Influenza: Seasonal, Avian, and Otherwise
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1 Influenza: Seasonal, Avian, and Otherwise Lisa Winston, MD University of California, San Francisco San Francisco General Hospital Influenza biology Antiviral medications Seasonal influenza Vaccination Diagnosis Infection Control Avian influenza Pandemic influenza Talk Outline: 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 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 Influenza Biology Hemagglutinin attaches to cellular sialic acid receptors Neuraminidase cleaves sialic acid releasing infectious virus particles Segmented genome with 8 RNA fragments 1
2 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 : Asian flu : Hong Kong flu Influenza Antivirals Influenza Antivirals Two classes of drugs Adamantanes: interfere with influenza A virus M2 ion channel protein; inhibit virus uncoating Amantadine and rimantadine Neuraminidase inhibitors: inhibit cleavage of influenza A and B viruses from host cell surface Zanamivir and oseltamivir Adamantane Drugs Give within 48 hrs. of symptom onset Decrease viral shedding Reduce clinical illness by apx. 1 day Chemoprophylaxis: 70 90% effective in preventing illness due to influenza A Adamantane Drugs Amantadine Approved for treatment and prophylaxis age > 1 year GI and CNS side effects (including seizures) Rimantadine Approved for treatment of adults and prophylaxis age > 1 year Fewer CNS side effects than amantadine; preferred for older adults 2
3 Adamantane Resistance High levels reported during influenza season H1N1: 2 of 8 (25%) H3N2: 192 of 209 (92%) Therefore, should not use amantadine or rimantadine for influenza treatment or prophylaxis at this time Follow up U.S. isolates: H1N1: 1 of 91 (1%) H3N2: 3 of 10 (33%) Neuraminidase Inhibitors Zanamivir (Relenza) Orally inhaled, powdered drug Approved for treatment age > 7 years Not approved for prophylaxis Not recommended if underlying respiratory disease Dose: 10 mg (2 inhalations) q 12 hrs. x 5d Start within 48 hrs. of illness onset Reduces duration of symptoms by about 1 day Neuraminidase Inhibitors Oseltamivir (Tamiflu) Capsule or oral suspension Approved for treatment and prophylaxis age > 1 year Main side effects are nausea and vomiting Start within 48 hrs. of illness onset Reduces duration of symptoms by about 1 day Treatment dose for adults: 75 mg PO bid x 5 days Prophylaxis dose for adults: 75 mg PO daily Neuraminidase Inhibitors Oseltamivir (Tamiflu) Based on meta-analysis, in patients with confirmed influenza, decreases in Lower respiratory tract complications Overall antibiotic use Hospitalization for any cause (.7% vs. 1.7%) Kaiser et al, Arch Int Med, 2003:163: Good data on efficacy of prophylaxis No clinical trial data regarding treatment after complications develop Neuraminidase Inhibitors - Resistance Resistance in human influenza A less common than with adamantanes Recent U.S. surveillance <0.5% Probably more common following treatment Viruses with resistance mutations may be less fit and less transmissible (?) Viruses resistant to oseltamivir may still be inhibited by zanamivir and novel neuraminidase inhibitors Resistance may be a problem in H5N1 Antivirals - Cost Amantadine 5 day supply: ~ $8.00 Rimantadine 5 day supply: ~$25.00 Zanamivir 5 day supply: ~ $60.00 Oseltamivir 5 day supply: ~ $
4 Pneumonia and Influenza Mortality Seasonal Influenza Composition Vaccine Vaccine always tri-valent 2 strains influenza A 1 strain influenza B Same strains in inactivated and live, attenuated vaccines strains: A/Solomon Islands/3/2006-like (H1N1) - new A/Wisconsin/67/2005-like (H3N2) B/Malaysia/2506/2004-like Vaccine Supply At least 4 manufacturers in U.S Sanofi Pasteur, Inc. GlaxoSmithKline, Inc. Novartis Vaccine Medimmune Vaccines Inc. (live, attenuated) ~ 130 million doses projected Vaccine Indications Adults > 50 years Children 6 59 months > 6 months with a chronic medical condition Includes asthma; excludes isolated hypertension Residents of long-term care facilities Pregnancy during influenza season Healthcare workers Healthy persons with high-risk contacts ~ 218 million people targeted in U.S.: 73% of population Projected vaccination rate : 32% of targeted population Influenza Vaccines Injectable, inactivated vaccine Grown in eggs severe egg allergy only definitive contraindication Can t get the flu from the vaccine Sore arm only common side effect compared with placebo Live attenuated intranasal vaccine (FluMist) Same strains as inactivated vaccine Attenuated, heat sensitive and cold adapted Approved for healthy persons ages 5 49, including healthcare workers and contacts of most high risk patients 4
5 Live Attenuated Influenza Vaccine Who should not get the LAIV? Outside recommended age ranges (recommendations likely will get younger) Chronic medical conditions, including asthma Pregnant women History of guillain-barre Anaphylaxis to eggs Contact with highly immunosuppressed patients, e.g. bone marrow transplant Live Attenuated Influenza Vaccine Runny/stuffy nose is common 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) Ohmit et al, N Engl J Med 2006;355: Improving Vaccination Rates in HCWs Multiple organizations working on recommendations / regulations Including Joint Commission on Accreditation of Healthcare Organizations (JCAHO) and California Department of Health Services Tracking of HCWs will be required Declination forms INFLUENZA VACCINE DECLINATION Influenza vaccination is the primary method for preventing influenza and its severe complications. Vaccination of health-care workers (HCWs) has been shown to reduce influenza infection among HCWs and their