Influenza:Basic Features

Influenza:Basic Features

Niranjan Bhat, MDInfluenza Branch

Division of Viral and Rickettsial Diseases

National Center for Infectious Diseases

Centers for Disease Control and Prevention

Niranjan Bhat, MDInfluenza Branch

Division of Viral and Rickettsial Diseases

National Center for Infectious Diseases

Centers for Disease Control and Prevention

Impact of InfluenzaImpact of Influenza• An annual public health problem• Substantial health impact• 10-35% of children each year• 5-20% of adults each year

• Substantial economic impact • Lost work / school days• Overwhelmed medical care systems

• “A singular global infectious disease threat”

• An annual public health problem• Substantial health impact• 10-35% of children each year• 5-20% of adults each year

• Substantial economic impact • Lost work / school days• Overwhelmed medical care systems

• “A singular global infectious disease threat”

What is InfluenzaWhat is Influenza• “The flu” = acute febrile respiratory illness

• Caused by infection with an influenza virus

• “The flu” = acute febrile respiratory illness

• Caused by infection with an influenza virus

•Fever ≥100F (37.8C)AND

•cough and/or sore throat•In the absence of a known cause other than influenza

•Fever >38.0 CAND

•cough and/or sore throat

CDC WHO

TransmissionTransmission• Highly contagious• Primarily person-to-person– Respiratory droplets: coughing and

sneezing– Direct and indirect contact– Airborne transmission occurs very rarely,

if ever• Incubation period: 1-4 days• Subclinical infection can occur

• Highly contagious• Primarily person-to-person– Respiratory droplets: coughing and

sneezing– Direct and indirect contact– Airborne transmission occurs very rarely,

if ever• Incubation period: 1-4 days• Subclinical infection can occur

TransmissionTransmission

Infectious period–May begin 1 day before symptom onset– Peak viral shedding on day 1 of symptoms– Adults shed for 4-6 days– Infants and children may shed longer– Immunocompromised patients can shed

for months

Infectious period–May begin 1 day before symptom onset– Peak viral shedding on day 1 of symptoms– Adults shed for 4-6 days– Infants and children may shed longer– Immunocompromised patients can shed

for months

Other FeaturesOther Features• Headache, fatigue, body aches

• Range of symptoms differ by age• Vomiting and diarrhea in children• Fever alone in infants

• Often confused with other illnesses• “Viral illness”• “Cold”• “Stomach flu”

• Headache, fatigue, body aches

• Range of symptoms differ by age• Vomiting and diarrhea in children• Fever alone in infants

• Often confused with other illnesses• “Viral illness”• “Cold”• “Stomach flu”

Influenza ComplicationsInfluenza Complications• Primary viral pneumonia/pneumonitis

• Exacerbation of chronic conditions• Congestive heart failure, emphysema

• New bacterial infections• Pneumonia, bacteremia, ear infections

• Neurologic• Encephalopathy, transverse myelitis, GBS, febrile

seizures

• Less common• Shock, myositis, myocarditis, Reye syndrome

• Primary viral pneumonia/pneumonitis

• Exacerbation of chronic conditions• Congestive heart failure, emphysema

• New bacterial infections• Pneumonia, bacteremia, ear infections

• Neurologic• Encephalopathy, transverse myelitis, GBS, febrile

seizures

• Less common• Shock, myositis, myocarditis, Reye syndrome

Influenza ComplicationsInfluenza Complications

• Complications can lead to hospitalization or death

• Certain groups are at higher risk

• Complications can lead to hospitalization or death

• Certain groups are at higher risk

High-Risk GroupsHigh-Risk Groups• Certain underlying conditions are associated

with increased risk of complications due to influenza:

Pulmonary diseaseCardiovascular diseaseMetabolic disordersRenal dysfunction

HemoglobinopathyImmunosuppressionLong-term aspirin therapyPregnancy

Conditions leading to compromise in respiratory function

Morbidity - InfectionsMorbidity - Infections

Monto et al. Am J Epidemiol 985;121(6):811-22

Influenza HospitalizationsInfluenza Hospitalizations• Average of >200,000 influenza-related hospitalizations/year

• Estimated by modeling studies using retrospective data and influenza surveillance data

• High rates in persons with chronic high-risk conditions in all age groups

• Children: • Highest rates in young children <2 years • Children 2-5 years next highest

• Adults: • Highest rates in persons 65 years

Simonsen, JID 2000; Izurieta, NEJM 2000; Neuzil, NEJM 2000; Thompson, JAMA 2004; Neuzil, JID 2002

Morbidity - HospitalizationsMorbidity - Hospitalizations

Glezen, et al. J Infect Dis 1987;155(6):1119-26.

