2010流感與禽流感之最新發展

衛生署 疾病管制局中區傳染病防治醫療網

王任賢 指揮官

Outline Overview 2009 pandemic Role of animal surveillance Bacterial superinfection of influenza Global monitoring of antiviral susceptibility of

pandemic influenza A(H1N1) 2009 virus

Overview of 2009 pandemic H1N1 influenza

As if 15 August 2010, 215 countries and territories have reported cases

18,631 laboratory-confirmed deaths in 125 countries

Official number significantly underestimate actual number

Widespread community transmission in all areas From April 2009 to August 2010

Pandemic Response Tools

1918 1957 1968 1997 2003 2009Spanish flupandemic

Asia flupandemic

HK flupandemic

H5N1 HK18 cases (C)6 deaths (D)

H5N1 Asia504 C299 D

A H1N12009

pandemic

PH measures (ie school closures, mask, mass gathering) Nonpharmaceutical intervention

Inactivated influenza vaccine (IIV)

1944

GISN

1952

Purified IIV, LAIV

1960

Fragmented IIV

Suo unit IIV

1980

AdjuvantedIIV

LAIVUSA

Cell-basedIIV

Vaccine

2007

AmantadaneFor influenza (1966)

Rimantadane(1993)

Neuraminidase inhibitorOseltamivir & Zanamivir (1999)

Antivirals

Infection and disease Broad spectrum of disease

High proportion of pauci or asymptomatic

10-50% of GI symptoms Severe viral pneumonia in health

adult 10-20% of hospitalizations

required ICU Groups at increased risk of

severe disease once infected (hospitalization, ICU, death) Chronic medical conditions Pregnancy women Very young and the elderly Obese Aboriginal/ethnic minorities 40% were previously healthy

Highest rate of clinical infection: Teens and young adult

Highest rate of hospitalization: Children < 5 (mediam age

20s-30s) Highest rate of death:

Adult 50-64 (median 35-51; younger age group compared to seasonal influenza)

How is this pandemic different ? First large scale response under the revised International Health

Regulation (2005) framework Global sharing of information and viruses through expert network

E.g. virus sharing: As of 5 May 2010, 155 countries share 26,066 specimens with WHO Collaborating Centers

Significant, previous pandemic preparedness efforts, including the area of risk communication E.g. 140 countries with pandemic preparedness plans before the

pandemic Access to:

Antibiotics, antiviral, vaccines (developed and available in 6 months), high-quality health cares (ie ICU)

Early detection and response at international level E.g. virus sequence made publicly available on 25 April 2009 RT-PCR kit available on 2 May 2009

Spread of pandemics 1957: Spread throughout China in 6 weeks

and throughout the world in 6 months 2009-2010: Started in North America; spread

to all continents in less than 9 weeks and throughout the world in 10 months Announcement of pandemic phase 6 on 11 June

2009 74 countries reporting cases of (H1N1) 2009 virus

West Africa reported A(H1N1) pandemic outbreak only in early 2010

Early responses to the pandemic

No travel restrictions Attempt to contain the spread with societal

measures (e.g. school closures or antiviral prophylaxis in close communities)

More information is needed to assess the impact and cost effectiveness of the various strategies

Challenges Surveillance and severity assessment Phases in preparedness guidelines Communications Naming of the pandemic Global health challenges

Surveillance and severity assessment Severity assessed and monitored with a basket of indicators

3 dimentions: Severity of the disease (clinical epidemiological and virological) Vulnerability of the population Capacity to spread

During the pandemic, the heterogeneity of systems and indicators has been a major challenge for global monitoring Different age groups No standardized definition of underlying factors No standardized definition of influenza deaths Different laboratory capacity

More than 100 countries have very limited or no influenza surveillance capacity

流感大流行各個時期之分配

1 - 3

Phases 5-6

有效人傳人

時間

以動物疫情為主，偶而傳給人

擴散期

5 - 6

4

後高峰期

後流行期

Phases in preparedness guidelines Since 1999, pandemic phases have been

used as a tool for planning pandemic responses at global and country levels

Pandemic phases were never used during a pandemic

Main challenge: Publication of new guidelines in early 2009 presented a communications challenge, namely helping the media and Member States (MS) understand the meaning of the phases.

