Influenza

Principles of Infectious Disease Epidemiology / EPI 220
UCLA School of Public Health / Department of Epidemiology

Instructor: Layne / Fall 2008
ACUTE RESPIRATORY INFECTIONS
GENERAL
Acute respiratory infections kill 4,000,000 annually worldwide.
Pneumococcal disease kills 1,600,000 annually worldwide.
Two-thirds of these deaths occur in the first year of life.
SUMMARY TABLE
__________________________________________________________
Type Anatomic Etiology Peak age Mortality
Diagnosis (months)
__________________________________________________________
Upper Pharyngitis Viral No
Respiratory
Otitis media Bacterial 6-7 No
Tonsillitis Viral & Bacterial Yes
Epiglottitis Bacterial 24 - 47 Yes
Lower Laryngitis (croup) Viral 12 - 23 Rare

Respiratory
Tracheobronchitis Viral & Bacterial none No
Bronchiolitis Viral 0 - 12 Yes
Pneumonia Viral & Bacterial 24 - 35 Yes

__________________________________________________________
Viruses that are major causes of acute respiratory disease.

Influenza
Parainfluenza
Rhinoviruses
Adenoviruses (SARS)
Respiratory Syncytial Virus
Respiratory coronaviruses
Reoviruses
Enteroviruses
Measles
–1–
Bacteria that are major causes of acute respiratory disease.

Streptococcus pneumoniae
Haemophilus influenzae
Bordetella pertussis
Corynebacterium diphtheriae
Heterogeneous group of viruses with common features.

Relatively short incubation period: 1 - 4 days.
Direct transmission by infective droplet nuclei.
Indirect transmission by hands to nasal or conjunctivae.
Increases the risk of bacterial superinfections.
All pathogens have worldwide distribution.
United States
Respiratory disease accounts for 75 - 80% of acute morbidity.
80% of respiratory diseases are viral.
On average, there are 3 - 4 respiratory illnesses per year per person.
Seasonality of respiratory illnesses.
Lowest in summer and highest in winter.
–2–
INFLUENZA
GENERAL
Influenza A — epidemics vs pandemics
In "epidemic" years, 10% - 20% of world’s population gets influenza.
Associated with 500,000 to 1,000,000 deaths worldwide.
Caused by genetic “drifts”
Point mutations in gene segments: H1 ---> H1
In "pandemic" years, over 25% of world’s population gets influenza.

Associated with a disproportionate number of deaths worldwide.
Caused by genetic “shifts”
Complete substitutions of gene segments: H1 ---> H5
Combined, yearly epidemics kill as many as sporadic pandemics.
WHO Influenza Program

Most extensive surveillance system in the world.
4 WHO Collaborating Centers (USA, UK, Japan, Australia).
112 national centers in 83 countries.
System collect 200,000 samples yearly.
About 5,000 samples are analyzed in detail.
Approximately 300 million doses of influenza vaccine manufactured yearly.

Vaccine strains are chosen twice yearly.
Southern Hemisphere / Northern Hemisphere.
Even though a common pathogen, relatively little is known about influenza.

When will the next pandemic occur? Answer: Unknown.
How severe will the next pandemic be? Answer: Unknown.
Why are pandemic strains so virulent? Answer: Unknown.
Influenza A is a zoonotic disease.

Humans
Farm animals (pigs, chickens, ducks)
Wild animals (migratory birds)
Nomenclature
A / Swine / Iowa / 15 / 30 (H1 N1)
type / host / location / strain number / year (H and N subtypes)
–3–
CLINICAL FEATURES
Acute influenza A syndrome
Incubation period is brief, ~2 days.
Onset of symptoms is abrupt, develops over a few hours.
Illness reaches maximum severity fast, within 6 - 12 hours
Acute symptoms (hit by a freight train)

Fever
Myalgias
Headache
Shaking chills
Dry cough
Acute symptoms persist for 2 - 5 days

Sometimes with worsening cough
Followed by gradual improvement
After one week, person feels better.
Lingering symptoms persist for 2 - 3 weeks

Fatigue
Weakness
Cough
Bacterial superinfections
Most common complication of influenza infection
Occurs during the acute or convalescent phase
Associated with worsening of patient’s condition
Most common bacteria include
Streptococcus pneumoniae
Haemophilus influenzae
Staphylococcus aureus
More severe manifestations of influenza A

Viral pneumonia
Viral meningitis
Viral myositis
Viral myocarditis
–4–
Reye’s syndrome
Develops 2 - 12 days after viral infection.
Severe fatty infiltration of liver.
Cerebral edema
Associated with aspirin use
Three ways that influenza A kills.