Influenza MortalityInfluenza Mortality• Average of >36,000 influenza-related deaths/year

• Estimated by modeling studies using retrospective data and influenza surveillance data

• Adults: • Majority of deaths (90%) occur among persons 65 years • Other high-risk groups include persons with chronic illness

• Children: • Estimated average of 92 influenza-related deaths among children

aged <5 years each year• 153 influenza-related deaths reported to CDC for the 2003-04

season• Fewer cases reported during 2004-05 season

Thompson, JAMA 2003; Bhat, NEJM 2005

MortalityMortality

Thompson, et al. JAMA 2003;289(2):179-86.

Note: rates are 10-fold lower than graph represents the for first four age groups

01000020000300004000050000600007000080000

Years

Num

ber

of D

eath

s

P & IR & CAll-cause

Deaths Related to InfluenzaU.S., 1976-1999

Thompson, JAMA 2003

Influenza VaccinationInfluenza Vaccination• Recommendations of the Advisory Committee on

Immunization Practices (ACIP)• Persons aged:• ≥65 years• 6-23 months• 50-49 years

• All high-risk persons ≥6 months of age • Household contacts of high risk persons and

health care workers

Influenza VaccineInfluenza Vaccine• Inactivated virus by intramuscular injection

• Approved for all persons ≥6 months old

• Live, attenuated virus by intranasal spray

• Approved for healthy persons 5-49 years old

• U.S. vaccine strains selected by FDA with CDC guidance (VRBPAC) (March)

• Annual vaccine production requires 6-8 months

• Must be administered annually

Influenza Antiviral Drugs

• Treatment• 5 day course • Should be started <48 hours from illness onset • Shown to reduce symptoms by approximately 1 day• Reduces viral shedding

• Chemoprophylaxis • 70 - 90% effective in preventing illness from influenza• Infection may still occur

Examples:• For control of nosocomial outbreaks• For patients who cannot receive vaccine

Influenza Antiviral DrugsInfluenza Antiviral Drugs

• Amantadine, rimantadine• Influenza A only

• Oseltamivir, zanamivir• Influenza A and B

• Approved ages vary by drug and indication

• No treatment or prophylaxis approved for children aged <1 year

• Amantadine, rimantadine• Influenza A only

• Oseltamivir, zanamivir• Influenza A and B

• Approved ages vary by drug and indication

• No treatment or prophylaxis approved for children aged <1 year

Influenza Antiviral DrugsInfluenza Antiviral Drugs

• Approved ages vary by drug and indication

• None are approved for children aged <1 year– Neither treatment nor prophylaxis

• Approved ages vary by drug and indication

• None are approved for children aged <1 year– Neither treatment nor prophylaxis

Indication Amantadine Rimantadine Oseltamivir Zanamivir

Treatment ≥1 year ≥13 years ≥1 year ≥7 years

Prophylaxis ≥1 year ≥1 year ≥1 year* NA

*New approval

Relative Cost of AntiviralTreatment for 5 days

Relative Cost of AntiviralTreatment for 5 days

Amantadine: $3.70

Rimantadine: $20.40

Oseltamivir: $63.40

Zanamivir: $51.40

Amantadine: $3.70

Rimantadine: $20.40

Oseltamivir: $63.40

Zanamivir: $51.40

Influenza TestingInfluenza Testing• Viral culture (gold standard)• Serology (requires paired samples)• Immunofluorescence (IFA, DFA)• Reverse-transcriptase polymerase chain reaction• Rapid diagnostic testing

• Specimens: nasopharyngeal swab is ideal• Also, nasal swab, NP or nasal aspirate• Best if close to illness onset (<4 days)

• Viral culture (gold standard)• Serology (requires paired samples)• Immunofluorescence (IFA, DFA)• Reverse-transcriptase polymerase chain reaction• Rapid diagnostic testing

