Palivizumab Prophylaxis, Respiratory Syncytial Virus, and Subsequent Recurrent Wheezing

Article Outline

• Abstract
• Methods
  • Patient Enrollment
  • Patient Follow-Up
  • Respiratory Assessment
  • Statistical Methods
  • Role of the Funding Source
• Results
• Discussion
• Appendix. 
  • The Palivizumab Long-Term Respiratory Outcomes Study Group
• References
• Copyright

Objective

Children who experience respiratory syncytial virus (RSV) lower respiratory tract infections (LRTIs) early in life have high rates of subsequent recurrent wheezing. Palivizumab, an anti-RSV monoclonal antibody, has 78% to 80% efficacy in preventing RSV hospitalization in premature infants without chronic lung disease. We hypothesized that palivizumab, by ameliorating or preventing early RSV LRTI in preterm infants, might decrease later recurrent wheezing.

Study design

A cohort of preterm infants who had received palivizumab and were not hospitalized for RSV (n = 191) or who never received palivizumab (n = 230; 76 who were hospitalized for RSV and 154 who were not), were prospectively followed for 24 months beginning at a mean age of 19 months. The subjects were assessed for recurrent wheezing by caretaker or physician report.

Results

The incidences of recurrent wheezing and physician-diagnosed recurrent wheezing were significantly lower in the 191 palivizumab-treated subjects (13% and 8%, respectively) compared with all 230 untreated subjects (26%, P = .001 and 16%, P = .011, respectively) and with the 154 patients in the subgroup not hospitalized for RSV LRTI (23%, P = .022 and 16%, P = .027, respectively). The effect of palivizumab treatment remained significant after adjustment for potential confounding variables.

Conclusions

Our study suggests that preventing RSV LRTI with palivizumab may reduce subsequent recurrent wheezing in premature infants.

Abbreviations: CI, Confidence interval, CLD, Chronic lung disease, HR, Hazard ratio, LRTI, Lower respiratory tract infection, RR, Relative risk, RSV, Respiratory syncytial virus

Respiratory syncytial virus (RSV) is the most important respiratory viral pathogen in childhood.¹ Although the immediate effects of severe disease are well known, RSV lower respiratory tract infection (LRTI; pneumonia and/or bronchiolitis) in early life has been associated epidemiologically with subsequent recurrent wheezing and asthma later in childhood.², ³, ⁴, ⁵, ⁶ Prospective studies have demonstrated rates of subsequent airway reactivity 50% to 100% greater in children who developed RSV LRTI in early life than in uninfected controls. Recurrent wheezing has been observed up to 11 years later⁴ and may extend into early adulthood.⁷

Preterm infants, even those without chronic lung disease (CLD), develop particularly serious RSV infections in the first year of life,⁸ are at higher risk for developing recurrent wheezing or asthma,⁹ and have persistent abnormal lung function.¹⁰ It has been demonstrated that the use of a polyclonal immunoglobulin, RSVIG-IV (RespiGam), can prevent serious RSV LRTI in children with CLD.¹¹, ¹² In another small study, infants with CLD who had received RSVIG-IV also had less severe chronic asthma, as defined by improved pulmonary function tests, decreased hospital visits, and decreased medication use, compared with control children.¹³

Palivizumab (Synagis), a humanized monoclonal antibody against the RSV fusion protein, has been demonstrated to substantially reduce hospitalization for severe RSV LRTI in large clinical trials involving preterm infants.¹⁴, ¹⁵ We hypothesized that the use of palivizumab in preterm infants, by ameliorating or preventing early RSV LRTI, might decrease later recurrent wheezing. We report here on respiratory outcomes in an international cohort of previously preterm infants age 36 months and younger without CLD who received palivizumab in the 1999-2000 respiratory season and were followed up prospectively for 2 years, compared with a matched cohort that had never received palivizumab.

