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“ Possibili future pandemie: siamo pronti?”
Prof. Giampiero Carosi
Istituto Malattie Infettive
Università di Brescia
“l’infettivologia del terzo millenio:
nonsoloAIDS”
Paestum, maggio 2006
Do we live in an artificially
created culture of fear?
Life today for citizens of the developed world is safer, easier, and healthier than for
any other people in history thanks to modern medicine, science, technology.
1950s-60s: Infectious diseases apparently
receding in developed countries
• Antibiotics and vaccines
• Pesticides to control mosquitoes
• Improved surveillance and control measures –
internationally coordinated
Early 1970s: Authorities proclaimed end of
infectious disease era. Premature!
• >30 new or newly-discovered human IDs over past 30 yrs
• We overlooked the ecological/evolutionary dimensions
Examples of Emerging and Re-Emerging
Infectious Disease: past 10 years A Fauci,
NIAID/NIH, 2005
Major and minor killers: global impact viewed
on a ‘Richter’ (logarithmic) scale
7
Tobacco
Infant/child ARI & diarrhoeal dis
Malaria
Road accidents
Non-HIV tuberculosis
HIV
Viruses
HBV + HCV
6
Measles
RSV, Rota virus
Influenza
Dengue
5
H Papilloma v
Hospital infection
Suicide
4
10,000-fold
difference in
impact
West Nile virus
3
SARS
Ebola
Polio
Hanta virus
2
vCJD
1
Log
10
Weiss & McMichael, 2004
The Global Village Concept
Those of us living in developed countries need continually to remind ourselves of
the concept of a global village: within 24 h serious microbes infecting a distant
population can be carried over oceans directly to our homes.
• the importance of clinicians recognizing a new syndrome
• the need for individuals and countries to report epidemics
• the role of information technology to communicate
• the key role for the WHO.
6
Days to Circumnavigate (
the Globe
350
)
400
5
300
4
250
200
3
150
2
100
50
1
0
0
1850
1900
Year
1950
2000
World Population in billions (
)
Speed of Global Travel in Relation to
World Population Growth
a. frightening rapidly spreading new pandemic (SARS/H5N1)
b. slowly and widely spreading old pandemic (AIDS/TB)
In a global world with global media coverage and
competition for sensational news, any hypothetical
doomsday scenario that could capture the public
imagination risks unleashing a media storm.
The perception of risk is then easily distorted from the
actual risk.
People intuitively overestimate the risk of rare
events and underestimate the risk of common
events.
People perceive unlikely and uncertain catastrophes
as more threatening than frequent and likely risks.
Human Influenza
Hippocrates
seems to have
been the first
observer to record an influenza
pandemic in the year 412 B.C.
Since 1580, there have been thirtyone
additional
flu
pandemics
recorded.
Pandemic of “ Spanish flu”
1918
H1N1
1933
epidemic
Smith W. Et al.,
A virus isolated from influenza patients.
1946
epidemic
Lancet 1933; 2: 66–68.
1957 Pandemic of “ Asian flu”
H2N2
1962
epidemic
1964
epidemic
1968
H3N2
There is an agreement that a new pandemic is
“inevitable and possibly imminent”. WHO 2004
Pandemic of
“ Hong Kong flu”
Condition for a new flu pandemic
- a new ‘novel’ virus emerges..
- which population has no
immunity to..
- and efficiently transmitted from
human to human causing diseases.
Avian flu fear
Dr. David Nabarro, chief avian flu coordinator for the United Nations:
'‘.…quite scared…''
'‘that rampant, explosive spread and the dramatic way it's killing poultry
so rapidly suggests that we've got a very beastly virus in our midst.''
On his first day in his current job, he predicted 5 million to 150 million deaths.
‘we spend billions to protect ourselves from threats that may not exist,
from missiles, bombs and human combatants. But pathogens from the
animal kingdom are something against which we are appallingly badly
protected, and our investment in pandemic insurance is minute.''
AVIAN FLU: THE WORRIER
By DONALD G. MCNEIL JR.
March 28, 2006
The H5N1 avian influenza viruses now circulating may be the most
likely candidates for triggering an influenza pandemic because of
ongoing reports of new cases in humans .
However,
other avian
influenza
viruses also
are being
monitored for
their potential
to infect and
cause disease
in humans.
A. Fauci, Emerging Infectious Diseases Vol. 12, No. 1, January 2
Areas reporting confirmed
occurence of H5N1 avian
influenza in poultry and wild
birds
since 2003
since January 2006
18/Apr/2006
H5N1 became lethal to humans
Affected areas with confirmed human cases of H5N1
avian influenza since 2003
Emerg Infect Dis.
