Influenza: Virus and Influenza: Virus and DiseaseDisease

Kenneth H. Fife, MD, PhDIndiana University School of Medicine

Centers for Disease Control and Prevention. Influenza Prevention and Control. Influenza. Available at: http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm.

Clinically Relevant Influenza Clinically Relevant Influenza VirusesViruses

Type AType A Potentially severe illnessPotentially severe illness

Epidemics and pandemicsEpidemics and pandemics

Rapidly changingRapidly changing

Type BType B Usually less severe illnessUsually less severe illness

EpidemicsEpidemics

Genetically more stableGenetically more stable

NeuraminidaseNeuraminidase

HemagglutininHemagglutinin

RNARNA

Influenza Surface ProteinsInfluenza Surface Proteins

MM22 protein protein

(only on type A)(only on type A)

H = Hemagglutinin and N = Neuraminidase

• Hemagglutinin allows the virus to bind to host cells

• Neuraminidase helps the virus to release itself from the highjacked cells in which it has reproduced

ROLE OF H AND N PROTEINSROLE OF H AND N PROTEINS

SubtypeSubtype HumanHuman SwineSwine HorseHorse BirdBird

H1H1

H2H2

H3H3

H4H4

H5H5

H6H6

H7H7

H8H8

H9H9

H10H10

H11H11

H12H12

H13H13

H14H14

H15H15

Hemagglutinin Subtypes of Hemagglutinin Subtypes of Influenza A VirusInfluenza A Virus

Adapted from Levine AJ. Viruses. 1992;165, with permission.

SubtypeSubtype HumanHuman SwineSwine HorseHorse BirdBird

N1N1

N2N2

N3N3

N4N4

N5N5

N6N6

N7N7

N8N8

N9N9

Neuraminidase Subtypes of Neuraminidase Subtypes of Influenza A VirusInfluenza A Virus

Adapted from Levine AJ. Viruses. 1992;165, with permission.

Influenza A Virus Constantly Influenza A Virus Constantly ChangesChanges

Antigenic driftAntigenic drift Small changes in H or N proteins that occur from Small changes in H or N proteins that occur from

year to yearyear to year Population is partially immune, but may be re-Population is partially immune, but may be re-

infected over time (periodic epidemics)infected over time (periodic epidemics)

Antigenic shiftAntigenic shift Acquisition of new H or N protein, possibly from an Acquisition of new H or N protein, possibly from an

animal virusanimal virus Population is not immune, everyone is susceptible Population is not immune, everyone is susceptible

(pandemics)(pandemics)

YearsYears FluFlu VirusVirus MortalityMortality

1918-191918-19 “Spanish”“Spanish” Type A (H1N1) Type A (H1N1) 20 million worldwide20 million worldwide550,000 US550,000 US

1957-581957-58 “Asian”“Asian” Type A (H2N2)Type A (H2N2) 70,000 US70,000 US

1968-691968-69 “Hong Kong”“Hong Kong” Type A (H3N2)Type A (H3N2) 34,000 US34,000 US

Glezen WP. Epidemiol Rev. 1996;18:65.Centers for Disease Control and Prevention. Influenza Prevention and Control. Influenza. Available at:http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm.

Influenza Pandemics in the Influenza Pandemics in the 20th Century20th Century

1918 “Spanish Flu” Pandemic1918 “Spanish Flu” Pandemic

Type A virus (H1N1)Type A virus (H1N1) 20-50 million deaths worldwide20-50 million deaths worldwide 550,000 deaths in the United 550,000 deaths in the United

StatesStates 21,000 Flu-Orphans in NYC21,000 Flu-Orphans in NYC

1918 Pandemic

• It killed more people in 25 weeks than AIDS has killed in 25 years

• It killed more people in a year than the plagues of the Middle Ages killed in a century

• Seven times as many people died of influenza than in the First World War

1957 Pandemic1957 Pandemic

1957-1958 Asian Flu1957-1958 Asian Flu Type A virus (H2N2)Type A virus (H2N2) First identified in China February 1957First identified in China February 1957 Spread to U.S. by June 1957Spread to U.S. by June 1957 70,000 deaths in the United States70,000 deaths in the United States

1968 Pandemic1968 Pandemic

1968-1969 Hong Kong Flu1968-1969 Hong Kong Flu Type A virus (H3N2)Type A virus (H3N2) First detected in Hong Kong early 1968First detected in Hong Kong early 1968 Spread to U.S. later that yearSpread to U.S. later that year Approx 34,000 deaths in the United StatesApprox 34,000 deaths in the United States