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Methods 

Patient Enrollment 

Because it is unethical to conduct a randomized placebo-controlled trial in premature infants (in whom palivizumab has been shown to reduce RSV hospitalization), we took advantage of incomplete uptake of palivizumab use and conducted a prospective multicenter, double-cohort, follow-up study in 27 centers in Spain, Germany, The Netherlands, Canada, Poland, and Sweden. The 27 sites were invited to participate in the study based on their use of palivizumab in some premature infants on a compassionate basis in the preceding respiratory season and ability to recruit and retain subjects for the 2-year duration of the study. Investigators reviewed medical records for preterm births and approached all who had received at least 3 doses of palivizumab in the first 12 months of life and had not had an RSV hospitalization (designated the “treated group”). Using chronologic age (±3 months) and gestational age (±4 weeks) for matching, subjects from the large group of premature infants who had not received palivizumab were matched to those in the palivizumab-treated group and were approached for participation in the study (designated the “untreated group”). An attempt was made to recruit equal numbers of RSV hospitalized and nonhospitalized subjects, each matched to 1 subject from the palivuzumab-treated cohort. All study participants were born prematurely (≤35 weeks gestational age) and had no CLD. Other exclusion criteria were mechanical ventilation at enrollment; congenital heart disease; renal, hepatic, or seizure disorder; life expectancy of <6 months; known immunodeficiency; or receipt of other RSV investigative vaccines or therapies. Most of the children (94%) were enrolled between mid-July 2001 and mid-March 2002 and were followed prospectively for 2 years after enrollment. Reasons for use or nonuse of palivizumab were not explored.

Written informed consent was obtained from each subject’s parent or legal guardian before the performance of any study-related procedures, after ethical review and approval by the institutional review board at each study site. The study was conducted in accordance with ICH Good Clinical Practice Guidelines and was monitored by Abbott Laboratories, Inc. An independent international steering committee (including the authors) was involved in the study design and data collection, and stipulated and oversaw all analyses reported in this article. At enrollment, a medical and sociodemographic history was obtained, a physical examination was performed, and serum samples were obtained for RSV-neutralizing antibody¹⁶ and IgE levels.¹⁷ The medical history included a validated respiratory questionnaire² and a questionnaire on family history, medical history, and underlying diagnosis/disease (RSV) and current medications, demographics (eg, number of people in home, number and ages of siblings, day care, passive smoke), environmental factors (eg, pets, wood-burning stoves), and parental smoking or history of atopy (eg, asthma, allergic dermatitis or allergic rhinitis) in family members.

Patient Follow-Up 

Monthly contact with the parents/caregivers was scheduled over the 24 months after enrollment. Visits to the study site were conducted at 6-month intervals; all other monthly contacts were conducted by telephone. Subject illnesses and other medical events occurring during the past month were recorded at each monthly follow-up contact. At 6-month intervals, physician records were reviewed for all intercurrent doctor visits, emergency visits, and hospitalizations for respiratory symptoms.

Respiratory Assessment 

Outcomes were assessed clinically using a system adapted from those used in other studies of the long-term respiratory outcome of RSV.², ³ Wheezing, defined as bronchial obstruction, was assessed at each visit. An episode of wheezing was defined in the protocol as 1 or more consecutive days of wheezing preceded and followed by a nonwheezing, healthy period of at least 1 week. A priori recurrent wheezing was defined as 3 or more episodes of wheezing in the last 12 months but not necessarily verified by a physician. Physician-diagnosed recurrent wheezing was defined as 3 or more episodes of wheezing in the last 12 months verified by a physician at a physician’s visit, emergency room visit, or hospitalization. At the study sites, the primary physicians making decisions regarding wheezing were not study physicians. The subjects’ parents or guardians were informed at enrollment that they should notify the investigating physician immediately if the child experienced any respiratory symptoms. During unscheduled (sick) visits, an interval medical history was obtained and a physical examination performed.

Statistical Methods 

A sample size of 200 patients per group was estimated to provide approximately 80% power for a 2-sided, .05-level test to detect a statistically significant difference in physician-diagnosed recurrent wheezing rates when the true rates are 10% for the untreated cohort and 3% for the palivizumab-treated cohort. Demographics and baseline characteristics were compared using 1-way analysis of variance for quantitative variables and Fisher’s exact test for categorical variables. The palivizumab-treated group was compared with both the combined untreated groups and the untreated non-RSV hospitalized group.

The primary efficacy endpoint was the incidence of recurrent wheezing over the 2-year (730-day) duration of the study. The secondary efficacy endpoint was the incidence of physician-diagnosed recurrent wheezing. For both definitions, the first wheezing event had to have occurred after informed consent was signed and the first study visit was completed.

