Palivizumab immunoprophylaxis effectiveness
in children with cystic fibrosis
Almut G. Winterstein,
1,2
PhD ,
Efe Eworuke, B.Pharm,
1
MSc ,
Dandan Xu,
1
MS,
Pamela Schuler,
3
MD
1Pharmaceutical
Outcomes and Policy, College of Pharmacy, 2Epidemiology, Colleges of Public Health and Health Professions and
Medicine, University of Florida, Gainesville, FL & 3Pediatrics, College of Medicine, University of Florida
INTRODUCTION
Although it seems intuitive that children with cystic fibrosis (CF) who are prone to frequent pulmonary inflammation and infection might benefit from palivizumab
immunoprophylaxis, the American Academy of Pediatrics (AAP) qualifies its recommendations with regard to CF due to lacking clinical trials evidence on palivizumab
efficacy in this population.1 Small CF prevalence imposes sample size challenges on efficacy or effectiveness studies.
Objectives: To alleviate the sample size problem, we assembled a population-based CF cohort from Medicaid fee-for-services (FFS) beneficiaries in 27 U.S. states from
1999 to 2006 to evaluate the effectiveness of palivizumab immunoprophylaxis in 0-2 year olds in clinical practice..
METHODS
Study Endpoints:
Data Sources:
Medicaid Analytical Extract (MAX) data from 27 US states retrieved for 1999-2006
including patients with at least 2 ICD-9-CM codes for CF. MAX data was linked to
the National CF patient registry to validate CF diagnosis. Death information
obtained from social security administration death file and National Death Index.
Definition of Respiratory Syncytial Virus (RSV) season:
Calculated monthly RSV hospitalization incidence calculated for each state, year
and month determined season onset and offset were . RSV risk categories were
classified as low (incidence of 0.1-0.33%), medium (0.33-0.67%) and high
(>0.67%).
Study Population:
Cohort entry: after the second CF-claim or first registry encounter date, whichever
came first, after state-specific season onset and after they had spent at least 30
days in ambulatory care, whichever came last.
Primary: Hospitalization for RSV pneumonia (ICD9-CM code 480.1), RSV
bronchiolitis (466.11), or RSV infections (079.6) if accompanied by a principal
diagnosis for upper respiratory tract infections (465.xx), acute bronchitis or
bronchiolitis (466.xx), infectious pneumonia (480.xx-483.xx, 485, 486), influenza
(487, 487.0, 487.1), other respiratory disease (519.8), or CF (277.0, 277.00,
277.02, 277.09)
Secondary: Primary or admission for upper respiratory tract infections (465.xx),
acute bronchitis or bronchiolitis (466.xx), infectious pneumonia (480.xx-483.xx,
485, 486), or CF pulmonary exacerbation (277.02)
Exposure definition:
Current use: 0-30 days after a palivizumab claim
Former use: 31-60 days after a palivizumab claim
No use: all days before the first and >60 days after a palivizumab claim.
Any subsequent palivizumab claim was set to override former or no use.
Covariate Adjustment:
Censoring criteria: end of the RSV season, at 2 years old, loss of Medicaid eligibility,
Exposure propensity scores included demographic characteristics, calendar year,
death, or hospitalized for any reason other than the study endpoints, whichever
state of residence at index date and indicators for disease severity.
came first. Patients could re-enter the study if they had not reached their second
Propensity scores as quintiles, age as time-dependent variable were included in the
birthday and met all study inclusion criteria.
final outcome models.
