BACKGROUND:

The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain.

METHODS:

We used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary–related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores.

RESULTS:

The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9–99.5) and did not (97.3; 95% confidence interval: 96.1–98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab.

CONCLUSIONS:

At the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.

What’s Known on This Subject:

The American Academy of Pediatrics recommends palivizumab for infants with cystic fibrosis and chronic lung disease and/or nutritional compromise. Palivizumab’sbeneficial impact on outcomes in children with cystic fibrosis was not confirmed by well-designed randomized controlled trials in this population.

What This Study Adds:

Sicker infants were more likely to receive palivizumab. After adjusting for potential confounding by indication, lung function, time to first positive Pseudomonas culture, and exacerbation-related hospitalizations, outcomes were similar among children who did and did not receive palivizumab as infants.

Palivizumab is recommended to reduce hospitalizations in children at high risk for severe respiratory syncytial virus (RSV) infection, including premature infants and those with complex cardiac and lung disease.1 Current American Academy of Pediatrics (AAP) guidelines do not recommend routine palivizumab use for infants with cystic fibrosis (CF) but do recommend consideration in infants with chronic lung disease or nutritional compromise.1 

This recommendation reflects concerns regarding potential adverse RSV impacts in infants with CF. Previous studies reveal that RSV infections resulted in pulmonary exacerbations requiring hospitalization, persistent hypoxemia requiring home oxygen, increased airway inflammation, increased risk of earlier bacterial pathogen acquisition (including Pseudomonas aeruginosa), and increased chronic respiratory signs and worse chest radiographic scores.2,4 These studies occurred in the 1980s and 1990s, when care practices and CF-related outcomes differed from the current era.

A beneficial impact of palivizumab on outcomes in infants with CF has not been confirmed by well-designed randomized controlled trials.5 Prescott and Hutchinson6 reviewed 1 small randomized trial of palivizumab in infants with CF in which researchers found similar hospitalization rates among those in active versus placebo arms. This trial was only published in abstract form.7 Kua and Lee8 recently conducted a systematic review of observational studies comparing outcomes, including RSV-related hospitalizations and hospital days among infants with CF who did or did not receive palivizumab. Whereas some studies reported reduction in RSV-related hospitalizations9,11 or hospital days,12 others did not demonstrate benefits associated with palivizumab.13,15 These studies had moderate to serious risk of bias and unmeasured or incompletely controlled confounding.

Thus, knowledge gaps remain regarding potential palivizumab benefits for infants with CF. Previous literature has been focused on short-term outcomes, but indications for palivizumab use could be expanded if there is a beneficial impact on longer-term outcomes. There are no randomized clinical trial data used to investigate long-term outcomes, and it is unlikely that a trial will ever be done. Therefore, the AAP Committee on Infectious Diseases asked the Cystic Fibrosis Foundation (CFF) if the Cystic Fibrosis Foundation Patient Registry (CFFPR) longitudinal data could be interrogated to assess potential longer-term benefits of palivizumab in infants and children with CF.16 We hypothesized that children with CF who received palivizumab in infancy would have improved outcomes, including better lung function, less P aeruginosa acquisition, and fewer hospitalizations related to pulmonary exacerbations compared with those who had not received palivizumab. Our objectives in this study were to compare the following longitudinal outcomes in children who did and did not receive palivizumab in infancy: (1) percent forced expiratory volume in 1 second (FEV1) predicted at 7 years of age, (2) time to first P aeruginosa acquisition, and (3) age-specific number of pulmonary-related hospitalizations during the first 8 years of life.

This retrospective study was conducted by using longitudinal CFFPR data from 2008 to 2016. The study start date (January 1, 2008) was the first year that the CFFPR included data on palivizumab receipt. The CFFPR includes individuals with CF who receive care at a CFF Care Center network–accredited program. The CFFPR population, data collection methods, validity, and generalizability were previously described by Knapp et al.16 

Infants eligible for this analysis were born between January 1, 2008, and December 31, 2015; were diagnosed with CF within the first 6 months of life; and had ≥1 calendar year of CFFPR data during their first 2 years of life. Infants without annual data during the first 2 years of life or without encounter data recorded before their first RSV season were excluded. Each participant was followed through December 31, 2016, or December 31st of the year in which they turned 7 years old. The Quorum Review Institutional Review Board approved this study (32599/1).

