Download Influenza Marc A Bellazzini, MD University of Wisconsin Objectives

Influenza
Marc A Bellazzini, MD
University of Wisconsin
Objectives
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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
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.
Case
On the second day she develops increasing respiratory
distress and dies at home. She is buried on Feb 24th, 1918.
Flu Timeline
Yearly Influenza United States
More than 200,00 hospitalized
36,000 deaths
5-20% of population get flu
Serious illness or death highest
in those >65 and less than 2 years
Asian flu pandemic H2N2
70,000 deaths United States
1957-58
1918-1919
Spanish flu pandemic H1H1
20-40% of population ill
20-40 million deaths worldwide
500,000 deaths United States
Attack rate highest in young
and middle aged
2000 - beyond
1968-1969
World wide
Severe illness 3-5 million cases
250,000-500,000 deaths
WHO information 2008
Hong Kong Flu pandemic H3N2
34,000 deaths in United States
Structure and Epidemiology of
Influenza Virus
Influenza Virus
Hemagglutinin (H) antigen
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Antibodies to H antigen major determinant of immunity
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Virus binds to cell receptor via H glycoprotein
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Sixteen different subtypes H1, H2, H3 ...
Neuraminidase (N) antigen
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Antibodies to N glycoprotein limit viral spread
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Nine antigenic subtypes N1, N2, N3 ....
Epidemics and Pandemics
Antigenic Shift
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Pandemic (10-15 year cycle)
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Major antigenic variation
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No immunity in population
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Change in H and or N
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H1N1 to H2N2 1957 pandemic
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Re-assortment of genes between animal and human
viruses
Antigenic Drift
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Minor antigenic variation
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Point mutation
Influenza Virus Nomenclature
A/Fujian/411/2002 (H3N2)
Virus
Type
Wikipedia Accessed 09/02/08
Geographic
Origin
Strain
Number
Year
Isolated
Virus
Subtype
Influenza
Influenza A
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Most common form of influenza
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Found in ducks, chickens, pigs, whales, seals, horses
Influenza B
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No H or N typing
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Found in humans only
Influenza C
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Typically minor respiratory illness
CDC 2008
University of Wisconsin Syndromic Surveillance 2007-2008
MARISSA UW Emergency Medicine Surveillance
Influenza Clinical Considerations
Transmission
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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
Clinical
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Abrupt onset of illness
Fever
Sore throat
Cough
Myalgia
Malaise
Rhinitis
Headache
Chills
Clinical Differences in Children
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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
NEJM Dec 2005
Influenza and bacterial co-infection in children
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Influenza and bacterial co-infection S. aureus increasing
2006-2007
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73 influenza deaths children
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30/69 (44%) cases bacterial co-infection
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73% of those co-infected had S. aureus
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15 children had co-infection with MRSA
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Pneumonia or Bacteremia associated with S. aeurus 5
fold increase compared to previous years.
www.cdc.gov accessed
01/03/08
Clinical Course
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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
Clinical Course
Exposure
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Incubation
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Illness duration
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Viral shedding adult
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Viral shedding child
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Cough and malaise
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Day 1
Day 3
Day 5
Day 7
Day 9
Day 11
Day 13
Day 15
Day 17
Complications of Influenza
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Primary influenza pneumonia
Secondary bacterial pneumonia
Uncommon
Myocarditis
Pericarditis
Encephalitis
Transverse myelitis
Reyes syndrome in those taking ASA
CDC 2008
UW Laboratory Testing
Rapid Antigen
Testing Binax NOW
EIA
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
Peak only – run on
arrival 24/7
Assay
Distinguishes A & B
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Off Peak - once daily
Run if negative Rapid
M-F. Peak – twice daily
Antigen and Negative
M-F once daily
DFA
weekends
Distinguishes A & B
Distinguishes A & B
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
Vaccination
Annual Influenza vaccination most effective method
of preventing influenza virus infection and its
complications. - CDC
Vaccination has been shown to reduce
hospitalizations and deaths in adults <65 years of
age with risk factors for influenza complications.
- CDC
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.
