Influenza A 6/23/2010. Lisa Winston, MD UCSF / San Francisco General Hospital Divisions of Infectious Diseases and Hospital Medicine

Transcription

1 Influenza Update in a Pandemic Year 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 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 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 A flu by any other name. Synonymous names Novel H1N1 Swine origin H1N Influenza A (H1N1) A (2009 H1N1) A/California/2009 (H1N1) Pandemic H1N Trifonov et al, New Engl J Med, 2009;361: Start of Novel H1N1 Start of Novel H1N1 April 2009: 2 children in Southern California with no epidemiologic link were identified with influenza A H1N1 of swine origin Both had mild disease starting end of March Identified through established surveillance protocols When isolates could not be subtyped, forwarded to CDC Enhanced surveillance put in place In Mexico in late March 2009, an unusual outbreak of respiratory disease noted associated with increased hospitalizations Most patients were young and many had no underlying illnesses In April 2009, cause determined to be influenza A H1N1 of swine origin Through May 2009, Mexico had greatest number of severe cases and deaths 3

4 Start of Novel H1N1 Spread in North America and then throughout the world quickly noted On June 11, 2009, WHO raised the level of influenza pandemic alert from level 5 to level 6 Novel strain already known to be circulating worldwide Delay related to moderate severity of disease Influenza continued through summer and into fall Influenza Activity - Peak 4

5 Influenza Activity - Current Pneumonia and Influenza Mortality Pediatric Mortality Seasonal Influenza Morbidity and Mortality ~ 200,000 hospitalizations / year in U.S. ~ 36,000 deaths / year in U.S. Severe disease tends to occur 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:

6 Epidemiology 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 Epidemiology Among person 65 years and older, hospitalization rates related to novel H1N1 are 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 Not completely clear whether independent risk factor MMWR, August 28, 2009;58(RR10):1-8 Electronically published 10/8/09 6/1 8/31/09: 722 patients admitted to ICU in Australia or New Zealand Persons < 1 year had highest rate of ICU admission 9.1% of patients were pregnant women (1% of population) 28.6% of patients had BMI > 35 (5.3% of population) 31.7% of patients had no known predisposing factor 16.9% mortality rate for ICU admissions (as of 9/7/09) Over 3 mo., accounted for 5.2% ICU bed days (peak percentage by region %) 6

7 January 7, 2010 Surveillance in reproductive aged women in CA with H1N1 who were hospitalized or died 94 pregnant, 8 postpartum, and 137 non-pregnant women hospitalized April 23 Aug 11, % pregnant women in 2 nd or 3 rd trimester and 34% had risk factors other than pregnancy 60% non-pregnant, reproductive aged women had risk factors In pregnant women, antiviral treatment within 2 days of symptoms associated with lower mortality and ICU The maternal mortality ratio was 4.3 per 100,000 live births Comparative Virulence Animal models In ferrets, transmissibility similar to seasonal influenza virus In mice, ferrets, and primates, bronchopneumonia more severe than seasonal influenza Itoh et al, Nature, 2009;460: Role of Bacterial Co-Infection CDC examined 77 post mortem lung specimens from U.S. fatal cases Evidence of concurrent bacterial infection in 22/77 (29%) 10 Streptococcus pneumoniae 7 Staphylococcus aureus 6 Streptococcus pyogenes 2 Steptococcus mitis 1 H. influenzae 4 cases multiple organisms MMWR, October 2, 2009;58: Influenza Vaccine Composition FDA s Vaccines and Related Biological Products Advisory Committee (VRBPAC) met 2/22/10 to decide composition of U.S. influenza vaccine for next season: A/California/7/2009 (H1N1)-like A/Perth/16/2009 (H3N2)-like new B/Brisbane/60/2008-like Same strains recommended by WHO for Northern Hemisphere 7

8 Seasonal Vaccine Indications Adults > 50 years Children 6 months 18 years > 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 Influenza Vaccine Indications All people older than 6 months Unless there is a contraindication * ~ 248 million people targeted in U.S.: 83% of population Herd Immunity JAMA, March 10, 2010 Vaccinating only children ages 3 15 (83% received vaccine) in Hutterite communities in Canada was about 60% effective in preventing influenza in nonvaccinated persons within the communities Influenza Vaccines Trivalent inactivated vaccine - TIV Approved for all persons 6 months and older Grown in eggs Sore arm most common side effect compared with placebo Live attenuated intranasal vaccine LAIV (FluMist) Same strains as inactivated vaccine Attenuated, heat sensitive and cold adapted Approved for healthy persons ages 2 49 Runny/stuff nose most common side effect compared with placebo Does not contain mercury 8

