Age-dependent Effectiveness of RSV Immunoprophylaxis
Almut G Winterstein
1Pharmaceutical
1,
2
PhD ,
Christian Hampp
4
PhD ,
Paul Kubilis MS1, Arwa Saidi
3
MBBCh
Outcomes and Policy, College of Pharmacy, 2Epidemiology, Colleges of Medicine and Public Health & Health Professions, 3Pediatrics, College of Medicine, University of Florida, Gainesville, FL
4Office of Surveillance and Epidemiology, CDER, FDA, Silver Spring, MD, United States
Introduction
Palivizumab efficacy shows variation between 45 to 78% reduction of hospitalizations
for respiratory syncytial virus (RSV) depending on the type of risk-group studied.
Based on RSV epidemiology and the risk groups that were targeted in clinical trials
current recommendations limit palivizumab utilization to specific age groups. While
evidence supports the effect of increasing age on decreasing infection risk, it is
unknown whether age modifies palivizumab effectiveness as well.
Results
Discussion
The analysis included 14,549 children and 21,825 child-seasons. Censoring occurred because of season end (n=9,001),
end of eligibility (n=8,889), 2nd birthday (n=3,341), non-RSV hospitalization (n=542), and death (n=52).
Age 2-12 months at index date
Palivizumab prophylaxis
Age 13-24 months at index date
RSV-related hospitalization
Palivizumab prophylaxis
RSV-related hospitalization
Female (%)
≥ 1 dose
(n= 2,553)
1,107 (43.4)
No dose
(n=10,121)
4,525 (44.7)
Yes
(n=458)
183 (40.0)
No
(n=12,216)
5,449 (44.6)
≥ 1 dose
(n= 1,173)
477 (40.7)
No dose
(n=7,978)
3,517 (44.1)
Yes
(n=159)
59 (37.1)
No
(n=8,992)
3,935 (43.8)
White (%)
546 (21.4)
2,172 (21.5)
109 (23.8)
2,609 (21.4)
219 (18.7)
1,689 (21.2)
30 (18.9)
1,878 (20.9)
Black (%)
517 (20.3)
2,008 (19.8)
73 (15.9)
2,452 (20.1)
235 (20.0)
1,624 (20.4)
29 (18.2)
1,830 (20.4)
Hispanic (%)
925 (36.2)
5,115 (50.5)
217 (47.4)
5,823 (47.7)
426 (36.3)
3,843 (48.2)
71 (44.7)
4,198 (46.7)
Other (%)
565 (22.1)
826 (8.2)
59 (12.9)
1,332 (10.9)
293 (25.0)
822 (10.3)
29 (18.2)
1,086 (12.1)
1,739 (68.1)
3,855 (38.1)
241 (52.6)
5,353 (43.8)
672 (57.3)
2,838 (35.6)
79 (49.7)
3,431 (38.2)
962 (37.7)
1,350 (13.3)
114 (24.9)
2,198 (18.0)
756 (64.5)
2,645 (33.2)
104 (65.4)
3,297 (36.7)
Chronic lung disease (%)
1,554 (60.9)
2,000 (19.8)
180 (39.3)
3,374 (27.6)
971 (82.8)
3,022 (37.9)
100 (62.9)
3,893 (43.3)
Study Design
Retrospective cohort study
Gestational age < 32 weeks (%)
1,698 (66.5)
1,447 (14.3)
142 (31.0)
3,003 (24.6)
795 (67.8)
1,965 (24.6)
65 (40.9)
2,695 (30.0)
308 (12.1)
893 (8.8)
53 (11.6)
1,148 (9.4)
109 (9.3)
697 (8.7)
23 (14.5)
783 (8.7)
1,452 (56.8)
8,424 (83.2)
325 (71.0)
9,551 (78.2)
443 (37.8)
5,368 (67.3)
79 (49.7)
5,732 (63.8)
Data source / study population
• Medicaid Extract Files (MAX), Vital Statistics Births and Death Certificates
• Children aged 0-2 eligible since birth for Medicaid fee-for-service in TX and FL
between 1999-2004
• At least 3 months eligibility between Aug-Mar of any study year
• Diagnosis for symptomatic (requiring drug treatment or oxygen) chronic lung
disease or hemodynamically significant congenital heart disease based on in- or
outpatient and pharmacy claims within 6 month before season
• Successfully matched to birth certificate via SSN and DoB
Cystic fibrosis (%)
14 (0.6)
16 (0.2)
ɸ
29 (0.2)
14 (1.2)
44 (0.6)
ɸ
57 (0.6)
SCID/AIDS (%)
31 (1.2)
106 (1.1)
ɸ
130 (1.1)
22 (1.9)
108 (1.4)
ɸ
126 (1.4)
Downs Syndrome (%)
76 (3.0)
329 (3.3)
33 (7.2)
372 (3.1)
30 (2.6)
241 (3.0)
18 (11.3)
253 (2.8)
Siblings up to 5 years older (%)
944 (37.0)
3,918 (38.7)
205 (44.8)
4,657 (38.1)
440 (37.5)
3,217 (40.3)
74 (46.5)
3,583 (39.9)
Multiple births (%)
416 (16.3)
516 (5.1)
34 (7.4)
898 (7.4)
190 (16.2)
590 (7.4)
20 (12.6)
760 (8.5)
Hospitalization at birth > 7 days (%)
Exposure
• Palivizumab use determined from pharmacy or physician charges
• Current use: claim date plus 30 days according to pharmakokinetics
• Former use: day 31 to 60 post claim; overridden by subsequent claim
• No use: period before first dose and after former use period(s)
Outcome
First RSV-related hospitalization (ICD9-CM 480.1, 466.11, 079.6)
Analysis
Cox regression, allowing interaction between younger (2-12 months at index date) and
older (13-24 months at index date) children and palivizumab use, while adjusting for
other RSV risk factors (see tables).
