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Pandemic Influenza Epidemiology & Mitigation, History & CurrentThreat Slides adapted (with thanks) from: WHO: www.who.int/ & www.influenzatraining.org/ European CDC: http://ecdc.europa.eu/en/ US CDC: www.cdc.gov/h1n1flu/index.htm Univ. of Pittsburgh Supercourse: www.pitt.edu/~super1/lecture/lec34601/ And several other sites Eric S. Starbuck, DrPH, MPH, Public Health Advisor, H2P Created April 24, 2006 – Last Updated Aug. 17, 2010 (Mitigation slides focused on interventions for low resource settings) (Use PowerPoint slide show mode for animation in several slides)

Flu threat

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Page 1: Flu threat

Pandemic InfluenzaEpidemiology & Mitigation, History & CurrentThreat

Slides adapted (with thanks) from:• WHO: www.who.int/ & www.influenzatraining.org/ • European CDC: http://ecdc.europa.eu/en/• US CDC: www.cdc.gov/h1n1flu/index.htm• Univ. of Pittsburgh Supercourse: www.pitt.edu/~super1/lecture/lec34601/ • And several other sites

Eric S. Starbuck, DrPH, MPH, Public Health Advisor, H2PCreated April 24, 2006 – Last Updated Aug. 17, 2010(Mitigation slides focused on interventions for low resource settings)

(Use PowerPoint slide show mode for animation in several slides)

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251 cases, 17% CFR(43% of cases were Health Care Workers)

1,755 cases, 17% CFR

China (excl. Hong Kong & Taiwan):5,327 cases, 7% CFR

Taiwan: 346 cases, 11% CFR

63 cases, 8% CFR

• Mutation for H2H respiratory transmission after jump from palm civets (used for food) in south China?• Local transmission in Canada, China, Hong Kong, Mongolia, Philippines, Singapore, Taiwan, & Viet Nam• 8,096 total cases in 26 countries + Hong Kong + Taiwan• 1,706 of these cases (21%) were Health Care Workers• 774 deaths - 10% case fatality

(Room 911)

238 cases, 14% CFR(41% of cases were Health Care Workers)

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Lessons from SARS (D. Nabarro)

• Global action is critical

• Give priority to well-being of front line personnel

• Engage communities

• Involve media

• Don’t withhold information

• Encourage responsible, science-based & effective responses

• Harness energies of multiple actors

• Supportive leadership & building effective coalitions are vital

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SARS Containment: Detect, Isolate, Quarantine

Some specific characteristics of the SARS virus helped the

world to “dodge the bullet.” (Unfortunately, flu is different.)

Page 5: Flu threat

Contents1. Links between avian, swine, seasonal, & pan. flu;

2. Meaning of “H” & “N” & links to virulence & immunity;

3. Natural reservoirs of Influenza A & evolution into pandemic strains;

4. Modes of person-to-person transmission (& serial interval, reproductive number, incubation period, etc.);

5. Pandemics of the 20th century (esp. 1918: waves, seasonality, attack rate, mortality, & risk groups);

6. Current distribution of H5N1 HPAI;

7. Human H5N1 & pandemic H1N1 (pH1N1)  (Distribution, transmission, clusters, risk groups, treatment, mortality);

8. Current pandemic threat & WHO Phases of Pandemic Alert;

9. Immunization, anti-virals, & non-pharmaceutical interventions (NPIs);

10. Potential pandemic social & economic impact, & key unpredictables.

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Three Different Kinds of Influenza

Seasonal FluSeasonal Flu

Related to each other, but public health implications are very different

Pandemic Flu

Bird Flu

(or, more generally, flu in animals, including swine)

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Seasonal Flu SymptomsRapid onset of one or more respiratory or general symptoms:

Fever, Muscle aches, Fatigue, Headache, Cough, Sore throat, Sneezing, and/or Runny or stuffy nose.

Particularly in children & in pH1N1: Nausea or vomiting, Abdominal cramps, and/or Diarrhea.

(Time Lines of Infection & Disease in Human Influenza: A Review of Volunteer Challenge Studies. Am J Epi 2008; 167: 775–785:http://aje.oxfordjournals.org/cgi/reprint/167/7/775)

(No algorithm for identification of flu cases based on symptoms can be both sensitive & specific.)

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U.S. Seasonal Flu-Associated Age-Specific Rates of Hospitalization & Death

*Thompson WW, JAMA, 2004

0

100

200

300

400

500

600

0 - 4 Yrs 5 - 49 Yrs 50 - 64 Yrs 65+ Yrs

Age Group

Ho

spit

aliz

atio

ns

Per

100

,000

Per

son

Yea

rs

100

0

60

40

20

80

Death

s Per 100,000 P

erson

Years

“In seasonal influenza, the overwhelming majority of severe morbidity & mortality occur in persons of 65 years of age or more.” (WHO, 5/18/09)

Annually in US, for all ages:• ~ 36,000 deaths • > 200,000 hospitalizations

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The flu virus must invade animal cells to replicate (which can cause illness in the animal).

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Influenza Type A Virus – The Cause of All Avian & Pandemic Flu & Much of the Seasonal Flu

Neuraminidase(N) protein facilitates virus detachment

Hemagglutinin(H) protein facilitates viral attachment onto animal cells for invasion & replication

8 RNA gene segments

The extent of illness in animals & humans is due to the expression of several genes in combination

(H & N are recognized by our immune system)

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Circulating Seasonal Influenza A Sub-Types& the 3 Pandemics of the 20th Century

1920 1940 1960 1980 2000

H1N1 Seasonal Flu H1N1 Seasonal Flu

H2N2

H3N2 Seasonal Flu

1918/19: H1N1 1957/58: H2N2 1968/69: H3N240-100 million deaths 1 - 4 million deaths 1 – 4 million deaths

5 pandemics since 1889 (H3N8?), with 11 to 41 years (average 30 years) between each = ~ 3% annual risk of pandemic onset (based on history)

1977 lab escape?

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• A pandemic will likely result in larger numbers of all types of cases than seasonal flu.

• The proportions of types of cases in a pandemic will depend on the severity of the pandemic.

(Infection does NOT = illness)

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1918, 1957, & 1968: US & UK Overall Clinical Attack Rates

Range: ~ 23% – 39%. (Slide from UK Dep. of Health)

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

1918 NewYork State

1918Manchester

1918Leicester

1918Warrington& Wigan

1957 SELondon

1957 SouthWales

1957Kansas City

1968Kansas City

cli

nic

al

att

ac

k r

ate

(%

)

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Case Fatality & Attack Rates in the US in 1918, 1957, & 1968, &Projected US Mortality of a Modern Pandemic (CDC, Feb. 2007)

(Mortality is driven mainly by case fatality, rather than by the attack rate.)

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Camp Funston, Kansas, March 1918: Sadly, the comparatively benign first wave was not at all predictive of what was to come

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Every Community Should Expect ~ 1 – 3 Waves / Outbreaks, Each Lasting ~ 6 – 12 Weeks (Over a Duration of a Year or More)

The 2nd wave was the killer that swept around the world, causing death from (?):• Primary viral pneumonia &

Acute Respiratory Distress Syndrome (ARDS), &

• Secondary bacterial infections, particularly pneumonia

Severity of one wave is NOT predictive of severity of subsequent wave(s).

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Pandemic flu waves may not coincide with flu season in northern & southern hemispheres. (Shaded columns below indicate normal seasonal patterns of influenza.)

(Miller, Viboud, Balinska, & Simonsen, NEJM, May 7, 2009)

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And, as the Second Wave Swept Around the World:

Called the “Spanish Influenza” because of extensive press coverage of it in Spain. The King got it & neutral Spain had no press censorship.

