Influenza

Marc A Bellazzini, MDUniversity of Wisconsin

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

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

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

Structure and Epidemiology of Influenza Virus

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 ....

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

Influenza Virus Nomenclature

A/Fujian/411/2002 (H3N2)

Virus Type

GeographicOrigin

Strain Number

Year Isolated

VirusSubtype

Wikipedia Accessed 09/02/08

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

CDC 2008

MARISSA UW Emergency Medicine Surveillance

University of Wisconsin Syndromic Surveillance 2007-2008

Influenza Clinical Considerations

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

Clinical

Abrupt onset of illness Fever Sore throat Cough Myalgia Malaise Rhinitis Headache Chills

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

NEJM Dec 2005

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

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

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

Complications of Influenza

Primary influenza pneumonia Secondary bacterial pneumonia Uncommon

Myocarditis Pericarditis Encephalitis Transverse myelitis Reyes syndrome in those taking ASA

CDC 2008

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

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.

- CDC

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

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 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

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

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.

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

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

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

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

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

Live Attenuated Influenza Vaccine Side Effects

Runny nose or nasal congestion Headache Sore throat

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

Annual Influenza vaccination can provide some protection against severe illness even if not well

matched to circulating strains. - CDC

Antiviral Therapy

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.

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

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

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

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.

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

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

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

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

2004 2005 2006 2007

0

20

40

60

80

100

120

140

CasesDeaths

Year

Nu

mb

er

of C

ase

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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

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

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

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.

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

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?

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.

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.

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

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?