• Specimens: nasopharyngeal swab is ideal• Also, nasal swab, NP or nasal aspirate• Best if close to illness onset (<4 days)

Influenza Viruses Influenza Viruses • Illness caused by infection

with an influenza virus

• Primarily infects the upper respiratory tract

• Negative single-stranded RNA virus

• 8 gene segments code for 10 proteins

• Influenza viruses classified into types A, B, and C

• Illness caused by infection with an influenza virus

• Primarily infects the upper respiratory tract

• Negative single-stranded RNA virus

• 8 gene segments code for 10 proteins

• Influenza viruses classified into types A, B, and C

Influenza A VirusesInfluenza A Viruses• Influenza A viruses further categorized by

subtype

• Subtypes are determined by two surface glycoproteins

–Hemagglutinin (HA)• Site of attachment to host cell surface receptors• Antibody to HA is protective

–Neuraminidase (NA)• Takes part in the release of virions from the cell

• Influenza A viruses further categorized by subtype

• Subtypes are determined by two surface glycoproteins

–Hemagglutinin (HA)• Site of attachment to host cell surface receptors• Antibody to HA is protective

–Neuraminidase (NA)• Takes part in the release of virions from the cell

Influenza A HA and NA Subtypes

H15,16H14H13H12H11H10

H3H2H1

H9H8H7H6H5H4

N9

N8

N7

N6

N5

N3

N4

N2

N1

Avian Influenza A VirusesH1 - H16N1 - N9

H1 - H3N1 - N2

Human Influenza A Viruses

Avian and Human Influenza A viruses

Antigenic “drift” Antigenic “drift”

Minor antigenic changes to the hemagglutinin protein

• Continuous process• Escapes immunity in the population• Vaccine strains must be updated each year• Two type A strains (H1N1, H3N2), one type B

strain

• Antigenic drift leads to seasonal epidemics

Minor antigenic changes to the hemagglutinin protein

• Continuous process• Escapes immunity in the population• Vaccine strains must be updated each year• Two type A strains (H1N1, H3N2), one type B

strain

• Antigenic drift leads to seasonal epidemics

Annual Influenza EpidemicsAnnual Influenza Epidemics

Annual Influenza EpidemicsAnnual Influenza Epidemics

Annual Influenza EpidemicsAnnual Influenza Epidemics

Global ImpactGlobal Impact• Seasonal epidemics in temperate regions

– U.S., Canada, Europe, Russia, China, Japan, Australia, Brazil, Argentina

• Year-round activity in tropical climates– Equatorial Africa, Southeast Asia

• Sporadic outbreaks among rural populations– Madagascar 2002; D.R. Congo 2002

• Sporadic outbreaks among travelers– Alaska, U.S., Yukon Territory, Canada 1998

• 3 pandemics in the 20th century

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

Argentina

• Year-round activity in tropical climates– Equatorial Africa, Southeast Asia

• Sporadic outbreaks among rural populations– Madagascar 2002; D.R. Congo 2002

• Sporadic outbreaks among travelers– Alaska, U.S., Yukon Territory, Canada 1998

• 3 pandemics in the 20th century

Antigenic “shift”Antigenic “shift”

• Emergence of a novel human influenza A subtype:

• Direct bird-to-human transmission• Through adaptation to a human host

or• Genetic reassortment between human and animal

influenza viruses • Co-infection within a human host• Co-infection within an intermediate host (eg, swine)

• Emergence of a novel human influenza A subtype:

• Direct bird-to-human transmission• Through adaptation to a human host

or• Genetic reassortment between human and animal

influenza viruses • Co-infection within a human host• Co-infection within an intermediate host (eg, swine)

Avianvirus

Human virus

Avianvirus

Reassortment in swine

Reassortment in humans

Transmission to Humans

Avianvirus

Influenza PandemicsInfluenza Pandemics

Requirements:• Emergence of a novel human influenza A

subtype (antigenic shift)

AND

• Efficient human-to-human transmission

A pandemic can result in:• Increased overall morbidity and mortality

• Higher proportion of deaths in younger adults

Requirements:• Emergence of a novel human influenza A

subtype (antigenic shift)