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• Sequestration protected American Samoa, & Australia from the 2nd wave, while Western Samoa lost 22% of its population

• Mortality varied over 30-fold across countries• Income differences contributed to this variation

(Murray CJL, Lopez AD, et al, Lancet 2006;368: 2211-18)

Published Pandemic Mortality Estimates for Selected Countries(Johnson NPAS & Mueller J. Bulletin of the History of Medicine (2002) 76:105-15)

(1918: 28% of current global population. http://birdfluexposed.com/resources/NIALL105.pdf)

USA: 675,000

Bangl./India/Pak.: 18.5 million

Nigeria:455,000

Egypt:139,000

Guatemala: 49,000

Afghan.:320,000

Indonesia:1.5 million

Philip.:94,000

Japan:388,000

Brazil: 180,000 South

Africa:300,000

Kenya:150,000

Global Total: 50 – 100 million

(WHO: 20-50 million)

Russia/USSR: 450,000

Spain: 257,000

Canada: 50,000

Chile: 35,000

Australia:15,000, in1919 only

British isles:249,000

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(Also had some shift in deaths to younger adults in 1957 & 1968)

typical for seasonal flu

U.S. life expectancy dropped by 12 years

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H1 N1H2 N2H3 N3H4 N4H5 N5H6 N6H7 N7H8 N8H9 N9H10H11H12H13H14H15H16

Haemagglutinin subtype Neuraminidase subtype

Influenza A Sub-Types: H1, H5, & N1 (stars), & Reservoirs (shaded)

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Origin of Pandemic Influenza

Migratory water birds

H 1-16

N 1-9

Domestic pig

Domestic birds

(All human flu pandemics comefrom flu in animals by 1 of 2 mechanisms)

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1.1. ConstantConstant MutationMutation: Small random changes in viral RNA : Small random changes in viral RNA during replication sometimes cause important change in shape during replication sometimes cause important change in shape

of H, N, etc., & in transmission or virulence, & are then of H, N, etc., & in transmission or virulence, & are then propagated through continuing infections of new individualspropagated through continuing infections of new individuals

Human Cells

Virus(Can onlyreplicate

insideanimalcells)

New H shape allows attachment to human cells or avoidance of

antibodies

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Migratory Water Birds

2. Re-Assortment: Animal & human viral RNA segments

exchanged in pig or human infected with both human &

animal flu at once, causes instantaneous big change in

virus

Pig or Human

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1918, 1957, & 1968 Pandemics from Mutation or Reassortment

Belshe RB. N Engl J Med 2005;353;21

The right combination of several mutations more likely after several years?

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Swine Flu• A respiratory disease caused by type A

influenza - regularly causes outbreaks in pigs.

• In 1918, humans passed H1N1 on to the pigs, which have had it ever since.

• A 1976 H1N1 swine flu outbreak at Fort Dix, New Jersey, USA, caused 230 cases, several cases of serious illness, & 1 death:

– Over 40 million people were immunized.

– Immunization stopped after over 500 cases of Guillain-Barre Syndrome, a severe paralyzing nerve disease.

• From Dec. 2005 to Feb. 2009, 12 human cases of swine flu were reported in the US.

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Edgar Hernandez, "Boy Zero," has a monument in the village square of La Gloria, in Veracruz, Mexico. A sample of his blood, drawn on March 2 later tested positive for pH1N1.

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Published by AAAS

Fraser et al., Science 324, 1557 -1561 (2009)

Results of a detailed investigation into an outbreak in the village of La Gloria

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Origin of “Swine-Origin”H1N1

(Garten, et al)

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Human & Swine Influenza A, 1918 – 2009

2009:

• A new H1N1 strain, not previously seen in humans or swine

• NOT a new sub-type for humans

• Reassorted gene segments from:

• Eurasian swine, &

• North American swine (with human & N. American avian gene segments) Morens D et al. N Engl J Med

2009; 10.1056/NEJMp0904819

= 1918, 1957, 1968, & 2009 pandemics

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Each of these are strains of the H1N1 or H1N2 sub-types of Influenza A

Phylogenetic Tree of Hemagglutinin H1: Swine vs. Seasonal

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• April 24: Gov. of Mexico activates the National Pandemic Preparedness & Response Plan, & announces closure of schools in metropolitan Mexico City.

• A mass media campaign is launched to promote respiratory hygiene & alert the public about flu transmission.

• Additional social distancing measures include closure of restaurants & entertainment venues, & cancellation of large public gatherings nationwide.

May 11: As schools reopen, parents are reminded to keep children with flu symptoms at home.

April 22–24: Canadian & US CDC labs identify novel swine-origin influenza A (H1N1) in specimens from Mexican patients.

(MMWR, June 5, 2009 – www.cdc.gov/mmwr )

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pH1N1 in Mexico, Wave 1Lab Confirmed Deaths by Age

Initial modeling of the Mexico outbreak suggested severity similar to that of the 1957 pandemic, with CFR ~ 0.4% +/- (?)

(That was moderate, US CDC Category 2, NOT “mild.”)

(Science, May 11, 2009)

(n = 97. MMWR, June 5, 2009 – www.cdc.gov/mmwr)

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Mexico Epidemic Curve – Confirmed Cases by Day

0

200

400

600

800

1000

1200

3/1/

2009

4/1/

2009

5/1/

2009

6/1/

2009

7/1/

2009

8/1/

2009

9/1/

2009

10/1

/200

9

11/1

/200

9

12/1

/200

9

Day

No

. o

f C

on

firm

ed C

ases

Source: Secretaria de Salud, Mexico

Total Number of Confirmed Cases = 66,415*As of December 09, 2009

*NOTE: Numbers can change

Epidemiological Alert

4/13/09

School Closure4/24/09

Suspension of Non-essential Activities5/1/09

School Open5/12/09

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Why reported

lab-confirmed cases are only the tip of the iceberg.

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• 4/15–17: CDC confirms first 2 US cases• 4/24: News that viruses in US & Mexico are the same

• 4/25: WHO declares a Public Health Emergency of International Concern

• 4/26: US declares a public health emergency & deploys ¼ of Strategic National Stockpile of Tamiflu to states

pH1N1 Cases Over Time (Wikipedia graph, WHO data)

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(Border closures & travel restrictions are not recommended –they may delay spread of the virus, but are unlikely to stop it.)

pH1N1 spread rapidly around the world (even though more of its genes are swine & human, than avian!)

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(June 3: Sustained community transmission in the 2nd WHO region)

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WHO Phases of Pandemic Alert (2009) (WHO phases apply to the whole world)

• Phase 6 = Sustained community transmission of a new flu virus in 2 or more WHO regions.

• “Designation of this phase will indicate that a global pandemic is under way.”

(www.who.int/csr/disease/avian_influenza/phase/en/index.html - See notes below)

“At this time, WHO considers the overall severity of the influenza pandemic to be moderate.” (June 11, 2009)

• 4/27/09: WHO declares Pandemic Alert Phase 4

• 4/29: WHO declares Pandemic Alert Phase 5

• 6/11: WHO declares Pandemic (Phase 6)

(8/10/2010: WHO declares Post Pandemic phase)

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Time Course of the H1N1 Pandemic for Select Countries*

Peak(s) (N.B. Not all countries have detected a "peak" in activity )

Peak(s) (N.B. Not all countries have detected a "peak" in activity)

Peak(s) (N.B. Not all countries have detected a "peak" in activity )

Sporadic Cases Detected

Cases detected

Data sources vary by country and include: country provided epi curves of case onset, ILI consultation rates, Virus isolates by date, % positive specimens collected, media source (first case report for some countries)

*Table developed by: Maria Van Kerkove PhD, MRC Centre for Outbreak Analysis and Modeling, Imperial College London

Page 45: Flu threat

(Semi-Log Scale)(Graph from Wikipedia)

Spread or rapid spread in: • Northern hemisphere Summer• Southern hemisphere Winter• & in some tropical countries

Many countries saw periods of several weeks or months between the first introduction of the virus & their first wave. In some northern countries: …. it appeared “that seeding events established by travelers from affected areas are occurring in …… schools. The spread of the virus within these settings causes an amplification of the viral reservoir ……. ultimately leading to community spread.” (Eurosurveillance, May 7, 2009)

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UK: Tamiflu Prescriptions by Telephone Hotline Goes Live July 23

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UK Experience with “Containment”: “There is insufficient information at present to draw firm conclusions about the effectiveness of the measures taken during the containment phase to slow the spread of infection in the population or to affect the ultimate size of the first wave of the pandemic in England which peaked in late July.”

“During June, mounting evidence of sustained community transmission suggested that the benefit of containment measures was increasingly doubtful, & preparations were made to move to a treatment only approach.” (www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1274088320581)

• Early detection of suspected cases

• Lab testing

• Isolation & treatment of cases

• Antiviral prophylaxis of close contacts

• Detailed investigation of cases & contacts

Page 50: Flu threat

Distribution by age & gender of influenza A(H1N1)v cases in 28EU/EEA countries, April 19 – Sep. 22 (n = 9,813. ECDC, Nov. 6, 2009)

Serology & age-specific rates of illness & hospitalization suggest those over 60 / 65 may be partially protected by exposure to similar H1N1 strains before 1950 / 1945.