Communications The first phase went well: Early announcement,

transparent communication Then things started to unravel: Conspiracy theories

started to spread in media and through networks on the internet

The consequence were: Misunderstanding of the public health response from the

general public and low uptake of vaccine in some countries A number of parliamentary enquiries and external reviews

of technical agencies’ response to the pandemic New sources of information dissemination have to

be taken into account in future pandemic preparedness plans: internet, blogs, virtual social networks

Naming of the pandemic Do pork products cause swine flu? Yes, just as the Rocky Mountains cause rocky

mountain fever….. Legionnaires’ cause Legionnaires disease Limes cause Lyme disease！

Global health challenges International mass gatherings Global solidarity Access to antivirals Deployment to 72 countries

Access to pandemic vaccines Deployment started in November 2009 As of 30 August 2010, reached 72 countries 73 million doses

Concluding observations Certain events were correctly anticipated Eventual emergence of a pandemic Spread was more rapid than in the past

Certain events theoretically acknowledged, but still a surprise Started in North America Origin of pandemic virus came from swine H1 viruses

Certain events were simply surprising Effectiveness of one vaccine dose

Preparedness was crucial but remains incomplete Impact of control measures on the spread and

severity of the disease are being assessed.

Characteristics of 2009 H1N1 influenzaApril 15 2009 to April 10 2010, USA

Deaths 12,470 (8.9K-19.3K) Hospitalizations 274,000 (195K-403K) Cases 61,000,000 (43M-89M)

www.cdc.gov/flu

Asssessing severity assessments

Mortality alone does not reflect the full pandemic impact 90% of deaths generally among > 65 yos For H1N1, 90% among < 65 yos Lab-confirmed cases underreported Estimates of years of potential life lost range

334K to 1.2M Many difficult decisions need to be made

early when limited data may be availablewww.cdc.gov/flu

Next steps for severity assessment Efforts underway at WHO to identify new approach

to severity assessment CDC gathering input on a new framework drafted by

Reed and Biggerstaff which allows for: Data collection from early virologic and field investigations,

as well as established systems Assessment based on categories of transmission and

clinical severity Translation of the findings into context-appropriate

recommendations

www.cdc.gov/flu

Role of animal surveillance

Influenza-Ecology in the Aquatic Bird Reservoir Migratory bird reservoirs of all influenza A (16

HA and 9 NA subtypes) viruses Divided globally into two major clades:

Eurasian and American Influenza viruses cause no apparent disease

in natural reservoir species Replicate predominantly in the intestinal tract Most interspecies transmissions are

transitory

Spread of H5N1: to Sep 2010 Poultry: +500 millions Human cases: 504 Human deaths: 299

Changes required for successful avian to mammalian spread of influenza A viruses

Avian Mammalian

Temperature 42℃ 37℃

Site of replication Intestinal Respiratory

Mode of spread Fecal/waterborne Respiratory

Receptor specificity SAα,2-3 SAα,2-6

Duck influenza Ducks are mostly resistant to disease signs

after influenza infection Ducks possess an influenza sensor (RIG-I),

chicken lack RIG-I RIG-I initiates production of interferon-β Leads to activation of antiviral innate immunity

gene Transfer of duck RIG-I to chicken cells permit

induction of antiviral response

Barber et al PNAS 2010

Animal surveillance: looking to the future Improve biosecurity- eliminate live poultry markets The burden of influenza in swine- locally and

globally Virological and serological surveillance in apparently

healthy pigs- The Hong Kong model Genomics of influenza viruses from reservoir

species Predict which viruses have pandemic potential

Bacterial super-infection of influenza

Secondary bacterial infections R.T.H Laennec was the first to describe

secondary bacterial infections following influenza

He noted that the prevalence of pneumonia increase during an epidemic of “la grippe” in 1803 in Paris

Today it is well-appreciated that many influenza-related deaths are due to secondary invaders such as S. pneumoniaeand S. aureus

Bacterial pneumonia and pandemics It is estimated that 95% of all deaths during the

1918 pandemic were complicated by secondary bacterial pneumonia (primarily S. pneumoniae)

Estimated at 50-70% in 1957 and 1968 This has been a key concern for pandemic planning The emergence of the novel pandemic H1N1 strain

has led to increased opportunities to study the epidemiology and pathogenesis of secondary bacterial infection following influenza

Influenza and S. aureus S. aureus was the primary secondary invader in 1957 In recent decades, however, it had not been a

prominent cause of pneumonia With the emergence of USA300 strains of MRSA,

necrotizing pneumonia, particularly in association with influenza, has become much more common

