Natural History of Disease and Biological Aspects of Pandemic Influenza A (H1N1)

Tim Uyeki MD, MPHInfluenza Division

US Centers for Disease Control and Prevention

Influenza A Viruses• Influenza A viruses categorized by subtype

• Classified according to two surface proteins

• Hemagglutinin (HA) – 16 known• Site of attachment to host cells• Antibody to HA is protective

• Neuraminidase (NA) – 9 known• Neuraminidase (NA) – 9 known• Helps release virions from cells• Antibody to NA can help modify disease severity

N

H

Influenza A Viruses� Aquatic birds reservoir for viruses with all HAs and NAs

• H1 - H16• N1 - N9

Aquatic birdsAquatic birds

HumansHumans PigsPigs HorsesHorsesPoultryPoultry

DogsDogsCatsCats

AquaticAquaticmammalsmammals

Influenza A Viruses

• Influenza A viruses are dynamic• Continue to evolve in strains – unpredictable • Antigenic monitoring needed• Genetic monitoring needed• Gene reassortment can occur with other influenza

A virusesA viruses• Antiviral susceptibility can change• Virulence to cause severe disease can change

Timeline of Emergence of Influenza Viruses in HumansTimeline of Emergence of

Influenza Viruses in Humans

PandemicvaccinesH7

H5H5H9

Avian

B

Seasonal vaccines

1918 1957 1968 1977 1997 2004

H1“Spanish”H2 “Asian”

“Hong Kong”H3

B

“Russian”H1

Seasonal Influenza - Hospitalizations (U.S.)

Average of >200,000 influenza-related hospitalizations/year• Estimated by modeling studies using retrospective d ata

and influenza surveillance data

Children:• High rates in young children <2 years • High rates in young children <2 years • Children 2-5 years next highest• High rates for children with chronic high-risk

conditions

• Adults:• Highest rates in persons ≥≥≥≥65 years • High rates in persons with chronic illness

Simonsen L, et al. JID 2000;181:831-837; Izurieta HS et al., NEJM 2000;342:232-239; Neuzil KM et al., NEJM 2000;342:225-231; Thompson WW et al., JAMA 2004;292:1333-1340;Neuzil KM et al. JID 2002;185:147-152

Seasonal Influenza-associated Mortality, U.S.

• Estimated average of • ~36,000 influenza-attributable deaths/year (all ages )• Highest mortality rates:

• Persons ≥≥≥≥65 years• Persons with chronic pulmonary and cardiac disease; other

chronic conditionschronic conditions

• Mortality data are limited for children

• 46 - 153 pediatric influenza-associated deaths reported to CDC/season (2003-09)

Izurieta HS, NEJM 2000; Neuzil KM, NEJM 2000; Thompson WW, JAMA 2004; Neuzil K, JID 2002; Thompson WW, JAMA 2003

Estimated Impact of Influenza PandemicsEstimated Impact of Influenza Pandemics

19181918--19 Spanish Flu (H1N1)19 Spanish Flu (H1N1)•• 2020--100 million estimated deaths worldwide100 million estimated deaths worldwide•• >600,000 U.S. deaths>600,000 U.S. deaths•• Estimated mortality = 2% Estimated mortality = 2%

19571957--58 Asian Flu (H2N2)58 Asian Flu (H2N2)•• 70,000 excess U.S. deaths70,000 excess U.S. deaths

19681968--69 Hong Kong Flu (H3N2)69 Hong Kong Flu (H3N2)•• 34,000 excess U.S. deaths34,000 excess U.S. deaths

20092009--10 H1N1 Pandemic???10 H1N1 Pandemic???

April 14 First Death Due to Novel H1N1 in Mexico (Identified Later)

Detection of Novel H1N1 Virus� March 2009

• 2 cases of febrile respiratory illness in children (un-related, no pig contact)

• Residents of adjacent counties in southern California, ill in late March

• Novel swine influenza A (H1N1) • Novel swine influenza A (H1N1) virus detected on April 15th,17th

� Both viruses genetically identical• Contain a unique combination of

gene segments previously not recognized among swine or human influenza viruses in the United States

April 15 First Case of Novel H1N1 Virus Recognized in California

Host and lineage origins for the gene segments of the 2009 A(H1N1) virus (Garten, et al Science 2009)

