Understanding mortality from pandemic and seasonal influenza

Transcription

1 Understanding mortality from pandemic and seasonal influenza Jonathan A. McCullers Associate Member Department of Infectious Diseases St. Jude Children s Research Hospital H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 The ecology of influenza viruses Timeline of viruses in humans and pigs Emergence of a pandemic strain H2N2 H2N2 H3N2 H3N2 H1N1 H3N2 H3N2 H1N2 H1N2 Novel Novel Human N.A. Avian Classic or Eurasian Swine Segments 1 PB2 2 PB1 3 PA 4 HA 5 NP 6 NA 7 M 8 NS H1N1 H3N Triple reassortant novel pandemic H1N1 influenza virus Pandemics in the last century Age Distribution 1918 fully avian H1N1 virus enters humans and pigs simultaneously, million deaths worldwide, endemic in pigs 1957 reassortant virus takes H2N2 surface proteins and PB1 from avian sources, other genes from human H1N1, ~ 2 million deaths worldwide 1968 reassortant virus takes H3 and PB1 from avian sources, other genes from human H2N2, ~ 1 million deaths worldwide [1977 H1N1 related to 1950 strain re-emerges from frozen source, has circulated together with H3N2 since] 2009 triple reassortant H1N1 emerges from pigs, novel H1N1 Reichert TA..McCullers JA. BMC Inf Dis

2 Clinical features of seasonal influenza - Sudden onset of symptoms - Incubation period 1 to 7 days, typically 2-3 days - Infectious period varies by age: - Adults shed virus typically 1 day before through 4-5 days after onset of symptoms - Children shed virus longer, typically 2-3 days before through 7-10 days after onset of symptoms - Novel H1N1 thought to be similar, infectious period may be longer (more like naïve subjects) Clinical manifestations of influenza Infants Children Adults Novel H1N1 * Fever Cough Myalgias Sore throat Headache Diarrhea Vomiting Rhinitis Maliase / lethargy Neurologic symptoms - rare, + uncommon, ++ common, +++ very common *Represents children and adult data combined McCullers JA. Infect in Med, November Vaccines against H1N1 influenza Treatment of novel H1N1 - Standard vaccines targeting H1N1 have been made and tested by same process we use every year - The vaccines are extremely safe and no problems were reported - Although plenty of vaccine was made, distribution problems limited access - Children, young adults, pregnant women, first responders, and persons with chronic illnesses were first priority - Novel H1N1 will replace seasonal H1N1 in the trivalent vaccine for Novel H1N1 viruses are susceptible to neuraminidase inhibitors (NAIs; oseltamivir, zanamivir) but resistant to adamantanes (amantadine, rimantadine) limited published experience with treatment outcomes - Prophylaxis has been undertaken with NAIs to prevent spread to close contacts - Development of resistance in this clinical scenario has been documented (H275Y mutation), but these strains have not spread widely WHO Diagnosis of novel H1N1 Risk factors for severe disease - Currently used antigen tests have 40-60% sensitivity for novel H1N1 compared to RT-PCR - Most available RT-PCR assays cannot distinguish novel H1N1 from seasonal strains - Targeted antiviral use will require development and widespread utilization of PCR based assays that can distinguish type (A vs. B), subtype (H3N2 vs. H1N1), and strain (seasonal vs. pandemic) - Sequencing based methods for rapid antiviral resistance determination could also be employed - Overall, similar to risk factors for seasonal influenza - Chronic medical conditions including cardiopulmonary disease and immunosuppression - Pregnancy - Neurodevelopmental delay - Obesity (this is not recognized as a risk factor for seasonal influenza) - Extremes of age have not been a risk factor for novel H1N1 MMWR 2009 / 58(30);

3 Complications of novel H1N1 Bacterial pneumonia and H1N1 - Viral pneumonia most common cause of death - Most severe disease in persons with no underlying risk factors has been in older children and young adults immunopathology? - Bacterial super-infections otitis media, pneumonia, sinusitis are being found more commonly with novel H1N1 - Few reports of bacterial superinfections in initial descriptions of severe pandemic related disease - However, most critically ill patients were treated with broad spectrum antibiotics, and invasive assays (e.g., pleural taps) were not commonly done - Several pathology series have shown 30-50% of all fatal cases had evidence of bacterial super-infection (S. aureus, S. pneumoniae, Group A Streptococcus) Dawood FS, et al. NEJM 2009;360(25): Perez-Padilla R, et al. NEJM 2009;June 29 th electronic publication. Dawood FS, et al. NEJM 2009;360(25): Gill JR et al., Arch Pathol Lab Med 2010;134: Mauad T et al., Am J Respir Crit Care Med 2010;181:72-9. CDC. MMWR 2009;58(38): Bacterial pneumonia and pandemics Questions about Mortality - It is estimated that 95% of all deaths during the 1918 pandemic were complicated by secondary bacterial pneumonia - Estimated at 50-70% in 1957 and This has been a key concern for pandemic planning - Now that the novel H1N1 has emerged, we need to understand influenza-bacterial interactions to better predict outcomes and more effectively treat cases We understand about half the deaths they are in persons with chronic medical conditions and the deaths are what we expect from seasonal influenza - Why is the clinical attack rate low in older adults? - Why are bacterial superinfections only accounting for ~30% of deaths? - Why are healthy, older children and young adults disproportionately affected by viral pneumonia? - Why is obesity a new risk factor? Morens DM, et al., J Infect Dis 2008;198: McCullers JA. J Infect Dis 2009;198: Questions about Mortality Natural immunity in older adults We understand about half the deaths they are in persons with chronic medical conditions and the deaths are what we expect from seasonal influenza - Why is the clinical attack rate low in older adults? - Why are bacterial superinfections only accounting for ~30% of deaths? - Why are healthy, older children and young adults disproportionately affected by viral pneumonia? - Why is obesity a new risk factor? Study Design: - Enrolled 126 adult employees of SJCRH who were 55 y.o. - Asked about receipt of 1976 swine flu vaccine Lee-Ann Van de Velde - Determined antibody titers to the 2009 novel H1N1, the seasonal H1N1, and the 1976 swine flu vaccine strain Hypothesis: Persons who recall receiving swine flu vaccine in 1976 will have higher antibody titers against the 2009 S-OIV than those who do not recall receiving vaccine 3

