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The influence of influenza

The influence of influenza. Janice K. Louie, MD, MPH California Department of Public Health. Influenza virus. Influenza type. Year of isolation. Hemagglutinin subtype. A / California / 7 / 04 ( H3 N2 ). Geographic source. Isolate number. Neuraminidase subtype.

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The influence of influenza

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  1. The influence of influenza Janice K. Louie, MD, MPH California Department of Public Health

  2. Influenza virus Influenza type Year of isolation Hemagglutinin subtype A/California/7/04 (H3N2) Geographic source Isolate number Neuraminidase subtype

  3. Hemagglutinin Subtypes of Influenza A Virus Subtype Human Swine Horse Bird H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 Adapted from Levine AJ. Viruses. 1992;165, with permission.

  4. Neuraminidase Subtypes of Influenza A Virus Subtype Human Swine Horse Bird N1 N2 N3 N4 N5 N6 N7 N8 N9 Adapted from Levine AJ. Viruses. 1992;165, with permission.

  5. Influenza Antigenic Changes • Structure of hemagglutinin (H) and neuraminidase (N) periodically change • Drift:Minor change, same subtype Point mutations in gene May result in epidemic • Shift:Major change, new subtype Exchange of gene segment May result in pandemic

  6. DIRECT Mechanisms of Influenza Virus Antigenic “Shift” 15 HAs 9 NAs Non-human virus Human virus Reassortant virus

  7. Seasonal Influenza

  8. Impact of Influenza-US • ~ 82 million infected annually • ~ 36,000 (range 8000-68,000) excess deaths per year • ~ 226,000 (range 55,000-431,000) excess hospitalizations per year • Kills as many or more people than breast cancer and three times as many as HIV • Higher mortality during seasons when influenza type A (H3N2) viruses predominate • 90% of influenza-related deaths occur among persons >65 years Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008 Aug 8;57(RR-7):1-60.

  9. Influenza-associated Hospitalizations

  10. The Burden of Pediatric Influenza: High Infection Rates • Children have higher rates of infection than adults • 40% of preschool children can be involved in an epidemic • 30% of school children can be involved in an epidemic • Children can be the primary vector in the family Neuzil KM, et al. N Engl J Med. 2000;342:225.

  11. Community Family/Household School-age children infected School absenteeism Increased visits for medical care Employee absenteeismHospitalization (esp. elderly) Employee absenteeismHospitalization (esp. elderly) Influenza Epidemic in the Community National Institute of Allergy and Infectious Diseases, 12/97.

  12. Onset of Influenza A -1 0 1 2 3 4 5 6 7 8 23 Days After Inoculation 100 Temp °F 99 97 Illness Headache, Malaise, Myalgia Nasal Obstruction and Discharge,Throat Pain, Cough Adapted from Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principlesand Practice of Infectious Disease. 5th ed. 2000:1831.

  13. Signs and Symptoms of Influenza Type of Symptoms Children <5 yrs Adults Elderly Respiratory  Rhinitis  Nonproductive cough  Nasal obstruction  Sore throat  Sore throat Constitutional or  Fever  Rapid onset  Fever >99.0°F systemic  Vomiting of symptoms  Lassitude  Diarrhea  Fever, usually >100°F  Confusion  Chills/sweats  Headache  Myalgia  Potentially severe, persistent malaise  Substernal soreness, photophobia and ocular problems

  14. Laboratory Diagnosis • Commercial rapid tests (ELISA) • Direct fluorescent antibody (DFA) • Viral culture • Polymerase chain reaction (PCR) • Serology (HIA and neut)

  15. Sensitivity* of Rapid Antigen Detection Tests *Using cell culture as the gold standard [Monto et al, Antiviral Res 2002(55):227-278].

  16. Influenza Routes of Transmission Poorly characterized • Common: large droplets (sneezing, coughing, contact with saliva) • Probably common: contact • Direct • Fomite • Rare: airborne

  17. Infection Control in Hospitals • Droplet Precautions (surgical mask-within 3 feet) • Contact Precautions (gloves, gown) • Eye protection • Standard Precautions (hand hygiene)

  18. Influenza Vaccine Content Updated yearly to protect against anticipated strains, consists of type A (2) and type B (1) Process Grown in embryonated chicken eggs and formalin inactivated Record 170 million doses available for 2008-09 season

  19. Timetable for interpandemic vaccine production

  20. 2009-2010 Northern Hemisphere Influenza Vaccine Recommendations • A/Brisbane/59/2007 (H1N1)-like virus • A/Brisbane/10/2007 (H3N2)-like virus • B/Brisbane/60/2008-like virus

  21. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008 Aug 8;57(RR-7):1-60.

  22. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008 Aug 8;57(RR-7):1-60.

