Influenza Tim Uyeki MD, MPH, MPP, FAAP Influenza Division - - PowerPoint PPT Presentation

Influenza

Tim Uyeki MD, MPH, MPP, FAAP

Influenza Division National Center for Immunization and Respiratory Diseases Coordinating Center for Infectious Diseases Centers for Disease Control and Prevention August 7, 2006

Influenza Influenza

• Acute febrile respiratory illness

Acute febrile respiratory illness

• Symptoms, signs may differ by age

Symptoms, signs may differ by age

• Etiology: Infection with influenza viruses

Etiology: Infection with influenza viruses

• Orthomyxoviridae

Orthomyxoviridae

• Negative single stranded RNA viruses

Negative single stranded RNA viruses

• 4 Genera: 3 Influenza virus types,

4 Genera: 3 Influenza virus types, Thogotoviruses Thogotoviruses

• Types A, B, C

Types A, B, C

• Types A and B are important for humans

Types A and B are important for humans

• 8 single stranded negative sense gene

8 single stranded negative sense gene segments code for at least 10 proteins segments code for at least 10 proteins

• Reassortment

Reassortment (gene exchange) occurs (gene exchange) occurs

• Type A viruses cause greatest morbidity and

Type A viruses cause greatest morbidity and mortality mortality

Influenza Virus

Surface proteins (major antigens)

• Hemagglutinin (HA)
• Site of attachment to host cells
• Antibody to HA is protective
• Neuraminadase (NA)
• Helps release virions from cells
• Antibody to NA can help

modify disease severity

Key I nfluenza Viral Features

NA HA

• Influenza A and B viruses infect and replicate in

epithelial cells of the upper respiratory tract: primarily shed in the upper respiratory tract (can infect lower

respiratory tract)

Viral shedding occurs the day before illness onset

• Peak viral shedding on Day 1 of illness
• Duration
• Adults may shed viruses for 4-6 days
• Young children may shed for longer periods
• Immunocompromised can shed for months
• Sub-clinical infection can occur

Best clinical specimens to detect influenza viruses

• Close to illness onset (<4 days)
• Nasopharyngeal or nasal swabs, aspirates, washes

Influenza Viral Shedding

Influenza Influenza

Transmission: person Transmission: person-

• to

to-

• person

person

• Large droplets

Large droplets: coughing, sneezing : coughing, sneezing

• Highly contagious to susceptible persons

Highly contagious to susceptible persons

• Replicates in large airway epithelial cells

Replicates in large airway epithelial cells

• Viremia

Viremia has rarely been reported has rarely been reported

Incubation period: 1 Incubation period: 1-

• 4 days

4 days

• Viral shedding can begin before symptom onset

Viral shedding can begin before symptom onset

• Peak viral shedding on first day of symptoms

Peak viral shedding on first day of symptoms

• Adults may shed for 4

Adults may shed for 4-

• 6 days

6 days

• Children may shed for longer periods

Children may shed for longer periods

• Immunosuppressed

Immunosuppressed, , immunocompromised immunocompromised can can shed for months shed for months

Viral Shedding

1 2 3 4 5 6 2 4 6 8 Days After Exposure

Log of Nasopharyngeal Virus Titer Average Onset of Symptoms

(Adapted from Murphy BR et. al. J Infect Dis 1973)

Exposure

“Antigenic Drift” Influenza Viruses are Dynamic

Point mutations in the hemagglutinin gene of influenza viruses cause minor antigenic changes to hemagglutinin protein

Gradual, continuous process Immunity against one strain may be limited

Vaccine strains must be updated each year

• 6-8 month process
• Targeted at high-risk (inactivated); healthy (LAIV)
• Bi-annual process for Northern and Southern Hemispheres