4 2000s Antibody titers Phylogenetic relationships between human H1N1 viruses 1990s 1980s 1970s s 97% of subjects received seasonal influenza vaccine; 36.5% recalled receiving swine flu vaccine in 1976 Reichert TA..McCullers JA BMC Inf Dis s 1940s 1976 Swine flu and 2009 pandemic H1N1 Antibody titers Effect of seasonal vaccine - Some advantage to prior vaccination in 1976 (not statistically significant); some advantage to age in a highly vaccinated cohort Some advantage for age against all 3 viruses Effect of seasonal vaccine Neutralization titers are low Unvaccinated persons in on the lower end of responses in the group 4

5 Answer: older adults What about bacterial pneumonia? - Older adults may have some crossprotective immunity against the novel H1N1 - Immunity increases with age, although neutralization responses are modest and do not increase with age - Receipt of the 1976 swine flu likely enhanced these responses (23.9% vs. 14.3% by neutralization) Should we be seeing more than we are? Julie McAuley Secondary pneumococcal pneumonia PB1-F2: newly identified protein Mouse model Pneumococcus = MLD 50 D39 Influenza = 0.05 MLD 50 PR8 Mock = PBS (diluent) 10 mice per group pictured Second challenge was 7 days after primary infection aa peptide with predicted amphipathic helical domain at C-terminal end in the +1 reading frame of the PB1 gene segment - sequence spanning aa targets peptide to mitochondria McCullers JA et al., J Inf Dis 2002;186: Gibbs JS et al., J Virol 2003;77: Bruns K. et al., J Biol Chem 2007;282(1): PB1-F2 supports bacterial super-infections Decreased necrosis and inflammation - mice infected with wt or KO virus then challenged 7 days later with pneumococcus A KO virus did not prime for bacterial pneumonia 10X WT PB1-F2-40X Lungs of mice with secondary bacterial pneumonia McAuley JL McCullers JA, Cell Host & Microbe, 2007;2: McAuley JL McCullers JA, Cell Host & Microbe, 2007;2:

6 PB1-F2 from pandemic strains promotes inflammation Conclusions - Inflammation - PB1-F2 has immunostimulatory activity C-terminal portion of PB1- F2 from 20 th century pandemic strains and H5N1 cause inflammation, recent H3N2 does not - inflammatory lung damage appears to play a role in both induction and severity of bacterial pneumonia following influenza - strain specific differences in PB1-F2 are important BAL fluid cell counts 3 days post exposure to PB1-F2 McAuley JL McCullers JA. Submitted for publication. McAuley JL McCullers JA. Submitted for publication. What about the novel H1N1 PB1-F2? Are other swine viruses a greater threat? PB1-F2 Motif Non- Inflammatory Highly Inflammatory - has 2 stop codons at positions 12 and 58 - has attenuating mutations at 75 and 79 - unlikely to be functional through reversion Groups of 5 mice infected i.n. with 0.1 MLD 50 of selected viruses followed 5 days later with 1000 CFU of S. pneumoniae strain A66.1 (type 3) Clear differences in support for bacterial superinfections among swine viruses Implications for novel H1N1 Conclusions Clinical - PB1 gene segment derived from human H3N2 precursors, but has 2 stop codons in PB1-F2 ORF - Could acquire full length PB1-F2 by mutation or reassortment with seasonal H3N2 strains - However, sequence analysis of C-terminal region predicts that in either scenario, PB1-F2 would be non-functional - Reassortment with avian or swine viruses to gain a full length functional PB1-F2 could herald enhanced secondary bacterial disease The current pandemic shares common features with past pandemics, it: - has a high clinical attack rate due to lack of immunity - transmits easily enabling worldwide spread - causes severe disease in some risk groups (but fortunately is milder than was anticipated) Children have occupied a central role in the pandemic: - highest clinical attack rate - main vectors of transmission - most severe disease in patients without chronic medical conditions 6

7 Conclusions Research - The sparing of older of older adults is likely due to exposure to antigenically similar viruses in childhood - The novel H1N1 pandemic strain lacks one of the key virulence factors that have helped previous pandemic strains cause severe disease and death in association with bacterial pneumonia - Other viruses in the avian and swine reservoirs are a much greater threat to cause a severe pandemic Acknowledgements Contributors from Julie McAuley the McCullers lab: Keith Wanzeck Lee-Ann van de Velde Amy Iverson Irina Alymova Our Collaborators: Pat Flynn Richard Webby Kim Allison Kris Branum Kelli Boyd Jacco Boon Robert Webster Tom Reichert Gerardo Chowell Hiroshi Nishuri Paul Thomas Julia Hurwitz Support: NIH (AI-49178, AI-54802, AI-66349) ALSAC 7