“l’infettivologia del terzo millenio: non solo AIDS ”

1. “ Possibili future pandemie: siamo pronti?” Prof. Giampiero Carosi Istituto Malattie Infettive Università di Brescia “l’infettivologia del terzo millenio: nonsoloAIDS” Paestum, maggio 2006

2. 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.

3. 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

4. Examples of Emerging and Re-Emerging Infectious Disease: past 10 years A Fauci, NIAID/NIH, 2005

5. 10,000-fold difference in impact Log 1 0 Major and minor killers: global impact viewed on a ‘Richter’ (logarithmic) scale 7 Tobacco HIV Infant/child ARI & diarrhoeal dis Malaria HBV + HCV 6 Road accidents Non- HIV tuberculosis Measles RSV, Rota virus Influenza 5 Dengue Viruses Hospital infection H Papilloma v 4 Suicide West Nile virus 3 SARS Ebola Polio 2 Hanta virus vCJD 1 Weiss & McMichael, 2004

6. 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.

7. 400 ) ) 350 5 ( 300 ( e t a s g 4 250 n i v o e a i l b l n i o 200 b m l 3 G u n i c e r 150 n i h C t o i 2 t o a t 100 l u s y p a o 1 P 50 D d l r o 0 0 W 2000 1850 1900 1950 Year Speed of Global Travel in Relation to World Population Growth 6

8. frightening rapidly spreading new pandemic (SARS/H5N1) • slowly and widely spreading old pandemic (AIDS/TB)

9. 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.

10. 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 thirty-one additional flu pandemics recorded. Pandemic of “ Spanish flu” 1918 H1N1 1933 epidemic Smith W. Et al., A virus isolated from influenza patients. Lancet 1933; 2: 66–68. 1946 epidemic Pandemic of “ Asian flu” 1957 H2N2 1962 epidemic 1964 epidemic 1968 Pandemic of “ Hong Kong flu” H3N2 There is an agreement that a new pandemic is “inevitable and possibly imminent”. WHO 2004

11. 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. H5N1 ?????

12. 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

13. 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

14. Areas reporting confirmed occurence of H5N1 avian influenza in poultry and wild birds since 2003 since January 2006 18/Apr/2006

15. H5N1 became lethal to humans

16. Affected areas with confirmed human cases of H5N1 avian influenza since 2003

17. 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.

19. Pharmaceutical interventions (vaccines, antiviral drugs) • Nonpharmaceutical interventions

20. Pharmaceutical interventions: antiviral drugs M2 inhibitors Neuraminidase inhibitors

21. 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

22. 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 Med354;8, 2006

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

24. 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 2005

25. Impact of Antiviral Therapy on Influenza ComplicationsRetrospective Analysis, Nursing Home Residents, Canada Percent Bowles et al. J Am Geriat Soc 2002

26. Oseltamivir: dosages 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.

27. “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”.

28. Antiviral drugs stockpilled in Europe. % population covered 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.

29. 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

30. Pharmaceutical interventions: vaccines Subbarao et al., Immunity 2006, 24, 5–9

32. H5N1 avian influenza: first steps towards development of a human vaccine 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.

33. 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

34. 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?

35. 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 Pandemic Response Components Pandemic influenza disease Impact Vaccination Time

36. Infectious diseases kill 1/3 worldwide

37. UNAIDS/WHO December 2005

38. 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

39. AIDS 2005, 19:1555–1564 Mean competitive advantage of historical isolates over recent isolates.

40. per 100 000 population < 10 10 to 24 25 to 49 50 to 99 100 to 299 300 or more No Estimate Estimated TB incidence rate (2003) Tuberculosis remains a global epidemic, with one-third of the population infected and 9 million active cases.

41. 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

42. MDR-TB prevalence (world): top countries 30% 6.5% World Health Organization. Anti-tuberculosis drug resistance in the world. Third global report. Geneva: WHO, 2004 (WHO/CDS/TB/2004.343)

43. 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

44. 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)

45. Conclusions • Infectious diseases still represent the 1st cause of death worldwide • Increasing rate of emerging pathogens • travels • man-animal interactions • drug resistance • New pathogens escape immunity • Defense weapons • new drugs • vaccines • surveillance and public health interventions • 5) Strenghtening supra-national coordination