AND

• Efficient human-to-human transmission

A pandemic can result in:• Increased overall morbidity and mortality

• Higher proportion of deaths in younger adults

Impact of Influenza PandemicsImpact of Influenza Pandemics

•1918-19 Spanish Flu (H1N1)1918-19 Spanish Flu (H1N1)• 20-50 million deaths worldwide20-50 million deaths worldwide• >500,000 U.S. deaths>500,000 U.S. deaths

•1957-58 Asian Flu (H2N2)1957-58 Asian Flu (H2N2)• 70,000 U.S. deaths70,000 U.S. deaths

•1968-69 Hong Kong Flu (H3N2)1968-69 Hong Kong Flu (H3N2)• 34,000 U.S. deaths34,000 U.S. deaths

Belshe, NEJM 353(21):2209-11, 2005

Infectious Disease Mortality(all causes), United States--20th Century

Infectious Disease Mortality(all causes), United States--20th Century

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

Estimated Impact of a Future Influenza Estimated Impact of a Future Influenza Pandemic in the U.S.Pandemic in the U.S.

Meltzer, Emerg Infect Dis 1999

DeathsDeaths 89,000 - 207,00089,000 - 207,000

HospitalizationsHospitalizations 314,000 - 734,000314,000 - 734,000

Outpatient visitsOutpatient visits 18 - 42 million18 - 42 million

Additional illnessesAdditional illnesses 20 - 47 million20 - 47 million

Economic impactEconomic impact $71.3 - 166.5 billion$71.3 - 166.5 billion

Population affectedPopulation affected 15-35%15-35%(U.S. population: 290 million)(U.S. population: 290 million)

Microbial Threats to Health: Emergence, Detection, and Response

Institute of Medicine report

Released March 18, 2003

Factors in Infectious Disease Emergence

Factors in Infectious Disease Emergence

• Ecological ChangesEcological Changes

• Human Demographics and BehaviorHuman Demographics and Behavior

• International Travel and CommerceInternational Travel and Commerce

• Technology and IndustryTechnology and Industry

• Microbial Adaptation and ChangeMicrobial Adaptation and Change

• Breakdown in Public Health InfrastructureBreakdown in Public Health Infrastructure

• Human Susceptibility to InfectionHuman Susceptibility to Infection

• Economic Development and Land UseEconomic Development and Land Use

• Climate and WeatherClimate and Weather

• War and FamineWar and Famine

• Lack of Political WillLack of Political Will

• Poverty and Social InequalityPoverty and Social Inequality

• Intent to HarmIntent to Harm

Timeline of Emergence of Timeline of Emergence of Influenza Viruses in HumansInfluenza Viruses in Humans

1918 1957 1968 1977 1997

1998/9

2003

H1

H1

B

H2SpanishInfluenza

AsianInfluenza

RussianInfluenza

Hong KongInfluenza

H3

Esta

blish

ed

Hu

man

V

iru

ses

Timeline of Emergence of Timeline of Emergence of Influenza Viruses in HumansInfluenza Viruses in Humans

1918 1957 1968 1977 1997

1998/9

2003

H1

H1

B

H2

H7H5H5

H9

SpanishInfluenza

AsianInfluenza

RussianInfluenza

AvianInfluenza

Hong KongInfluenza

H3

Avia

n V

iru

ses

Esta

blish

ed

Hu

man

V

iru

ses

• Seasonal influenza viruses– A public health problem every year– Circulate throughout the human population– Spread easily from person to person

• Avian influenza A (H5N1)– Devastating global outbreak in poultry– Rare but severe human infections– Does not spread easily from person to person

• Pandemic influenza viruses– Appears in the human population periodically– H5N1 is a likely candidate, but is not a pandemic virus yet

• Seasonal influenza viruses– A public health problem every year– Circulate throughout the human population– Spread easily from person to person

• Avian influenza A (H5N1)– Devastating global outbreak in poultry– Rare but severe human infections– Does not spread easily from person to person

• Pandemic influenza viruses– Appears in the human population periodically– H5N1 is a likely candidate, but is not a pandemic virus yet

Seasonal, Avian, and Pandemic InfluenzaSeasonal, Avian, and Pandemic Influenza