The exposure of interest was palivizumab receipt during the first 2 years of life. In this analysis, “age” describes age on December 31st of the calendar year. Infants were categorized as receiving palivizumab if during either or both of their first 2 years of life it was recorded in the registry. The CFFPR does not record the number and timing of doses.17 Infants were categorized as not receiving palivizumab if during either or both of their first 2 years of life palivizumab was recorded as “not given.” Sensitivity analyses were performed, removing infants with 1 year when palivizumab was recorded as not given and palivizumab receipt was unknown for the second year. Infants were excluded if this field was not completed for both of their first 2 years of life.

Three longitudinal outcomes were assessed: (1) annualized percent FEV1 predicted (average of the maximum measure from each quarter) during the 12 months before the seventh birthday,18 (2) time to first positive P aeruginosa culture result during the first 7 years of life, and (3) age-specific annual number of hospitalizations for pulmonary exacerbations or other pulmonary complications during the first 8 years of life. Lung function measures from between their sixth and seventh birthdays ensured participants were old enough to provide accurate pulmonary function measures. Percent predicted was calculated by using Global Lung Function Initiative reference equations. Infants with a positive culture result for P aeruginosa before palivizumab receipt were excluded from the analysis of time to first positive culture result for P aeruginosa.

Potential confounders of the association between palivizumab receipt and outcomes were explored. Demographic variables included year of birth, birth season (January–March, April–June, July–September, or October–December), sex, race, and ethnicity. Gestational age was categorized as ≥37, 32–<37, or <32 weeks or missing. CF diagnosis–related variables included cystic fibrosis transmembrane regulator (CFTR) mutation class (classes I, II, or III; classes IV and V; unclassifiable; or not genotyped)19 and method of diagnosis and/or symptoms at diagnosis. Individuals with 2 class I to III mutations are typically pancreatic insufficient with more severe lung disease, whereas those with ≥1 class IV or V mutation are typically pancreatic sufficient with milder lung disease. Symptoms at diagnosis were classified by using hierarchical categories: meconium ileus, respiratory symptoms, newborn screening, and other (eg, gastrointestinal symptoms or failure to thrive). Additional annual variables were categorized as present if recorded “yes” and absent if recorded “no” during the first 2 years of life. These variables included a smoker in the household, day care attendance, influenza vaccine receipt, and Medicaid. Household size, including the infant, was obtained during infants’ first years in the CFFPR and was categorized as 2 to 3 individuals, 4 to 6 individuals, and ≥7 individuals. Many variables collected annually had missing data; to minimize excluding otherwise eligible infants, a “missing” category was created for each annual variable.

We addressed the possibility that sicker infants were more likely to receive palivizumab (confounding by indication) by assessing clinical status during the time that clinicians and families considered palivizumab. We examined clinical status before first RSV season using CFFPR measures available before infants’ first November first, including number of clinic visits; last recorded length, weight, and weight-for-length percentiles20; Staphylococcus aureus, methicillin-resistant S aureus, Haemophilus influenzae, and P aeruginosa detected on any respiratory culture (yes or no for each); use of inhaled tobramycin, dornase alfa, hypertonic saline, and/or pancreatic enzyme replacement therapy (yes or no); and reported asthma in the CFFPR (yes or no).21 Infants without clinical encounters from birth to their first RSV season were excluded.

Bivariate analyses used χ2 tests for categorical variables and t tests for continuous variables. We created propensity scores to adjust for potential confounding by indication, calculated using logistic regression models to predict the probability of receiving palivizumab. To create the propensity model, we first created models to determine variables that were associated with each outcome of interest. All variables included in those models with P < .1 were included in the final propensity model.

For each outcome of interest, we compared those who did and did not receive palivizumab. We performed unadjusted regression analyses, then adjusted for the propensity score. Multivariate linear regression was used to estimate difference in percent FEV1 predicted. Kaplan-Meier curves and Cox proportional hazards models were used to estimate timing and hazard of first P aeruginosa acquisition. Lastly, negative binomial Poisson models were used to model annual count of hospitalizations for pulmonary complications and generate rate ratios (RRs).