In the 2008-2009 season, 44% of pediatric deaths from influenza (of those tested) had bacterial super-infection, 75% of the etiologic agents were S. aureus

Bacterial pneumonia and pH1N1 Few reports of bacterial superinfections in initial

descriptions of severe pandemic related disease However, most critically ill patients were treated with

broad spectrum antibiotics, and invasive assays (e.g. pleural taps) were not commonly done

Recent evaluations of severe and fatal cases show 25-50% have evidence of bacterial super-infection (S. pneumoniae, S. aureus, S. pyogenes), with 14-46% mortality

4 deaths in healthy children in Memphis from S. aureus super-infection during the H1N1 pandemic

Mechanism of viral-bacterial synergisum Factors enhancing bacterial adherence

Epithelial damage Alteration of epithelium through sialidase activity Upregulation of receptors for bacterial adherence

Factors facilitating bacterial access to normally sterile sites Mechanical alterations to airway or E tube function Changes in tropism of virus (ability to access the lower lung)

Factors altering innate immune response Increase inflammation through expression of cytotoxins Anergy of responses to bacteria during resolution of inflammation Dysregulation of protective immune pathways Alteration of bacterial clearance through effects on immune cells

Complementation of the virus by bacteria Clearance of influenza virus HA by bacterial proteases Complementation of PB1-F2 by bacterial cytotoxins

Timing of secondary infections 0-7 days after influenza infection

Virus replication in lung Innate immunity Pro-inflammatory state Onset of acute lung injury Influx of macrophages, neutrophils

7-14 days after influenza infection Regeneration of airway cells Transition to adaptive immunity Acute lung injury peaks then begins to resolve Influx of T-cells

7-14 days after influenza infection Antibody production Wound healing Anti-inflammatory state transition to memory anergy of innate

responses

PB1-F2: newly identified protein 87 aa peptide with predicted highly cationic,

amphipathic helix at C-terminal end Sequence spanning aa 63-75 targets peptide to

mitochondria Resembles some anti-microbial peptides What is the role of PB1-F2 in pathogenesis ? PB1-F2 from pandemic strains promote inflammation and

responds to morbidity PB1-F2 is important in secondary staphylococcal

pneumonia (yes for H5N1, pH1N1, not for H3N2)

Conclusion: inflammation PB1-F2 has immunostimulatory activity – C-terminal

portion of PB1-F2 from pandemic strains and H5N1 cause inflammation, recent H3N2 does not

Inflammatory lung damage appears to play a role in both induction and severity of bacterial pneumonia following influenza

PB1-F2 from 1918 and H5N1 viruses contribute to virulence in mice and to secondary bacterial pneumonia, 1995 H3N2 PB1-F2 does not

Global monitoring of antiviral susceptibility of pandemic

influenza A(H1N1) 2009 virus

Background Pre-pandemic (seasonal) H1N1 Sporadic oseltamivir resistance up to 2007 Global spread of oseltamivir resistance H275Y virus from

2007 Apparently independent of drug use Change in fitness of H275Y virus prior to spread

Growing public health interest in antiviral drug susceptibility NISN→GISN

Antiviral susceptibility of pandemic H1N1 2009 NAI only (Gubareva et al May 2009)

Why monitor ? Integral part of pandemic monitoring and

assessment Monitor changes to virus, clinical presentation or

epidemiology Risk assessment (including under IHR) Responsibility to inform global community

Implications for clinical management Treatment guidance Reduction in risk for selection of resistant virus

Role of prophylaxis Treatment regimens Infection control

Results I

Western pacific

Euro Americas Africa South-East Asia

Estimated Med

No. of oseltamivir resistance isolate

120 99 82 1 0 1

Test in WHO

1350 1505 8456 140 47 59

Test in other lab.

++ ++ ++ ? ? ?

303/304 had H275Y substitution

Results II Associated with postexposure prophylaxis:

19.6% Immunosuppressed patients: 86.28% Associated with treatment: 98.33% No association with drug use: 28.9% Preliminary notification: 73.24%

Conclusions No evidence of widespread community circulation of

NAI resistance virus Sporadic, geographic dispersed cases Few examples of limited case to case transmission 3 case cluster

Focal, local transmission only Vietnam cluster highest potential public health risk

Severely immunocompromised a vulnerable patient population Presumptive treatment Infection control

Zanamivir remains treatment option where oseltamivir resistance likely or known

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