U-shaped mortality (young and old)
W-shaped mortality (1918 pandemic)
1. Worsening of underlying chronic disease (usually the elderly)

Cardiovascular disease
Pulmonary disease
2. Superinfections
Bacterial pneumonia
Disseminated bacterial infections
3. Direct rapid progression

Severe viral pneumonia
EPIDEMIOLOGY
Influenza A circulates in three major pools of animals.
In humans, infection spread by respiratory-droplet route.
In wild birds, infection spread by fecal-oral route.
In farm animals, infection spread by both routes
Swine (respiratory-droplet)
Chickens and ducks (fecal-oral)
Is southeast Asia an epidemic and pandemic incubator?

People live in close proximity to farm animals.
Farm animals and wild animals cross-infect.
Seasonality
Higher rates of infection in winter months.
Reason for seasonal cycles is unclear.
Seasons in Southern and Northern Hemispheres are 6 months apart.
–5–
Epidemics
Involve 10% - 20% of world’s population.
Kill 500,000 to 1,000,000 people yearly.
Predictable, yearly.
Driven by “drift” mutations.
Changes confined to hemagglutinin (H) and neuraminidase (N).
Pandemics
Involve more than 25% of world’s population.
Number of deaths varies.
Unpredictable, sporadic.
Driven by “shift” mutations.
Adaptation of animal-like to human-like strains.
Adaptation involves all 8 gene segments (polygenic selection).
Pandemics
__________________________________________________________
Year Subtypes Name Excess Mortality
1890 ? — —
1900 ? — —
1918 H1 N1 Spanish flu 40,000,000
1957 H2 N2 Asian flu 70,000
1968 H3 N2 Hong Kong flu 31,000
1977 H3 N2 and H1 N1 — 32,000
1997 H5 N1 Chicken flu 18

2003/4 H5 N1 Bird Flu >200*
__________________________________________________________
*pandemic potential
–6–
PATHOGEN’S FEATURES
Orthomyxoviruses
Influenza A and B
Enveloped and Pleomorphic
8 gene segments code for 10 proteins
Single-stranded RNA viruses (13.6 kB)
RNA exhibits high mutation rates
Genes and Proteins of Influenza A

RNA Size in Name and Major Function Copies per
Segment Bases Abbreviation Particle
1 2,341 Polymerase, PB1 30–60
2 2,341 Polymerase, PB2 RNA transcription/replication 30–60
3 2,233 Polymerase, PA 30–60
4 1,778 Hemagglutinin, HA Viral attachment/penetration 500
5 1,565 Nucleoprotein, NP Viral RNA synthesis/stability 1,000
6 1,413 Neuraminidase, NA Viral release 100
7 1,027 Matrix, M1 Assembly/regulation 3,000
Channel, M2 Viral entry/pH regulation 20–60
8 890 Nonstructural, NS1 Interferon antagonist –
Nuclear export, NEP Viral assembly ?
Steps in viral replication

Virus attaches to cell surface via hemagglutinin-sialic acid binding
Virus enters cell via endocytosis (~10 minutes)
Virus moves to endosome
Hemagglutinin changes conformation at pH ~5.0 (fusion peptide exposed)
Ribonucleoprotein core enters cytoplasm and moves to cell nucleus
Influenza mRNA (– strand) are manufactured from the 8 viral RNA
(– strand) mRNA transcribed to (+ strand) mRNA by PB2, PB1, PA
(+ strand) RNA enters cytoplasm
Transcription of viral proteins takes place in the cytoplasm
(+ strand) mRNA switches function to making new (– strand) viral RNA
Ribonucleoprotein core assembled in cell nucleus
Viral core migrates to plasma membrane of cell
Final virus assembly takes place at plasma membrane
Viral buds are formed
Intact virions are released from the cell surface
Shedding of progeny virions goes on for hours until infected cell dies
–7–
Antigenic Shifts and Pandemic Strains

