Nothing to disclose. Influenza Update. Influenza Biology. Influenza Biology. Influenza A 12/15/2014

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1 Influenza Update Nothing to disclose. Lisa Winston, MD UCSF / San Francisco General Hospital Divisions of Infectious Diseases and Hospital Medicine Influenza Biology 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 A 16 different HA subtypes 9 different NA subtypes Human influenza A viruses: H1N1, H1N2, H2N2, H3N2 1

2 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 Trifonov et al, New Engl J Med, 2009;361: Matrix proteins Nonstructural proteins 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 : Spanish flu, million deaths; H1N1 virus : Asian flu; H2N2 virus : Hong Kong flu; H3N2 virus : H1N1 virus Belshe, New Engl J Med, 2005;353:

3 Swine is presumed mixing vessel for 2009 H1N1 Pigs have receptors for human and avian influenza A viruses Trifonov et al, New Engl J Med, 2009;361: 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 older Thompson et al, JAMA 2003;289: Revised estimates of deaths associated with seasonal influenza 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); Novel H1N1 vs. Seasonal Influenza FIGURE. Distribution by age group of persons hospitalized with laboratory-confirmed influenza,* --- United States, winter influenza season and April 15--August 11, 2009 Median age hospitalization: 20 years Highest incidence of hospitalization children < 4 years Median age of persons who died: 37 years MMWR, August 28, 2009;58(RR10):1-8 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 3

4 Current Influenza Activity Influenza Vaccine (same as ) 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: 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 4

5 Influenza Vaccine Indications All people older than 6 months Unless there is a contraindication Estimated that in the influenza season, vaccination prevented 7.2 million illnesses, 3.1 million medically attended illnesses, and 90,000 hospitalizations MMWR 2014;63: 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: 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: 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 years Local reactions are more common 5

6 Live Attenuated Influenza Vaccine Attenuated, heat sensitive and cold adapted Approved for healthy persons ages 2 49, including healthcare workers and contacts of 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 influenza season: decreased efficacy compared with inactivated vaccine, especially against influenza B (poor matches for both influenza B and H3N2 drifted strain) LAIV Surveillance in military ages over 3 influenza seasons ( ) 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 Ohmit et al, N Engl J Med 2006;355: Clin Infect Dis 2013;56:

7 LAIV now preferred for some children Starting , 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: Nichol et al, JAMA 1999;281: Vaccination decreases influenza infection in HCP and may decrease absenteeism Wilde et al, JAMA 1999;281: Saxen et al, Pediatr Infect Dis J 1999;18: 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: Note that efficacy of vaccination varies from year-to-year and is influenced by vaccine match 7

8 12/15/2014 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 of 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

9 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 observational 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: 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: 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 9

10 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 10