Seasonal and PandemicInfluenza: Children,

Immunocompromised Hosts, Pregnant Women and Nursing Home Residents

Richard Whitley, MDProfessor of Pediatrics, Microbiology, Medicine

and NeurosurgeryUAB Center for Biodefense and Emerging Infections

University of Alabama at BirminghamBirmingham, AL

NVSN Influenza Laboratory-Confirmed Cumulative Hospitalization Rayes for Children 0-4 Years, 2004-05

and Previous 4 SeasonsP

olul

atio

n-B

ased

Rat

e pe

r 10

,000

Chi

ldre

n

2004-05 Influenza Season 2 Week Reporting Period

14

12

10

8

6

4

2

040-4142-43 44-4546-4748-49

2000-2001 2001-2002 2002-2003 2003-2004 2004-2005

50-5152-1 2-3 4-5 6-7 8-9 10-11 12-1314-15 16-17

Hospitalization Rates for Patients by Age and Risk Groups (Interpandemic Years)

Hospitalization rates per 100,000

Age, y High risk Low risk

<4 3,562 509

5–14 274 39

15–64 873 125

65–74 4,235 605

>75 8,797 1,257

www.cdc.gov.

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.

CNS Effects of Influenza

• Encephalitis

• Myelitis

• Guillain Barré Syndrome

• Post Infectious Encephalitis

Influenza Associated Pneumonia

• Primary Viral Pneumonia

• Bacterial Pneumonia (“superinfection”)

– S. pneumonia

– H. influenzae

– S. aureus

• Mixed Viral/Bacterial Pneumonia

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

Cas

es

2004-05 Influenza Season 2 Week Reporting Period9

8

6

5

2

0

Date of Onset of Illness

1

3

4

7

Oct-4

Nov 1

Nov 2

9

Dec 2

7

Jun

24

Jun

24

Mar

20

Apr 1

7

Distribution of Cases and Mortality Rates According to Geographic Location and Age Group among 153 Children

with Fatal Influenza - United States, 2003-2004 Season

Variable No. of Children (%) Deaths per 100,000Children (95% CI)*

Overall 153 (100) 0.21 (0.18-0.24)

Geographic census regionNortheast 13 (8) 0.10 (0.05-0.17)Midwest 36 (24) 0.22 (0.15-0.31)South 67 (44) 0.25 (0.20-0.32)West 37 (24) 0.21 (0.15-0.29)

Age group†<6 mo 18 (12) 0.88 (0.52-1.39)6-11 mo 12 (8) 0.59 (0.30-1.02)1 yr 31 (20) 0.77 (0.52-1.09)2 yr 14 (9) 0.35 (0.19-0.58)3 yr 9 (6) 0.23 (0.11-0.44)4 yr 12 (8) 0.31 (0.16-0.54)5-10 yr 26 (17) 0.11 (0.07-0.16)11-17 yr 31 (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.

Influenza-Associated Mortality Rates According to Age Group - United States,

2003-2004 Season

Influ

enza

-Ass

ocia

ted

Mor

talit

y(d

eath

s pe

r 10

0,00

0 ch

ildre

n)

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 mo 6-11 mo 1 yr 2 yr 3 yr 4 yr 5-10 yr 11-17 yr

Bhat, N. et al. N Engl J Med. 2005;353:2559-2567.

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 conditionsAll chronic conditions 10 (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.

Goals for Pediatric Patients

• Educational Programs in the School System

• Prevention by vaccination

• Early Diagnosis and Treatment

0

10

20

30

40

50

60

70

80

90

Panama Fujian-like Panama Fujian-like

LAIV TIV

% S

ero

c on

v er s

i on

(>

=4 -

fold

ris

e)

* Vaccine strain

P<0.001 P<0.001

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

1120

4

78

13

65

4

*

Mendelman et al. PIDJ 2004;23:1053

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%

N Median Time (h)

Placebo 235 137 h (5.7 d)

Oseltamivir 217 101.3 h (4.2 d)

(2 mg/kg b.i.d.)

% Reduction 26%

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.

Influenza Treatment in Children: Secondary Endpoint

N Median Time (h)

Placebo 235 111.7 h (4.7 d)

Oseltamivir 217 67.1 h (2.8 d)*

(2 mg/kg b.i.d.)

% Reduction 40%

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.

Influenza Treatment in Children: Tertiary Endpoint

N Day 1 toDay 10

Post Initiation

Placebo 200 41 (21%) 53 (27%)

Oseltamivir (2 mg/kg b.i.d.) 183 22 (12%) 29 (16%)

Risk reduction41%

40%

CI (0.36, 0.95) (0.40, 0.90)

Number of subjects with Otitis Media(without OM at baseline)

Oseltamivir Exposure in Children (2 mg/kg)

Oo et al. Paediatr Drugs. 2001;3:229.

Y = 0.45x + 9.49R2 = 0.59P < 0.001

9

8

7

6

5

4

3

Act

ive

met

abol

ite R

enal

Cle

aran

ce (

ml/m

in/k

g)

2

1

0

Age (y)

0 2 4 6 8 10 12 14 16 18

(approximate adult value)

Detection Of Antiviral Resistant Influenza During Treatment

Frequency of resistance

Oseltamivir M2 inhibitor

Out-patient adults

Out-patient children

0.4%

5.5%

~30%

~30%

Inpatient children 18% 80%

Immunocompromised ? >33%

Roberts N. Phil. Trans R Soc Lond. 2001;356:1895.Kiso et al. Lancet. 2004;364:759.

Adjusted Incidence Rates of Acute CardiopulmonaryEvents 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.

Adjusted Incidence Rates of Acute CardiopulmonaryEvents 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.

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

H3N2

H3N2

H3N2

H3N2

H3N2

H3N2

H3N2

H1N1

H1N1 H1N1

B

B

B

BB

B

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

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 influenzain the BMT populations

– 23% mortality in a pediatric transplant population

Influenza in Transplant Recipients: Outcomes

No. Cases Fever

LRT/Pneumonia Death

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%

Influenza in Transplant Recipients: Virology

Prolonged Viral Shedding

Kaplan-Meier survival estimates, by donor2

Analysis Time

0 10 20 30 40

0.00

0.25

0.50

0.75

1.00

donor2 1

donor2 2

Treatment of Influenza in Immunocompromised

Population (Study)

Drug No. episodes

Outcomes

BMT, leukemia

(Englund, 1998)

M2 inhibitor 15 Resistant virus in 33%

Influenza deaths in 2 (13%)

HSCT, leukemia

(LaRosa, 2001)

M2 inhibitor 55

(total)

Progression to pneumonia in 35%

vs 76% without Rx (P <0.01)

HSCT

(Nichols, 2004)

Rimantadine

Oseltamivir

8

9

Progression to pneumonia 13% vs 18% without Rx (n=34)

0/9 progressed to pneumonia

BMT

(Machado, 2004)

Oseltamivir 38

(15 A, 23 B)

Progression to pneumonia 5%

No mortality

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 StatusYes No

No. % No. %

Resident vaccination status<80% 12 54.5 10 45.5>80% 5 21.7 18 78.3

Total* 17 37.8 28 62.2

Size, no. of beds<100 7 25.0 21 75.0>100 10 58.8 7 41.2

Total* 17 37.8 28 62.2

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

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?

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