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Influenza:
Basic Features
Niranjan Bhat, MD
Influenza Branch
Division of Viral and Rickettsial Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Impact 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”
What is Influenza
• “The flu” = acute febrile respiratory illness
• Caused by infection with an influenza virus
CDC
•Fever ≥100F (37.8C)
AND
•cough and/or sore
throat
•In the absence of a known cause
other than influenza
WHO
•Fever >38.0 C
AND
•cough and/or sore
throat
Transmission
• 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
Transmission
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 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”
Influenza 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
Influenza Complications
• Complications can lead to hospitalization or
death
• Certain groups are at higher risk
High-Risk Groups
• Certain underlying conditions are associated
with increased risk of complications due to
influenza:
Pulmonary disease
Cardiovascular disease
Metabolic disorders
Renal dysfunction
Hemoglobinopathy
Immunosuppression
Long-term aspirin therapy
Pregnancy
Conditions leading to compromise in respiratory
function
Morbidity - Infections
Monto et al. Am J Epidemiol 985;121(6):811-22
Influenza 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 - Hospitalizations
Glezen, et al. J Infect Dis 1987;155(6):1119-26.
Influenza 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
Mortality
Thompson, et al. JAMA 2003;289(2):179-86.
Note: rates are 10-fold lower than graph represents the for first four age groups
Deaths Related to Influenza
80000
70000
60000
50000
40000
30000
20000
10000
0
P&I
R&C
All-cause
76
-7
7
78
-7
9
80
-8
1
82
-8
3
84
-8
5
86
-8
7
88
-8
9
90
-9
1
92
-9
3
94
-9
5
96
-9
7
98
-9
9
Number of Deaths
U.S., 1976-1999
Years
Thompson, JAMA 2003
Influenza 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 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 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
Influenza Antiviral Drugs
• Approved ages vary by drug and indication
Indication
Amantadine Rimantadine Oseltamivir
Zanamivir
Treatment
≥1 year
≥13 years
≥1 year
≥7 years
Prophylaxis
≥1 year
≥1 year
≥1 year*
NA
• None are approved for children aged <1 year
– Neither treatment nor prophylaxis
*New approval
Relative Cost of Antiviral
Treatment for 5 days
Amantadine: $3.70
Rimantadine: $20.40
Oseltamivir: $63.40
Zanamivir:
$51.40
Influenza 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)
Influenza Viruses
• Illness caused by infection
with an influenza virus
• Primarily infects the
upper respiratory tract
• Negative singlestranded RNA virus
• 8 gene segments code
for 10 proteins
• Influenza viruses
classified into types A,
B, and C
Influenza 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 HA and NA Subtypes
H1
H2
H3
H4
H5
H6
H7
H8
H9
H10
H11
H12
H13
H14
H15,16
N1
N2
N3
N4
N5
N6
N7
N8
N9
Avian and Human Influenza A
viruses
Human Influenza
A Viruses
Avian Influenza
A Viruses
H1 - H16
N1 - N9
H1 - H3
N1 - N2
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
Annual Influenza Epidemics
Annual Influenza Epidemics
Annual Influenza Epidemics
Global 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
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)
Transmission to Humans
Avian
virus
Avian
virus
Reassortment
in humans
Avian
virus
Human
virus
Reassortment
in swine
Influenza 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
Impact of Influenza Pandemics
• 1918-19 Spanish Flu (H1N1)
• 20-50 million deaths worldwide
• >500,000 U.S. deaths
• 1957-58 Asian Flu (H2N2)
• 70,000 U.S. deaths
• 1968-69 Hong Kong Flu (H3N2)
• 34,000 U.S. deaths
Belshe, NEJM 353(21):2209-11, 2005
Infectious Disease Mortality
(all causes), United States--20th Century
Armstrong, et al. JAMA 1999;281:61-66.
Estimated Impact of a Future Influenza
Pandemic in the U.S.
Deaths
89,000 - 207,000
Hospitalizations
314,000 - 734,000
Outpatient visits
18 - 42 million
Additional illnesses
20 - 47 million
Economic impact
$71.3 - 166.5 billion
Population affected
Meltzer, Emerg Infect Dis 1999
15-35%
(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
•
•
•
•
•
•
•
•
•
•
•
•
•
Ecological Changes
Human Demographics and Behavior
International Travel and Commerce
Technology and Industry
Microbial Adaptation and Change
Breakdown in Public Health Infrastructure
Human Susceptibility to Infection
Economic Development and Land Use
Climate and Weather
War and Famine
Lack of Political Will
Poverty and Social Inequality
Intent to Harm
B
Established Human
Viruses
Timeline of Emergence of
Influenza Viruses in Humans
Russian
Influenza
Hong Kong
Influenza
Asian
Influenza
H1
Spanish
Influenza
H1
1918
H3
H2
1998/9
1957 1968 1977
1997
2003
Avian
Influenza
B
H7
H5
Established Human
Viruses
H9
H5
Russian
Influenza
Hong Kong
Influenza
Asian
Influenza
H1
Spanish
Influenza
H1
1918
H3
H2
1998/9
1957 1968 1977
Avian
Viruses
Timeline of Emergence of
Influenza Viruses in Humans
1997
2003
Seasonal, Avian, and Pandemic Influenza
• 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