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“On July 24, 2009 official reporting of individual cases of confirmed and probable novel H1N1 infection was discontinued.”

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“Over 99% of all subtyped influenza A viruses being reported to CDC were 2009 influenza A (H1N1) viruses.” (CDC, 12/18/09)

(Some reporting bias: CDC believes there was no increase in seasonal flu cases in weeks 17 - 19.)

(through week 39, ending Oct. 3)

Page 55: Flu threat

• The extent of pH1N1 transmission has looked different in different parts of the US.• Most suspected cases are no longer being tested.• CDC estimated on 7/24 that there had been well over 1 million cases in the US to date

(suggesting quite modest wave 1 penetration of the population of over 300 million).

This shows the extent of flu (ILI & lab confirmed) reported within each state.

(The 2nd Wave has come to an end in the US)

Page 56: Flu threat

The 2nd Wave in the US peaked in October (as did H1N1 in 1918).

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(John Barry. The Great Influenza.)

“Few” countries have the staff, facilities, equipment, & hospital beds needed to cope .… (in a severe pandemic wave - WHO, Oct. 2005)

Pandemic: A total of 25% to 45% of everyone on earth gets sick with the flu. (WHO, April 2009)

In May 2009, New York City hospitals used tents in their parking lots to expand emergency department surge capacity because of care seeking for non-severe illness, even after public communications discouraging this.

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Ages of Hospitalized Patients with Novel Influenza A (H1N1) The 1st Wave in New York City – Cumulative as of 7/7/09 (n = 909)

NYC Health Department (www.nyc.gov/health)

The highest rates of hospitalization (by far) are in kids <5.

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Age Distribution of Hospitalized Pandemic H1N1 CasesRates in Australia, New Zealand, Argentina, & Chile, 2009

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Shortnes

s of b

reat

h

Musc

le p

ain

Runny nose

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• ……….. “an increased concentration of severe respiratory illness admitted to the intensive-care units, which is higher in number than previous influenza outbreaks. 

• “The majority of the cases are in people of Aboriginal descent.  ……

• “Manitoba ….. is reporting a surge in the number of people requiring intensive care for ILI.

Government of the Province of Manitoba, June 8, 2009(http://news.gov.mb.ca/news/index.html?archive=2009-06-01&item=6046)

June 16: Government of Manitoba seeking doctors & nurses to “provide additional coverage in First Nations communities”

WHO, 8/21/09: “Many countries, including Australia, Canada, New Zealand, & the U.S. have noted that their indigenous peoples appear to be at increased risk of severe disease ……. While it still has not been clearly determined how much of the increased risk ……… is due to issues related to access to care, high rates of chronic medical conditions ………. , or other factors, countries with indigenous & other vulnerable populations should carefully evaluate the situation & consider ways to mitigate the impact of the pandemic in the coming season in these populations.”

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A small subsets of patients rapidly develop very severe progressive pneumonia.

In these patients, severe pneumonia is often associated with failure of other organs, or marked worsening of underlying asthma or chronic obstructive airway disease.

• Primary viral pneumonia is the most common finding in severe cases & a frequent cause of death.

• Respiratory failure & refractory shock are the most common causes of death.

• Secondary bacterial infections are found in ~ 30% of fatal cases, including Streptococcus pneumoniae & Staph. aureus (incl. methicillin-resistant strains)

• Prompt treatment with oseltamivir or zanamivir reduces severity & deaths.

• Many severe cases occur in previously healthy young people.

• Risk of severe or fatal illness is highest in three groups:

•Pregnant women, especially during the third trimester of pregnancy,

•Children younger than 2 years of age, &

•People with chronic lung disease, including asthma.

• Neurological disorders can increase risk of severe disease in children.

WHO on Severe Cases of pH1N1

(Oct. 16, 2009: www.who.int/csr/disease/swineflu/notes/h1n1_clinical_features_20091016/en/index.html)

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“Even if the current pattern of usually mild illness continues, the impact of the pandemic

during the second wave could worsen as larger numbers of people become infected.

Larger numbers of severely ill patients requiring intensive care are likely to be the most

urgent burden on health services, creating pressures that could overwhelm intensive

care units & possibly disrupt the provision of care for other diseases.” (WHO, Aug. 28, 09)

Low: Demands on health-care services not above usual levels. Moderate: Demands on services above usual demand levels, but still below maximum capacity. Severe: Demands on services exceed capacity.

Impact on Health Care Services – Week 49 – Nov. 30 - Dec. 6 (WHO, Dec. 18, 2009)As of 11/29/09, Albania, Kazakhstan, Kyrgyztan, Moldova, Mongolia, Sri Lanka, & Ukraine had reported severe impact for 1 to 3 weeks each.

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So far, mortality of pH1N1 (in all age

groups combined) appears no

worse than for seasonal flu.

(As of January 2, 2010)

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Credible Estimates of CFR in Developing Countries

• Mexico, April 2009: CFR ~ 0.4% www.sciencemag.org/cgi/reprint/324/5934/1557.pdf

• Thailand, June 2009: CFR ~ 0.58% www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19292

• Pune, India, Aug. – Oct. 2009: CFR ~ 0.86% www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010540

Was it really this high, or did all 3 studies under-estimate the denominator?

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0.0067

0.0269 0.0263

0.000

0.010

0.020

0.030

0-17 years 18-64 years 65 yearsand older

0-17 years32%

18-64 years58%

65 years and older10%

Total Estimated Cases =60,000,000

0-17 years32%

18-64 years58%

65 years and older10%

0-17 years10%18-64 years

77%

65 years and older13%

Total Estimated Hospitalizations = 270,000

Total Estimated Deaths = 12,270

CDC Estimates for the US by Age, April, 2009 – March 13, 2010(CDC, April 19, 2010: www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm)

Case Fatality Rate = ~ 0.02%

(1 in 5,000)

Correction factors: For every reported lab-

confirmed death, there were actually ~ 3.9 deaths.

For every reported lab-confirmed hospitalization, there were actually ~ 5.7 hospitalizations.

These 10,700 deaths in those < 65 is 3 times the average in seasonal flu < 65 In the US in 1918, H1N1 was ~ 100 times as deadly (~ 2% CFR) as in 2009

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• In the US, the 1st wave did not result in a substantial increase in mortality in the total population (across all age groups).

• However, the 2nd wave had an impact on P&I mortality: “The proportion of deaths attributed to pneumonia and influenza (P&I) was above the epidemic threshold for the eleventh consecutive week.” (CDC, 12/18/09)

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• Deaths <65: pH1N1 stands out.

• Unlike most of the US, NYC had a more substantial 1st than 2nd wave.

• Wave 1 mortality peaked ~ 3 – 4 weeks after the peak in care seeking for ILI.

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(Week ending May 22, 2010)

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Apparent Pandemic H1N1 Case Fatality by Age CDC, JULY 16, 2009 (n = 262 US deaths – CFR is over-estimated)

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From last European CDC daily update, Jan. 19, 2010 (over 14,000 reported lab-confirmed deaths)

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Pandemic (H1N1) 2009 - update 110, 23 July 2010 – “As of 18 July 2010, worldwide more than 214 countries & overseas territories or communities have reported laboratory confirmed cases of pandemic influenza H1N1 2009, including over 18366 deaths.”

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• H5N1 & the 20th century pandemics had shaped expectations

• H5N1 epizootic in birds

• H5N1 case fatality in humans

• Emergence in Asia expected

• Origin in birds, not pigs

• Planning for H5N1 dominated

• Focus on 1918-like scenarios

H1N1 from pigs in Mexico was not the pandemic the world had been preparing for:

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H5N1’s Global Genetic Roulette Table

Persistence & spread ofH5N1 is historicallyunprecedented for HPAI

63 countries(incl. Nepal in 2009& Bhutan in 2010)

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Current Global Spread c/o Trade in Bird Products & Bird Migration

Highly Pathogenic H5N1 Influenza Virus in Smuggled Thai Eagles, Belgium (CDC)

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As of Aug. 16, 2010: 504 lab.-confirmed cases in 15 countries, including 299 deaths (Case Fatality: `59%)

Expect human cases in all areas with substantial human exposure to H5N1 HPAI+ birds

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Is this strong seasonal pattern because flu transmission is favored by lower temperature, lower humidity, and/or less sunlight (vitamin D)?

