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Influenza: Pandemic Practicalities

Influenza: Pandemic Practicalities. Ned Calonge, MD, MPH, Chief Medical Officer Colorado Department of Public Health and Environment. Disclosures. No conflicts of interest Off-label use of drugs Most current FDA approved indication for oseltamivir (2008):

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Influenza: Pandemic Practicalities

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  1. Influenza: Pandemic Practicalities Ned Calonge, MD, MPH, Chief Medical Officer Colorado Department of Public Health and Environment

  2. Disclosures • No conflicts of interest • Off-label use of drugs • Most current FDA approved indication for oseltamivir (2008): “Tamiflu is indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been asymptomatic for no more than 2 days.” • Addition use in this presentation is based on CDC recommendations

  3. Objectives • Discuss the historical background of influenza in the context of novel H1N1 • Discuss learnings from this year’s H1N1 epidemic • Present predictions for H1N1 in the future • Influenza for 2010-11

  4. Excess mortality from influenza Morens DM, NEMJ 2009;361:225-229 4

  5. H1N1 in Swine • Probably introduced to swine from humans in 1918 • H1N1 first isolated from swine in 1930, antigenically highly similar to reconstructed 1918 H1N1 virus (likely share a common ancestor) • From 1930 to 1990s, circulated in swine and remained antigenically stable T. M. Tumpey, Proc. Natl. Acad. Sci. U.S.A. 101,3166 (2004) Garten RJ. Science. 2009;325:197-201

  6. H1N1 in humans • Originally caused the 1918 pandemic • Circulated in humans until 1957, antigenic drift • 1950s H1N1 re-emerged in humans in 1977 • Further drift from 1977-2009 resulted in 8 updates of H1 component of vaccine • Substantial drift of A(H1N1) in humans away from 1918 virus created an antigenic gap between swine H1 and human seasonal H1 • Swine became a reservoir with pandemic potential • Little immunity to current pandemic

  7. Host and Lineage Origins For The Gene Segments of 2009 A(H1N1) Garten RJ. Science 2009; 325:17-201

  8. Genetic divergence of 2009 H1N1 vs. seasonal H1N1 • 2009 H1N1 shares only ~73% amino acid identity in HA1 portion of the hemagglutinin molecule with seasonal H1N1 (~98% among seasonal strains) • No protection from expected from seasonal vaccine CDC MMWR May 22, 2009. 58(19);521-524

  9. Cross-reactive antibody to 2009 H1N1 influenza after seasonal vaccine • Stored serum samples from persons vaccinated against recent seasonal influenza • No antibody against 2009 H1N1 elicited in children 6 months to 9 years (n=124) • Adults elicited antibody against 2009 H1N1 in • 12% 18 - 40 years (n=83) • 22% 18 - 64 years (n=148) • 0-5% 60 years or older (n=50) Hancock K. NEMJ 2009;361

  10. Neutralizing Antibody Titers Against 2009 H1N1 By Birth Decade (n=417) • 34% born before 1950 had antibody titers > 80 • 4% born after 1980 had antibody titers > 40 Hancock K. N Engl J Med. N Engl J Med 2009;361.

  11. Laboratory-Confirmed 2009 H1N1 24 JUL 2009 (n=37,030*) Fiore A. Presentation to ACIP July 29,2009.

  12. Hospitalization with laboratory-confirmed 2009 H1N1 influenza 24 JUL 2009 (n=4,738*) Fiore A. Presentation to ACIP July 29,2009.

  13. Age distribution of hospitalizations with laboratory-confirmed influenza, seasonal vs. 2009 H1N1 Fiore A. Presentation to ACIP July 29,2009

  14. Underlying Medical Conditions Among Hospitalized Persons by Age Group (n=268) Fiore A, Presentation to ACIP, July 29,2009.

  15. H1N1 Influenza in Pregnant Women Pregnant women at higher risk from complications with H1N1 influenza Risk of hospitalization: 0.32 per 100,000 pregnant women vs 0.076 per 100,000 normal population Mortality: 6 deaths in 32 confirmed cases (18%) between April 15 to May 18, 2009 Jamieson DJ. Lancet. 2009; Early Online Publication, 29 July 2009

  16. Transmissibility and severity • Case fatality ratio estimated at 0.4% (0.3%-1.8%) • Less than 1918, comparable to 1957 pandemic • Mean number of secondary cases from typical single infected case = 1.4 to 1.6 • Genetic analysis estimate = 1.2 • Substantially higher than seasonal flu • Comparable to lower estimates from past pandemics C Fraser, et al. Science 324, 1557 (2009)

