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Influenza
Marc A Bellazzini, MDUniversity of Wisconsin
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Objectives
Summarize history of influenza Describe influenza viral structure, antigenic composition
and virus types Differentiate antigenic shift from drift Describe clinical presentation, course and complications of
influenza Discuss laboratory assays for influenza Describe anti-viral therapy for influenza Summarize vaccination options for influenza
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Case
A 9 year old girl returns from school with high fever, chills, muscle aches and cough. Several other school children are
sick. Her illness progresses over 24 hours and her fever remains high. Her parents are now showing similar signs and
symptoms.
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Case
On the second day she develops increasing respiratory distress and dies at home. She is buried on Feb 24th, 1918.
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Flu Timeline
1918-1919
Spanish flu pandemic H1H120-40% of population ill20-40 million deaths worldwide500,000 deaths United StatesAttack rate highest in young and middle aged
1957-58
Asian flu pandemic H2N270,000 deaths United States
1968-1969
Hong Kong Flu pandemic H3N234,000 deaths in United States
2000 - beyond
Yearly Influenza United StatesMore than 200,00 hospitalized36,000 deaths5-20% of population get fluSerious illness or death highestin those >65 and less than 2 years
World wideSevere illness 3-5 million cases250,000-500,000 deathsWHO information 2008
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Structure and Epidemiology of Influenza Virus
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Influenza Virus
Hemagglutinin (H) antigen Antibodies to H antigen major determinant of immunity Virus binds to cell receptor via H glycoprotein Sixteen different subtypes H1, H2, H3 ...
Neuraminidase (N) antigen Antibodies to N glycoprotein limit viral spread Nine antigenic subtypes N1, N2, N3 ....
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Epidemics and Pandemics
Antigenic Shift Pandemic (10-15 year cycle) Major antigenic variation No immunity in population Change in H and or N
H1N1 to H2N2 1957 pandemic Re-assortment of genes between animal and human
viruses
Antigenic Drift Minor antigenic variation Point mutation
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Influenza Virus Nomenclature
A/Fujian/411/2002 (H3N2)
Virus Type
GeographicOrigin
Strain Number
Year Isolated
VirusSubtype
Wikipedia Accessed 09/02/08
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Influenza
Influenza A Most common form of influenza Found in ducks, chickens, pigs, whales, seals, horses
Influenza B No H or N typing Found in humans only
Influenza C Typically minor respiratory illness
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CDC 2008
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MARISSA UW Emergency Medicine Surveillance
University of Wisconsin Syndromic Surveillance 2007-2008
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Influenza Clinical Considerations
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Transmission
Large particle respiratory droplets – cough & sneezing main method of transmission
Contact transmission with respiratory droplet contaminated surfaces possible
Airborne suspended small particle (< 5 um) transmission thought to be possible
- CDC
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Clinical
Abrupt onset of illness Fever Sore throat Cough Myalgia Malaise Rhinitis Headache Chills
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Clinical Differences in Children
Gastrointestinal – Vomiting and diarrhea Fever and cough less likely to be reported High mortality in children under 2 years of age School aged children have highest attack rates of
influenza Children major source of transmission of influenza
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NEJM Dec 2005
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Influenza and bacterial co-infection in children
Influenza and bacterial co-infection S. aureus increasing 2006-2007
73 influenza deaths children 30/69 (44%) cases bacterial co-infection 73% of those co-infected had S. aureus 15 children had co-infection with MRSA Pneumonia or Bacteremia associated with S. aeurus 5
fold increase compared to previous years.