• Our seasonal flu kills 36,000Our seasonal flu kills 36,000 Virus still circulating todayVirus still circulating today

1977 Pandemic1977 Pandemic

H1N1 reintroduced in 1977 “Russian Flu”H1N1 reintroduced in 1977 “Russian Flu”

Affected mostly young adults not exposed to Affected mostly young adults not exposed to influenza before 1957influenza before 1957

Still circulatingStill circulating

Natural History of Influenza Natural History of Influenza VirusesViruses

Topley and Wilson’s Microbiology and Microbial Infections. 9th ed, Vol 1, Virology. Mahy and Collier, eds, 1998, Arnold, page 387, with permission.

18801880 18901890 19001900 19101910 19201920 19301930 19401940 19501950 19601960 19701970 19801980 19901990 20002000

H3N2H3N2

H1N1H1N1

H2N2H2N2

H3N8

H2N?

H1N1H1N1

Serum antibody prevalenceSerum antibody prevalence

Virus isolationVirus isolation

Influenza Type A (H5N1)Influenza Type A (H5N1)

First appeared in humans in Hong Kong, 1997First appeared in humans in Hong Kong, 1997

Primarily associated with avian species Primarily associated with avian species

Fatal epidemic among Hong Kong poultry in 1997Fatal epidemic among Hong Kong poultry in 1997

Continuing avian epidemics through 2006Continuing avian epidemics through 2006

To date, 225 human cases with 128 deathsTo date, 225 human cases with 128 deaths

No sustained human-to-human transmissionNo sustained human-to-human transmission

Human Cases of H5N1 Avian Flu: Human Cases of H5N1 Avian Flu: 2003-20062003-2006

CountryCountry Total CasesTotal Cases DeathsDeaths

AzerbaijanAzerbaijan 88 55

CambodiaCambodia 66 66

ChinaChina 1919 1212

DjibuotiDjibuoti 11 00

EgyptEgypt 1414 66

IndonesiaIndonesia 4949 3737

IraqIraq 22 22

ThailandThailand 2222 1414

TurkeyTurkey 1212 44

VietnamVietnam 9393 4242

TotalTotal 227227 129129

As of 06/16/06 Source: World Health Organization (laboratory confirmed cases)

Distribution of H5N1 Distribution of H5N1 Infection – 2006Infection – 2006

Epizootiology - BirdsEpizootiology - Birds

Natural HostsNatural Hosts Domestic fowl, ducks, geese, turkeys, guinea fowl, quail, and Domestic fowl, ducks, geese, turkeys, guinea fowl, quail, and

pheasantspheasants

Source of InfectionSource of Infection Domestic flocks felt to be primary sourceDomestic flocks felt to be primary source Migratory waterfowl may spread over wide areasMigratory waterfowl may spread over wide areas

SpreadSpread Rapid in flocks by direct contactRapid in flocks by direct contact Viral shed in feces and nasal and ocular dischargesViral shed in feces and nasal and ocular discharges

Implications of H5N1 Implications of H5N1 InfectionInfection Potential for pandemic infection by little-known pathogen Potential for pandemic infection by little-known pathogen

Morbidity and mortality in both young and oldMorbidity and mortality in both young and old

No previous human exposure; no vaccine No previous human exposure; no vaccine

Signals need for Signals need for Pandemic readiness planPandemic readiness plan Rapid detection and diagnosis of new viral strainsRapid detection and diagnosis of new viral strains Veterinary surveillanceVeterinary surveillance Continuing research for new antiviral agentsContinuing research for new antiviral agents

Lee, Mak, Saw. Public Health and Epidemiology Bulletin. 1999;8:1-7.

