1. William W. Thompson, PhD Immunization Safety Office Office of the Chief Science Officer Centers for Disease Control and Prevention Impact of Seasonal Influenza in the US

2. Collaborators David Shay, CDC Influenza Branch Eric Weintraub, CDC, OCSO/ISO Lynnette Brammer, CDC Influenza Branch Nancy Cox, CDC Influenza Branch Joe Bresee, CDC Influenza Branch Keiji Fukuda, WHO

3. Impact of Seasonal Influenza in the US Describe variation in deaths in US –Seasonal Variation –Age Variation Describe alternative models for estimating influenza-associated morbidity and mortality Compare alternative model estimates Review estimates of influenza impact –Deaths –Hospitalizations –Other morbidity

4. Seasonal Variation in Deaths Currently, there are approximately 2.4 million deaths in the United States annually –65,000 Underlying Pneumonia and Influenza deaths No direct measure of impact of influenza Strong seasonal component in US deaths –Peaks typically occur in December and January –Peaks tend to be associated with increases in influenza activity

5. Seasonal Variation in All-Cause Deaths (1972-2001) 0 10000 20000 30000 40000 50000 60000 70000 Jun-71Jun-72 Jun-73 Jun-74 Jun-75Jun-76Jun-77Jun-78Jun-79Jun-80Jun-81Jun-82Jun-83Jun-84Jun-85Jun-86Jun-87 Jun-88Jun-89Jun-90Jun-91Jun-92 Jun-93 Jun-94 Jun-95Jun-96Jun-97Jun-98Jun-99Jun-00Jun-01Jun-02 Year Weekly All-Cause Deaths

6. Seasonal Variation in Underlying P&I Deaths (1972-2001) 0 1000 2000 3000 4000 5000 Jun-71Jun-72Jun-73Jun-74Jun-75Jun-76Jun-77Jun-78Jun-79Jun-80Jun-81Jun-82Jun-83Jun-84Jun-85Jun-86Jun-87Jun-88Jun-89Jun-90Jun-91Jun-92Jun-93Jun-94Jun-95Jun-96Jun-97Jun-98Jun-99Jun-00Jun-01Jun-02 Year Weekly P&I Deaths

7. Population Growth in Urban Areas of the US 1970-2000 0 25 50 75 100 125 150 175 200 225 250 1970198019902000 Year Millions

8. Population Growth in Numbers of Elderly in the US 1970-2000 Millions 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0 65-7475-8485+ Age Group 19702000

9. Age Variation in Numbers of Deaths in the US 1970-2003 - 100,000 200,000 300,000 400,000 500,000 600,000 700,000 800,000 0-4 Yrs 5-14 Yrs 15-24 Yrs25-34 Yrs35-44 Yrs45-54 Yrs55-64 Yrs65-74 Yrs75-84 Yrs 85+ Yrs Age Group Deaths 19702003

10. RR of All-Cause Death Versus Underlying P&I Death (NCHS 2000) 19702003 59 83 147 93 58 62 57 43 24 13 0 20 40 60 80 100 120 140 160 0-4 years 5-14 years 15-24 years25-34 years35-44 years45-54 years55-64 years65-74 years75-84 years 85+ years Age Group RR of Death due to All-Cause versus P&I

11. Alternative Models for Estimating Impact of Influenza in US Simonsen et al. (1997) –Linear Regression Model –Modeled National Center for Health Statistics (NCHS) weekly death data from 1972-1992 Outcomes –Underlying P&I Deaths (Most specific) –All-Cause Deaths (Least specific, most sensitive) Model Y t = a + b*t +c*t 2 + d*cos (2 t  /52) + f*sin(2 t  /52) + e t

12. Simonsen et al. 1997 Model 0 500 1000 1500 2000 2500 3000 3500 4000 Jul-89Jul-90Jul-91Jul-92Jul-93Jul-94Jul-95 P&I Deaths

13. Alternative Models for Estimating Impact of Influenza in US Thompson et al. (2003) –Poisson Regression Model –Modeled National Center for Health Statistics (NCHS) weekly death data from 1976-2000 –Incorporated WHO Influenza Surveillance Data Outcomes –Underlying P&I Deaths (Most specific) –Underlying Respiratory & Circulatory Deaths –All-Cause Deaths (Least specific) Model Y t =  exp (a + b*t +c*t 2 + d*cos (2 t  /52) + f*sin(2 t  /52) + g * A(H1N1)% + h * A(H3N2)% + i * B%)

14. Circulation of A(H3N2) Viruses and Underlying P&I Deaths Year P&I Deaths Per 100,000 A(H3N2)% Positive P&I Death RateA(H3N2)% 0 10 20 30 40 50 60 70 80 90 100 110 199019911992199319941995199619971998 0% 10% 20% 30% 40% 50% 60%

15. Alternative Models for Estimating Impact of Influenza in US Barker & Mullooly (1980;1982) Two Types of Baseline Rates –Peri-Season Baseline Rate October through May when influenza is not circulating above 10% –Summer Season Baseline June through September Excess Rate = (Flu Rate) – (Non Flu Baseline Rate)

