Nothing to disclose. Influenza Update Lisa Winston, MD UCSF / San - - PowerPoint PPT Presentation

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Influenza Update

Lisa Winston, MD UCSF / San Francisco General Hospital Divisions of Infectious Diseases and Hospital Medicine

Nothing to disclose….

Influenza Biology

Influenza viruses are single stranded, enveloped RNA viruses

Divided into types A, B, ( C ) Influenza A viruses infect humans, pigs, horses,

sea mammals and birds

Influenza B viruses infect humans (and seals) Two surface glycoproteins hemagglutinin (HA) and

neuraminidase (NA) used to subtype influenza A viruses

Influenza Biology

Influenza A

16 different HA subtypes 9 different NA subtypes Human influenza A viruses: H1N1,

H1N2, H2N2, H3N2

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Influenza Biology

Hemagglutinin attaches to cellular sialic acid receptors Neuraminidase cleaves sialic acid releasing infectious virus particles

Segmented genome with 8 RNA fragments

• Polymerase PB2
• Polymerase PB1
• Polymerase PA
• Hemaglutinin
• Nuclear protein
• Neuraminidase
• Matrix proteins
• Nonstructural proteins

Trifonov et al, New Engl J Med, 2009;361:115-119

Influenza Drift and Shift

“Antigenic Drift” – minor changes due to point mutations “Antigenic Shift” – major changes which may be due to reassortment of RNA segments

In setting of infection with 2 different

viruses

Pandemic Influenza

Pandemics occur when little immunity to circulating virus

Potentially due to shift, recirculation of

previous virus, or direct transmission from animal to human

1918 – 1919: “Spanish flu,” 20-25 million deaths; H1N1 virus 1957-1958: “Asian flu;” H2N2 virus 1968-1969: “Hong Kong flu;” H3N2 virus 2009-2010: H1N1 virus Belshe, New Engl J Med, 2005;353: 2209 - 11

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Trifonov et al, New Engl J Med, 2009;361:115-119

Swine is presumed “mixing vessel” for 2009 H1N1 Pigs have receptors for human and avian influenza A viruses

Seasonal Influenza Morbidity and Mortality

Old estimate: 36,000 deaths per year in U.S. Severe disease in the elderly, very young, and those with significant comorbidities

90% influenza-associated deaths occur in persons 65 and

• lder

Thompson et al, JAMA 2003;289:179-86

Revised estimates of deaths associated with seasonal influenza 1976 – 2007

Average 23,607 deaths (range 3,349 to 48,614) When influenza A(H3N2) prominent, death rate 2.7x higher

MMWR August 27, 2010 / 59(33);1057-1062

Novel H1N1 vs. Seasonal Influenza

• FIGURE. Distribution by age group of persons hospitalized with laboratory-confirmed

influenza,* --- United States, 2007--08 winter influenza season and April 15--August 11, 2009

MMWR, August 28, 2009;58(RR10):1-8 Median age hospitalization: 20 years Highest incidence of hospitalization children < 4 years Median age of persons who died: 37 years

Novel H1N1 Epidemiology

Among person 65 years and older, hospitalization rates related to novel H1N1 were less than 20% of those usually seen in the winter with seasonal influenza A About 2/3 of patients hospitalized have a known medical risk factor for severe disease (including pregnancy) Hospitalization among pregnant women is about 4 times higher than in the general population Obesity, especially morbid obesity, may be a new risk factor

MMWR, August 28, 2009;58(RR10):1-8

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Current Influenza Activity 2014-15 Influenza Vaccine

(same as 2013-2014)

A/California/7/2009 (H1N1)-like A/Texas/50/2012 (H3N2)-like B/Massachusetts/2/2012-like (Yamagata lineage) For quadrivalent vaccine add:

B/Brisbane/60/2008-like (Victoria lineage)

MMWR 2014;63:483-90

• Nationwide this season: 82% A, 18%B
• A almost all H3N2: 52% are different (drifted) from vaccine strain
• B split Yamagata and Victoria lineages