We performed sensitivity analyses of population subsets to compare this analysis with other literature on palivizumab and to reflect subgroups indicated in the AAP recommendations. We examined risk of death ever in the first 2 years of life and specifically during the RSV season. We also restricted the analysis of hospitalization to the first 2 years of life and focused specifically on those occurring during RSV season. Lastly, we analyzed all outcomes of interest only among infants categorized as high risk, defined as either having a weight or weight-for-length percentile of <5% or having a hospitalization for a pulmonary exacerbation or other pulmonary complications before their first RSV season.

Analyses were conducted by using SAS version 9.4 (SAS Institute, Inc, Cary, NC).

Between 2008 and 2015, 6032 infants were diagnosed with CF within the first 6 months of life. From these, we excluded 516 with missing data for palivizumab receipt in both years, 333 infants without annualized data in the first 2 years of life, and 916 infants without clinical encounters before their first RSV season. Therefore, the study sample included 4267 infants, with 1588 (37%) reported as receiving palivizumab in the CFFPR during ≥1 of the first 2 years of life. Of these, 31% received palivizumab in both years, 38% in year 1 only, 10% in year 2 only, 9% in year 1 and unknown in year 2, and 12% in year 2 and unknown in year 1.

Among the 2679 children reported as not receiving palivizumab, 971 (36%) had 1 year in which palivizumab was reported as not given but another year in which palivizumab receipt was reported as “unknown” or was missing. The percentage of infants at each care site reported as receiving palivizumab varied (median: 37%; interquartile range [IQR]: 18%–64%).

Table 1 reveals study population demographics and clinical characteristics. Infants receiving palivizumab were more likely to be born in 2008–2012, born between April and September, have a <37-week gestational age, have 2 CFTR class I to III mutations, and meconium ileus at birth. Before their first November first, infants receiving palivizumab had lower height and weight percentiles; were more likely to have been prescribed dornase alfa, hypertonic saline, and pancreatic enzyme replacement therapy; and were more likely to have asthma reported in the CFFPR.

TABLE 1

Demographic and Clinical Characteristics of Infants With CF Who Did Not and Did Receive Palivizumab