16. Seasonal Variation in Underlying P&I Deaths Summer Baseline Summer Baseline Winter Baseline Influenza Period Influenza Period 0 1000 2000 3000 4000 Jul-89 Sep-89Nov-89 Jan-90 Mar-90 May-90 Jul-90 Sep-90Nov-90 Jan-91 Mar-91 May-91 Jul-91 Sep-91Nov-91 Jan-92 Mar-92 May-92 Jul-92

17. Influenza-Associated All-Cause Deaths by Model in the US (1976-2000) Alternative Models Annual Influenza-Associated Deaths in US 31,467 29,473 43,958 73,635 35,463 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 Simonsen 97Simonsen 05PeriSummerPoisson

18. Correlations Between Estimates of Influenza- Associated All-Cause Deaths In the US (1976-2000) Simonsen 97Simonsen 05PeriSummerPoisson Simonsen 971.00 Simonsen 050.931.00 Peri0.850.931.00 Summer0.790.870.961.00 Poisson0.780.870.90 1.00

19. Correlation Between Estimates for Simonsen 2005 and Peri-Season Models y = 1.3305x + 4744.5 R 2 = 0.8729 0 20000 40000 60000 80000 100000 120000 010000200003000040000500006000070000 Simonsen 2005 Estimates Peri Season Estimates

20. Influenza-Associated Underlying R&C Death Rates by Age For Peri-Season Model 2.4 0.4 8.7 26.0 46.8 85.5 165.9 445.3 0 100 200 300 400 500 <1 1 - 4 5 - 49 50 - 6465 - 6970 - 7475 - 7980 - 84 >= 85 Age Group Deaths Per 100,000

21. Influenza-Associated Underlying R&C Deaths by Age For Peri-Season Model Age Group Influenza-Associated Deaths 92 52 719 2,945 2,457 3,651 5,017 6,220 13,267 - 2,500 5,000 7,500 10,000 12,500 15,000 <1 1 - 4 5 - 49 50 - 6465 - 6970 - 7475 - 7980 - 84 >= 85

22. Surveillance of Influenza-Associated Deaths Among Children in the US 2003/2004 influenza season was severe compared to other recent seasons, especially among children CDC implemented surveillance of childhood deaths associated with influenza Reviewed case reports, medical records, autopsy reports

23. Surveillance of Influenza-Associated Deaths Among Children in the US Results –153 deaths among children aged < 18 years –96 deaths among children aged < 5 years –29% of the children died within 3 days of onset of the illness –47% of the children had previously been healthy CDC made influenza deaths among children a national reportable condition in October 2004

24. Influenza-Associated Hospitalizations Thompson et al (2004) National Hospital Discharge Survey Examined data from 1979-2001 Incorporated WHO Influenza Surveillance data Outcomes –Primary P&I (Most Specific) –Any Listed P&I –Primary R&C –Any-Listed R&C (Least Specific) Model Y t =  exp (a + b*t +c*t 2 + d*cos (2 t  /12) + f*sin(2 t  /12) + g * A(H1N1)% + h * A(H3N2)% + i * B%)

25. Influenza-Associated Primary R&C Hospitalization Rates By Age (1979-2001) 0 200 400 600 800 1000 1200 1400 < 5 Yrs 5-49 Yrs 50-64 Yrs65-69 Yrs70-74 Yrs75-79 Yrs80-84 Yrs 85+ Yrs Age Group Influenza-Associated Primary R&C Hospitalizations Per 100,000

26. Influenza-Associated Primary R&C Hospitalizations By Age (1979-2001) Age Group Influenza-Associated Primary R&C Hospitalizations 20,031 34,867 29,447 18,301 26,501 27,516 28,578 40,813 - 10,000 20,000 30,000 40,000 50,000 < 5 Yrs 5-49 Yrs 50-64 Yrs65-69 Yrs70-74 Yrs75-79 Yrs80-84 Yrs 85+ Yrs

27. Influenza-Associated Hospitalizations Among Children Aged < 5 Years By Study 1.2 0.9 1.4 1.1 0.6 2.6 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Barker (1982) Neuzil (2000) Izurieta (2000) Neuzil (2002) Thompson (2004) Iwane (2004) Study Hospitalizations Per 1,000 Person Years

28. Excess P&I Hospitalization Rates By Risk Status Barker & Mullooly (1980, 1982) 0 100 200 300 400 500 600 700 800 0 - 45-1415-4445-6465+ Age (Years) Excess P&I Hospitalizations Per 100,000 Persons Low RiskHigh Risk

29. Other Influenza-Associated Morbidity Nichol et al (1999) LAIV Trial Aged 18-64 –Severe febrile illness –Work days missed –Doctors visits –Antibiotic use Bridges at al (2000) TIV Trial Aged 18-64 –Febrile illness –Worked days missed –Doctors visits

30. Summary and Recommendations Influenza infections are associated with substantial morbidity and mortality every year –Improve vaccine coverage for at-risk populations currently recommended for annual influenza vaccination by ACIP The very elderly are at substantially increased risk for influenza-associated morbidity and mortality –Encourage development of vaccines with improved immunogenicity for older adults The aging of the US population is leading to substantially more seasonal influenza-associated morbidity and mortality every year –Prepare public health officials for the increasing burden of disease associated with seasonal influenza over the next decade