www.cdc.gov accessed 01/03/08
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Clinical Course
Respiratory transmission – cough and sneezing Abrupt onset of malaise, chills, fever, headache Incubation 1-4 days Young children may be infectious several days prior to
symptom onset Adults may be infectious one day prior to symptoms Illness will usually resolve in 5 days Viral shedding decreases 4-5 days after onset Children may be infectious for more than 10 days Cough and malaise may persist for two weeks
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Clinical Course
Exposure __Incubation __________ Illness duration ________________ Viral shedding adult ________________________Viral shedding child __________________________________________Cough and malaise __________________________________________________
Day 1 Day 3 Day 5 Day 7 Day 9 Day 11 Day 13 Day 15 Day 17
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Complications of Influenza
Primary influenza pneumonia Secondary bacterial pneumonia Uncommon
Myocarditis Pericarditis Encephalitis Transverse myelitis Reyes syndrome in those taking ASA
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CDC 2008
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UW Laboratory Testing
DFA Culture
Sample Method NP W/A/NS NP W/A/NS NP W/A/NS
Sensitivity 50.0% 85.0% Gold Standard
Time 15-30 min 2.5 hours 24-48 hours
Frequency Run
Assay Distinguishes A & B Distinguishes A & B Distinguishes A & B
Rapid Antigen Testing Binax NOW
EIA
Peak only – run on arrival 24/7
Off Peak - once daily M-F. Peak – twice daily
M-F once daily weekends
Run if negative Rapid Antigen and Negative
DFA
NP W/A Nasopharyngeal Wash Aspirate NS Nasal swab use flocked swab with UTM transport media Culture performed in house. Must notify lab if concern for H5N1 then culture will be sent to state FluMist may result in false positive EIA, DFA, PCR if administered within 21 days. DFA only performed during respiratory virus season
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Vaccination
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Annual Influenza vaccination most effective method of preventing influenza virus infection and its
complications. - CDC
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Vaccination has been shown to reduce hospitalizations and deaths in adults <65 years of age with risk factors for influenza complications.
- CDC
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Impact of Vaccination
Vaccination of nursing home health care providers has significantly reduced mortality in nursing home patients. Reductions in respiratory tract infections observed in household contacts of children who received influenza vaccination. Studies also suggest reduction in respiratory illness in a community where school aged children were targeted for vaccination.
- CDC
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Vaccine preparation
Current vaccine composition based on last years surveillance dataVaccine strains must be selected by Feb of each year Takes 6-8 months for vaccine preparation
- CDC
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Trivalent inactivated influenza vaccine (TIV) can be used for any person aged >6 months.
Live, attenuated influenza vaccine (LAIV) may be used for healthy, nonpregnant persons aged 2-49
years. - CDC
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Vaccination Composition
2007-2008 A/Solomon Islands/3/2006 (H1N1) like - changed A/Wisconsin/67/2005 (H3N2) like B/Malaysia/2506/2004 like
2008-2009 A/Brisbane/59/2007 (H1N1) like - changed A/Brisbane/10/2007 (H3N2) like - changed B/Florida/4/2006 like - changed
WHO Global Influenza Surveillance Network recommends Vaccine Composition
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Vaccination Timing
Should ideally be administered October-November May be started in September Can be administered later in season Takes two weeks for immunity to build Need yearly vaccination due to waning immunity and drift
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Inactivated Influenza Vaccine Dose
Intramuscular administration 3 years of age to adult dose 0.5 ml 6 months up to 35 months dose 0.25 ml Children 6 months through 8 years of age should receive
two doses of vaccine separated by 4 weeks if first time vaccination.
Contraindicated in those with significant egg allergy or allergy to influenza vaccine.
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Inactivated Influenza Vaccine
Efficacy 70-90% effective in reducing laboratory confirmed
influenza in healthy adults less than 65 years old less effective in elderly may be less effective in those with chronic medical
conditions and immune compromised.