CharacteristicTotal (N = 4267)Reported as Not Receiving Palivizumab (N = 2676)Reported as Receiving Palivizumab (N = 1588)P
Female sex, n (%) 2103 (49) 1341 (50) 762 (48) .2 
Birth y, n (%)     <.001 
 2008 511 (12) 274 (10) 237 (15)  
 2009 538 (13) 320 (12) 218 (14)  
 2010 541 (13) 299 (11) 242 (15)  
 2011 525 (12) 307 (11) 218 (14)  
 2012 597 (14) 376 (14) 221 (14)  
 2013 558 (13) 368 (14) 190 (12)  
 2014 502 (12) 387 (14) 115 (7)  
 2015 495 (12) 348 (13) 147 (9)  
Birth season, n (%)a    <.001 
 January–March 1139 (27) 751 (28) 388 (24)  
 April–June 1220 (29) 740 (28) 480 (30)  
 July–September 1018 (24) 571 (21) 447 (28)  
 October–December 890 (21) 617 (23) 273 (17)  
Race and/or ethnicity, n (%)     
 White 3961(92) 2477 (92) 1484 (93) .2 
 Hispanica 450 (11) 290 (11) 160 (10) .1 
Gestational age, wk, n (%)    <.001 
 ≥37 2504 (59) 1583 (59) 921 (58)  
 32–<37 321 (8) 168 (6) 153 (10)  
 <32 31 (1) 13 (1) 18 (1)  
 Missing 1411 (33) 915 (34) 496 (31)  
Mutation class group, n (%)a    .01 
 Classes I–III 3042 (71) 1867 (69) 1175 (74)  
 Classes IV–V 445 (10) 306 (11) 139 (9)  
 Unclassified 719 (17) 467 (17) 252 (16)  
 Not genotyped 61 (1) 39 (1) 22 (1)  
Mode of diagnosis, n (%)    <.001 
 Meconium ileus 636 (15) 330 (12) 306 (19)  
 Respiratory symptoms 79 (2) 47 (2) 32 (2)  
 Newborn screening 3023 (71) 1953 (73) 1070 (67)  
 Other 529 (12) 349 (13) 180 (11)  
Smoker in household, n (%)a 481 (11) 323 (12) 158 (10) .5 
Attended day care, n (%) 700 (16) 443 (17) 257 (16) .8 
Received influenza vaccine, n (%)a 3796 (89) 2336 (87) 1460 (92) .2 
Medicaid, n (%) 2584 (61) 1654 (62) 930 (59) .04 
No. individuals in the household, n (%)    .2 
 2–3 1346 (32) 817 (30) 529 (33)  
 4–6 2331 (55) 1441 (54) 890 (56)  
 ≥7 243 (6) 163 (6) 80 (5)  
 Missing 347 (8) 258 (10) 89 (6)  
No. clinic visits, n (SD) 5.5 (3.6) 5.5 (3.6) 5.5 (3.6) .46 
Length, percentile (SD)a 32.1 (29.2) 33.0 (29.0) 30.6 (29.7) .017 
Wt, percentile (SD)a 34.4 (28.6) 35.9 (28.7) 31.8 (28.2) <.001 
Wt-for-length, percentile (SD)a 47.7 (30.1) 48.5 (30.1) 46.3 (30.1) .008 
Positive culture result, n (%)b     
 Cultures obtained 40 202 (94) 2533 (95) 1487 (95) .2 
S aureus 1961 (49) 1242 (49) 719 (48) .7 
 MRSAa 293 (7) 179 (7) 114 (8) .5 
H influenzae 551 (16) 357 (14) 194 (14) .4 
P aeruginosa 648 (16) 400 (16) 248 (17) .5 
Prescribed treatments, n (%)     
 Data reported 4198 (98) 2637 (98) 1561 (98) .7 
 Inhaled tobramycin 362 (9) 221 (8) 141 (9) .5 
 Dornase alfaa 947 (22) 570 (22) 377 (24) .06 
 Hypertonic salinea 323 (8) 177 (7) 146 (9) .002 
 Pancreatic enzyme replacement therapya 3628 (86) 2246 (85) 1382 (89) .002 
Asthma reported in the CFFPR, n (%)a 116 (3) 62 (2) 54 (3) .04 
CharacteristicTotal (N = 4267)Reported as Not Receiving Palivizumab (N = 2676)Reported as Receiving Palivizumab (N = 1588)P
Female sex, n (%) 2103 (49) 1341 (50) 762 (48) .2 
Birth y, n (%)     <.001 
 2008 511 (12) 274 (10) 237 (15)  
 2009 538 (13) 320 (12) 218 (14)  
 2010 541 (13) 299 (11) 242 (15)  
 2011 525 (12) 307 (11) 218 (14)  
 2012 597 (14) 376 (14) 221 (14)  
 2013 558 (13) 368 (14) 190 (12)  
 2014 502 (12) 387 (14) 115 (7)  
 2015 495 (12) 348 (13) 147 (9)  
Birth season, n (%)a    <.001 
 January–March 1139 (27) 751 (28) 388 (24)  
 April–June 1220 (29) 740 (28) 480 (30)  
 July–September 1018 (24) 571 (21) 447 (28)  
 October–December 890 (21) 617 (23) 273 (17)  
Race and/or ethnicity, n (%)     
 White 3961(92) 2477 (92) 1484 (93) .2 
 Hispanica 450 (11) 290 (11) 160 (10) .1 
Gestational age, wk, n (%)    <.001 
 ≥37 2504 (59) 1583 (59) 921 (58)  
 32–<37 321 (8) 168 (6) 153 (10)  
 <32 31 (1) 13 (1) 18 (1)  
 Missing 1411 (33) 915 (34) 496 (31)  
Mutation class group, n (%)a    .01 
 Classes I–III 3042 (71) 1867 (69) 1175 (74)  
 Classes IV–V 445 (10) 306 (11) 139 (9)  
 Unclassified 719 (17) 467 (17) 252 (16)  
 Not genotyped 61 (1) 39 (1) 22 (1)  
Mode of diagnosis, n (%)    <.001 
 Meconium ileus 636 (15) 330 (12) 306 (19)  
 Respiratory symptoms 79 (2) 47 (2) 32 (2)  
 Newborn screening 3023 (71) 1953 (73) 1070 (67)  
 Other 529 (12) 349 (13) 180 (11)  
Smoker in household, n (%)a 481 (11) 323 (12) 158 (10) .5 
Attended day care, n (%) 700 (16) 443 (17) 257 (16) .8 
Received influenza vaccine, n (%)a 3796 (89) 2336 (87) 1460 (92) .2 
Medicaid, n (%) 2584 (61) 1654 (62) 930 (59) .04 
No. individuals in the household, n (%)    .2 
 2–3 1346 (32) 817 (30) 529 (33)  
 4–6 2331 (55) 1441 (54) 890 (56)  
 ≥7 243 (6) 163 (6) 80 (5)  
 Missing 347 (8) 258 (10) 89 (6)  
No. clinic visits, n (SD) 5.5 (3.6) 5.5 (3.6) 5.5 (3.6) .46 
Length, percentile (SD)a 32.1 (29.2) 33.0 (29.0) 30.6 (29.7) .017 
Wt, percentile (SD)a 34.4 (28.6) 35.9 (28.7) 31.8 (28.2) <.001 
Wt-for-length, percentile (SD)a 47.7 (30.1) 48.5 (30.1) 46.3 (30.1) .008 
Positive culture result, n (%)b     
 Cultures obtained 40 202 (94) 2533 (95) 1487 (95) .2 
S aureus 1961 (49) 1242 (49) 719 (48) .7 
 MRSAa 293 (7) 179 (7) 114 (8) .5 
H influenzae 551 (16) 357 (14) 194 (14) .4 
P aeruginosa 648 (16) 400 (16) 248 (17) .5 
Prescribed treatments, n (%)     
 Data reported 4198 (98) 2637 (98) 1561 (98) .7 
 Inhaled tobramycin 362 (9) 221 (8) 141 (9) .5 
 Dornase alfaa 947 (22) 570 (22) 377 (24) .06 
 Hypertonic salinea 323 (8) 177 (7) 146 (9) .002 
 Pancreatic enzyme replacement therapya 3628 (86) 2246 (85) 1382 (89) .002 
Asthma reported in the CFFPR, n (%)a 116 (3) 62 (2) 54 (3) .04 