  17. 2009 H1N1 virulence (animal models) • Pandemic H1N1 virus replicates more efficiently in the lungs • More pronounced tropism for lower respiratory tract with prominent bronchitis, alveolitis, and presence of virus • Marked induction of pro-inflammatory cytokines/ chemokines not seen with seasonal H1N1 • More severe lung lesions • Inflammatory infiltrates, severe thickening of alveolar walls • Comparable transmission vs. seasonal influenza in ferrets Itoh Y, Shinya K, Kiso M, et al. Nature 2009 Jul 13 early online edition

  18. ICU Patients With Severe 2009 H1N1 Michigan, June 2009 • 10 patients with 2009 H1N1and ARDS transferred to a tertiary care SICU specializing in advanced ventilation for severe ARDS • 10 required high-frequency oscillatory or bilevel ventilation with high mean airway pressures [32-55 cm H20] • 9 had multi-organ dysfunction syndrome • 9 had BMI ≥30, of whom 7 had BMI ≥40 • 5 had pulmonary emboli; 2 others hypercoagulable • 3 died • Time from illness onset to death = 17 to 30 days • 2 autopsies confirmed bilateral hemorrhagic viral pneumonitis with interstitial inflammation and diffuse alveolar damage, bilateral pulmonary emboli • Median days from illness onset to antivirals was 8 days MMWR Weekly July 17, 2009 / 58(27);749-752

  19. The Canadian ICU experience • 168 critically ill patients in 38 ICUs Apr 16-Aug 12, 2009 • Median (SD) age was 32y (21.4), 64% female, 30% children • 25% Aboriginal Canadians • 24% of patients were morbidly obese • BMI not different between survivors and non-survivors • Median time from symptoms to admit= 4d [IQR, 2-7 d] • 81% required mechanical ventilation on the first ICU day • 14% received inhaled nitric oxide; 12% required HFOV; 4% required EMCO, and 3% prone positioning. • Median duration of ventilation = 12 days [IQR, 6-20 d] • Overall mortality at 90 days = 17.3% [95% CI, 12.0%-24.0%] Kumar A, Zarychanski R, Pinto R; et al. Canadian Critical Care Trials Group H1N1 Collaborative. Critically ill patients with 2009 influenza A(H1N1) infection in Canada [published online October 12, 2009].

  20. Critical care services and 2009 H1N1 influenza in Australia and New Zealand • Multicenter inception-cohort study June 1 through August 31, 2009 in all 187 ICUs in Australia and New Zealand (n= 722) • 92.7% under 65 years, 1/3 healthy • 9.1% pregnant • 65% required mechanical ventilation. • 20% had a bacterial co-infection • Median length of stay 8 days • 14% died • Increased risk in infants, adults 25 to 64 y, pregnant, BMI > 35, indigenous The ANZIC Investigators. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. NEJM 2009. http://content.nejm.org/cgi/content/full/NEJMoa0908481. Accessed October 21, 2009.

  21. Characteristics 2009 H1N1–associated ARDS treated with ECMO • 68 patients in 15 ICUs treated with ECMO • Median age 34.4 y; none> 65y • BMI>30 (50%); asthma (28%); Diabetes (15%); Pregnancy/postpartum (15%) • 28% had secondary bacterial infection • 21% died • Mortality rate lower than the 30% to 48% seen in other ARDS cases requiring ECMO ANZ ECMO influenza investigators. Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome JAMA. 2009. http://jama.ama assn.org/cgi/content/full/2009.1535.

  22. Summary of ICU Experience • Many severe cases occur in previously healthy young people (mean age 32-44 years) • In severe cases, patients deteriorate after 3 to 5 days, develop respiratory failure within 24 hours • Advanced ventilatory measures sometimes needed • Prompt treatment improves outcomes • Co-infection with bacteria can contribute to severity • Groups at greatest risk: Pregnant women ( 3rd trimester); Children < 2 years; lung disease; possibly indigenous populations; possibly obesity

  23. Interpretation of rapid test with influenza circulating in the community Positive for Influenza B Positive for Influenza A Negative for Influenza A or B Sensitivity= 10-70% Influenza A Infection Likely Influenza B Infection Likely Cannot Rule Out Influenza Treat with Antivirals Consider Additional Testing to Determine Viral Subtype Treat with Antivirals Clinical Symptoms Guide Therapy Consider Further Testing Consider whether additional testing and/or empiric therapy for bacterial co-infection is warranted CDC: http://www.cdc.gov/h1n1flu/guidance/rapid_testing.htm

  24. Treatment (antivirals) • Treatment based on suspected H1N1 • Only treat specific patients • Hospitalized • High risk for complications • Severe illness • Prophylaxis only for exposed high risk patients • No antiviral treatment for otherwise well patients with uncomplicated illness