Because no children included in the palivizumab cohort were previously hospitalized for RSV LRTI, we compared all treated outcomes with the non-RSV hospitalized subgroup of the untreated cohort as well as with the entire untreated cohort. For both endpoints, we compared the palivizumab-treated group with both the combined untreated groups and the untreated non-RSV hospitalized group using Fisher’s exact test; we also calculated the relative risk (RR) and 95% confidence interval (CI) for the RR.

We compared the incidence rates of recurrent wheezing and physician-diagnosed recurrent wheezing per 100 child-years between the palivizumab-treated group and both the combined untreated group and the untreated non-RSV hospitalized group. For the gestational age categories of <29, 29 to 32, and >32 weeks, we calculated the incidence rates and the RR and 95% CI for the RR of palivizumab treatment compared with no treatment (comparisons with the combined untreated groups and with the untreated non-RSV hospitalized group) for both endpoints.

We used a multiple logistic regression model to assess the association of baseline characteristics with the incidence of respiratory outcomes. A forward stepwise selection procedure was used to identify statistically significant relationships. P values to enter or stay in the model were set at .15; only variables significant at the .05 level in the final model are displayed. Variables assessed included palivizumab treatment, history of RSV hospitalization before enrollment, history of recurrent wheezing, sex, age at enrollment, baseline RSV-neutralizing antibody titers (log₂RSV antibody level), family history of asthma, gestational age at birth, birth weight, multiple birth status, number of adults in the home, number of siblings in the home, number of siblings in day care, and presence of a wood-burning stove in the home.

We compared the time to onset of recurrent wheezing or physician-diagnosed recurrent wheezing between the palivizumab-treated group and both the combined untreated groups and the untreated non-RSV hospitalized group using both the Cox proportional hazards model and the log-rank test. Kaplan-Meier estimates of the time to onset of respiratory outcomes were computed and displayed graphically. We used a multivariable Cox proportional hazards model to assess the association of baseline characteristics on the time to onset of respiratory events, and a forward stepwise selection procedure to identify statistically significant relationships, as described earlier.

Role of the Funding Source 

This study was funded by Abbott International. The sponsors of the study collaborated on study design, data collection, and data analysis. The corresponding author and all members of the steering committee had full access to all data in the study and had the final responsibility of submitting the report for publication.

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Results 

We studied 193 infants and children who had received palivizumab and 231 subjects who had not received palivizumab (76 with a history of RSV hospitalization and 155 without RSV hospitalization) at study onset. Three children (2 who received palivizumab and 1 untreated non-RSV hospitalized child) who did not meet entry criteria and were not followed for more than 1 day were excluded from analysis. The mean ages of the subjects at enrollment were comparable (ie, 18.7 months in the palivizumab-treated cohort, 20.0 months in the combined untreated cohort, and 19.5 months in the untreated nonhospitalized subgroup), as were the mean durations of follow-up (23.4, 23.3, and 23.4 months, respectively). In the palivizumab-treated cohort, the mean age at the time of the last palivizumab dose was 7.5 months, and the mean age at time of last RSV hospitalization for subjects in the RSV hospitalized subgroup was 4.3 months. Differences at baseline between the 2 cohorts were observed in gestational age, birth weight, multiple birth status, mean number of siblings, siblings in daycare, and those with no RSV antibody. IgE levels were comparable between the groups, as were other demographic factors (Table I). Because there were no RSV hospitalizations before enrollment in the palivizumab-treated cohort (by exclusion criteria), we also compared this cohort with the subjects not treated with palivizumab and not hospitalized with RSV before enrollment. Table I shows 3 variables (multiple births, siblings in day care and RSV antibody) that differ significantly between the palivizumab-treated and untreated groups but not between the palivizumab-treated and palivizumab untreated non-RSV hospitalized groups.