MRSA, methicillin-resistant S aureus.

a

Included in the propensity score model.

b

The percent positive for microbiology cultures was among those with a culture.

Variables included in the propensity model are noted in the Table 1 footnote. There was considerable overlap of calculated propensity scores. Infants who received palivizumab had a median propensity score of 0.41 (IQR: 0.33–0.48), and infants who did not receive palivizumab had a median propensity score of 0.35 (IQR: 0.28–0.42).

Of the 4267 cohort participants, 1323 (31%) had lung function data recorded in the CFFPR between ages 6 and 7; 593 of these children had received palivizumab and 730 had not. Mean percent FEV1 predicted at 7 years of age was similar among those who received palivizumab (98.2; 95% confidence interval [CI]: 96.9–99.5) and did not receive palivizumab (97.3; 95% CI: 96.1–98.5), adjusting for propensity scores. The sensitivity analysis that removed infants who had 1 year in which palivizumab was recorded as not given and palivizumab status was unknown for the other year did not change these results (data not shown).

There were 3619 infants who had negative P aeruginosa culture results reported in the CFFPR at the beginning of their first RSV season (1340 had received palivizumab and 2279 had not) and thus were included in analysis of time to first P aeruginosa–positive culture result. During follow-up, 1865 children (52%) had P aeruginosa–positive culture results. Unadjusted Kaplan-Meier curves in Fig 1A suggest those who received palivizumab had significantly greater risk of acquiring P aeruginosa (log-rank test, P = .007). After stratification by propensity score quartiles, the differences were no longer significant (Quartile 1, lowest propensity to receive palivizumab P = .8; Quartile 2, P = .2; Quartile 3, P = .2; Quartile 4, highest propensity to receive palivizumab P = .8). Figure 1B reveals Kaplan-Meier curves for infants in the quartile with lowest propensity to receive palivizumab and Fig 2 shows curves for those with highest propensity. The unadjusted hazard ratio for acquisition of P aeruginosa was 1.1 (95% CI: 1.0–1.2) and after propensity score adjustment, the hazard ratio was 1.1 (95% CI: 0.96–1.2). Estimate of effect did not change when we restricted analysis to unexposed infants whose palivizumab status was known for both years (data not shown).