Antigenic “Drift” causes seasonal epidemics

Global Influenza Surveillance

• WHO Global Influenza Programme
• Goals
• Monitor and identify human influenza viruses

for global influenza vaccine strain selection

• Detect emergence of novel influenza A viruses

with human pandemic potential

• 4 WHO Collaborating Centers
• Melbourne, Tokyo, London, CDC
• >110 National Influenza Centers
• Bi-annual influenza vaccine strain

selection process

• Northern Hemisphere
• Southern Hemisphere

U.S. Influenza Surveillance

CDC

Laboratories Sentinel Providers State and Territorial Epidemiologists Vital Statistics Registrars Other Public Health Officials Physicians Media Public

Health Departments

Pediatric Hospitalization (EIP & NVSN) Pediatric Mortality

Influenza-like Illness: Case definitions for surveillance

• CDC: temperature ≥100.0 °F (37.8 °C)

and either cough or sore throat

• WHO: temperature >38.0 °C and either

cough or sore throat, in the absence of any other known diagnoses

• Both are non-specific for influenza

U.S. Virologic Surveillance

• ~130 participating WHO/NREVSS

laboratories

• Report weekly:
• # specimens tested
• # positive for influenza: type, subtype, age
• Laboratories submit subset of isolates to

CDC strain surveillance lab for:

• Detailed antigenic characterization
• Sequencing of some isolates
• Antiviral resistance testing

Hospitalizations Attributable to Influenza (U.S.)

Average of >200,000 influenza-related hospitalizations/year

• Estimated by modeling studies using retrospective data

and influenza surveillance data

Children:

• 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

Outpatient and Emergency Room Presentations

Lab-confirmed influenza illness

• Febrile upper respiratory illness
• Febrile lower respiratory illness (pneumonia)
• Gastrointestinal (with dehydration)
• Sepsis-like syndrome (fever without a source)
• Common complications
• Otitis media
• Exacerbation of chronic illness
• Other complications
• Myositis (gastrocnemius)
• Febrile seizures

Hospitalized conditions

• Exacerbation of chronic illness
• Coronary artery disease (myocardial infarction,

congestive cardiac failure)

• Respiratory disease
• Bronchitis, Croup, Bronchiolitis
• Pneumonia
• Secondary Bacterial (S. pneumoniae, MSSA, MRSA)
• Primary viral
• Sepsis-like syndrome (fever without a source)
• Dehydration, Gastrointestinal illness
• Uncommon complications
• Myocarditis, rhabdomyolysis
• Invasive bacterial infection (GAS, N. meningitidis)
• Neurological complications
• Toxic shock

Influenza Influenza-

• Associated Hospitalizations

Associated Hospitalizations By Age Group* By Age Group*

115 22 90 472 100 200 300 400 500 600 0 - 4 Yrs 5 - 49 Yrs 50 - 64 Yrs > 65 Yrs Age Group Hospitalizations Per 100,000 Person Years

* Thompson, CDC, 2004, unpublished data

Mortality attributable to Influenza (U.S.) Average of >36,000 influenza-related deaths/year

• Estimated by modeling studies using retrospective data

and influenza surveillance data

Children:

• Limited data
• Estimated average of 92 influenza-related deaths

among children aged <5 years each year

Adults:

• Majority of deaths occur among persons ≥65 years
• Other high-risk groups include persons with chronic

illness

Thompson WW et al., JAMA 2003;289:179-186

Influenza Influenza-

• Associated Deaths By Age Group*

Associated Deaths By Age Group*

0.6 0.4 0.5 7.5 98.3 20 40 60 80 100 120 < 1 Yrs 1 - 4 Yrs 5 - 49 Yrs 50 - 64 Yrs 65+ Yrs Age Group R&C Deaths Per 100,000 Person Years

* Thompson, et al. JAMA 2003

Deaths related to Influenza Increasing, U.S., 1976-1999

10000 20000 30000 40000 50000 60000 70000 80000 7 6

• 7

7 7 8

• 7

9 8

• 8

1 8 2

• 8

3 8 4

• 8

5 8 6

• 8

7 8 8

• 8

9 9

• 9

1 9 2

• 9

3 9 4

• 9

5 9 6

• 9

7 9 8

• 9

9 Years Number of Death P & I R & C All-cause

Thompson et al. JAMA 2003;289:179-86.