One cell infected with two different influenza A strains
2 viruses x 8 gene segments
28 = 256 combinations
A(H3N2) + A(H1N1) ---> A(H3N2) ---> A(H3N2)

A(H1N1) ---> A(H1N1)
A(H1N2) ---> A(H1N2)
A(H3N1) ---> A(H3N1)* ---> pandemic
* adapted strain
Shifted virus must pick up adaptations in other proteins

Pandemic strains emerge from a combination of shifts and adaptations
Adaptations involve proteins other than H and N (polygenic)
Human-like strains
Avian-like strains
Swine-like strains
Antigenic Drifts and Epidemic Strains

Reproduction of virus in 600 million to 1,200 million people yearly
Mutation rates in RNA transcription average 1 per 104 bases
Selection is based on immune evasion (fitness) in large populations
Most common selections occur in Hemagglutinin and/or Neuraminidase
Example of drift
A/Texas/1/77(H3N2) ---> A/Bangkok/1/79(H3N2)
Pathogenesis (Humans)
Influenza invades respiratory epithelium.
Viral particles are directly toxic.
Impairs mechanical and cellular host responses.
Elicits acute inflammatory response
Leads to ciliary abnormalities.
Desquamation of ciliated and mucus-producing cells.
Loss of mechanical clearance of respiratory tract (no escalator).
Normal respiratory epithelium restored 2 - 10 weeks after infection.
Damage renders host susceptible to invasive bacterial superinfections

Virus in blood is detected rarely.
–8–
Humoral immunity
Anti-hemagglutinin antibody is most protective.
Anti-neuraminidase antibody is second most protective.
Anti-channel antibody is third most protective.
Laboratory Characterization
Typing
Influenza A
Influenza B
Subtyping (Influenza A only)
H1 - H16
N1 - N9
Immunologic relatedness
Hemagglutinin (binding) inhibition assays
Neuraminidase (enzyme) inhibition assays
PREVENTION
Vaccines are the only way to manage influenza’s impact worldwide.
Current inactivated vaccines are trivalent (two A types viruses and one B type).
300 million doses of inactivated trivalent vaccine manufactured yearly.
Vaccinate high-risk populations
People over 55 years of age
People with respiratory / cardiovascular illnesses
Growing evidence that children may benefit from influenza vaccination.
Live attenuated (intra-nasal) vaccine also licensed in United States.
Antiviral drugs have a limited role for small populations.
Inactivated vaccines
Single annual dose prior to each influenza season.
Guillain-Barré syndrome develops in 1 per 100,000 doses
Vaccine efficacy in elderly people (≥ 65 years)
22% (15 – 28) respiratory disease
27% (21 – 33) preventing hospitalization
24% (18 – 30) cardiac disease
47% (39 – 51) all-cause mortality
–9–
Live attenuated vaccines

Intranasally administered
Derived from cold-adapted influenza viruses
Contain hemagglutinin and neuraminidase genes of wild-type viruses
Efficacies comparable to or better than inactivated vaccines.
Antiviral agents
AMANTADINE
RIMANTADINE
Both oral agents
M2 protein antagonist
Must be given within 48 hours of onset of symptoms
Short-term (weeks) prophylaxis against influenza A
Exposure ---> give AMANTADINE plus VACCINE
Antiviral drug protects until vaccine induces immune response
Effectiveness against pandemic strains ?
Resistance increasing (>90% North America)
ZANAMAVIR*
OSELTAMIVIR**
Inhalation* and oral** agents
Neuraminidase competitive inhibitor
Must be given within 24 – 48 hours upon onset of symptoms
More expensive than AMANTADINE
Effectiveness against pandemic strains ?
Resistant strains after treatment
Treatment
Symptomatic care
Rest
Adequate fluid intake
Analgesics
Antitussives
Start AMANTADINE within first 12 - 24 hours of illness
Bacterial superinfections
Antibiotic prophylaxis is of little benefit
Does not reduce the likelihood of complications
– 10 –
AVIAN H5N1 INFLUENZA OUTBREAK (as of September 26, 2008)
Country Total cases Deaths