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Source of infection is unclear in 25%+ of cases.Environmental exposure? (Visiting live poultry markets. Fomites? Fertilizer? Aerosolized Feces?) Very few cases in presumed high-risk groups (Commercial poultry workers, workers at live poultry markets, cullers, veterinarians, & health staff caring for patients without using protective equipment)

90% of clusters involve blood relatives, some due to person-to-person transmission (genetics?)

Preparing or disposing of diseased birds

Handling fighting cocks

Handling poultry, esp. asymptomatic ducks

Consuming uncooked duckblood (& undercooked poultry?)

H5N1 in Humans Remains Rare:Currently Implicated Exposures

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One theory is that most people have bird-like receptors only on cells deep in their lungs, while some families have more in their upper airways (though things may be more complex).

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• Clusters indicate possible person-to-person transmission;

• Or common exposure to an environmental source, like birds.

• Here, a cluster is defined as 2 or more persons:

• Who have been in contact with each other, &

• Who became very sick with a respiratory disease, &

• At least 1 of whom is a WHO lab-confirmed H5N1 case.

More than 1/4 of cases are in clusters

http://h5n1flu.blogspot.com/

This kind of adistribution of illness onset dates would be suggestive of person-to-person transmission.

R0=2, v=5.5 days

(www.fluwikie.com lists 40 clusters in 10 countries, from Dec. 2003 through Apr. 2007)

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established in 1812 January 27, 2005 vol. 352 no. 4

Probable Person-to-Person Transmissionof Avian Influenza A (H5N1)

Kumnuan Ungchusak, M.D., M.P.H., Prasert Auewarakul, M.D., Scott F. Dowell, M.D., M.P.H.,Rungrueng Kitphati, M.D., Wattana Auwanit, Ph.D., Pilaipan Puthavathana, Ph.D., Mongkol Uiprasertkul, M.D., Kobporn

Boonnak, M.Sc., Chakrarat Pittayawonganon, M.D., Nancy J. Cox, Ph.D., Sherif R. Zaki, M.D., Ph.D., Pranee Thawatsupha, M.S., Malinee Chittaganpitch, B.Sc., Rotjana Khontong, M.D., James M. Simmerman, R.N., M.S., and Supamit Chunsutthiwat, M.D.,

M.P.H.

(http://birdflubook.com/resources/Ungchusak333.pdf)

Thailand, Sep. 2004:A. 11 year old girl died in

Kamphaeng Phet province without H5N1 test.

B. Mother from BKK visited daughter in hospital, H5N1+ without poultry exposure, & died.

C. Aunt H5N1+, recovered

Page 97: Flu threat

April /May 2006 Karo, N. Sumatra cluster

• Limited WHO/MOH containment activities

• No transmission beyond this family

• Local people resist chicken culling & demand departure of WHO team

"Thank God, the result came back negative," MOH official on 1 of 4 nurses with flu symptoms after caring for H5N1 cases, Jakarta Post, June 4, 2006. (3+ cases in health workers = trouble)

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Human cases of H5N1 in NWFP, Pakistan,Oct. – Nov. 2007: The Peshawar family cluster

Conclusion ……. “evidence supports a chain of transmission beginning with poultry-to-human transmission followed by human-to-human transmission for 3 generations of transmission. Despite thorough investigation and active surveillance, there was no evidence of sustained transmission in the community.”

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(54 clustersin 11 countries)

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“Should the virus improve its transmissibility by acquiring, through a reassortment event, internal human genes, then the lethality of the virus would most likely be reduced.

“However, should the virus improve its transmissibility through adaptation as a wholly avian virus, then the present high lethality could be maintained during a pandemic.” (page 15)

… “some modelling studies have suggested that pandemic spread could not be fully sustained in the presence of very high mortality.

“All such matters remain difficult to predict.” (page 16)

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… “ferrets were co-infected with recent avian H5N1

…. & human H3N2 …. viruses. ..… approximately

9% of recovered viruses contained genes from

both progenitor viruses. .…. No transmission by

direct contact between infected and naïve ferrets

was observed. These studies indicate that

reassortment between H5N1 avian influenza &

H3N2 human viruses occurred readily in vivo….. it

is reasonable to conclude that continued exposure

of humans & animals to H5N1 alongside seasonal

influenza viruses increases the risk of generating

H5 subtype reassortant viruses” ………..

Journal of Virology, June 5, 2009

Reassortment between Avian H5N1 & Human H3N2 Influenza Viruses in Ferrets:

A Public Health Risk Assessment S Jackson, N Van Hoeven, L Chen, TR Maines, NJ Cox, JM Katz, & RO

Donis Influenza Division, US CDC, Atlanta, GA (http://jvi.asm.org/cgi/content/abstract/83/16/8131)

How much more likely is H5N1 reassortment after pH1N1 has become widespread in H5N1 endemic countries?

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“Here, we co-infected cultured cells with the pandemic swine-

origin influenza virus (S-OIV) and a contemporary H5N1 virus

and found that these two viruses have high genetic

compatibility. Studies in human lung cell lines indicated that

some reassortants had better growth kinetics than their parental

viruses. We conclude that reassortment between these two

viruses can occur and could create pandemic H5N1 viruses.”

(http://jvi.asm.org/cgi/content/short/JVI.01140-10v1?rss)

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“These data show that influenza virus A/Indonesia/5/05 potentially requires only a single amino acid substitution to acquire human receptor specificity, while at the same time remaining replication competent, thus suggesting that the pandemic threat posed by HPAI H5N1 is far from diminished.”

(http://jvi.asm.org/cgi/content/abstract/JVI.02737-09v1)

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Continuing Widespread H5N1 HPAI = Continuing Serious H5N1 Pandemic Threat

H5N1 HPAI in poultry is now endemic in several countries, including Bangladesh, China, Egypt, Indonesia, & Viet Nam.

35 countries in 2007,28 countries in 2008,17 countries in 2009(www.oie.int/eng/info_ev/en_AI_factoids_1.htm)

(All of these countries, including all “high burden” H5N1 countries, have reported pH1N1 cases.)

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Pandemic H1N1 has already reassorted in pigs.

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WHO Interim Protocol Rapid Operations to Contain the Initial

Emergence of Pandemic Influenza Updated October 2007

….. “containment of a pandemic might be possible at the initial stages” ….

Emphasis within the Containment Zone:

• Antivirals for treatment & prophylaxis• Movement restrictions in & out• Non-pharmaceutical interventions

Emphasis in both zones:

• Surveillance & laboratory testing• Communications & social mobilization

• WHO had a stockpile of 3 million 10-capsule courses of Tamiflu for this.

• But “containment” may be more likely to delay onset than prevent a pandemic.

• News of this = warning of high risk of imminent pandemic onset

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• In 2007, the US Centers for Disease Control started conducting agency-wide simulations of pandemic spread to the US, with initial case fatality of ~ 20%. 

• If CFR stayed at ~ 20%, there would be ~ 15 – 27 million deaths in the US alone (assuming the expected 25% - 45% attack rate).

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Three Requirements for a Flu Pandemic:

1. Novel flu virus for humans Yes Yes, +/-

2. Ability to replicate in humans Yes Yes & cause illness

3. Ability to pass easily Not Yet Yes from person to person (signaled by growing clusters / outbreaks of human cases)

H5N1 pH1N1

“The question remains open: what is needed for the H5N1 virus to transmit efficiently from one human to another?

Overall, the genetic controls of cross-species infectivity and transmissibility of influenza viruses are complex and not yet fully understood.” WHO, Nov. 2006.

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“In Phase 3, an animal or human-animal influenza reassortant virus has caused sporadic cases or small clusters of disease in people, but has not resulted in human-to-human transmission sufficient to sustain community-level outbreaks. Limited human-to-human transmission may occur under some circumstances, for example, when there is close contact between an infected person and an unprotected caregiver. However, limited transmission under such restricted circumstances does not indicate that the virus has gained the level of transmissibility among humans necessary to cause a pandemic.”