The authors have no conflict of interest.
The study was funded in part by the Florida Agency for Healthcare Administration. It was conducted in
collaboration with the University of Florida Center for Medicaid and the Uninsured.
The authors thank Public Health Statistics, Office of Vital Statistics, Florida Department of Health and the
Texas Department of State Health Services for the provision of birth and death certificates; and the
Centers for Medicare and Medicaid for provision of MAX data.
Congenital heart disease (%)
Age at index date (± std, days)
192.1 (±95.0) 172.0 (±104.6) 166.2 (±99.8) 176.4 (±103.1) 497.8 (±91.1) 544.0 (±106.9) 484.9 (±80.3) 539.0 (±106.3)
Age at index date < 6 months (%)
1,226 (48.0)
5,693 (56.3)
286 (62.5)
6,633 (54.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Respiratory problems past 1-30 days (%)
1,615 (63.3)
5,405 (53.4)
285 (62.2)
6,735 (55.1)
691 (58.9)
3,823 (47.9)
86 (54.1)
4,428 (49.2)
≥3 MD/ ED visits past 1-30 days (%)
2,272 (89.0)
6,202 (61.3)
353 (77.1)
8,121 (66.5)
999 (85.2)
3,452 (43.3)
110 (69.2)
4,341 (48.3)
Bronchodilators past 1-30 days (%)
1,691 (66.2)
4,049 (40.0)
271 (59.2)
5,469 (44.8)
974 (83.0)
3,845 (48.2)
117 (73.6)
4,702 (52.3)
ɸ Data cannot be displayed based on CMS requirement to omit cells with <11 observations.
A total of 617 RVS-related hospitalizations occurred during 2,496,942 days of follow-up (90.2 per 1,000 patient-years
during season). The six-months mortality of children hospitalized for RSV infections was 4 per 617 hospitalizations
(0.65%).
Hazard Ratios for all RSV Risk Factors, Palivizumab Use, and the Interaction between Use and Age
Age (per day)
Gender (male)
Race
White
Black
Hispanic
Others
Hospitalization at birth > 7 days
Bronchodilators past 1-30 days
Respiratory problems past 1-30 days
≥ 3 MD/ED visits past 1-30 days
Eligibility due to Disability
Chronic lung disease
Gestational age < 29 weeks
Gestational age 29-<32 weeks
Gestational age 32– 35 weeks
Congenital heart disease
Cystic fibrosis
SCID/AIDS
Downs Syndrome
Siblings ≤ 5 years of age
Multiple Birth
HR
95% CI
0.997
1.14
0.996-0.998
0.97-1.34
1
0.8
0.76
0.84
1.28
2.33
1.65
1.76
1.95
1.63
1.03
1.09
1.42
1.21
0.77
1.5
2.33
1.29
0.88
0.62-1.04
0.62-0.94
0.62-1.14
1.07-1.52
1.94-2.79
1.38-1.97
1.47-2.12
1.56-2.45
1.21-2.20
0.80-1.34
0.82-1.45
1.10-1.84
0.91-1.60
0.20-3.11
0.82-2.75
1.71-3.16
1.09-1.52
0.65-1.19
Palivizumab Use, ≤12 months of age
Current Use
Former Use
No Use
Palivizumab Use, >12 months of age
Current Use
Former Use
No Use
Palivizumab Use, >12 months vs. ≤ 12 months
Current Use
Former Use
No Use
HR
95% CI
0.51
0.76
1
0.38-0.68
0.42-1.37
0.88
0.97
1
0.58-1.33
0.36-2.65
1.73
1.28
1.09
1.06-2.83
0.41-4.06
0.77-1.54
Crude and Adjusted RSV-Risk per Age Stratum
Age at
index
date
Cohort Set-up
• Entry during any RSV season month (Oct-Mar) after 2 months in ambulatory care
• Children could re-enter for a second season
• Censoring at end of season, loss of eligibility, death, hospitalization for other reason
Gestational age 32– 35 weeks (%)
>12
months
Methods
Eligibility due to Disability (%)
2-12
months
Objectives: To estimate the effect of age on palivizumab effectiveness in
preventing RSV hospitalizations in high-risk children.
The single most important risk factor for RSV
infections was age. With every day of age, RSV risk
decreased by 0.34% (95% CI: 0.24-0.44), amounting
to 9.66% (6.94-12.30) per month of age.
Consequently, children at 6 months of age experience
a 34% reduction in RSV risk, 51% reduction at age 9
months, 64% at 12 months, 80% at 18 months and
89% at 24 months, each compared to 2 month old
infants (Figure).
Palivizumab Patient RSV
Use
years hospitalization
Crude rate
Adjusted
(per 1000
rate
patient-years)
118
118
No use
3,264
385
Current use
601
61
101.5
59.7
Former use
90
12
133.3
89.3
No use
2,546
126
49.5
49.5
Current use
298
29
97.3
43.4
Former use
42
4
95.2
48.1
Given the age-related decreasing risk and differences
in palivizumab effectiveness, numbers needed to
treat for the two age strata are as follows:
Age 2-12 months: NNT=34 per 6-months season
Age 13-24 months: NNT=327 per 6-months season
Limitations
RSV hospitalizations may be misclassified as nonspecific pneumonia or bronchiolitis.
Residual (unmeasured) confounding may exist.
Conclusions
Age appears to be a significant effect modifier of the
impact of palivizumab on RSV hospitalization risk.
Given the rapid decrease of RSV risk with increasing
age and the effect modification, careful examination of
age thresholds for immunoprophylaxis is warranted.