Global Impact of Influenza

• Seasonal epidemics in temperate regions
• U.S., Canada, Europe, Russia, China, Japan,

Australia, Brazil, Argentina

• Severity varies from year-to-year
• Year-round activity in tropical climates
• Equatorial Africa, Southeast Asia
• Sporadic outbreaks
• Rural populations
• Madagascar 2002; D.R. Congo 2002
• Travelers:
• Alaska, U.S., Yukon Territory, Canada 1998
• 3 pandemics in the 20th century

Influenza Activity and Seasonality, Thailand

Wet Dry

Influenza Surveillance in Indonesia NAMRU2, 1999-2005 Influenza Surveillance in Indonesia NAMRU2, 1999-2005

40 80 120 160 September October November December January February March April May June July August

Flu A Flu B

Influenza A Viruses Influenza A Viruses

• Subtypes based on surface

Subtypes based on surface glycoproteins glycoproteins

• Hemagglutinin

Hemagglutinin (HA) and Neuraminidase (NA) (HA) and Neuraminidase (NA)

• Current human influenza A virus subtypes:

Current human influenza A virus subtypes:

• H1N1

H1N1, H1N2, , H1N2, H3N2 H3N2

• Cause epidemics and pandemics

Cause epidemics and pandemics

• Infect multiple species

Infect multiple species

• Humans

Humans

• Birds (wild birds, domestic poultry)

Birds (wild birds, domestic poultry)

• Other animals: pigs, horses, dogs,

Other animals: pigs, horses, dogs, marine mammals (seals, whales) marine mammals (seals, whales)

Avian Influenza A Viruses H1 - H16 N1 - N9

H1 - H3 N1 - N2

Human Influenza A Viruses Natural reservoir for new human influenza A Natural reservoir for new human influenza A virus subtypes: virus subtypes: Wild waterfowl, aquatic ducks Wild waterfowl, aquatic ducks

Antigenic “shift” causes pandemics

Emergence of a new human influenza A virus subtype (new HA subtype) through:

• Genetic reassortment (human and animal viruses)
• Direct animal (poultry) to human transmission

A pandemic can occur if:

• (1) A novel influenza A virus infects humans; and
• (2) Causes disease; and
• (3) Efficient and SUSTAINED virus transmission
• ccurs among humans (sustained person-to-person

spread)

A pandemic can result in:

• Widespread morbidity and mortality worldwide
• High proportion of deaths among young adults

Avian-human pandemic reassortant virus

Huma n virus

Avian virus Avian reassortant virus Avian virus Reassortment in swine Reassortment in humans

Goose/Guangdong/1/96 (H5N1)

Quail/HK/G1/97 (H9N2) Teal/HK/W312/97 (H6N1) A/HK156/97 (H5N1)

Antigenic “Shift” Pandemic

Model of the emergence

• f a pandemic

influenza virus

Estimated Impact of Influenza Pandemics Estimated Impact of Influenza Pandemics 1918 1918-

• 19 Spanish Flu (H1N1)

19 Spanish Flu (H1N1)

• 20

20-

• 50 million deaths worldwide

50 million deaths worldwide

• >500,000 U.S. deaths

>500,000 U.S. deaths

1957 1957-

• 58 Asian Flu (H2N2)

58 Asian Flu (H2N2)

• 70,000 U.S. deaths

70,000 U.S. deaths

1968 1968-

• 69 Hong Kong Flu (H3N2)

69 Hong Kong Flu (H3N2)

• 34,000 U.S. deaths

34,000 U.S. deaths

Infectious Disease Mortality, United States--20th Century

Armstrong, et al. JAMA 1999;281:61-66.