9 High Dose TIV Vaccine 12/09 FDA licensed Fluzone High-Dose for persons 65 and older Contains 60 µg of hemagglutinin per strain of virus compared with 15 µg of hemagglutinin per strain of virus in regular dose TIV In Phase 3 trial of adults 65 and older, enhanced immune response with high dose compared with standard dose vaccine Local reactions (mild to moderate) more common with high dose vaccine Falsey et al, J Infect Dis, 2009;200: No trials to date regarding high dose vaccine and prevention of influenza Who should not get LAIV? Outside recommended age ranges Most chronic medical conditions Including wheezing in past 12 months Pregnant women History of Guillain-Barre (same as for TIV) Anaphylaxis to eggs (same as for TIV) Contact with highly immunosuppressed patients, e.g. recent bone marrow transplant * Note that breast feeding is not a contraindication LAIV vs. TIV - Efficacy In children, 85 90% effective in preventing influenza A compared with placebo In children, several studies suggest better efficacy than inactivated vaccine In adults, LAIV appears to be less efficacious than TIV? Live attenuated viruses unable to infect persons with past exposure to similar strains? May be a particular issue in annually immunized populations Ohmit et al, N Engl J Med 2006;355: Monto et al, N Engl J Med 2009;361: Wang et al, JAMA 2009;301: Influenza Vaccination of Healthcare Personnel Many elderly and debilitated 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 9

10 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 Lemaitre et al, J Am Geriatr Soc 2009; epub Note that efficacy of vaccination varies from year-to-year and is influenced by vaccine match Data summary: MMWR Recomm Rep, Influenza Vaccination of Health-Care Personnel. 2006(55):1-16 Required Vaccination or Declination Infection Prevention: Which Masks? Influenza mostly spread by droplets Controversy regarding importance of airborne spread of small droplet nuclei CDC and Institute of Medicine recommending fittested N95 masks for healthcare personnel for pandemic influenza Professional organizations including Society for Hospital Epidemiology of America (SHEA), Association for Professionals in Infection Control (APIC), and Infectious Diseases Society of America (IDSA) disagree 10

11 6/23/2010 Infection Prevention: Which Masks? Clinical data are quite limited Abstract presented at ICAAC 9/15/09: found N95 masks superior to surgical masks in Beijing hospitals Influenza Antivirals Two classes of drugs C. Macintyre et al; presentation K-1918b New analysis presented at IDSA 10/31/09 at request of peer reviewers results no longer statistically significant Study published electronically 10/1/09: found N95 masks and surgical respirators to be equivalent in Ontario hospitals Amantadine and rimantadine All influenza antivirals Decrease viral shedding Reduce clinical illness by about 1 day Are effective for chemoprophylaxis, if they have activity against the virus Neuraminidase inhibitors: inhibit cleavage of influenza A and B viruses from host cell surface Zanamivir (inhaled) and oseltamivir (oral) Peramivir (intravenous) emergency use Loeb et al, JAMA 2009;302: When given to outpatients within 48 hours of symptom onset Adamantanes: interfere with influenza A virus M2 ion channel protein; inhibit virus uncoating Oseltamivir Some data on prevention and treatment of more severe disease Meta-analysis: in outpatients with confirmed influenza, oseltamivir decreased Lower respiratory tract complications Overall antibiotic use Hospitalization for any cause (.7% vs. 1.7%) Kaiser et al, Arch Int Med, 2003:163: Treatment of hospitalized adults with oseltamivir associated with decreased mortality McGreer et al, Clin Infect Dis, 2007:45:

12 6/23/2010 Resistance to Antivirals Most seasonal influenza A (H1N1) viruses from are resistant to oseltamivir Many seasonal influenza A (H3N2) viruses are resistant to adamantanes Novel influenza A (H1N1) viruses Are resistant to adamantanes Occasional isolates have been resistant to oseltamivir but susceptible to zanamivir In season to date, almost all currently circulating influenza has been novel influenza A (H1N1) Treatment with oseltamivir (or zanamivir) is appropriate 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: Patients with influenza-like illness and negative rapid tests who have indications for antiviral treatment should be treated More sensitive tests such as real-time reverse transcription polymerase chain reaction (rrtpcr) or viral culture should be prioritized for hospitalized patients Priority for Treatment with Antivirals More severe illness, especially hospitalized patients Children younger than 2 years old Adults 65 years and older Pregnant women Significant co-morbidities predisposing to severe influenza Children receiving long-term aspirin What happened to avian influenza H5N1??? Avian influenza in Miami 12

13 Avian influenza (H5N1) Sporadic human cases continue in several countries As of 6/8/10: 499 worldwide human cases H5N1 reported to WHO (2003 present) 295 deaths 60% case fatality ratio has remained stable Likely issues of case finding and reporting H5N1 influenza still does not spread efficiently person-to-person Final Reflections Comparative case fatality ratios pandemic influenza: < 2% (most populations) but perhaps as high as 2.5% 1957 and 1968 pandemics: ~.1% Novel influenza A (H1N1) using CDC data: < 0.1% (~.02%) 3/12/10: U.S. estimates 59 million infected with novel H1N1 between 4/09 2/13/10; 265,000 hospitalized; 12,000 deaths 13