A/Ohio/07/2009 H1N1A/New York/18/2009 H1N1A/California/05/2009 H1N1A/Texas/04/2009 H1N1A/Mexico/4108/2009 H1N1A/California/04/2009 H1N1

A/Swine/Indiana/P12439/00 H1N2A/swine/Guangxi/13/2006 H1N2

A/Wisconsin/10/1998 H1N1A/Wisconsin/87/2005 H1N1

A/Swine/Ohio/891/01 H1N2A/swine/Korea/PZ14/2006 H1N2

A/swine/Korea/CAS08/2005 H1N1A/Iowa/CEID23/2005 H1N1

A/swine/Iowa/00239/2004 H1N1A/swine/Memphis/1/1990 H1N1

A/swine/Ratchaburi/NIAH1481/2000 H1N1A/Ohio/3559/1988 H1N1A/swine/Indiana/1726/1988 H1N1

Phylogenetic Tree of Hemagglutinin H1: Swine vs. Seasonal Influenza Viruses

Swine H1

Novel H1N1 OutbreakHuman cases of swine H1Seasonal H1

A/swine/Indiana/1726/1988 H1N1A/Philippines/344/2004 H1N2

A/swine/Iowa/2/1985 H1N1A/swine/Chonburi/05CB1/2005 H1N1

A/Thailand/271/2005 H1N1A/swine/Ontario/4/1981 H1N1

A/New Jersey/8/1976 H1N1A/swine/Wisconsin/2/1970 H1N1

A/swine/Wisconsin/1/1957 H1N1A/swine/Iowa/15/1930 H1N1A/swine/Jamesburg/1942 H1N1

A/Minnesota/01/2009 H1N1A/Brisbane/59/2007 H1N1

A/Solomon Islands/03/2006 H1N1A/New Caledonia/20/1999 H1N1

A/New York/630/1995 H1N1A/USSR/90/77 H1N1

A/Memphis/16/1983 H1N1A/Fort Worth/50 H1N1

A/Denver/57 H1N1A/Weiss/43 H1N1A/Puerto Rico/8/34 H1N1

A/South Carolina/1/18 H1N1

0.02

Seasonal H1

(Garten, et al Science 2009)

Avianvirus

Avian reassortant

virus

Possible Pathways for Generation of Pandemic Influenza A Viruses

Avian-human pandemic

reassortant virus

Human

virus

Avianvirus

Reassortment in swine

Reassortment in humans

April 23 Mexican Cases of Severe Respiratory Illness are Confirmed as Novel H1N1

April 25 First Cases of the Novel Influenza A H1N1 Virus Recognized in Canada

April 25 First Cases of the new Influenza A H1N1 Virus Recognized Outside of North

America

April 29 WHO Raises Pandemic Alert Level to Phase 5

June 11 WHO Declares Phase 6 Level of Pandemic Influenza Alert

Epidemiology/SurveillancePandemic (H1N1) - 25 JUN 2009

U.S. WHO/NREVSS Collaborating Laboratories Summary, 2008-09

2000

2500

3000

3500N

umbe

r of P

ositi

ve S

peci

men

s

34384246505458626670

Per

cent

Pos

itive

A(H1N1-Sw ine)

A(Could not be subtyped)

A(H3)

A(H1)

A(Unknow n)

B

Percent Positive

* Percentage of all positive influenza specimens that are Novel Influenza

33%*

50%*

63%*

80%*

81%*

84%*

83%*

0

500

1000

1500

10/4

10/1

811

/111

/15

11/2

912

/13

12/2

71/

101/

24 2/7

2/21 3/7

3/21 4/4

4/18 5/2

5/16

5/30

6/13

6/27

7/11

7/25 8/8

8/22

Week ending

Num

ber o

f Pos

itive

Spe

cim

ens

-22610141822263034

Per

cent

Pos

itive

Novel Influenza A(H1N1) or Influenza A (unable to subtype) for the week indicated

97%*

Weekly Frequency of Influenza Virus Isolation

Viboud C, Alonso W, Simonsen L (2006)

Seasonality

Argentina

USA

Mexico

Columbia

Brazil

1

50

40

30

20

10

Viboud C, Alonso W, Simonsen L (2006)

Impact of Pandemic H1N1 in 2009-2010???