Side Effects soreness at vaccination site fever, malaise, myalgia may occur
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Inactivated Influenza Vaccine and GBS
1976 swine influenza vaccine 1 additional case of GBS per 100,000 vaccinated
Annual incidence of GBS 10-20 per 1 million adults Conflicting studies since 1976 however no definitive link
between Influenza vaccination and GBS In studies which showed increased incidence of GBS the
increased risk would be 1 additional case of per 1 million vaccinated
Benefits far outweigh risks
CDC 2008
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Live Attenuated Influenza Vaccine
Indicated in healthy non-pregnant persons 2-49 years old Intranasal administration 0.2 ml half dose sprayed in each nostril Children 2-8 years of age should receive two doses
separated by 4 weeks if previously un-immunized
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Live Attenuated Influenza Vaccine (LAIV)
85-92% effective Not indicated for individuals with chronic serious medical
conditions or immune compromise. Should not be used in children less than 5 with wheezing Should not be given to children who take ASA Should not be given to those with egg allergy
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Live Attenuated Influenza Vaccine (LAIV)
Those who come in contact with immune compromised individuals should not be vaccinated with LAIV
Those who receive LAIV may shed live virus at low levels Shedding diminishes after 3 days from vaccination Rarely transmitted to un-vaccinated persons
CDC 2008
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Live Attenuated Influenza Vaccine Side Effects
Runny nose or nasal congestion Headache Sore throat
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2004 Vaccine Shortage – Dose Sparing Administration
Half of US influenza supply lost to contamination Study of 100 healthy adults randomized to full dose IM vs
intradermal of 1/5 standardized IM dose influenza vaccine Intradermal injection elicited same or better
immunogenicity than standard IM full dose.
Kenny, RT et al Dose Sparing with Intradermal Injection of Influenza Vaccine NEJM 2004; 351: 2295-301
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Annual Influenza vaccination can provide some protection against severe illness even if not well
matched to circulating strains. - CDC
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Antiviral Therapy
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Adamantane Class
Amantadine and Rimantadine Historically effective for influenza A only Inhibits M2 protein and inhibit virus uncoating
When resistance not prevalent Effective in shortening clinical illness by one day if
administered within two days of illness onset. 70-90% effective for preventing influenza A illness
when used as prophylaxis.
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Amantadine and Rimantadine Side Effects
Nervousness, anxiety, insomnia, lightheadedness with both medications but more significant with Amantadine
Delirium, hallucinations and seizures with higher doses but uncommon.
Fewer CNS side effects in elderly with Rimantadine Anorexia and nausea 1-3% of population
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Bad News for 2005-2006 and Beyond
Adamantane class no longer recommended for treatment or prophylaxis until susceptibility re-established.
2006 national H3N2 resistance 92% 2005 national resistance 6% Point mutation
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Neuraminidase Inhibitors
Zanamivir & Oseltamivir Effective against influenza A & B Reduce severity and duration of illness when started
within two days of symptom onset Treatment duration 5 days May be used for prophylaxis 70-90% effective in
preventing influenza Consider for use in those at hight risk for complications
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Zanamivir
Dose – two inhalations twice daily (10mg total) Approved for treatment in those 7 years of age or older Approved for prophylaxis in those 5 years of age or older Not recommended for those with reactive airway
disease. May induce bronchospasm.
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Oseltamivir
Adult treatment dose 75 mg PO twice daily for 5 days Prophylactic dose 75 mg PO once daily Pediatric dose weight based Approved for treatment and prophylaxis in those 1 year
of age or greater Side effects nausea, vomiting May induce transient neuropsychiatric events delirium or
self-injury – case reports Japan. Resistant H1N1 strains identified in US and other
countries H274Y Mutation
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Oseltamivir Resistance
2007-2008 influenza season H1N1 mutation June 27, 2008 7.6% of influenza A viruses tested
resistant to Oseltamivir. Influenza B resistance not yet identified Above strains still sensitive to zanamivir H274Y Mutation
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Case
A father brings his three children aged 15, 14 and 11 to a local clinic with a complaint of fever. The children are evaluated and
discharged from the clinic with a diagnosis of an upper respiratory tract infection. The children's illness becomes
worse and the father returns to the clinic this time incidentally noting that the children were playing with several of the family
chickens that appeared ill.
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Case
All the children were admitted to the hospital and diagnosed with H5N1 Influenza. Despite supportive management they all
died several days later.
Turkey – January 2006
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Avian Influenza H5N1
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Avian Influenza H5N1 Key Facts
Migratory waterfowl wild ducks natural reservoir. Found in chickens, turkeys. Viral shedding nasal secretions, saliva, faeces
Emerged in Hong Kong 1997 Humans 6/18 died. All close contact with infected poultry. 1.5 million birds destroyed. First time avian influenza transmitted directly to humans and caused high mortality.