Pandemic ResponsePandemic Response

Many communities throughout the U.S. will be Many communities throughout the U.S. will be affected at the same time, others will be at riskaffected at the same time, others will be at risk

Each community will have to deal with the Each community will have to deal with the pandemic mostly on their ownpandemic mostly on their own

Society as a whole will have to work together to Society as a whole will have to work together to minimize the impact of the pandemicminimize the impact of the pandemic

Influenza Illness (Typical Influenza Illness (Typical Case)Case)

Incubation period (time between exposure and Incubation period (time between exposure and symptoms) short – 1-3 dayssymptoms) short – 1-3 days

Infected person may shed virus for 12-24 hours Infected person may shed virus for 12-24 hours before onset of symptomsbefore onset of symptoms

Viral shedding peaks on day 2 or 3 then Viral shedding peaks on day 2 or 3 then declinesdeclines

Virus may be present as long as there are Virus may be present as long as there are symptoms (usually 5-10 days)symptoms (usually 5-10 days)

Influenza SpreadInfluenza Spread

Nearly all spread is person-to-personNearly all spread is person-to-person

Spread is by small droplets (as from a cough or Spread is by small droplets (as from a cough or sneeze) inhaled by a susceptible personsneeze) inhaled by a susceptible person

Inanimate object (doorknobs, towels) and Inanimate object (doorknobs, towels) and physical contact (handshaking) may contribute physical contact (handshaking) may contribute to spread, but their role is minorto spread, but their role is minor

Signs and SymptomsSigns and Symptoms Abrupt onset of symptomsAbrupt onset of symptoms

Fever, usually over 100°F Fever, usually over 100°F

Cough with little or no sputumCough with little or no sputum

Chills and/or sweats Chills and/or sweats

HeadacheHeadache

Muscle achesMuscle aches

Sore throatSore throat

Potentially severe, persistent malaisePotentially severe, persistent malaise

Chest soreness, light sensitivity, and eye painChest soreness, light sensitivity, and eye pain

Differences Between H5N1 and Differences Between H5N1 and Current Strains Current Strains

Typical influenza involves only the upper respiratory tractTypical influenza involves only the upper respiratory tract Persons with underlying medical problems (lung Persons with underlying medical problems (lung

disease, heart disease, cancer) or the elderly are at disease, heart disease, cancer) or the elderly are at increased risk of secondary bacterial pneumoniaincreased risk of secondary bacterial pneumonia

Influenza viral pneumonia is rareInfluenza viral pneumonia is rare

H5N1 has the ability to infect the upper and lower H5N1 has the ability to infect the upper and lower respiratory tract (including the lung)respiratory tract (including the lung) Anyone who is susceptible to H5N1 can get pneumonia Anyone who is susceptible to H5N1 can get pneumonia

caused by the influenza viruscaused by the influenza virus The resulting influenza virus pneumonia is severe and The resulting influenza virus pneumonia is severe and

may be fatalmay be fatal

Economic Costs of Influenza Economic Costs of Influenza OutbreakOutbreak

Total annual costs of influenza are estimated at Total annual costs of influenza are estimated at $14.6 billion in the US$14.6 billion in the US

10%: Direct costs of increased medical care10%: Direct costs of increased medical care

90%: Indirect costs (lost productivity, 90%: Indirect costs (lost productivity, employee absenteeism)employee absenteeism)

American Lung Association. Fact Sheet – Influenza, at http://www.lungusa.org/diseases/influenza_factsheet.html. Accessed 3/25/99.

Inactivated Influenza Virus Inactivated Influenza Virus VaccineVaccine

HistoryHistory First developed in 1940sFirst developed in 1940s

ContentContent Updated yearly to protect againstUpdated yearly to protect againstanticipated strains, consists of type A anticipated strains, consists of type A (2) and type B (1) (2) and type B (1)

ProcessProcess Grown in embryonated chicken eggs Grown in embryonated chicken eggs and formalin inactivatedand formalin inactivated

MMWR. 1999;48:4-5.

Influenza Virus VaccineInfluenza Virus Vaccine Most effective in young, healthy peopleMost effective in young, healthy people

Often prevents infection, usually prevents serious Often prevents infection, usually prevents serious diseasedisease

Less effective in the elderlyLess effective in the elderly Many develop infection, but vaccine reduces the Many develop infection, but vaccine reduces the

frequency of serious disease and deathfrequency of serious disease and death Response directly related to overall state of healthResponse directly related to overall state of health

ZanamivirZanamivir OseltamivirOseltamivir

(Relenza(Relenza®®)) (Tamiflu(Tamiflu®®))

IndicationIndication Treatment Treatment Treatment,Treatment,ProphylaxisProphylaxis

SpectrumSpectrum Type A, type BType A, type B Type A, type BType A, type B

AdministrationAdministration Inhaled Inhaled Oral Oral 2 puffs bid 2 puffs bid 1 tablet bid 1 tablet bid for 5 days for 5 days for 5 days for 5 days

Selective Neuraminidase Selective Neuraminidase Inhibitors Currently AvailableInhibitors Currently Available