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Avian Flu: Confirmed Human CasesFrom Sub-Types other than H5N1

(H5N1 is Not the Only Avian Threat)(See map: http://ec.europa.eu/health/ph_threats/com/Influenza/ai_human_en.htm)

• H7N2 in the USA, 2002-2003: 2 cases

& H7N2 in the UK in 2007: 4 cases

• H7N3 in Canada in 2004: 2 cases

& H7N3 in the UK in 2006: 1 case

• H7N7 in the Netherlands, 2003: 89 cases, 1 death

• H9N2 in Hong Kong, 1999-2003: 3 cases

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Flu Pandemic Gravest Threat to UK Security: Could Claim Up to 750,000 Lives

Friday, 8 August 2008

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Potential Impact Beyond Flu-Related Mortality: In 1918, Worker Absenteeism Led to

Social & Economic Disruption

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In the 21st Century (in a severe pandemic wave):Pandemic Wave Peak Worker-Absenteeism ~50% (?)

+ Long Supply Lines & Just-In-Time Delivery of Goods = Big Impact on Availability of Goods & Services?

(www.cidrap.umn.edu/index.html)

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Categories of Risk: Pandemic Flu

LivelihoodsLivelihoods

Human HealthHuman Health

Governance &Security

Governance &Security

Social & Humanitarian Needs

Social & Humanitarian Needs

Economic SystemsEconomic Systems

• Food & income loss from decreased economic activity

• High illness & potentially high death rates• Overstretched health facilities• Disproportionate impact on vulnerable

• Increased demand for governance & security• Higher public anxiety• Reduced capacity due to illness & death

• Deterioration of coping & support mechanisms• Interruption in public services

• Trade & commerce disruptions• Degraded labour force (up to 50% ??)• Interruption of regular supply systems

UNSIC

Slideadapted from:

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A Whole-of-Society ApproachTo Pandemic Preparedness

(WHO slide, May 2008)

Business continuity

Surge capacity

Critical interdependencies

Clear command and control

Social distancing

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(16 recommended actions, 3 pages, 8/09)

www.cdc.gov/h1n1flu/business/toolkit/quickreference.htm

www.med.govt.nz/upload/27552/Business-Continuity-Planning.pdf

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(Health Sector)

(+ antibiotics for 20 bacterial pneumonia)

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Students receiving H1N1 vaccinations at a hospital in Suining, China, near the end of 2009 (Reuters)

Pandemic Vaccine

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Current (~1950’s!) flu vaccine technology requires slow production in eggs (though recent progress includes growth of virus in cell cultures instead) & targets strain-specific surface antigens (don’t work for all strains of sub-type)

SeasonalVaccineAntigensA

Strain of Type A

Subtype H1N1

A Strain

of Type B

AStrain

of Type ASubtype H3N2

Recent seasonal flu vaccines appear to provide little or no protection against pH1N1.

Page 122: Flu threat

Annual Process of Development, Manufacturing, & Distribution of Seasonal Flu Vaccine

The time lag between vaccineproduction & seasonal flu outbreaks (often 6 months or more) can result in a mismatch between the vaccine & thecirculating virus.

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(for USA)

(In millions of courses for the US market)

• Global flu vaccine production capacity does not yet meet global need.

• The US goal is to be able (by 2011) to immunize the entire US population within 6 months of pandemic onset. (Long-term

goal is auniversal influenza A vaccine)

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Recommendations for Immunization of the US Population, Advisory Committee on Immunization Practices, 7/29/09

(Health Care Personnel & Emergency Medical Services)(Contacts of infants under 6 months)

Time & Increasing Vaccine Availability

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2009 H1N1 Vaccine Doses Allocated, Ordered, & Shipped in the U.S.CDC, December 1, 2009

(It looks like the US is a long way from achieving its 2011 goal.)

December 20: H1N1 vaccine for the President

(The 2nd wave in the US peaked in October.)

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The most surprising news since April 24, 2009?

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Tamiflu! (oral)

Ralenza (inhaled)

(Older drugs)

(Viral resistance to these is more common, including all pH1N1)

IV Peramivir: US FDA Emergency Use Authorization (Oct. 23, 2009)

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In Seasonal Flu & pH1N1, Early Treatment with Tamiflu can

• Decreasing duration of uncomplicated illness; &• Reducing lower respiratory tract complications,

antibiotic use, & hospitalizations.• So far, most pH1N1 is sensitive to Tamiflu, but most

seasonal H1N1 became resistant, in most countries.

Reduce the number of viral particles released from infected cells, thereby:

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Pandemic Flu Prevention & Treatment Challenge

1.5 - 2 day mean incubation period for 2009 H1N1 (WHO/WER, 11/13/09)

High levels of virus (& sometransmission?), 1 day

before symptoms!

Most transmission within 5 days after symptom onset?(Longer in kids & immune suppressed.)Peak

transmission

(nothing like SARS)

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Modes of Person-to-Person Transmission: Close Exposure (1 - 2 meters / 3 - 6 feet):

1. Large droplets from coughing, sneezing, & talking, to other’s nose & mouth (& eyes?);

2. Contact: direct (hand-to-hand) & indirect (hand-to-surface-to-hand – less common?);

3. Airborne / aerosol / droplet nuclei: By aerosol-generating medical procedures & in shared air spaces with poor air circulation? Can remain suspended in air for longer, but NOT long distance or in ventilation systems?

Courtesy of CDC

(Nothing to do with the birds or pigs!)(WHO: www.cdc.gov/ncidod/EID/vol12no01/05-1370.htm

www.cidrap.umn.edu/cidrap/content/influenza/panflu/biofacts/panflu.html)

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In 1918,

Some of the Guidance to the Public

(& Even Some of the Advertising)

Reflected a Good Understanding

of the Modes of Transmission

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Infection Prevention

(To reduce risk of infectionin spite of close exposure)

1957 (no longer recommended) Current focus for the general public

(How much betterwill we be in the21st century?)

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Interventions to reduce transmission (even hand washing!) can have unintended consequences.

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Seattle, Nov. 1918: No mask, no ride.Schoolgirls wear masks to

protect against the flu in Tokyo

In 1918, Masks Were Popular in Many Areas,

& Required in Some

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Medical masks (surgical / procedure) help protect against droplets

N95 also for aerosols (important for suctioning, nebulizer treatment, etc.), but should be fit-tested using a kit

Neither protect eyes or prevent contact transmission

Better on cases than on uninfected?

Limited effectiveness data for flu

Must discard after dirty or moist

Will likely be in short supply

Woven cloth masks: Little data

(CDC: www.cdc.gov/Features/MasksRespirators/WHO: www.cdc.gov/ncidod/eid/vol12no01/05-1371.htm)

1918 (& 21st Century?)

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(WHO recommends medical masks for staff caring for patients with suspected/confirmed pH1N1, & N-95/FFP2 respirators when performing aerosol-generating procedures.)

(CDC & OSHA: N-95s for all staff caring for patients with suspected/ confirmed pH1N1.)

(CDC has recently proposed revised guidance consistent with WHO.)

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(As the scientific debate on medical masks vs. N-95 respirators for H1N1 raged on in the US, this protest focused on inadequate hospital suppliesof N-95s)

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Even full PPE with N-95 mask may not always be completely protective

(Good hand hygiene & minimizing exposure are also important.)

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In a pandemic wave of mild severity, interventions to reduce transmission should include:

• Isolating the ill,

• Hand washing,

• Respiratory etiquette, &

• May include additional guidance to help protect high risk groups.

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www.flu.gov/individualfamily/healthconditions/index.html

• Limit contact with crowds & avoid crowded places. • If you can’t avoid crowded settings, consider wearing a facemask or respirator. • Seek medical attention if you have a fever & symptoms of the flu.• Take antiviral drugs if your doctor recommends them.

(4 pages, Aug. 2009)

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Community Mitigation: Multiple “Layered”

Non-Pharmaceutical Interventions (NPIs)(To reduce contacts between potentially infectious & susceptible persons)

(Because No Single NPI is Effective Enough)

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(Nothing like SARS: Ro = 3, v = 9 days: From 1 to 4 cases in 9 days, & 40 by Day 30)

Flu: From 1 to a cluster of 15 cases in 9 days, & 2,047 by Day 30!

(R0 = the average number of secondary cases of disease generated by a typical primary case in a susceptible population.)

(Reproductive Number: R0 for flu = 1.5 – 3.0, but higher in closed settings & among children. ForpH1N1 R0 = 1.2 – 1.7?)

Explosive flu outbreaks are due to this short generation time (due to short incubation period & peak infectivity early in illness.For pH1N1, v = 2.5 – 3 days?)

(www.who.int/wer/2009/wer8434.pdf)

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NPIs Can Reduce R0 by Reducing the Number of ContactsBetween Infectious & Susceptible Persons

(In both scenarios, above, ¼ of contacts become ill.)