Table I. Demographics and baseline characteristics

	Palivizumab-treated (n = 191)	Palivizumab-untreated (n = 230)	Palivizumab-untreated Non-RSV hospitalized (n = 154)
Mean birth weight, kg ± SD (range)	1.36±0.44(0.6,3.2)	1.62±0.51‡(0.6,3.8)	1.57±0.45‡(0.6,2.7)
Mean gestational age, weeks ± SD (range)	29.9±2.23(25,35)	31.4±2.50‡(24,35)	31.1±2.45‡(24,35)
Female sex (%)	48.2	45.2	46.1
White race (%)	95.3	95.2	96.1
Multiple birth (%)	25.1	37.0⁎	34.4
Mean enrollment age, months ± SD (range)	18.7±7.79(4,40)	20.0±9.62(1,38)	19.5±10.30(1,38)
Mean enrollment weight, kg ± SD (range)	10.23±2.26§(3.8,19.3)	10.17±2.79(2.6,16.6)	9.89±2.82(3.1,16.6)
Breast-fed (%)	62.8	60.9	60.4
Mean number of siblings ± SD (range)	0.8±0.90(0,5)	1.2±1.03‡(0,5)	1.1±0.97⁎(0,4)
Siblings in daycare (%)	34.0	45.7⁎	43.5
Subject in daycare (%)	22.5	26.1	27.9
Smokers in home (%)	46.6	45.7	49.4
Caregiver smokes (%)	27.7	24.3	27.9
Pets in home (%)	35.6	30.9	31.2
Wood-burning stove (%)	15.2	14.3	17.5
Family history of asthma (%)	23.6	25.7	25.3
RSV neutralizing antibody (%<1:4)	43.0	29.8†	38.8
IgE antibody (% <5 IU/mL)	54.9	51.6	53.3

Significantly smaller proportions of palivizumab-treated children had recurrent wheezing episodes or physician-diagnosed recurrent wheezing during the 24 months of follow-up (Figure 1A). There was a 49% relative reduction in the proportion of children with recurrent wheezing and a 51% relative reduction in the proportion of children with physician-diagnosed recurrent wheezing in the palivizumab-treated group (P ≤ .01). Statistically significant relative reductions were also observed when comparing the palivizumab-treated group with the untreated, non-RSV hospitalized group. Similar results were observed in the assessment of incidence of recurrent wheezing and physician-diagnosed recurrent wheezing per 100 child-years, with statistically significant differences for all comparisons (Figure 1A). The effect of gestational age on the reductions of recurrent and physician-diagnosed recurrent wheezing was examined by univariate analysis (Table II) but not by multivariate analysis, because the individual strata were small. For all strata in both the palivizumab-treated and untreated groups, the rate of recurrent wheezing (physician-diagnosed or not) varied inversely with gestational age. For recurrent wheezing, the RRs were similar in all 3 groups. For physician-diagnosed recurrent wheezing, the RRs varied inversely with gestational age, but only the 29- to 32-week age group had large numbers of subjects and showed significance.

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• Figure 1. 

  A, Comparison of respiratory outcomes between the palivizumab-treated (treated) and untreated groups. Results are expressed as frequency of respiratory outcomes or incidence rates per 100 child-years of observation for respiratory outcomes in univariate analyses. The results are graphically represented as point estimates of the RR and 95% CIs. B, Kaplan-Meier plot showing time to the third episode of recurrent wheezing in palivizumab-treated versus combined untreated (P = .001) and palivizumab-treated versus untreated and not hospitalized for RSV LRTI (P = .013) cohorts. C, Kaplan-Meier plot showing time to third episode of physician-diagnosed recurrent wheezing in palivizumab-treated (solid gray line) versus combined untreated (solid black line) (P = .009) and treated versus untreated and not hospitalized for RSV LRTI (dashed line) (P = .020) cohorts.

Table II. Effect of palivizumab treatment on recurrent wheezing or physician- diagnosed recurrent wheezing within gestational age categories

