“l’infettivologia del terzo millenio:

nonsoloAIDS”Paestum, maggio 2006

“ “ Possibili future pandemie: siamo pronti?”Possibili future pandemie: siamo pronti?”Prof. Giampiero Carosi

Istituto Malattie InfettiveUniversità di Brescia

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.

Do we live in an artificially created culture of fear?

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

2

HIV

Dengue

H Papilloma v

Ebola

Hanta virus

West Nile virus

Tobacco

Malaria

Non-HIV tuberculosis Road accidents

3

5

6

Influenza

Polio

SARS

vCJD

Measles HBV + HCV

4

Log 10

RSV, Rota virus

7

Hospital infection

Suicide

Major and minor killers: global impact viewed on a ‘Richter’ (logarithmic) scale

Weiss & McMichael, 20041

Viruses

Infant/child ARI & diarrhoeal dis

10,000-fold difference in impact

• 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.

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.

Wor

ld P

opul

atio

n in

bill

ions

(

)

Day

s to

Circ

umna

viga

te (

)

the

Glo

be

Year1850

0

400

350

300

250

200

150

100

50

2000

0

1900 1950

1

2

3

4

5

6

Speed of Global Travel in Relation to World Population Growth

a.a. frightening rapidly spreading new pandemic (SARS/H5N1)frightening rapidly spreading new pandemic (SARS/H5N1)

b.b. slowly and widely spreading old pandemic (AIDS/TB)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.

Hippocrates seems to

have been the first observer to record an influenza pandemic in the year 412 B.C.Since 1580, there have been thirty-one additional flu pandemics recorded.

Human Influenza

1918Pandemic of “ Spanish flu”

H1N1

1957 Pandemic of “ Asian flu”

H2N2

1968 Pandemic of “ Hong Kong flu”

H3N2

1962 epidemic

1964 epidemic

1933 epidemic

1946 epidemicSmith W. Et al., A virus isolated from influenza patients.

Lancet 1933; 2: 66–68.

There is an agreement that a new pandemic is “inevitable and possibly imminent”. WHO 2004

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.

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.''

AVIAN FLU: THE WORRIERBy DONALD G. MCNEIL JR.

March 28, 2006

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 fear

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 2006

Areas reporting confirmed occurence of H5N1 avian influenza in poultry and wild birds

since 2003

18/Apr/2006

since January 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

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

M2 INHIBITORS BIAS: RESISTANCE

F.G. Haiden, N Engl J Med 354;8, 2006

Monto, A. S. N Engl J Med 2005;352:323-325

Neuraminidase inhibitors

Q. Mai Le et al., Nature, vol 437, 20 oct 2005

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

Impact of Antiviral Therapy on Influenza Complications

Retrospective Analysis, Nursing Home Residents, Canada

0

10

20

30

40

50

60

Comp Hosp Death

No Rx (23)

Amantadine (19)

Osel <48 h (50)

Osel >48 h (23)

Pe

rce

nt

Bowles et al. J Am Geriat Soc 2002

Body Weight in kg

RecommendedDose

Treatment (for 5 Days)Prophylaxis*

Number of Bottles

Needed to Obtain

the Recomme

ndedDose

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

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.

Oseltamivir: dosages

“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”.

BELGIUM 30% by the end of 2007

FRANCE 24% by the end of 2006

GERMANY 10%GREECE 2%ITALY 10% NETHERLANDS 16% by the end of 2006 ROMANIA 3.5%RUSSIA 100%SPAIN 5%UK 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.

Antiviral drugs stockpilled in Europe.

% population covered

Department of Health and Human Services Pandemic Planning UpdateA Report from Secretary Michael O. LeavittMarch 13, 2006

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.

Pharmaceutical interventions: vaccines

Subbarao et al., Immunity 2006, 24, 5–9

19 AUGUST 2005, 80th YEAR No. 33, 2005, 80, 277–288http://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: firststeps towards developmentof a human vaccine

Department of Health and Human Services Pandemic Planning UpdateA Report from Secretary Michael O. LeavittMarch 13, 2006

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.

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 co-workers?

Who provides essential community services?

Time

Provide quality medical care

Infection control in medical & long term care settings

Antiviral treatment & prophylaxisIm

pact

Pandemic influenza disease

Pandemic Response Components

Vaccination

Interventions to decrease transmission

Maintain essential community services/emergency response activities

Infectious diseases kill 1/3 worldwide

UNAIDS/WHO December 2005

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

THE ROAD TO UNIVERSAL ACCESS

AIDS 2005, 19:1555–1564

Mean competitive advantage of historical isolates over recent isolates.

25 to 49

50 to 99

100 to 299

< 10

10 to 24

300 or more

No Estimate

per 100 000 population

Estimated TB incidence rate (2003)

Tuberculosis remains a global epidemic, with one-third of the population infected and 9 million active cases.

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

14,2 14,2 13,7 13,2 12,2 10,4 9,4 9,3 7,8 6,6

56,4

43,640,2

45,3

53,3

36,6 38,2

58,3

42,4

New cases Previously-treated cases

MDR-TB prevalence (world): top countries

World Health Organization. Anti-tuberculosis drug resistance in the world. Third global report. Geneva: WHO, 2004 (WHO/CDS/TB/2004.343)

30%

6.5%

0%

20%

40%

60%

80%

100%

Estonia Latvia Orel Peru Philippines Tomsk

Patients resistant to HR only Patients resistant to HRES Patients resistant to HRES and second-line drugs

Pattern of the anti-TB resistance

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 worldwide2) Increasing rate of emerging pathogens

travelsman-animal interactionsdrug resistance

3) New pathogens escape immunity4) Defense weapons

new drugsvaccinessurveillance and public health interventions

5) Strenghtening supra-national coordination