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Good Understanding of Modes of Transmission Led to Non-Pharmaceutical InterventionsBut Guidance in the US was Inconsistent & Communities Made Very Different Decisions

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“Protective Sequestration” in Gunnison, Colorado 1 of only 7 U.S. towns & residential institutions to escape the 2nd wave(Escape Community Digital Document Archive, Center for the History of Medicine, Univ. of Michigan:

www.med.umich.edu/medschool/chm/influenza/)

Site: Small mountain town, far from major population centers, but on a major rail line.

Population: 1,329 in town

Flu Cases: 0 in town

Flu Deaths: 0 in town

Non-Pharmaceutical Interventions Barricades on roads for 4 months; Rail travel restricted; Quarantine of arrivals & jailing of

those in violation; Isolation of suspected cases; Schools & all institutions closed; No public gatherings, per state law

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Current modeling (with uncertain assumptions), & analysis of 1918 data, suggest that early & sustained use of multiple

partially effective non-pharmaceutical interventions (NPIs), can:

Delay the outbreak peak;

Reduce peak burden on hospitals & infrastructure; &

Modestly reduce total # of cases & deaths.

(US CDC, Feb., 2007: www.pandemicflu.gov/plan/community/mitigation.html)

Excess pneumonia & flu mortality over 1913–1917 baseline in Philadelphia & St. Louis, Sep. 8–Dec. 28, 1918

(Hatchett RJ, Mecher CE, Lipsitch et al. Public health interventions & epidemic intensity during the 1918 influenza pandemic. PNAS 2007:

http://www.pnas.org/cgi/content/abstract/0610941104v1)

NPIs 16 daysafter 1st case

NPIs 2 days after 1st case

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200,000 crowd to see the biggest parade in the city’s history, 2 weeks after the first civilian cases, & the day after 200 were admitted to hospital!

“By mid-October Philadelphia was reeling. ….. the city had to secure five supplementary morgues. ….. Many families, especially in the slums, had no adult well enough to prepare food & in some cases had no food at all because the breadwinner was sick or dead.” Alfred Crosby

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“In Philadelphia the number of dead quickly overwhelmed the city’s ability to handle bodies.

It was forced to bury people, without coffins, in mass graves and soon began using steam shovels to dig the graves.”

(John Barry, The Great Influenza)

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Implementation of NPIs & Excess Mortality in St. Louis

0

2000

4000

6000

8000

10000

12000

14000

9/14

/191

8

9/21

/191

8

9/28

/191

8

10/5

/191

8

10/1

2/19

18

10/1

9/19

18

10/2

6/19

18

11/2

/191

8

11/9

/191

8

11/1

6/19

18

11/2

3/19

18

11/3

0/19

18

12/7

/191

8

12/1

4/19

18

12/2

1/19

18

12/2

8/19

18

Date

Dea

th R

ate

/ 10

0,00

0 P

op

ula

tio

n

(An

nu

al B

asis

)

Oct. 5: First cases in civilians

reported

Oct. 7: Mayor closes “theaters, moving picture shows, schools, pool & billiard halls, Sunday schools, cabarets, lodges, societies, public funerals, open air meetings, dance halls, & conventions, until further notice.”

Nov. 14: Closing order withdrawn(but was again re-instituted)

Source: Hatchett R, Mecher C, Lipsitch M. (www.pnas.org/cgi/reprint/104/18/7582)

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In St. Louis, Missouri, the Red Cross Motor Corps transports a flu victim from a house at Etzel & Page Avenues (St. Louis Post Dispatch file photo)

The Situation in Saint Louis During the Peak of the Second Wave Never Approached that in Philadelphia

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St. Louis - 200?

Time

Cases of

Influenza

Social Collapse

Municipal Service Collapse

Goal of 21Goal of 21stst Century Century Preparedness Efforts & Community MitigationCommunity Mitigation

(St. Louis County Dep. of Health, 2006: www.pandemicprep.org/)(St. Louis County Dep. of Health, 2006: www.pandemicprep.org/)

Lower

Raise

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In Connecticut “local health departments ….. currently note, somewhat incredulously, that, in the

event of Pandemic Flu, they are responsible for:

• “Community quarantine & isolation ....... ;

• “Instituting ….. social distancing ……… ;

• “Mass Care, i.e., taking care of those too ill to be at home ….. when the hospitals have exhausted surge capacity & shut their doors;

• “Mass Fatalities, i.e., collecting large numbers of bodies when the ordinary medical examiner & mortuary processes have collapsed;

• …… “without any assistance from any outside source, as it is assumed that every community is undergoing the same crisis.”

(From a local health department in Connecticut, Feb. 2007)

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Non-Pharmaceutical Interventions for Pandemic

Influenza: National & Community Measures. WHO, Jan. 2006.

(www.cdc.gov/ncidod/eid/vol12no01/05-1371.htm)

WHO recommendations, based on limited data, varyby transmission pattern, &by illness severity & extent.

Ill persons should remain home, but forced isolation & quarantine are ineffective & impractical;

Nonessential travel to affected areas should be deferred; Mask use should be based on setting & risk; Hand & respiratory hygiene should be routine; Contaminated household surfaces should be disinfected; & If the pandemic is severe, social distancing measures,

such as school closures, should be considered.

1918 NPIs for the 21st Century!

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(US CDC, Feb. 2007)

WHO notes that estimating CFR during a pandemic wave is difficult, & that severity depends on:

• viral virulence, &

• population vulnerability, &

• response capacity; &

will thus vary from population to population; &

• may change over time.

(1918)

(1889, 1957, & 1968 = Cat. 2)

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Community Strategies by Pandemic Flu Severity (1)From U.S. CDC (& 15 Other Federal Agencies!) Feb. 1, 2007

Pandemic Severity(Based Mostly on Case Fatality Ratio)

Interventions by Setting Cat. 1 Cat. 2 or 3 Cat. 4 or 5

Workplace/CommunityAdult social distancing

–decrease number of social contacts (e.g., encourage teleconferences, alternatives to face-to-face meetings)

Generally not recommended

Consider Recommend

–increase distance between persons (e.g., reduce density in public transit, workplace)

Generally not recommended

Consider Recommend

–modify, postpone, or cancel selected public gatherings to promote social distance (e.g., stadium events, theater performances)

Generally not recommended

Consider Recommend

–modify workplace schedules and practices (e.g., telework, staggered shifts)

Generally not recommended

Consider Recommend

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Community Strategies by Pandemic Flu Severity (2)(www.pandemicflu.gov/plan/community/mitigation.html)

Pandemic Severity(Based Mostly on Case Fatality Ratio)

Interventions by Setting CFR < 0.1% 0.1% - <1% CFR = 1% +

Home

Voluntary isolation of ill at home (adults and children); combine with use of antiviral treatment as available and indicated

Recommend Recommend Recommend

Voluntary quarantine of household members in homes with ill persons (adults and children); consider combining with antiviral prophylaxis if effective, feasible, and quantities sufficient

Generally not recommended

Consider Recommend

School

Child social distancing–dismissal of students from schools and school-based activities, and closure of child care programs

Generally not recommended

Consider:≤ 4 weeks

Recommend:≤ 12 weeks

–reduce out-of-school contacts and community mixing

Generally not recommended

Consider:≤ 4 weeks

Recommend:≤ 12 weeks

(In late April & early May 2009, CDC guidance on school closing was consistent with that for a pandemic wave of moderate severity – Cat. 2 – 3, now consistent with Cat. 1)

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Schools: Difficult Decisions Closing vs. dismissal of students

May be proactive or reactive.

Immediate community-wide impact from a single policy decision?

If kids stay away from other kids.

But data on impact of closing on community transmission is limited.

& Closing will cause substantial adverse socio-economic impacts:

How many health workers will stay home with their kids?

Parents’ lost income & jobs;

Child nutrition?

These consequences must be considered & planned for.

http://press.thelancet.com/tlidschools.pdf

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Brazil, Aug. 5 At least 14 million students out of class in 5 states because of government decision intended to contain the advance of the new flu.

(School closures have been reported in many countries.)

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Interventions focused on students (such as immunization & school closure) could be particularly effective if age-specific attack rates are like those in 1957.

Attack rates have been higher in older children, adolescents, &/or younger adults, than in older adults, but the most affected group has been different in different pandemics.

