Mobile pediatric neurosurgery: rapid response neurosurgery ...
Richard Whitley, MD Professor of Pediatrics, Microbiology, Medicine and Neurosurgery
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Transcript of Richard Whitley, MD Professor of Pediatrics, Microbiology, Medicine and Neurosurgery
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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
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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
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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.
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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.
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CNS Effects of Influenza
• Encephalitis
• Myelitis
• Guillain Barré Syndrome
• Post Infectious Encephalitis
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Influenza Associated Pneumonia
• Primary Viral Pneumonia
• Bacterial Pneumonia (“superinfection”)
– S. pneumonia
– H. influenzae
– S. aureus
• Mixed Viral/Bacterial Pneumonia
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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
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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.
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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.
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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.
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Goals for Pediatric Patients
• Educational Programs in the School System
• Prevention by vaccination
• Early Diagnosis and Treatment
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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
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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%
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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.
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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.
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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)
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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)
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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.
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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.
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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.
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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
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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
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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
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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%
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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
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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
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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
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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
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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?
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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