1. Seasonal and Pandemic Influenza: Children, Immunocompromised Hosts, Pregnant Women and Nursing Home Residents Richard Whitley, MD Professor of Pediatrics, Microbiology, Medicine and Neurosurgery UAB Center for Biodefense and Emerging Infections University of Alabama at Birmingham Birmingham, AL

3. NVSN Influenza Laboratory-Confirmed Cumulative Hospitalization Rayes for Children 0-4 Years, 2004-05 and Previous 4 Seasons Polulation-Based Rate per 10,000 Children 2004-05 Influenza Season 2 Week Reporting Period 14 12 10 8 6 4 2 0 40-4142-4344-4546-4748-49 2000-20012001-2002 2002-2003 2003-20042004-2005 50-5152-12-34-56-78-910-1112-1314-1516-17

4. Hospitalization Rates for Patients by Age and Risk Groups (Interpandemic Years) Hospitalization rates per 100,000 Age, yHigh riskLow risk <4<43,562509 5–1427439 15–64873125 65–744,235605 >758,7971,257 www.cdc.gov.

5. Influenza In Children… Flu symptoms in school-age children and adolescents are similar to those in adults. –Temperature of 101°F or above –Cough –Muscle ache –Headache –Sore throat –Chills –Tiredness –Feeling lousy all over Children tend to have higher temperatures than adults, ranging from 103°F to 105°F. Flu in preschool children and infants is hard to pinpoint, since its symptoms are so similar to infections caused by other viruses. If the symptoms mentioned above are present and the flu is in your area, please contact your doctor immediately.

6. CNS Effects of Influenza Encephalitis Myelitis Guillain Barré Syndrome Post Infectious Encephalitis

7. Influenza Associated Pneumonia Primary Viral Pneumonia Bacterial Pneumonia (“superinfection”) –S. pneumonia –H. influenzae –S. aureus Mixed Viral/Bacterial Pneumonia

8. Timing of 153 Cases of Fatal Influenza in Children - United States, 2003-2004 Season Bhat, N. et al. N Engl J Med. 2005;353:2559-2567. No. of Cases 2004-05 Influenza Season 2 Week Reporting Period 9 8 6 5 2 0 Date of Onset of Illness 1 3 4 7 Oct-4 Nov 1 Nov 29Dec 27Jun 24 Mar 20Apr 17

9. Distribution of Cases and Mortality Rates According to Geographic Location and Age Group among 153 Children with Fatal Influenza - United States, 2003-2004 Season VariableNo. of Children (%) Deaths per 100,000 Children (95% CI)* Overall 153 (100)0.21 (0.18-0.24) Geographic census region Northeast13 (8)0.10 (0.05-0.17) Midwest36 (24)0.22 (0.15-0.31) South67 (44)0.25 (0.20-0.32) West37 (24)0.21 (0.15-0.29) Age group† <6 mo18 (12)0.88 (0.52-1.39) 6-11 mo12 (8)0.59 (0.30-1.02) 1 yr31 (20)0.77 (0.52-1.09) 2 yr14 (9)0.35 (0.19-0.58) 3 yr9 (6)0.23 (0.11-0.44) 4 yr12 (8)0.31 (0.16-0.54) 5-10 yr26 (17)0.11 (0.07-0.16) 11-17 yr31 (20)0.11 (0.07-0.15) *CI denotes confidence interval. †Ages are those on the date of the onset of the illness or, if that information was unavailable, at the date of death. P for trend <0.001 by a chi-square test of age-specific mortality rates. Bhat, N. et al. N Engl J Med. 2005;353:2559-2567.

10. Influenza-Associated Mortality Rates According to Age Group - United States, 2003-2004 Season Influenza-Associated Mortality (deaths per 100,000 children) Age Group 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00 <6 mo6-11 mo1 yr2 yr3 yr4 yr5-10 yr11-17 yr Bhat, N. et al. N Engl J Med. 2005;353:2559-2567.

11. Underlying Health Status of 149 of 153 Children with Fatal Influenza - United States, 2003-2004 Season Underlying Health Status No. of Children Age <6 Mo (N=17) Age ≥6 Mo (N=132) Chronic conditions All chronic conditions10 (59)54 (41) Chronic condition without a concurrent ACIP- defined high-risk condition 5 (29)25 (19) Neurologic or neuromuscular disorder§4 (24)45 (34) Gastrointestinal disorder¶3 (18)15 (11) Upper-airway abnormality║1 (6)8 (6) Bhat, N. et al. N Engl J Med. 2005;353:2559-2567.

12. Goals for Pediatric Patients Educational Programs in the School System Prevention by vaccination Early Diagnosis and Treatment

14. % Seroconversion (>=4-fold rise) * Vaccine strain P<0.001 Seroconversion to H3N2 Strains after One Dose of LAIV or TIV in Seronegative Children --------HAI assay---------Neutralization assay-- * P=0.094 68 11 20 4 78 13 65 4 * Mendelman et al. PIDJ 2004;23:1053

15. CAIV-T and TIV in Children 6-59 Months CP-111: pivotal phase 3, direct comparison study during 2004-5 season –8,492 children, 249 sites, 16 countries Culture-confirmed influenza (TIV vs CAIV-T): –Matched strains: 1.4% vs 2.4% (44% reduction) –Mis-matched strains: 6.2% vs 2.6% (58% reduction) –All strains: 8.6% vs 3.9% (55% reduction) AE and SAE rates comparable –Post-immunization (to day 42) wheezing in primary vaccinees < 2 yr old: 2.0% vs 3.2%

16. N Median Time (h) Placebo235137 h (5.7 d) Oseltamivir217101.3 h (4.2 d) (2 mg/kg b.i.d.) % Reduction26% Time to resolution of all illness Influenza Treatment in Children: Primary Endpoint *P<0.001 compared to placebo recipients, using weighed Mantel-Henszel test, stratified for region and otitis media.