patients. Hospitalbased influenza outbreaks frequently occur where unvaccinated health-care workers are employed. The Centers for Disease Control and Prevention (CDC), the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), and the Centers for Medicare and Medicaid Services (CMS) strongly recommend that ALL health care workers receive influenza vaccine annually. I understand that I am being given the opportunity, at no cost to myself, to receive immunization against influenza from the Occupational Health Service of San Francisco General Hospital. I have been informed of the risk to myself, family or others close to me, and to my patients if I do not accept influenza immunization. However, I hereby decline influenza immunization at this time. I understand that by declining this vaccine I am at increased risk of becoming ill with influenza and spreading the disease to others. I further understand that if an influenza outbreak occurs, I may have to refrain from working in a health care setting for a period of time. I understand that I may change my mind and receive the vaccine while it is seasonally appropriate, and if vaccine is available. Influenza Diagnosis Fever and cough during influenza season are most helpful symptoms but not ideally sensitive or specific Nasal washing specimens preferred Negative rapid test does not rule out influenza Culture should be obtained if rapid test negative and suspicion moderate to high Call ID / Infection Control / local DPH / your lab if H5N1 suspected Influenza Institutional Infection Control Infectious from 24 hours before until 5 days after symptom onset Mostly spread by droplet route Droplet and body substance precautions indicated Private room with closed door, surgical mask for HCWs in room / patients upon leaving room 5
6 Avian Influenza Birds, Pigs, and People human domestic pig domestic poultry Avian influenza in Miami waterfowl and seabirds (reservoir) Why Pigs? Pigs have receptors for avian influenza viruses and human influenza viruses Putative mixing vessel Avian Influenza Wild birds reservoir for all subtypes HA and NA Typically not sick Avian influenza very contagious among birds Domestic birds (chickens, ducks, turkeys) ill Avian influenza classified as highly pathogenic (HPAI) or low pathogenic (LPAI) based on severity of illness in domestic birds H5 and H7 viruses can be HPAI or LPAI AI Transmission to Humans First detected Hong Kong 1997: H5N1 18 people hospitalized; 6 died Rare person-to-person transmission 1.5 million chickens killed H9N2 China & Hong Kong 1998,1999, 2003 Few cases, likely bird to human transmission H7N2 U.S. single cases in 2002 and 2003 H7N7 Netherlands 2003 Netherlands: 89 people infected, mostly conjunctivitis; one veterinarian died H7N3 Canada 2004: conjunctivitis H5N1 Re-emerges in Asia China and Hong Kong 2003: 2 cases in a Hong Kong family that had traveled to China; one death December 2003 March 2004: 12 cases in Thailand, 23 in Vietnam; 23 deaths December tigers and 2 leopards die in Thailand zoo Fed fresh chicken carcasses First case influenza in wild felids 6
7 H5N1 as of 2007 Cases have been reported in poultry and/or wild birds in Asia, Africa, Europe, Middle East Surveillance is incomplete Human cases have now been reported from 12 countries Human Cases H5N1 to 9/10/07 Country Cases Deaths Azerbaijan 8 5 Cambodia 7 7 China Djibouti 1 0 Egypt Indonesia Iraq 3 2 Lao PDR 2 2 Nigeria 1 1 Thailand Turkey 12 4 Viet Nam Human Cases H5N1 to Date Totals 9/10/07: 200 deaths / 328 cases ~ 60% mortality (stable) Avian infections since 2003 Human Cases January 1, 2007 April 10,
8 New Engl J Med, Nov 2006 Emerging Infectious Diseases, Feb Phase of Alert in the World Health Organization Global Influenza Preparedness Plan H5N1 What can we do? Travelers Advisory Current notice to travelers No recommendation to avoid travel Avoid poultry farms and bird markets Poultry products thoroughly cooked Hand hygiene Inform medical providers of travel history if sick H5N1 - Response Enhanced mechanisms for detection in U.S. Poultry surveillance Information to health departments, providers, and public to identify human cases Initiatives to improve surveillance in other parts of the world Including atypical presentations (e.g. diarrhea) Laboratory methods for faster detection Planning for pandemic on all levels Global, national, state, regional, local, hospital 8
9 5HN1 Treatment Current H5N1 viruses resistant to amantadine and rimantadine Susceptible in vitro to neuraminidase inhibitors oseltamavir and zanamavir No clinical studies Possible rapid resistance Medication stockpiles at several levels H5N1 Vaccine Development H5N1 prototype strains for pandemic vaccine development are available through WHO Complicated by two distinct clades (1 & 2) Clade 2 has at least 3 geographically distributed subclades Sanofi Pasteur and Novartis Vaccine have vaccine devlopment contracts with the National Institutes of Health From Vietnamese patient 2004 (clade 1) Phase 1 human testing began 2005 H5N1 Vaccine Trial Sanofi Pasteur vaccine trial in 451 subjects Subjects received 90, 45, 15, or 7.5 μg of hemagglutinin antigen or placebo in 2 doses 28 days apart Of subjects in the 90 μg group who received 2 doses, only 54% had a protective neutralization antibody titer FDA approved 4/07; National Stockpile H5N1 Vaccine Trial - Beijing Lancet, September 2006 (Beijing) Two doses of placebo or inactivated whole virion vaccine: doses 1.25 μg, 2.5 μg, 5 μg, 10 μg (24 subjects in each arm) Aluminum hydroxide adjuvant Dose dependent response 78% met seropositivity threshold after two doses with 10 μg 9
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