Emergence of Influenza A Viruses in Humans Emergence of Influenza A Viruses in Humans

Influenza A reservoir

1918 1957 1968 1977

Spanish Influenza Asian Influenza Hong Kong Influenza

H1N1 H2N2 H3N2 H1N1

Ag drift Ag shift Russian Influenza

H7 H5 H5 H9

Avian Influenza

H5

1997 1998/9 2003 2004

U.S. Impact Estimates for the Next Influenza Pandemic

Deaths: 89-207,000 Hospitalizations: 314-733,000 Outpatient care: 18-42 m Total infected: 43-100 m

15-35% 6-15% .1-.3% .03-.07%

Health related economic impact Estimated: $71 to $166 billion

Meltzer M, et al. Emerging Infectious Diseases 1999;5:659-671

Prevention of Influenza Influenza vaccine (trivalent)

• WHO biannual strain selection
• Northern Hemisphere strains (February)
• One Type B strain, 2 type A strains (H1N1, H3N2)
• U.S. strains selected by FDA VRBAC
• 6-8 months to produce vaccine for the U.S.
• Inactivated, for intramuscular injection
• Live, attenuated, intranasal spray

*U.S. Children: 7.4% received 1 or 2 doses; 4.4% fully vaccinated (2002-03 season)

*CDC. MMWR 2004;53:863-866.

Influenza Testing

Influenza viruses primarily infect epithelial cells of the upper respiratory tract

Adults shed viruses for approximately 5 days Young children and immunosuppressed can shed viruses for longer periods

Clinical specimens to detect human influenza viruses

• Close to illness onset (<4 days)
• Respiratory specimens:
• Nasopharyngeal swabs, nasal swabs,
• NP aspirates, nasal aspirates
• Tests:
• Viral Culture - isolation (“gold standard”)
• Immunofluorescence (DFA, IFA)
• Rapid diagnostic test
• RT-PCR, rRT-PCR
• Serology (requires paired sera)

Antiviral Medications for Influenza

• Treatment of Influenza A virus infections

Treatment of Influenza A virus infections 4 approved drugs 4 approved drugs Amantadine, Rimantadine Amantadine, Rimantadine Oseltamivir, Zanamivir Oseltamivir, Zanamivir

• Treatment of Influenza B virus infections

Treatment of Influenza B virus infections 2 approved drugs 2 approved drugs Oseltamivir, Zanamivir Oseltamivir, Zanamivir All drugs can decrease viral shedding and All drugs can decrease viral shedding and symptoms of influenza by one day symptoms of influenza by one day

• CDC does not recommend use of

CDC does not recommend use of Amantadine Amantadine or

• r

Rimantadine Rimantadine due to widespread resistance, 2006 due to widespread resistance, 2006

Influenza Antiviral Drugs

• Treatment of influenza
• Treatment should be started <48 hours

from illness onset, for 5 days

• Can reduce symptoms by one day
• Chemoprophylaxis
• 70 - 90% effective in preventing illness from

influenza (infection may still occur) Examples: Control nosocomial outbreaks, Patients who cannot receive vaccine

Summary

• Human influenza virus infection causes

substantial morbidity and mortality worldwide, including seasonal outbreaks

• Because influenza viruses are

continuously experiencing “antigenic drift,” surveillance is needed year-round for vaccine strain selection

• “Antigenic shift” can rarely lead to human

pandemics with high global morbidity and mortality

WHO Global Preparedness Plan 2005

• WHO revised plan (April 2005)
• Redefines pandemic phases, associated public health risk
• 3 periods (interpandemic, pandemic alert, pandemic)
• 6 phases
• Outlines WHO actions to be taken during each phase and

provides guidance for countries to develop national pandemic plans

• Objectives and actions:
• Planning and coordination
• Situation monitoring and assessment
• Prevention and containment (non pharmaceutical public

health interventions, vaccines, antivirals)

• Health system response
• Communications

WHO Pandemic Periods and Phases, Revised, 2005