2005 Feb;11(2):210-5.
Cross-sectional seroprevalence survey among hospital
employees exposed to 4 confirmed and 1 probable H5N1
case-patients or their clinical specimens.
Ninety-five percent reported exposure to >1 H5N1 casepatients;
59 (72.0%) reported symptoms, and 2 (2.4%) fulfilled the definition
for a possible H5N1 secondary case-patient.
No study participants had detectable antibodies to
influenza A H5N1.
• Pharmaceutical interventions (vaccines, antiviral drugs)
• Nonpharmaceutical interventions
Pharmaceutical interventions: antiviral drugs
M2 inhibitors
Neuraminidase inhibitors
If available in sufficient supply, antiviral agents
could potentially play a valuable role in the initial
response to pandemic influenza, particularly in the
likelihood that an effective vaccine is unavailable.
Depending on available supply, they might reduce
morbidity, hospitalizations and other demands on
the health care system, and possibly mortality.
WHO/CDS/CSR/RMD/2004.8
M2 INHIBITORS BIAS: RESISTANCE
Resistance to both drugs
develops
quickly
for
all
influenza A viruses.
The current H5N1 virus that
has occurred widely in
Southeast Asia has been
shown to have a resistant site
in the M gene, so the M2 ion
channel inhibitors could not
be used to control this virus.
Resistant strains spread quickly
in institutions, such as nursing
homes, where the drugs are
often used prophylactically in
the face of an outbreak .
M. J. Brooksa et al., Current Opinion
in Pulmonary Medicine 2004, 10:197–
203
F.G. Haiden, N Engl J Med 354;8, 2006
Neuraminidase inhibitors
Monto, A. S. N Engl J Med 2005;352:323-325
Oseltamivir
treatment
reduced viral titres in animals
infected
with
the
drugsensitive virus (P0.048),
but not in animals infected
with the resistant virus
(P0.23)
However, all of the viral
clones, including those highly
resistant to oseltamivir, were
sensitive to zanamivir (IC50,
0.5–3.1 nM).
Oseltamivir
Bound to
Neuraminidase
and Location of
Key Resistance
Codons
Q. Mai Le et al., Nature, vol 437, 20 oct 200
Impact of Antiviral Therapy on Influenza Complications
Retrospective Analysis, Nursing Home Residents, Canada
60
No Rx (23)
Amantadine (19)
Osel <48 h (50)
Osel >48 h (23)
50
Percent
40
30
20
10
0
Comp
Bowles et al. J Am Geriat Soc 2002
Hosp
Death
Oseltamivir: dosages
Recommended
Dose
Treatment (for 5 Days)
Prophylaxis*
Number of
Bottles
Needed to
Obtain
the
Recomme
nded
Dose
15 kg
30 mg twice (once) daily
1
>15 kg to 23 kg
45 mg twice (once) daily
2
>23 kg to 40 kg
60 mg twice (once) daily
2
>40 kg
75 mg twice (once) daily
3
Body Weight in kg
following close contact with an infected individual for at least 10 days.
prophylaxis during a community outbreak of influenza:. the duration of protection lasts for as
long as dosing is continued. Safety and efficacy have been demonstrated for up to 6 weeks.
“WHO recommends that countries with sufficient resources invest in a
stockpile of antiviral drugs for domestic use, particularly at the start of a
pandemic when mass vaccination is not an option and priority groups,
such as frontline workers, need to be protected”.
Antiviral drugs stockpilled in Europe.
% population covered
BELGIUM
FRANCE
GERMANY
GREECE
ITALY
NETHERLANDS
ROMANIA
RUSSIA
SPAIN
UK
30% by the end of 2007
24% by the end of 2006
10%
2%
10%
16% by the end of 2006
3.5%
100%
5%
25%
In april 2005 the EC proposed the establishment of a solidarity fund: it
will pay up to € 1 billion or 0.5% of the GNP of affected Countries.
President Bush explained that
vaccines and antiviral drugs are
“the foundation of our influenza
virus infection control strategy.”
The President’s plan proposes to
spend $1 billion to build a
national reserve of antiviral
medications such as Tamiflu and
Relenza, enough for 20 million
doses.
Department of Health and Human Services
Pandemic Planning Update
A Report from Secretary Michael O. Leavitt
March 13, 2006
Pharmaceutical interventions: vaccines
Subbarao et al., Immunity 2006, 24, 5–9
19 AUGUST 2005, 80th YEAR
No. 33, 2005, 80, 277–288
http://www.who.int/wer
At present, 90% of
production capacity for
all influenza vaccines
is concentrated in
Europe and North
America in countries
that account for only
10% of the world’s
population.
H5N1 avian influenza:
first
steps towards
development
of a human vaccine
President Bush asked
Congress for $7.1
billion to fund
preparations, and in
December 2005
Congress appropriated
$3.8 billion to help the
Nation prepare.
Department of Health and Human Services
Pandemic Planning Update
A Report from Secretary Michael O. Leavitt
March 13, 2006
When will it be available?