(Lancet Infect Dis 2009; 9: 473–81)

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New influenza A (H1N1) virus: WHO guidance on public health measures, 11 June 2009

Guidance for countries with widespread community-level transmission

Control measures

• The primary focus should be the appropriate management of patients, either at home or in health-care facilities.

• The health-care system should be protected & supported so that it can continue to operate.

• Most people with pandemic infection can be diagnosed clinically without the need for laboratory testing.

• Community-level measures such as school closures & cancellations of mass gatherings should be considered on a case-by-case basis to slow increases in infection & to try and reduce pressure on the health-care system. In implementing such measures, consideration should be given to the disruption they may cause, & the feasibility & sustainability of their implementation.

(2 pages)

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http://ecdc.europa.eu/en/publications/Publications/0906_TER_Public_Health_Measures_for_Influenza_Pandemics.pdf

…… “the intention with this document is to present a menu of possible measures, giving public health & scientific information on what is known or can be said about their likely effectiveness, costs (direct & indirect), acceptability, public expectations & other more practical considerations.

“This is to help European Member States & EU institutions, individually or collectively, decide which measures they will apply.”

(56 pages, June & Sep. 2009)

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(if the net holds up)How feasible are these NPIs going to be for real people to practice?

Incomplete use / coverage of NPIs is assumed: Thus, the importance of effectively promoting multiple NPIs.

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The epidemic curve in each country is the cumulative result of the many & different curves of its smaller jurisdictions.

Country

Smallerjurisdictions

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Three possible profiles: one following the UK planning profile exactly, & 2 others showing possible local variations. Each has a 30% clinical attack rate (the area under each curve). (UK Cabinet Office & Dep. of Health, July 16 & Sep. 3, 2009)

UK “Reasonable Worst Case” Planning Assumptions for the First Major Pandemic Wave - Percentage of Persons Ill in Local Outbreaks

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• Implementing interventions before the local outbreak will likely result in economic & social hardship without public health benefit, & intervention compliance fatigue.

• Implementing after extensive local spread will likely limit the public health benefits.

• The geopolitical trigger should be defined as a cluster of cases occurring within a U.S. State or proximate epidemiological region (e.g., a metropolitan area that spans more than one State). (US HHS/CDC, Feb. 2007)

(Adapted from US CDC slide)

Intervals AInitiation

CPeak

Transmission

DDecel-eration

EResolution

RecognitionInvestigation

Local trigger to

initiate community

mitigation

interventions

BAccel-eration

Intervals in Local Epidemic Curves & Triggers for Community Mitigation

Different communities will be at different intervals during national waves/ epidemics

Detect cases & clusters early

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….... “because early implementation of pandemic mitigation interventions may reduce the virus’s basic reproductive number, a mitigated pandemic wave may have lower amplitude but longer wavelength than an unmitigated pandemic wave. Communities should therefore be prepared to maintain these measures for up to 12 weeks” ….... www.pandemicflu.gov/plan/community/mitigation.html

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Effective Communication

Will Be Important

Start early to prevent rumors & misinformation, & to prepare the public for the crisis. Acknowledge that early information may change.

Understanding the public is critical to effective communication. Thus, crisis communication should be a dialogue.

Trust: Communicate in ways that builds, maintains, or restores trust. Acknowledge uncertainty & avoid excessive reassurance.

Transparency: People are more likely to over-estimate the risk if information is withheld. Public panic is rare when people are candidly informed.

www.who.int/csr/resources/publications/WHO_CDS_2005_28/en/index.html

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WHO is Developing Detailed Guidance

During the pandemic, most ill people will be cared for at home.

In some families, all caretakers will be ill at the same time.

Woodson’s 17-page guide fills a critical gap for the US setting:

“Preventing or treating dehydration in people with flu will save more lives than any other intervention during the influenza pandemic.”

Community Health Workers in resource-poor settings urgently need detailed guidance to help them help families.

(August 29, 2006)

(www.BirdFluManual.com)

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See: Reducing Excess Mortality from Common Illnesses During an Influenza Pandemic: WHO Guidelines for Emergency Health Interventions in Community Settings: www.who.int/diseasecontrol_emergencies/common_illnesses2008_6.pdf

Common illnesses, such as HIV, TB, diarrhea, malaria, & particularly pneumonia, will need treatment: CHWs may be good for this in some settings

In the

northwestern

mountains of

Nepal in 1987, a

CHW (who uses

antibiotics to treat

childhood

pneumonia) takes

the respiratory

rate of an infant

using a sand

timer. In a

pandemic,

should he also

treat pneumonia

in older kids &

adults?

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Family / Household LevelCommunity / District Level (Depending on pandemic severity)

Prevention Keep your distance.Wash your hands.Cover your coughs & sneezes.Isolate your ill (including

ventilation, cleaning, masks, & HH members minimizing interaction with others if pandemic is severe).

Educating families on prevention.Limiting public crowding, gathering, mixing, contacts, etc., including:Closing schools & child care centers

&Advising on travel & transport.Training community workers in infection control.

CareCare for those ill with the flu (ILI):

RestFeverMedicationsFluidsNutritionCare seeking

Educating families on home care.Assisting the neediest/ sickest households (incl. care, food, water, psychiatric first aid?, burial?).Community case management (including antibiotics for pneumonia) where feasible.Continuity of care for selected conditions (such as HIV & TB medications) if feasible.

Cross-Cutting Content:What is pandemic flu? / Symptoms / Transmission.Keeping communities informed (numbers, location, &severity of cases; & best sources of info. & guidance.)Addressing community perceptions & concerns.

Generic Content for Basic Community Health Response in Developing Countries

12/11/08 draft for in-country adaptation. Health Working Group, Humanitarian Pandemic Preparedness (H2P) Initiative(Based on the document, “Health Interventions, Tools, & Modules” available at: www.coregroup.org/h2p/)

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Two training

curricula were

key products of

collaborative

work of the H2P

(Humanitarian

Pandemic

Preparedness

Initiative) Health

Working Group.

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Pandemic Influenza Preparedness & Response: Guidance & Template for Country Planning on Overarching Actions & Health Interventions

H2P, May 5, 2009 Draft

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In Nepal, H2P supported MOH development of plans & materials for key interventions, including NPIs, at district & community levels.

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So, what’s different with swine flu, compared to seasonal?

1. Somewhat higher attack rates during local waves;

2. Dramatically younger age distribution of hospitalized & fatal cases (sparing the elderly, so far);

3. Thus, more severe for those <50 & much less common for those >60 (so far);

4. Swine Flu Paradox?: Low mortality, but crowded Intensive Care Units (in some settings).

5. Late vaccine availability; &

6. More unpredictable severity (over time & in vulnerable populations).

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The 2009 Pandemic: Reminders (“Lessons Learnt”) & A Surprise

• Good communication is vital.

• Classification of severity of the wave is vital for good communication & an appropriate response.

• NPIs are important, but their use should reflect severity.

• Pandemic vaccine becomes available, only for some, only towards the end of the pandemic.

• Surprise: pH1N1 caused a pandemic even though seasonal H1N1 had been circulating globally since 1977.

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Novel Swine-Origen H1N1Remaining Uncertainties?

1. How much more severe was it in developing countries (with more vulnerable populations & weaker health systems)?

2. Will it get more severe over time / in subsequent waves?

3. How much will immunization contribute to reducing mortality?

4. Will pH1N1 remain susceptible to the newer antivirals?

5. How much economic & social disruption will we see?

6. How will H5N1 “behave” under H1N1 pandemic pressure?

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H5N1Key Unpredictables

1. How will H5N1 “behave” when exposed to pH1N1?

2. Will efficient person-to-person transmission develop? (Overnight or over months?)

3. Will it hit next week, next year, next decade, never?

4. What roles will immunization & anti-virals play?

5. How high will mortality be? (1968, 1918, ~H5N1?)

6. How much economic & social disruption?

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Severe Pandemic Flu: A Unique Set of Challenges for Preparedness & Response

1. Limited recent experience (1918)

2. Unpredictable onset

3. Unpredictably high mortality

4. Person-to-person respiratory transmission (Folks at home, work, school, are a threat.)

5. Infeasibility of containment (except at onset?)

6. Global scale (↓ domestic & international aid)

7. Extended duration

8. Limited benefits of vaccines & anti-virals

9. NPIs: Important, but have substantial negative socio-economic consequences

10. Substantial social & economic disruption

11. Responding facilities & organizations themselves challenged

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Conclusions (H5N1)

Bird flu is NOT a substantial direct threat to public health (pandemic flu is)

Pandemic flu onset & severity are signaled by:

WHO updates on phases of pandemic alert:

The size & growth of human clusters,

Due to H5N1 or another new flu,

Anywhere in the world, &

Severity of illness in these human cases,

NOT by the arrival of H5N1 in birds in any country.