China 30 20
Vietnam 106 52
Thailand 25 17
Cambodia 7 7
Indonesia 135 110
Laos 2 2
Bangladesh 1 0
Pakistan 3 1
Turkey 12 4
Iraq 3 2
Egypt 50 22
Azerbaijan 8 5
Djibouti 1 0
Nigeria 1 1
Total 385 243
Source http://www.fluwikie.com/
• First case identified Jan 04

• Case fatality ratio = 200/328 = 63%
• Limited evidence of efficient human-to-human transmission.
• To date, >200 million of birds have been destroyed to contain outbreak.
• Are wild birds are spreading H5N1 influenza?
• QUESTION: Is a pandemic in the making?
1997 A(H5N1) “CHICKEN FLU” INCIDENT

• May 97, a child dies in Hong Kong.
• Aug 97, the index case was identified as H5N1.
• Nov - Dec 97
17 more cases reported with 5 deaths.
Surveys on 5 of 29 poultry workers in Hong Kong are H5N1-positive.
Surveys on 0 of 419 people in Hong Kong are H5N1-positive.
20% of chicken flock in Hong Kong is found to be H5N1-positive.
• No evidence of direct human-to-human transmission.
• Dec 97, destruction of all 1.5 million chickens in Hong Kong was completed.
• QUESTION: Was the H5N1 pandemic averted?
– 11 –
1976 “SWINE FLU” INCIDENT

• Jan 1976, febrile respiratory illnesses reported in Army recruits Fort Dix, NJ.
• Jan 29th, 19 throat washings sent to NJ Department of Public Health.
Two samples could not be identified.
Five samples gave unclear test results.
• Seven samples sent to the CDC in Atlanta, GA.
• Feb 4th, one of the ill recruits dies after a forced five-mile march.
• Feb 12th, four isolates were typed and subtyped as influenza A H1.
• Alert: H1 had not been seen in people since 1918 pandemic.
• Feb 13th, emergency meeting of scientists and researchers was held.
• Feb 19th, CDC press conference announces “swine flu” at Fort Dix, NJ.
• Feb 20th, widespread news coverage of the breaking story.
• Feb 27th, Fort Dix virus delivered to four vaccine-manufacturing companies.
• Swine flu seen in Minnesota, Wisconsin, Pennsylvania, Virginia, Mississippi.
• March 9th, estimated 500 recruits at Fort Dix test positive to swine flu.
• March 24th, President Ford meets with experts and holds press conference.
• Mid-April, President signs bill authorizing funds for national vaccine programs
• May - June, vaccine production begins with goal of making 196 million doses
• July, insurance carriers decline to provide liability insurance to manufacturers
• Drug companies plan to halt vaccine production.
• Aug 2nd, outbreak of respiratory disease among Legionnaires in Philadelphia.
• Growing fear that mysterious outbreak was due to swine flu.
• Aug 12th, Congress passes a vaccine protection bill.
• Poll indicates that 52% of Americans want the swine flu vaccine.
• Oct 1st, swine flu vaccination program begun at Indiana State Fair.
• Oct 11th, 3 vaccine recipients are dead.
• Oct 14th, 12 more vaccine recipients are died.
• President and family are immunized on national television.
• 54 cases of Guillain-Barré syndrome are reported (30 received vaccine).
• Growing lack of evidence for swine flu pandemic.
• Growing deaths or complications associated with vaccination.
• Growing call for a more cautious attitude.
• Dec 16th, one-month suspension of immunization program.
• Jan 1977, new President sworn in.
• Feb 4th, $11 million in damage claims had been filed.
• Feb 8th, vaccinations are resumed.
• March 1977, next year s vaccine did not include H1N1 swine flu.
• RESULT: It took decades to rebuild public trust in influenza surveillance.
– 12 –
BOTTOM LINES
Faster surveillance is needed.
Better influenza vaccines are needed.
Influenza has unique strategies for outmaneuvering the immune system.
Human and animal reservoirs facilitate epidemics and pandemics.
Pandemic potential of avian H5N1 influenza: UNKNOWN.
READING
• Webster RG, et al. H5N1 Outbreaks and Enzootic Influenza. Emerging

