a public education campaign

Olsen et al. EID 2005;11:

Police Powers in Epidemics and

Emergencies
Who can quarantine or isolate? (Laws
usually say quarantine.)
State health officer
County board of health, usually acting
through health officer

Any detention is least restrictive

means necessary

Police Powers in Epidemics and

Emergencies
Who can declare a public health
emergency?
Governor
(Federal authorities can preempt)

Legal Control of Zoonoses

Authority is shared through a welter of
regulations by:

CDC: public health, inspection, detention

Customs/Border: inspection, seizure, destruction
Plant protection: formerly part of USDA
DOT: approval to transport
Fish and Wildlife: reporting, licensing, destruction
FDA: similar to CDC
USDA: farm issues

Legal Control of Zoonoses

WV specifically regulates rabies
Very little clarity about exotics

Good News . . . And Bad

For avian flu, its inability to make much
headway in the human population (so
far) may mean that it cannot do so.
If not, some pandemic is still
predictable.
Average time between 20th-century
pandemics: 30 years.
Last pandemic: 1968.

Rank Order of Treatment

Priorities in a Shortage
1. Treat patients hospitalized with flu
2. Treat health care (direct patient
contact) and EMS
3. Treat pandemic health, public safety,
key government
4. Treat other high-risk patients
5. Nontreatment group: Post-exposure
prophylaxis
6. Treat outpatients

Pandemic Priority Groups for

Vaccination and Antivirals:
Priority Group 1 Critical Response and Most Vulnerable
Group

US #

A. Direct patient care and support,

including vaccine and drug
production.

9.1 million

B. High risk: > 65 with chronic

disease; < 65 with 2 chronic
diseases; hospitalized in past
year for flu, pneumonia, chronic
disease

25.8 million

C. Pregnant; households with

infants or immunocompromised

10.7 million

D. Government and public health

leaders

0.15 million

Source: National Vaccine Advisory Committee,

July 19, 2005

Pandemic Priority Groups for

Vaccination and Antivirals:
Other Priority Groups: 2-4
Group

US #

2. Seniors; other emergency

responders; transportation
workers

59 million

3. Funeral home directors and

other government workers

0.5 million

4. Everyone else

180 million

Source: National Vaccine Advisory Committee,

July 19, 2005

Reasons for Optimism

No H5 subtype has ever caused a
pandemic (the 1918 avian source was
an H1N1 virus)
The current H5N1 virus has been
circulating for 8 years, without
reassorting for efficient human-human
transmission.

Munchs Self-Portrait after the Spanish

Influenza

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