However, the H5N1 threat will likely continue as long as H5N1 causes disease in humans & in poultry.

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1918, 1957, & 1968 were quite different, & H5N1 & pH1N1 have been unprecedented

Expect the Unexpected & Keep Plans & Actions Flexible & Based on Current Best Evidence

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Conclusions

• …… "the present threat to international public health is sufficiently serious to call for emergency actions calculated to provide the greatest level of protection & preparedness as quickly as possible.”

(WHO Strategic Action Plan for Pandemic Influenza 2006–2007, page 4. WHO, 2006)

• While responding to H1N1, we also need to prepare, now, for a severe wave, as best we can:

–www.coregroup.org/ & www.pandemicpreparedness.org

–www.savethechildren.org/publications/technical-resources/avian-flu/

• “All concerned should keep in mind that no health emergency on the scale of a severe influenza pandemic has confronted the international community for several decades.”

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Extra Slides

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Low Pathogenic & Highly Pathogenic Avian Influenza in Migratory Water Birds & Poultry

LPAI

LPAI(H1-16)

HPAI (H5/H7)Mutation

Only H5N1 HPAI istransmitted back to migratory birds & then on to poultry in other areas (?)

Reservoir

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Controlling Highly Pathogenic Avian Influenza (HPAI)

• Clean & disinfect farms & live markets

• Control movement of birds, workers, & potentially contaminated materials

• Segregate different species & batches of poultry from each other, & from pigs & waterfowl

• Vaccination

• Disease surveillance

• Rapid culling of infected & at risk poultry, with incentives to farmers

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The age-specific incidence per 10 million population (below), indicates that the distribution of cases by age (left) partly reflects the young population of Viet Nam.

(Indonesia has higher incidence in the young.)

Higher incidence in the young may be due to:

• Greater exposure to the virus,

• More severe disease, and/ or,

• More thorough investigation of pneumonia,

in the young?

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This “case-fatality distribution among H5N1 cases is reminiscent of those observed during previous pandemics, particularly in 1918” (WHO, June 2006, re. a similar distribution)

(Except for in Hong Kong in 1997, serological studies have found very few sub-clinical infections & mild illnesses.)

36%

74%69%

72%

52%50+: 37%

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Use of Antivirals for H5N1

From Osterholm, 2/14/06:

• H5N1 & 1918 H1N1 cause a very different disease than H3N2 (seasonal flu).

• Virus storm may lead to cytokine storm (particularly in those with strongest immune response?)

From WHO, September 2007:

•Tamiflu reduces mortality if given in early stages of illness.

•May need to double dosage, and/or double duration of treatment.

•Optimal dose regimen is uncertain.

•Viral resistance to Tamiflu may develop.

(For close contacts of H5N1 cases, WHO recommends Tamiflu or Ralenza prophylaxis. This would have big drug supply implications in a pandemic.)

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(September 2007 Slide)

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(September 2007 Slide)

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(September 2007 Slide)

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0

5

10

15

20

25

30

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Most Cases Not Hospitalized in Time to Get Maximal Benefit of Tamiflu

# hu

man

H5N

1 ca

ses

and

deat

hs

Lab-confirmed H5N1 cases in humans reported to WHO between November 2003 and November 12, 2007 for which there is symptom onset and health status data.

Days between symptom onset and hospitalization

22% CFR

76% case fatality rate (CFR)

mean = 4.6 days

maximumTamiflu efficacy

= cases

= deaths

46% CFR

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March 2005 H5N1 viral pneumonia / ARDS survivor in Hanoi.

Supportive care, incl. ventilator, O2, & hydration

(+ antibiotics for secondary bacterial infections) are important.

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(From: Responses to Avian Influenza and State of Pandemic Readiness -Fourth Global Progress Report. UN System Influenza Coordinator & The World Bank, October 2008, page 58.)

Most Countries have had Plans in Place to Implement NPIsBut in Most, Logistical & Legislative Provisions were Unclear

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Hong Kong/156/97

Vietnam/JP14/05 ck/Cambodia/013LC1b/05

Vietnam/1194/04 Vietnam/1203/04

Vietnam/HN30408/05 Thailand/16/04

Vietnam/JPHN30321/05

Clade 1

Hong Kong/213/03 Indonesia/CDC523/06

Indonesia/CDC699/06 Indonesia/CDC326/06

Indonesia/5/05 Indonesia/CDC184/05

Indonesia/7/05 dk/KulonProgoBBVET9/04

ck/Indonesia/CDC25/05 Indonesia/6/05

ck/Brebes/BBVET2/05

Indonesia/CDC594/06* ck/Dairi/BPPVI/05

Clade 2.1

ck/Yunnan/374/04 ck/Yunnan/115/04

ck/Yunnan/493/05 ck/Yunnan/447/05

dk/Guangxi/13/04 ck/Guangxi/12/04

whooping swan/Mongolia/244/05 bar headed gs/Qinghai/1A/05 *

Turkey/65596/06 Turkey/15/06 Iraq/207NAMRU3/06

ck/Nigeria/641/06 mld/Italy/332/06

turkey/Turkey/1/05 Egypt/2782NAMRU3/06 Djibouti/5691NAMRU3/06

ck/Nigeria42/06 migratory dk/Jiangxi/2136/05

gs/Kazakhstan/464/05 ck/Krasnodar/01/06

Azerbaijan/011162/06 swan/Iran/754/06

Clade 2.2

dk/Laos3295/06 Anhui/1/05

Anhui/2/05 Japanese white-eye/Hong Kong/1038/06 ck/Malaysia935/06

Vietnam/30850/05 Guangxi/1/05

dk/Hunan/15/04 qa/Guangxi/575/05

dk/Vietnam/Ncvdcdc95/05

Clade 2.3

migratory dk/Jiangxi/1653/05

gs/Guangdong/1/96

* Karo cluster Indonesia/CDC625/06*

Strains in yellow: Vaccine strains

Vietnam

Thailand

Cambodia

Indonesia

Middle east

Europe

Africa

China

Laos

WHO, 2/16/07:

16 manufacturers from 10 countries developing prototype H5N1 pandemic vaccines.

“For the first time, …… vaccines can bring about a potentially protective immune response against strains of H5N1 virus found in a variety of geographical locations.”

“Some ….. work with low doses of antigen, which means that significantly more vaccine doses can be available in case of a pandemic.”

There are many strains of H5N1 (& of H1N1)

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If 2 < R0 < 3, and v = 3 Days (each mouse click)

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Modeled Spread in the US

1.2M

RiskAnalysis &DecisionSupportSystems

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• How much will international airline travel be affected?

• For how long?

• What will the triggers be for governments & for airlines?

• Will ports of entry be closed?

(Hypothetical scenario of severe pandemic onset & trigger for international evacuation)

(Person-to-person transmission will be particularly efficient in crowded planes, trains, & buses.)

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In 2006, 2007, & 2008, US Health Secretary Mike Leavitt noted at pan flu state planning summits around the country that,

“Any community that fails to prepare with the expectation that the federal government will at the last moment be able to come to the rescue will be tragically wrong, not because the federal government lacks will, not because we lack wallet, but because there is no way in which 5,000 different communities can be responded to simultaneously, which is a unique characteristic of a human pandemic.”

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Pandemic Influenza Preparedness, Response, & Recovery Guide for Critical Infrastructure & Key Resources (Sep. 2006)

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Spheres of Progress in Influenza Research

…… “Points of overlap among the three circles illustrate how the findings in each area have implications for the other two areas. The major challenges within each area of research are noted around the periphery of that circle.” (R Salomon & RG Webster. Cell, Feb. 6, 2009)

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(Proceedings of the National Academy of Sciences, Apr. 6, 2007)

(Journal of the American Medical Association,Aug. 8, 2007)

www.pnas.org/content/104/18/7582.full.pdf

http://jama.ama-assn.org/cgi/reprint/298/6/644.pdf

1918 Influenza: TheMother of All Pandemics

Jeffery K. Taubenberger & David M. Morens(Emerging Infectious Diseases, Jan. 2006)

www.cdc.gov/ncidod/EID/vol12no01/05-0979.htm

The Best of the Best Papers on 1918