RESULTS
Final cohort: 1974 unique patients representing 2875 patient-seasons
Incidence for RSV (1°endpoint) = 3.9/1,000 season-months
Incidence for respiratory infections (2°endpoint) = 26.2/1,000
Palivizumab users were more often in-registry, had history of failure to thrive,
pancreatic insufficiency, severe and acute respiratory symptoms (table 1)
Table 1: Cohort characteristics among palivizumab
users and non-users
Characteristics n (%)
Race, White
Gender, female
Presence in registry
History (Hx) of failure to thrive
Hx of pancreatic insufficiency
Hx of inhaled tobramycin
Hx of inhaled corticosteroid use
Hx of oral corticosteroid use
Hx of inhaled bronchodilator use
Hx of Dnase or N-acetylcysteine use
Hx of leukotriene antagonist use
Hx of severe respiratory problems
Hx of acute respiratory problems
(≤10 days index date)
Figure 1: Exposure Propensity Score
Distribution among users/non-users
Patient-seasons of Patient-seasons of no
palivizumab use
palivizumab use
(n=575)
(n=2300)
384 (66.78)
273 (47.48)
392 (68.17)
102 (17.74)
73 (12.7)
97 (16.9)
171 (29.7)
80 (13.9)
338 (58.8)
158 (27.5)
23 (4.0)
184 (32)
87 (15.13)
1556(67.65)
1088(47.3)
1311(57)
170 (7.39)
130 (5.65)
187 (8.1)
407 (17.7)
227 (9.9)
884 (38.4)
334 (14.5)
59 (2.6)
554 (24.09)
172 (7.48)
• The cohort was trimmed because of non-overlapping propensity score
distributions at both tails (0.08 and 0.8)
• HR for 1 endpoint = 0.57 (95 CI 0.20 – 1.59)
Propensity scores for exposed patients
Propensity scores for unexposed patients
Density
•
•
•
•
Propensity score
DISCUSSION
• To our knowledge this is the first large population-based study evaluating the effectiveness of
palivizumab in CF.
• Overall we found low incidence rates for RSV hospitalization compared to other high-risk groups.
Previous reports2,3,4 suggest that clinical practice may not always test for RSV or follow up with a high
sensitivity test to confirm RSV.
• On the other hand, CF progression in early infancy may be limited, resulting in similar lung function as
healthy children.
• Restricting the analysis to only RSV-related outcomes (primary endpoint) suggest a trend towards
effectiveness but confidence intervals are wide.
• Employing a broader endpoint to circumvent possible misclassification of non-tested RSV
hospitalization resulted in little or no effect of palivizumab immunoprophylaxis (HR:0.85 95% CI:0.591.21, table 2).
• We observed a linear drop for acute respiratory infections hospitalizations with increasing age despite
the possibility of progressive CF disease in the first 2 years of life.
• Thus if palivizumab immunoprophylaxis is to be considered, it should focus on early infancy where the
risk of RSV is highest.
Limitations:
• Misclassification of RSV-related hospitalizations
• Residual confounding: unknown or unmeasured confounders may exist
• Possible misclassification of exposure: some palivizumab doses charged to Medicaid may not have
been administered; to address this, we required a physician visit to accompany each pharmacy claim.
Table 2: Effect of palivizumab on respiratory
hospitalization (2°endpoint)
Hazard
Ratio
Parameter
Age (month)
Low season category
High Season category
Medium Season category
No use
Current Exposure
Former Exposure
Propensity score quintile 1
Propensity score quintile 2
Propensity score quintile 3
Propensity score quintile 4
Propensity score quintile 5
0.942
reference
2.289
1.378
reference
0.789
0.932
reference
1.442
1.540
1.277
2.846
95% Hazard Ratio
Confidence Limits
0.916
0.969
0.926
0.933
5.658
2.036
0.504
0.398
1.234
2.186
0.810
0.871
0.702
1.638
2.565
2.723
2.325
4.946
REFERENCES
1. Committee on Infectious D. From the American Academy of
Pediatrics: Policy statements--Modified recommendations for use
of palivizumab for prevention of respiratory syncytial virus
infections. Pediatrics. 2009;124(6):1694-1701.
2. Hiatt PW, Grace SC, Kozinetz CA, Raboudi SH, Treece DG, Taber
LH, et al. Effects of viral lower respiratory tract infection on lung
function in infants with cystic fibrosis. Pediatrics. 1999;103(3):619626.
3. Armstrong D, Grimwood K, Carlin JB, Carzino R, Hull J, Olinsky A,
et al. Severe viral respiratory infections in infants with cystic
fibrosis. Pediatric Pulmonology. 1998;26(6):371-379.
4. Abman SH, Ogle JW, Butler-Simon N, Rumack CM, Accurso FJ.
Role of respiratory syncytial virus in early hospitalizations for
respiratory distress of young infants with cystic fibrosis. The
Journal of pediatrics. 1988;113(5):826-830.
Acknowledgement: This study was funded by a
grant from the Florida Agency of Healthcare
Administration, AHCA. It was conducted in
collaboration with the University of Florida Center for
Medicaid and the Uninsured. We are grateful to the
National Cystic Fibrosis Foundation for the provision
of the Patient Registry data.