Influenza Vaccines

Inactivated vaccine given by injection

Trivalent: 2 influenza A strains, 1 influenza B

strain

Quadrivalent: 2 influenza A strains, 2 influenza

B strains

Few contraindications

Severe egg allergy – risk assessment, referral Severe previous reaction Guillain-Barre (relative contraindication)

Live attenuated intranasal vaccine (FluMist)

Same strains as inactivated vaccine

Quadrivalent

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Influenza Vaccine Indications

All people older than 6 months

Unless there is a contraindication

Estimated that in the 2013-14 influenza season, vaccination prevented 7.2 million illnesses, 3.1 million medically attended illnesses, and 90,000 hospitalizations MMWR 2014;63:1151-4

Newest influenza vaccines licensed in U.S.

Three quadrivalent inactivated vaccines: 2 influenza A and 2 influenza B strains; intramuscular

Fluarix, FluLaval, Fluzone

FluBlok: baculovirus expression system (recombinant), no exposure to eggs – age 18+ Flucelvax: cell culture derived (canine kidney cells) – age 18+ Afluria trivalent vaccine can be administered by jet injector (FDA approved August 2014 ages 18-64)

High Dose Inactivated Vaccine

Fluzone High-Dose licensed for those 65 and older Trivalent; contains 60 µg of hemagglutinin per virus strain compared with 15 µg in regular dose Enhanced immune response in those 65 and older with high dose vs. standard dose Local reactions (mild to moderate) more common with high dose vaccine J Infect Dis 2009;200:161-3 2-year study with 31,989 participants randomized to high dose vs. standard dose: 1.4% vs. 1.9% with confirmed influenza (relative efficacy 24.2%)

New Engl J Med 2014;371:635-45.

Intradermal Influenza Vaccine

Fluzone intradermal vaccine approved by FDA in 2011 Needle is about one-tenth of standard length Contains 9 mcg hemagglutinin per strain versus standard 15 mcg

Dose is 0.1 mL versus standard 0.5 mL

Approved ages 18 – 64 years Local reactions are more common

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Live Attenuated Influenza Vaccine

Attenuated, heat sensitive and cold adapted Approved for healthy persons ages 2 – 49, including healthcare workers and contacts

• f most high risk patients

Runny/stuffy nose is common

Live Attenuated Influenza Vaccine

Who should not get LAIV?

Outside recommended age ranges Chronic medical conditions, including asthma Pregnant women History of Guillain-Barre (relative

contraindication)

Severe egg allergy – risk assessment, prefer

TIV

Contact with highly immunosuppressed

patients, e.g. bone marrow transplant

Live Attenuated Influenza Vaccine (LAIV)

Efficacy

In children, 85 – 90% effective in preventing

influenza A compared with placebo

In children, several studies suggest better

efficacy than inactivated vaccine

Study in adults in Michigan 2004 – 2005

influenza season: decreased efficacy compared with inactivated vaccine, especially against influenza B (poor matches for both influenza B and H3N2 “drifted” strain) Ohmit et al, N Engl J Med 2006;355:2513 - 22

LAIV

Surveillance in military ages 18 – 49 over 3 influenza seasons (2006 – 2009) Compared influenza like illness, influenza, and pneumonia in those vaccinated with LAIV compared with inactivated vaccine: 41,670 vaccination events Excluded those with contraindications to LAIV Controlled for sociodemographics, occupation, geographic area No differences found by vaccine group Clin Infect Dis 2013;56:11-19

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LAIV now preferred for some children

Starting 2014-15, CDC now preferentially recommends LAIV for healthy children ages 2 – 8 years if no contraindications and vaccine is immediately available

MMWR 2014;63:691-7

Influenza Vaccination of Healthcare Personnel

Many elderly, chronically ill, and immunocompromised persons do not have a robust immune response to the vaccine Influenza is transmitted in healthcare facilities

HCP both transmit and acquire influenza HCP frequently work when they are ill Influenza is shed before symptoms develop;

some infections are asymptomatic

Does Influenza Vaccination of HCP Help?