Infectious Diseases 2006; 12: 3 – 8.
• Kilbourne ED. Influenza Pandemics of the 20th Century. Emerging Infectious

Diseases 2006; 12: 9 – 14.
• Tubenberger JK, Morens DM. 1918 Influenza: the Mother of All Pandemics.
Emerging Infectious Diseases 2006; 12: 15 – 22.
• Monto AS. Vaccines and Antiviral Drugs in Pandemic Preparedness. Emerging

Infectious Diseases 2006; 12: 55 – 60.
• Layne SP. Human influenza surveillance: the demand to expand. Emerging

Infectious Diseases 2006; 12: 562 - 568.
– 13 –
FIGURE 1
– 14 –
FIGURE 2
– 15 –
FIGURE 3
– 16 –
FIGURE 4
– 17 –
FIGURE 5
– 18 –
FIGURE 6
– 19 –
FIGURE 7
– 20 –
FIGURE 8
– 21 –
FIGURE 9
– 22 –

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Principles of Infectious Disease Epidemiology / EPI 220

UCLA School of Public Health / Department of Epidemiology

ACUTE RESPIRATORY INFECTIONS

Pneumococcal disease kills 1,600,000 annually worldwide.

Two-thirds of these deaths occur in the first year of life.

Tonsillitis Viral & Bacterial Yes

Epiglottitis Bacterial 24 - 47 Yes

Lower Laryngitis (croup) Viral 12 - 23 Rare

Tracheobronchitis Viral & Bacterial none No

Bronchiolitis Viral 0 - 12 Yes

Pneumonia Viral & Bacterial 24 - 35 Yes

Viruses that are major causes of acute respiratory disease.

Bacteria that are major causes of acute respiratory disease.

Heterogeneous group of viruses with common features.

In "pandemic" years, over 25% of world’s population gets influenza.

Combined, yearly epidemics kill as many as sporadic pandemics.

WHO Influenza Program

Approximately 300 million doses of influenza vaccine manufactured yearly.

Even though a common pathogen, relatively little is known about influenza.

Influenza A is a zoonotic disease.

Acute symptoms (hit by a freight train)

Acute symptoms persist for 2 - 5 days

Lingering symptoms persist for 2 - 3 weeks

More severe manifestations of influenza A

Three ways that influenza A kills.

1. Worsening of underlying chronic disease (usually the elderly)

3. Direct rapid progression

Is southeast Asia an epidemic and pandemic incubator?

1997 H5 N1 Chicken flu 18

Genes and Proteins of Influenza A

Steps in viral replication

Antigenic Shifts and Pandemic Strains

A(H3N2) + A(H1N1) ---> A(H3N2) ---> A(H3N2)

Shifted virus must pick up adaptations in other proteins

Antigenic Drifts and Epidemic Strains

Damage renders host susceptible to invasive bacterial superinfections

Live attenuated vaccines

AVIAN H5N1 INFLUENZA OUTBREAK (as of September 26, 2008)

Country Total cases Deaths

• First case identified Jan 04

1997 A(H5N1) “CHICKEN FLU” INCIDENT

1976 “SWINE FLU” INCIDENT

Better influenza vaccines are needed.

Influenza has unique strategies for outmaneuvering the immune system.

Human and animal reservoirs facilitate epidemics and pandemics.

Pandemic potential of avian H5N1 influenza: UNKNOWN.

• Webster RG, et al. H5N1 Outbreaks and Enzootic Influenza. Emerging

• Kilbourne ED. Influenza Pandemics of the 20th Century. Emerging Infectious

• Monto AS. Vaccines and Antiviral Drugs in Pandemic Preparedness. Emerging

• Layne SP. Human influenza surveillance: the demand to expand. Emerging

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