FIGURE 1

A, Unadjusted risk of acquiring P aeruginosa comparing infants who received palivizumab and did not receive palivizumab. B, Stratified risk of acquiring P aeruginosa among those in the lowest-quartile propensity score.

FIGURE 1

A, Unadjusted risk of acquiring P aeruginosa comparing infants who received palivizumab and did not receive palivizumab. B, Stratified risk of acquiring P aeruginosa among those in the lowest-quartile propensity score.

FIGURE 2

Stratified risk of acquiring P aeruginosa among those in the highest-quartile propensity score.

FIGURE 2

Stratified risk of acquiring P aeruginosa among those in the highest-quartile propensity score.

Table 2 reveals RRs for hospitalizations by age. During follow-up at any age, the percent of children with ≥1 hospitalization each year ranged from 13% to 20%. The adjusted RR was highest between ages 1 and 2 (RR: 1.1; 95% CI: 0.92–1.3) and lowest between ages 7 and 8 (RR: 0.75; 95% CI: 0.54–1.0). Overall, unadjusted RR were attenuated after adjustment for propensity score.

TABLE 2

Annual Rate of Hospitalizations Among Infants With CF Who Did Not and Did Receive Palivizumab, Unadjusted and Adjusted by Propensity Score

Age, yReported as Not Receiving Palivizumab, n (%) With >1 hospitalizationaReported as Receiving Palivizumab, n (%) With >1 hospitalizationaAll Infants, Unadjusted RR (95% CI)bAll Infants, Adjusted RRc (95% CI)High-Risk Infants, RR (95% CI)
<1 338 (13) 237 (15) 1.2 (0.98–1.3) 0.94 (0.79–1.1) 0.91 (0.72–1.2) 
1–<2 420 (16) 291 (18) 1.2 (1.0–1.4) 1.1 (0.92–1.3) 0.96 (0.77–1.2) 
2–<3 324 (14) 210 (15) 1.0 (0.87–1.3) 0.91 (0.75–1.1) 0.85 (0.66–1.1) 
3–<4 240 (13) 185 (14) 1.2 (0.95–1.4) 0.99 (0.81–1.2) 0.89 (0.66–1.2) 
4–<5 217 (15) 161 (15) 1.1 (0.86–1.3) 0.91 (0.73–1.1) 1.0 (0.75–1.4) 
5–<6 178 (16) 161 (18) 1.2 (0.93–1.5) 1.0 (0.82–1.3) 1.1 (0.83–1.6) 
6–<7 152 (18) 128 (20) 1.0 (0.79–1.3) 0.96 (0.74–1.2) 1.1 (0.75–1.6) 
7–<8 100 (18) 78 (18) 0.81 (0.59–1.1) 0.75 (0.54–1.0) 0.65 (0.40–1.0) 
Age, yReported as Not Receiving Palivizumab, n (%) With >1 hospitalizationaReported as Receiving Palivizumab, n (%) With >1 hospitalizationaAll Infants, Unadjusted RR (95% CI)bAll Infants, Adjusted RRc (95% CI)High-Risk Infants, RR (95% CI)
<1 338 (13) 237 (15) 1.2 (0.98–1.3) 0.94 (0.79–1.1) 0.91 (0.72–1.2) 
1–<2 420 (16) 291 (18) 1.2 (1.0–1.4) 1.1 (0.92–1.3) 0.96 (0.77–1.2) 
2–<3 324 (14) 210 (15) 1.0 (0.87–1.3) 0.91 (0.75–1.1) 0.85 (0.66–1.1) 
3–<4 240 (13) 185 (14) 1.2 (0.95–1.4) 0.99 (0.81–1.2) 0.89 (0.66–1.2) 
4–<5 217 (15) 161 (15) 1.1 (0.86–1.3) 0.91 (0.73–1.1) 1.0 (0.75–1.4) 
5–<6 178 (16) 161 (18) 1.2 (0.93–1.5) 1.0 (0.82–1.3) 1.1 (0.83–1.6) 
6–<7 152 (18) 128 (20) 1.0 (0.79–1.3) 0.96 (0.74–1.2) 1.1 (0.75–1.6) 
7–<8 100 (18) 78 (18) 0.81 (0.59–1.1) 0.75 (0.54–1.0) 0.65 (0.40–1.0) 
a

Because of censoring, the number of infants included in the model decreased as age increased.

b

RRs reflect the rate of hospitalizations among infants treated with palivizumab as compared with infants not treated with palivizumab.

c

Adjusted for propensity score.