Based on results of double blind, RCTs: Vaccination can decrease some manifestations of influenza infection and absenteeism in working adults

Bridges et al, JAMA 2000;284:1655-63 Nichol et al, JAMA 1999;281:137-44

Vaccination decreases influenza infection in HCP and may decrease absenteeism

Wilde et al, JAMA 1999;281:908-13 Saxen et al, Pediatr Infect Dis J 1999;18:779-83

Does Influenza Vaccination of HCP Help?

HCP influenza vaccination is associated with decreased patient mortality in long-term care

Potter et al, J Infect Dis 1997;175:1-6 Carman et al, Lancet 2000;355:93-7 Hayward et al, BMJ 2006;333:1241 Lemaitre et al, J Am Geriatr Soc 2009;57:1580-6

Note that efficacy of vaccination varies from year-to-year and is influenced by vaccine match

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Required Vaccination or Declination

Influenza Antivirals

Adamantanes: interfere with influenza A virus M2 ion channel protein; inhibit virus uncoating

Amantadine and rimantadine Not used at this time due to resistance

Neuraminidase inhibitors: inhibit cleavage of influenza A and B viruses from host cell surface

Zanamivir (inhaled) and oseltamivir (oral) Peramivir (intravenous) – investigational, may not be

effective when oseltamivir resistance

Zanamivir (intravenous) – investigational, okay if resistant Laninamivir (inhaled) – long acting/single inhalation (Japan)

(Favipiravir – experimental RNA polymerase inhibitor; interest in using for Ebola and other viruses)

All influenza antivirals…

When given to outpatients within 48 hours

• f symptom onset

Decrease viral shedding Reduce clinical illness by about 1 day Are effective for chemoprophylaxis, if they

have activity against the virus

Neuraminidase inhibitors controversy

Cochrane review updated 2014 looked at neuraminadase inhibitors for preventing and treating influenza in healthy adults in children Data from published and unpublished (first time available) RCTs Conclusions:

Small effect on reducing length of symptoms in adults Effective for prophylaxis Unclear whether influenza complications reduced Concerns about side effects: nausea and vomiting,

renal, and psychiatric

Jefferson et al, Cochrane Database Syst Rev 2014

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CDC response

No change in recommendations Emphasis on early treatment for severely ill or at greatest risk for complications Other reviews have come to different conclusions –

• bservational data not included in Cochrane review

Studies of healthy people underpowered to detect influenza complications Meta-analysis of neuraminidase inhibitors in reducing mortality in hospitalized patients with influenza A (H1N1pdm)

More than 29,000 patients > 16 years 25% mortality reduction compared with no treatment

Muthuri et al, Lancet Resp Med 2014;2:395-404

Treatment with Antivirals - CDC

More severe illness, especially hospitalized Children younger than 2 years old Adults 65 years and older Pregnant or post partum women Significant co-morbidities predisposing to severe influenza Children receiving long-term aspirin Residents of chronic care facilities / SNF Immunosuppressed persons, including HIV American Indians/Alaskan Natives Morbidly obese

Influenza Diagnosis

Fever and cough when influenza is circulating are most helpful symptoms but not ideally sensitive or specific Rapid influenza tests are not sensitive

Ranged from 40 – 69% in one study using clinical

specimens MMWR, August 7, 2009;58:826-829

Consider treatment for patients with influenza-like

illness and negative rapid tests who have indications for antivirals

More sensitive tests such as real-time reverse

transcription—polymerase chain reaction (rRT- PCR) or viral culture should be prioritized for hospitalized patients

Infection Prevention: Which Masks?

Influenza mostly spread by droplets

Controversy regarding importance of airborne

spread of small droplet nuclei – do you need an N95 mask?

Most important to recognize influenza-like illness

Mask for the patient unless/until inpatient

isolation

Mask and eye protection for the provider –

remember for specimen collection

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What about H7N9?

Avian virus - poultry Human infections first reported in China in March 2013 Associated with severe respiratory illness

Death in one-third of cases

Most cases associated with direct exposure to poultry or contaminated environment

Limited person-to-person spread