How much will there be?

Who will own it?

Who should get it?

How should it be
delivered?

All vs selected HCWs and
public safety workers?

…and if selected workers,
who selects and is it legal,
feasible, and ethical to
define priorities among coworkers?

Who provides essential
community services?

Pandemic Response Components
Pandemic influenza disease
Interventions to decrease transmission
Provide quality medical care
Infection control in medical & long term care settings
Maintain essential community services/emergency response activities
Antiviral treatment
& prophylaxis
Vaccination
Time
Infectious diseases kill 1/3 worldwide
UNAIDS/WHO December 2005
INTENSIFYING PREVENTION:
THE ROAD TO
UNIVERSAL ACCESS
Studies show that HIV prevention efforts work
best
when
they
are
intensive,
i.e.
comprehensive and long term. For example,
intensive prevention programmes in the
Mbeya region of Tanzania led to an increase in
the use of condoms and the treatment of
sexually transmitted infections between 1994
and 2000. Those changes were accompanied
by a decline in HIV prevalence among 15–24
year-old women from 21% to 15% in the same
period (Jordan-Harder et al., 2004). But in the
Mwanza region of the country, less intensive
and isolated HIV prevention efforts did not
yield similar results; in fact, HIV prevalence
increased in this area from 6% in 1994-1995, to
8% in 1999-2000 (Mwaluko et al., 2003).
UNAIDS/WHO December 2005
AIDS 2005, 19:1555–
1564
Mean competitive
advantage of historical
isolates over recent
isolates.
Estimated TB incidence rate (2003)
per 100 000 population
< 10
10 to 24
25 to 49
50 to 99
100 to 299
300 or more
No Estimate
Tuberculosis remains a global epidemic, with onethird of the population infected and 9 million active
Control of tuberculosis, which is undermined by the
human immunodeficiency virus (HIV) epidemic, is
seriously jeopardized by multidrug resistant strains,
for which treatment is complex, more costly, and less
successful
MDR-TB prevalence (world): top countries
58,3
56,4
53,3
43,6
45,3
42,4
40,2
36,6
38,2
30%
13,7
13,2
12,2
10,4
9,4
9,3
R
Is
us
ra
si
el
an
a
(T
(K
om
ar
ak
sk
al
)
pa
ks
ta
n)
C
Es
hi
to
na
ni
(L
a
ia
on
in
g)
Li
th
ua
ni
a
La
C
hi
tv
na
ia
(H
en
an
)
Eq
ua
R
do
us
r
si
a
(O
re
l)
Eg
yp
t
6,6
New cases
Previously-treated cases
U
zb
ek
is
t
K
az
ak
hs
ta
n
6.5%
7,8
m
an
14,2
O
14,2
World Health Organization. Anti-tuberculosis drug resistance in the world. Third global report. Geneva:
WHO, 2004 (WHO/CDS/TB/2004.343)
Pattern of the anti-TB resistance
100%
80%
60%
40%
20%
0%
Estonia
Patients resistant to HR only
Latvia
Orel
Patients resistant to HRES
Peru
Philippines
Tomsk
Patients resistant to HRES and second-line drugs
Mono- and multidrug resistance in 6 World Health Organization (WHO)
regions have been assessed in 40% of the global cases diagnosed by
positive results of sputum testing
GeoSentinel
•
•
•
•
istituito nel 1996
30 istituti di malattie infettive e tropicali nel mondo
Sorveglianza globale delle patologie di importazione in viaggiatori/migranti
Networking tra GeoSentinel e networks affini (TropNet Europe)
Conclusions
1) Infectious diseases still represent the 1st cause of death worldwide
2) Increasing rate of emerging pathogens
travels
man-animal interactions
drug resistance
3) New pathogens escape immunity
4) Defense weapons
new drugs
vaccines
surveillance and public health interventions
5) Strenghtening supra-national coordination