We conducted numerous sensitivity analyses. Unadjusted risk of death before age 2 was 0.1% among infants who did and 0.2% among those who did not receive palivizumab (P = .5). Restricting to deaths during the RSV season, risk was the same (0.1%) among infants treated and not treated with palivizumab (P = .6). Small sample sizes precluded additional analyses. RR for hospitalizations before age 2 was 1.0 (95% CI: 0.89–1.2) comparing those who received and did not receive palivizumab. Restricting to hospitalizations during RSV season, the RR was 0.98 (95% CI: 0.84–1.1).

Overall, 1426 infants were categorized as high risk, 604 (38%) of those treated with palivizumab and 822 (31%) of infants not treated with palivizumab. Restricting analyses to these high-risk infants, 462 infants were included in the lung function analysis. Mean percent FEV1 predicted was the same in those who received and did not receive palivizumab (95.3 vs 95.0; P = .9). The hazard ratio for acquisition of P aeruginosa was 1.0 (95% CI: 0.86–1.2) among 1103 high-risk infants, comparing those who did versus did not receive palivizumab. Table 2 reveals RRs restricted to high-risk infants, suggesting potential for decreased hospitalizations in younger ages.

To our knowledge, this is the first large population-based study evaluating association of palivizumab receipt in infancy with long-term outcomes in children with CF using propensity scores to minimize indication bias. As expected, infants receiving palivizumab were more likely to be born preterm and before RSV season; have severe CFTR mutations; be diagnosed because of meconium ileus; be diagnosed with asthma; and be treated with dornase alfa, hypertonic saline, and pancreatic enzymes. These factors were likely considered by providers and families when prescribing palivizumab and are somewhat consistent with AAP recommendations for palivizumab in infants with CF with chronic lung disease and/or nutritional compromise. After adjustment for propensity scores, we found no association between palivizumab and lung function at age 7, time to first P aeruginosa–positive culture result, or rate of pulmonary-related hospitalizations.

Authors of other observational studies evaluating long-term outcomes of palivizumab did not overall find impact of palivizumab on these outcomes. In Northern Ireland, investigators examined time to first P aeruginosa, lung function, and growth parameters in children with CF born before (n = 47) and after (n = 45) introduction of palivizumab in 2002.9 Like our study, lung function and growth parameters were similar; however, unlike our study, the “after” group had a significantly shorter time until first P aeruginosa–positive culture result compared with the “before” group (median: 57 vs 96 months, respectively). In France, investigators examined the acquisition of selected microorganisms in infants who had (n = 40) or had not (n = 140) received palivizumab.13 Among infants who had and had not received palivizumab, age at first positive culture result was similar for P aeruginosa (10.4 vs 12.3 months, respectively) and for S aureus (6.4 vs 3.8 months, respectively). Those who had received palivizumab were more likely to be positive for S aureus at age 3 than those who had not (97% vs 85%, respectively). Growth outcome measures were similar in both groups throughout the first 3 years of life.

Authors of 1 randomized placebo-controlled study assessed outcomes associated with palivizumab in infants with CF.7 At a 12-month follow-up, proportions of infants with positive culture results for P aeruginosa were similar, as were weight-to-height ratios and rates of RSV hospitalizations.5 Authors of this study also examined safety. Overall adverse event (AE) incidence was similar: 86 of 92 (93%) infants in the palivizumab group and 90 of 94 (96%) in the placebo group had a reported AE, and 19 of 92 (21%) infants in the palivizumab group and 16 of 94 (17%) in the placebo group experienced a serious AE. Although an adequately powered, randomized controlled trial is ideal for studying the safety and efficacy of palivizumab in infants with CF, many have concluded that the sample size needed to establish safety and efficacy of palivizumab in infants with CF would be too large to be feasible.