  23. Randomized blinded trial of 340 healthy women vaccinated in the 3rd trimester • Mothers and infants followed for 24 weeks after birth • Results showed: • - lower risk of laboratory-confirmed influenza in infants by 63% • - lower risk of any febrile respiratory illness in infants (20%) and mothers (36%)

  24. Elderly persons have diminished immune response • Most studies of elderly have been observational and varied greatly in conclusions • Advantages of this study: • - Large dataset: 18 HMO cohorts and 713,872 person-seasons • - Over 10 flu seasons, including mismatch years • - Multiple sites (MN, WI, WA, NYC) • - Multiple attempts to control for bias • Conclusions: influenza vaccination reduced the risk of hospitalization by 27% and death by 48%

  25. Move to Universal Vaccination • Recognition of suboptimal vaccine effectiveness among groups at highest risk for influenza complications (e.g. elderly, persons with chronic illness) • Potential for reducing community transmission through vaccinating school children and healthy adults if high coverage can be achieved • Better understanding of health and economic impact of influenza among older children and adults • Lessened concerns about vaccine supply • Increased concern about an influenza pandemic-need to lean how to vaccinate an entire population against influenza. • Belief that current low coverage for most recommended groups might be improved by a simple universal recommendation

  26. Proposed ACIP Timeframe • 2007-08: Expand recommendations to include all school age children (5-18 year olds) • 2010-2011: Expand recommendations to include household contacts and caregivers of school-aged children • 2012-2013: Expand to universal vaccination

  27. Antivirals: Adamantanes and Neuraminidase Inhibitors NA inhibitors HA blockers

  28. Adamantanes • Inexpensive • Amantadine ~ $0.60/pill • Rimantidine ~ $2.20/pill • Not effective against influenza B • Resistance due to a single point S31N substitution in the M2 protein • >90% of currently circulating influenza A/H3 • Usefulness for monotherapy of seasonal influenza now unclear

  29. Treatment with Neuraminidase Inhibitors • Oseltamivir: 75 mg bid x 5 days • Zanamivir (>7 yrs):10 mg inhaled bid • Evidence for effectiveness based on studies of outpatients with uncomplicated influenza • If treatment begun within 48 hours of onset of symptoms, reduction in symptoms by ~1 day • Inconsistent data, but likely reduces viral shedding MMWR July 13, 2007 / 56(RR06);1-54

  30. Toronto Invasive Bacterial NetworkProspective Cohort Study • Significant reduction in mortality in highly vaccinated population (71%) of adults and children with laboratory confirmed influenza (odds ratio 0.21, CI 0.06-0.80). Benefit seen even when oseltamivir started >48 hr after onset. • Significant reduction in mortality in small number of adults admitted to ICU for laboratory-confirmed influenza (none treated within 48 hours of onset) McGeer et al, Clin Infect Dis 2007;45:1568, ICAAC 2007.

  31. Moscona, A. Global transmission of oseltamivir-resistant influenza. N Engl J Med. 2009 Mar 5;360(10):953-6. Epub 2009 Mar 2

  32. Antiviral resistance

  33. Swine influenza: 2009

  34. Typical influenza illness-like in 2 childrenCalifornia CDPH notified April 14, 2009 • Case Patient A, San Diego county. March 30, 2009 • Previously healthy 10 year old boy with fever, cough, vomiting x 1 week • No exposure to pigs • Mother and brother had respiratory illness preceding case patient • Flew to Dallas, Texas on April 3rd while febrile • Case Patient B, Imperial county. March 28, 2009 • Previously healthy 9 year old girl with fever to 104°F and cough x 1 week • No direct exposure to pigs • Attended state fair where pigs exhibited but never saw pigs • Traveled to Mexicali, Mexico 2 weeks prior • 13 year old brother and 13 year old cousin with respiratory symptoms

  35. Typical influenza-like illness in 2 childrenCalifornia • Cases occurred 80 miles apart • Samples collected by different people at different times • Samples never went through the same lab • Both cases positive for influenza A by PCR but untypeable for human H1 or H3 • Reference testing at CDC: swine flu A/H1N1

  36. Early Confirmed Cases of SIV No known epidemiologic link between the Texas and California cases Case Patient A Flew to Dallas, Texas Number of Confirmed Cases

  37. Mexicali

  38. April 24, 2009

  39. WHO Definition of a Pandemic • Isolation from humans of an influenza A virus with a novel hemagglutinin or a novel hemagglutinin and neuraminidase gene, and susceptibility (lack of antibody) to this novel virus in a large proportion of the population. • Demonstrated ability of the virus to replicate and cause disease. • Efficient transmission from person-to-person.

  40. WHO Pandemic Influenza stages

  41. Swine influenza in swine • Swine influenza first identified in 1930 • Endemic in pig herds throughout the world • Herd level seroprevalence 50-90% • Cause respiratory symptoms (cough, runny nose, lethargy, decreased feeding) • Secondary bacterial infections common • Herds often vaccinated

  42. Human Swine influenza-US (2005- 2008) • 11 human cases identified since 2005 by CDC • Median age: 10 years (range 16 mo-48 yrs) • Four with underlying illness (asthma, immunosuppression, excema) • Mild upper respiratory illness common (diarrhea in 30%; four hospitalized and two adults required mechanical ventilation • 9 had direct or indirect pig exposure at farms/fairs • All had genetically similar viruses commonly circulating in pigs • All triple reassortant viruses

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