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- CDC
Vaccine preparation
Current vaccine composition based on last years surveillance
data
Vaccine strains must be selected by Feb of each year
Takes 6-8 months for vaccine preparation
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- CDC
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
Vaccination Composition
2007-2008
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A/Solomon Islands/3/2006 (H1N1) like - changed
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A/Wisconsin/67/2005 (H3N2) like
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B/Malaysia/2506/2004 like
2008-2009
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A/Brisbane/59/2007 (H1N1) like - changed
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A/Brisbane/10/2007 (H3N2) like - changed
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B/Florida/4/2006 like - changed
WHO Global Influenza Surveillance Network recommends Vaccine Composition
Vaccination Timing
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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
Inactivated Influenza Vaccine Dose
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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.
Inactivated Influenza Vaccine
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Efficacy
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70-90% effective in reducing laboratory confirmed
influenza in healthy adults less than 65 years old
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less effective in elderly
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may be less effective in those with chronic medical
conditions and immune compromised.
Side Effects
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soreness at vaccination site
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fever, malaise, myalgia may occur
Inactivated Influenza Vaccine and GBS
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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
Live Attenuated Influenza Vaccine
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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
Live Attenuated Influenza Vaccine (LAIV)
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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
Live Attenuated Influenza Vaccine (LAIV)
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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
Live Attenuated Influenza Vaccine Side Effects
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Runny nose or nasal congestion
Headache
Sore throat
2004 Vaccine Shortage – Dose Sparing
Administration
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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
Annual Influenza vaccination can provide some
protection against severe illness even if not well
matched to circulating strains. - CDC
Antiviral Therapy
Adamantane Class
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Amantadine and Rimantadine
Historically effective for influenza A only
Inhibits M2 protein and inhibit virus uncoating
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When resistance not prevalent
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Effective in shortening clinical illness by one day if
administered within two days of illness onset.
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70-90% effective for preventing influenza A illness
when used as prophylaxis.
Amantadine and Rimantadine Side Effects
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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
Bad News for 2005-2006 and Beyond
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Adamantane class no longer recommended for
treatment or prophylaxis until susceptibility reestablished.
2006 national H3N2 resistance 92%
2005 national resistance 6%
Point mutation
Neuraminidase Inhibitors
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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
Zanamivir
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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.
Oseltamivir
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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
Oseltamivir Resistance
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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
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.
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
Avian Influenza
H5N1
Avian Influenza H5N1 Key Facts
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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
Worldwide Confirmed Human H5N1
Cases and Mortality
WHO
140
Number of Cases
120
100
80
Cases
60
Deaths
40
20
0
2004
2005
2006
Year
2007
Avian Influenza H5N1 Key Facts
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Most cases in Indonesia and Viet Nam
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Cumulative cases 385 as of 06/19/08
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Cumulative deaths 243 as of 06/19/08
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Mortality rate 63%
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1918 H1N1 Pandemic mortality rate approx 5%.
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Rare, limited, unsustained person to person spread
Avian Influenza H5N1 Clinical Presentation Range
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Incubation period estimated 7 days
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Fever, cough, sore throat, myalgia
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Diarrhea, vomiting, abdominal pain, chest pain
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Lower respiratory tract signs symptoms much more
common than typical influenza.
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Severe respiratory illness with rapid deterioration
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May present with GI symptoms and fever not respiratory
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Multi-system organ failure median time to death 9-10d
Avian Influenza H5N1 Summary Testing Criteria
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Moderate or severe febrile respiratory illness that
requires hospitalization
AND
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Close contact with a person known or suspected to
have H5N1 or with poultry in an area where H5N1 has
been reported
Avian Influenza H5N1 Testing
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RT-PCR analysis (notify lab of suspicion for H5N1)
Throat / OP swab more sensitive than nasal due to
higher viral load.
Avian Influenza H5N1 Treatment
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Isolation
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Supportive care
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H5N1 generally resistant to adamantane class
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Recommended therapy with neuraminidase inhibitor
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Consider combination therapy in susceptible areas
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Some resistance to Neuraminidase inhibitors reported
Avian Influenza H5N1 Vaccination
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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?
Take Home Points
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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.
Take Home Points
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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.
Take Home Points
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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
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.
Learning Assessment
This is the first case of influenza the student has seen and she
asks you about treatment options.
What is your response?
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?
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?
Learning Assessment
The patient told the medical student she was vaccinated
against influenza.
What are some possible reasons the patient was infected
despite vaccination?
Learning Assessment
The student asks if the clinical presentation of influenza can be
different in a child.
What do you tell the student?
Questions?