Authors of more recent large population-based studies provide evidence that RSV is a risk factor for hospitalization in infants with CF. In Denmark, risk and severity of RSV hospitalizations were assessed in infants <2 years of age with chronic conditions, including CF.22 RSV-related hospitalizations were responsible for 18% of all hospitalizations, representing a 4.32-fold increased risk of RSV hospitalization compared with otherwise healthy children. During the study period (1997–2003), RSV was detected by antigen, which has a lower sensitivity than the assays currently in widespread use today, suggesting underestimation of RSV-related hospitalizations. Similarly, in England, among 11 infants with CF hospitalized with RSV and/or bronchiolitis during a study conducted from April 2007 to March 2008, the rate of admission was 2.66-fold higher in infants with CF than otherwise healthy term infants.23 

Nonetheless, lack of quality evidence for benefit, high cost, and operationalizing the complex monthly administration of palivizumab has led to variability in use in the United States, United Kingdom, and Canada.10,11,24 We noted similar variability in the US CF care center network, as the median percentage of infants receiving palivizumab at individual care centers was 37% (IQR: 18%–64%). Furthermore, infants born from 2008 to 2012 were more likely to have received palivizumab than infants born from 2013 to 2015, which may reflect growing uncertainty about the potential benefits of palivizumab and/or more barriers restricting access to this therapy.

This registry-based observational study has several limitations. In this large cohort of infants with CF, 29% of the potential study sample was excluded because of missing data, potentially impacting generalizability of results. Approximately 81% to 84% of people with CF in the United States are included in the CFFPR, but the precise proportion of infants and children included in the CFFPR is unknown.16 Infants with missing data on palivizumab receipt were more likely to be born in recent years, be nonwhite, and have low gestational age. There was likely some misclassification of palivizumab exposure status, which could have biased our results toward the null. Palivizumab prescribed by primary care or other non-CF care center clinicians may not be recorded accurately in the CFFPR. Number of palivizumab doses received in each season, which can potentially impact effectiveness, is not captured in the CFFPR. The CFFPR does not contain RSV disease data, and thus hospitalizations secondary to RSV could not be assessed during treatment, the traditional benefit of treatment. Our propensity scores may not have adjusted completely for indication bias and could only include measured confounders. Finally, pulmonary function data were only available for a study population subset because most had not turned 7 years old by the end of the observation period.

We found no evidence of long-term benefits associated with palivizumab in infants with CF on a population level. The fact that, after adjustment for indication bias, those who did or did not receive palivizumab had similar long-term outcomes could be seen as reassuring. However, current AAP guidelines recommend palivizumab for high-risk infants with CF (ie, those with chronic lung disease and nutritional compromise). An appropriate next step to evaluate outcomes of palivizumab among high-risk infants would be to embed a prospective study within the CFFPR. First, concise case definitions for chronic lung disease and nutritional compromise for infants with CF need to be developed. Then, outcomes would be tracked by using current CFFPR data. Additionally, accuracy of palivizumab receipt, dose timing, RSV hospitalizations, and hospital and ICU days could be collected by linking the CFFPR to administrative claims data.

Dr Fink substantially contributed to the study conception and design, acquisition of data, and analysis and interpretation of data and drafted the manuscript; Drs Byington and Rosenfeld and Ms Loeffler substantially contributed to the study conception and design and revised the manuscript critically for important intellectual content; Dr Saiman substantially contributed to the study conception and design and drafted the manuscript; Dr Graff substantially contributed to the study conception and design and the analysis and interpretation of data and revised the manuscript critically for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found at www.pediatrics.org/10.1542/peds.2019-0153.

We thank the CFF for the use of CFFPR data to conduct this study. In addition, we thank the patients, care providers, and clinic coordinators at CF centers throughout the United States for their contributions to the CFFPR.

     
  • AAP

    American Academy of Pediatrics

  •  
  • AE

    adverse event

  •  
  • CF

    cystic fibrosis

  •  
  • CFF

    Cystic Fibrosis Foundation

  •  
  • CFFPR

    Cystic Fibrosis Foundation Patient Registry

  •  
  • CFTR

    cystic fibrosis transmembrane regulator

  •  
  • CI

    confidence interval

  •  
  • FEV1

    forced expiratory volume in 1 second

  •  
  • IQR

    interquartile range

  •  
  • RR

    rate ratio

  •  
  • RSV

    respiratory syncytial virus

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.