17. Influenza Treatment in Children: Secondary Endpoint N Median Time (h) Placebo235111.7 h (4.7 d) Oseltamivir21767.1 h (2.8 d)* (2 mg/kg b.i.d.) % Reduction40% Time to return to normal health and activity *P<0.001 compared to placebo recipients, using weighed Mantel-Henszel test, stratified for region and otitis media.

18. Influenza Treatment in Children: Tertiary Endpoint N Day 1 to Day 10 Post Initiation Placebo20041 (21%)53 (27%) Oseltamivir (2 mg/kg b.i.d.)18322 (12%)29 (16%) Risk reduction 41% 40% CI(0.36, 0.95)(0.40, 0.90) Number of subjects with Otitis Media (without OM at baseline)

19. Oseltamivir Exposure in Children (2 mg/kg) Oo et al. Paediatr Drugs. 2001;3:229. Y = 0.45x + 9.49 R 2 = 0.59 P < 0.001 9 8 7 6 5 4 3 Active metabolite Renal Clearance (ml/min/kg) 2 1 0 Age (y) 024681012141618 (approximate adult value)

20. Detection Of Antiviral Resistant Influenza During Treatment Frequency of resistance OseltamivirM2 inhibitor Out-patient adults Out-patient children 0.4% 5.5% ~30% Inpatient children 18% 80% Immunocompromised ?>33% Roberts N. Phil. Trans R Soc Lond. 2001;356:1895. Kiso et al. Lancet. 2004;364:759.

22. Adjusted Incidence Rates of Acute Cardiopulmonary Events per 10,000 Women-Months of Observation by Medical Risk and Pregnancy Status, Among Women High Risk Women Neuzil et al. Amer J Epidemiol. 1998;148:1098.

23. Adjusted Incidence Rates of Acute Cardiopulmonary Events per 10,000 Women-Months of Observation by Medical Risk and Pregnancy Status, Low Risk Women Neuzil et al. Amer J Epidemiol. 1998;148:1098.

24. Excess Acute Cardiopulmonary Events per 10,000 Person-Months During Influenza Season by Year and Risk Group for High-Risk and Low-Risk Women Neuzil et al. JAMA. 1999:281:905. H3N2 H1N1 B B B B B B

26. Influenza in Transplant Recipients: Clinical Immunocompromised patients suffer more complications and have higher morbidity and mortality from influenza infection –High rate of hospitalization and ICU admissions –Higher rate of pulmonary complications 50% of BMT and 13% renal transplant patients had lower respiratory tract infections 50% of BMT and 7% of renal transplant patients with influenza complicated by pneumonia 63% progressed to pneumonia –43% mortality

27. Influenza in Transplant Recipients: Clinical Higher rate of extrapulmonary complications –42% incidence of neurologic symptoms Rejection or graft dysfunction –Hepatic decompensation –High rate of rejection Increased mortality –13-40% mortality secondary to influenza in the BMT populations –23% mortality in a pediatric transplant population

28. Influenza in Transplant Recipients: Outcomes No. CasesFever LRT/ PneumoniaDeath Bone marrow Adult Pediatric 48 5 94% 80% 52% 20% 21% 20% Solid organ Adult Pediatric Influenza A Influenza B 12 30 22 20 100% 97% 95% 100% 33% 30% 27% 35% 8% 17% 9% 20%

29. Influenza in Transplant Recipients: Virology Prolonged Viral Shedding Kaplan-Meier survival estimates, by donor2 Analysis Time 010203040 0.00 0.25 0.50 0.75 1.00 donor2 1 donor2 2

30. Treatment of Influenza in Immunocompromised Population (Study) DrugNo. episodes Outcomes BMT, leukemia (Englund, 1998) M2 inhibitor15Resistant virus in 33% Influenza deaths in 2 (13%) HSCT, leukemia (LaRosa, 2001) M2 inhibitor55 (total) Progression to pneumonia in 35% vs 76% without Rx (P <0.01) HSCT (Nichols, 2004) Rimantadine Oseltamivir 8989 Progression to pneumonia 13% vs 18% without Rx (n=34) 0/9 progressed to pneumonia BMT (Machado, 2004) Oseltamivir38 (15 A, 23 B) Progression to pneumonia 5% No mortality

32. The Association of Resident Influenza Vaccination Status in Nursing Home Size with the Occurrence of Influenza Outbreaks *P =.023. Arden et al. Amer J Pub Health. 1995;85:399-401. Resident Outbreak Status YesNo No.% % Resident vaccination status <80%1254.51045.5 >80%521.71878.3 Total*1737.82862.2 Size, no. of beds <100725.02175.0 >1001058.8741.2 Total*1737.82862.2

33. Conditional Logistic Regression Analyses of Influenza Vaccine Effectiveness in Preventing Influenza-like Illness and Pneumonia Ohmit et al. JAGS. 1999;47:165-171. Odds Ratio 95% Confidence Interval Vaccine Effectiveness (1-OR) X 100 p-value Age 65-84 years.54(.36-.81)46%.003 Age > 84 years.66(.43-1.02)34%.063

34. Research Needs Natural History of Influenza in High Risk Populations: –Immunocompromised host and –Pregnant women Clinical Trials of Antiviral Agents in At-Risk Patients –Monotherapy –Combination Therapy –Will resistance occur more frequently?

35. Pediatric Initiatives Current vaccine recommendations are for administration at 6 and 23 months. What about older children –Extend recommendations –Use of cold adapted influenza vaccine Oseltamivir can not be administered to infants < 1 year of age –Neurotoxicology assessments in animal models –PK and PD studies in infants