May survive in bird faeces for 35 days in cold temperatures. Warm temperatures reduce survival time.
WHO – Accessed 09/02/08
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Worldwide Confirmed Human H5N1 Cases and Mortality
WHO
2004 2005 2006 2007
0
20
40
60
80
100
120
140
CasesDeaths
Year
Nu
mb
er
of C
ase
s
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Avian Influenza H5N1 Key Facts
Most cases in Indonesia and Viet Nam
Cumulative cases 385 as of 06/19/08
Cumulative deaths 243 as of 06/19/08
Mortality rate 63%
1918 H1N1 Pandemic mortality rate approx 5%.
Rare, limited, unsustained person to person spread
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Avian Influenza H5N1 Clinical Presentation Range
Incubation period estimated 7 days
Fever, cough, sore throat, myalgia
Diarrhea, vomiting, abdominal pain, chest pain
Lower respiratory tract signs symptoms much more common than typical influenza.
Severe respiratory illness with rapid deterioration
May present with GI symptoms and fever not respiratory
Multi-system organ failure median time to death 9-10d
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Avian Influenza H5N1 Summary Testing Criteria
Moderate or severe febrile respiratory illness that requires hospitalization
AND
Close contact with a person known or suspected to have H5N1 or with poultry in an area where H5N1 has been reported
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Avian Influenza H5N1 Testing
RT-PCR analysis (notify lab of suspicion for H5N1)
Throat / OP swab more sensitive than nasal due to higher viral load.
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Avian Influenza H5N1 Treatment
Isolation
Supportive care
H5N1 generally resistant to adamantane class
Recommended therapy with neuraminidase inhibitor
Consider combination therapy in susceptible areas
Some resistance to Neuraminidase inhibitors reported
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Avian Influenza H5N1 Vaccination
FDA approved H5N1 vaccine stockpiled by US government April 2007 – Sanofi – Pasteur
Research into tissue culture vaccine instead of Embryonated eggs may speed vaccination production
What happens if there is antigenic drift of H5N1?
Will the H5N1 vaccine at least attenuate the illness if it does not cover the existing strain?
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Take Home Points
Influenza causes significant yearly worldwide morbidity and mortality
Pandemics are caused by antigenic shift when new H or N combinations occur in a population with no previous immunity.
Yearly influenza vaccination is necessary due to antigenic drift resulting from minor mutations in the influenza virus.
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Take Home Points
Peak influenza season occurs in February
Signs and symptoms – abrupt onset, fever, chills, malaise, myalgia, cough, sore throat.
Illness lasts 5 days but individual may be infectious before and after clinical onset
GI symptoms may be prominent in pediatric cases
Vaccination does not confer 100% immunity especially in the elderly.
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Take Home Points
Influenza is now highly resistant to Adamantane antivirals
Neuraminidase inhibitors are effective in treatment and prophylaxis of influenza A & B.
Avian influenza H5N1 has a mortality rate of 63% and is transmitted by close contact with diseased poultry.
There are rare and unsustained cases of human to human transmission of H5N1
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Learning Assessment
It is the middle of February on a slow early Sunday morning ED shift. You and a medical student examine an elderly patient who presents with abrupt onset of fever, chills, cough, myalgia and profound fatigue 12 hours before arrival. The patient has
a history of COPD and diabetes. The student diagnosis is influenza and a rapid nasopharyngeal aspirate assay confirms
her suspicions.
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Learning Assessment
This is the first case of influenza the student has seen and she asks you about treatment options.
What is your response?
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Learning Assessment
This is the first case of influenza the student has seen and she asks you about treatment options.
Would your treatment be different if the patient was a young healthy business woman?
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Learning Assessment
This is the first case of influenza the student has seen and she asks you about treatment options.
Would your treatment be different if the original patient presented 3 days after the onset of illness?
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Learning Assessment
The patient told the medical student she was vaccinated against influenza.
What are some possible reasons the patient was infected despite vaccination?
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Learning Assessment
The student asks if the clinical presentation of influenza can be different in a child.
What do you tell the student?
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Questions?