  25. Influenza antiviral sensitivity http://www.cdc.gov/h1n1flu/recommendations.htm

  26. Antiviral therapy–unresolved issues • Some experts advocate high dose oseltamivir (150 mg bid) for severe disease • Safety is acceptable • No evidence for increased efficacy • IV agents are or may be available under Emergency Use Authorization (EUA) • IV peramivir • IV zanamivir (possible) • IV oseltamivir (possible)

  27. High risk groups for treatment • Pregnant women • Children under 2 years • Those with chronic illnesses • COPD, asthma, heart disease, kidney disease, liver disease, blood disorders, neurologic disorders, diabetes, impaired immune systems (from medication or HIV), under age 19 and on long-term aspirin therapy • Those 65 and older

  28. Novel H1N1 resistance to oseltamivir • Sporadic cases of H1N1 resistant oseltamivir reported worldwide • 28 confirmed from >10,000 isolates tested by WHO • 12 associated with oseltamivir use as postexposure prophylaxis • In US, 9 of 1678 isolates (0.6%) have tested positive for resistance to novel H1N1 WHO, http://www.who.int/csr/disease/swineflu/notes/h1n1_antiviral_use_20090925/en/index.html CDC, http://www.cdc.gov/flu/weekly/. Accessed September 28, 2009.

  29. Single dose H1N1 vaccine efficacy (n=240) Antibody titers >40:1 following single dose Percent Greenberg ME. N Engl J Med. 2009;361:E-pub ahead of print. September 10, 2009

  30. Vaccine priority groups • Pregnant women • Healthcare and emergency medical services personnel • Household contacts/caretakers of children under 6 months • Children, adolescents and young adults 6 months to 24 years • Adults 25 to 64 with chronic disease

  31. Guillain-Barré Syndrome and TIV • 1976 swine influenza vaccine associated with 1 additional case of GBS per 100,000 persons • No consistent evidence for causal relation between subsequent vaccines and GBS • Influenza virus infection is a trigger of GBS • Frequency of influenza-related GBS was 4-7 times higher than vaccine-associated GBS • Persons with prior GBS have a greater likelihood of subsequent GBS • Persons not at high risk for severe influenza and known to have GBS within 6 weeks should not be vaccinated Haber P. JAMA 2004;292:2478—81; Lasky T. NEMJ 1998;339:1797--80 Schonberger LB. Am J Epidemiol 1979;110:105--23H

  32. The Phantom of the N-95 Mask Or, PPE and the perfect (bureaucratic) storm • HHS asks IOM to review the evidence and make a recommendation for mask use, ignoring feasibility and cost • IOM recommends N-95 use on the basis of • empiric evidence (size of viron) and • unpublished study that N-95s are more effective at preventing HCW infection • Despite pleas from ICPs and ID docs nationwide, CDC adopts N-95 recommendation

  33. PPE recommendations (cont.) • OHSA picks up CDC recommendation and states hospitals out of compliance will be fined, and recommendations must be followed for seasonal flu as well • JAMA article published that reports effectiveness is equivalent with surgical masks • Original study is discredited as fatally flawed

  34. The future of H1N1 • “It’s difficult to make predictions, especially about the future” • Kerr White, MD

  35. The future of H1N1 • No precedent for a second wave this season (already IS the second wave) • Did not “go away” during last spring and summer • May stay at a sporadic/localize outbreak level for rest of 2010 • Likely to return as the dominant H1N1 strain next influenza season

  36. The future of H1N1 • Likelihood of mutation to more severe strain not covered by current vaccine: • Has remained genetically very stable since emergence last spring (97% genetic match) • Such major change would be unprecedented

  37. What do you need to know? • H1N1 is still circulating as the dominant strain, with no seasonal influenza activity documented in the community • Over all severity is not greater than seasonal flu, but • There are individuals who have severe illness and “go south” very quickly

  38. Vaccination • Next year’s seasonal vaccine very likely will replace usual H1N1 coverage with 2009 H1N1 (already done for Southern Hemisphere vaccine) • Vaccine demand will likely depend on severity of early cases, though there may be residual interest from this year • New high-dose vaccine approved by FDA or use in 65+ age group

  39. Antiviral treatment • Observational studies (few) support early use for severe disease • Recognize that clinical observational studies are ALWAYS biased towards effectiveness • NO SINGLE RCT HAS FOUND REDUCTIONS IN HOSPITALIZATIONS, DEATH OR LOWER RESPIRATORY INFECTION

  40. Antiviral treatment • Heightened controversy given BMJ publications about potential obfuscation of RCT results and meta-analysis by manufacturer • Recent UK meta-analyses concluded • treatment of otherwise well children does more harm than good • prophylaxis in children only 8% effective • Still—the only treatment available

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