	Palivizumab-treated	Palivizumab-untreated	RR (95% CI)
Recurrent wheezing
Combined untreated groups
>32 weeks gestational age	2/20(10%)	20/85(24%)	0.43(0.11,1.67)
29 to 32 weeks gestational age	13/117(11%)	27/111(24%)	0.46(0.25,0.84)
<29 weeks gestational age	10/54(19%)	12/34(35%)	0.52(0.26,1.08)
Untreated non-RSV hospitalized group
>32 weeks gestational age	2/20(10%)	9/49(18%)	0.54(0.13,2.30)
29 to 32 weeks gestational age	13/117(11%)	16/80(20%)	0.56(0.28,1.09)
<29 weeks gestational age	10/54(19%)	10/25(40%)	0.46(0.22,0.97)
Physician-documented recurrent wheezing
Combined untreated groups
>32 weeks gestational age	0/20(0%)	11/85(13%)	N/M
29 to 32 weeks gestational age	6/117(5%)	18/111(16%)	0.32(0.13,0.77)
<29 weeks gestational age	9/54(17%)	8/34(24%)	0.71(0.30,1.66)
Untreated non-RSV hospitalized group
>32 weeks gestational age	0/20(0%)	5/49(10%)	N/M
29 to 32 weeks gestational age	6/117(5%)	12/80(15%)	0.34(0.13,0.87)
<29 weeks gestational age	9/54(17%)	7/25(28%)	0.60(0.25,1.42)

N/M, not meaningful; 0/20 palivizumab-treated subjects had physician-diagnosed recurrent wheezing, resulting in a noninformative relative risk calculation.

Final logistic regression models demonstrated that palivizumab treatment was significantly associated with fewer events of recurrent wheezing and physician-diagnosed recurrent wheezing (55% to 65% reduction in the odds of an event) compared with either the combined untreated group or the untreated, non-RSV hospitalized group (Table III). Greater gestational age was associated with a reduced risk of a wheezing event in all models (11% to 21% reduction in the odds of an event per 1 week increase in gestational age). In 3 of the 4 comparisons, a family history of asthma was associated with an approximate 2-fold increase in risk for recurrent wheezing or physician-diagnosed recurrent wheezing. In one comparison, the presence of a wood-burning stove in the home was associated with a 2-fold increase in recurrent wheezing.

Table III. Factors associated with occurrence of recurrent wheezing or physician-diagnosed recurrent wheezing by multiple logistic regression

Variable	Odds ratio (95% CI)
	Recurrent wheezing		Physician-diagnosed recurrent wheezing
	Versus combined untreated groups	Versus untreated non-RSV hospitalized group	Versus combined untreated groups	Versus untreated non-RSV hospitalized group
Palivizumab treatment	0.42(0.23,0.76)	0.45(0.25,0.82)	0.35(0.18,0.68)	0.35(0.17,0.72)
Gestational age (per 1-week increase)	0.89(0.80,0.99)	0.87(0.77,0.98)	0.84(0.74,0.95)	0.79(0.68,0.92)
Family history of asthma	1.83(1.06,3.16)	n/a	2.22(1.19,4.14)	2.27(1.10,4.68)
Wood-burning stove in home	2.08(1.07,4.04)	n/a	n/a	n/a

Variables shown are statistically significant at the .05 level. “n/a” indicates that the variable was not included in the final model.

In multivariable analyses using a backward-elimination selection procedure, palivizumab treatment was significantly associated with lower risk of recurrent wheezing or physician-diagnosed recurrent wheezing in all models (data not shown). Enrollment at individual investigational sites generally was too small to enable evaluation of center effects. When sites were grouped by country, the hypothesis of homogeneity of odds ratios was not rejected.

Kaplan-Meier estimates of the time to onset of recurrent wheezing or physician-diagnosed recurrent wheezing are shown in Figure 1B and 1C. Palivizumab treatment was associated with a 47% to 54% reduction in the risk of adverse respiratory outcomes. Palivizumab-treated subjects demonstrated significantly longer times to onset of the first episode of recurrent wheezing (hazard ratio [HR] = 0.46, 95% CI = 0.29 to 0.74) and physician-diagnosed recurrent wheezing (HR = 0.46; 95% CI = 0.25 to 0.83) compared with the combined untreated group. The results were similar when palivizumab-treated subjects were compared with the untreated non-RSV hospitalized group for time to onset of recurrent wheezing (HR = 0.53; 95% CI = 0.32 to 0.88) and physician-diagnosed recurrent wheezing (HR = 0.47; 95% CI = 0.25 to 0.90).

The potential influence of baseline characteristics on the time to onset of adverse respiratory outcomes was explored using the Cox proportional hazards model. The final models demonstrated that palivizumab treatment remained associated with a significantly longer time to onset of both recurrent and physician-diagnosed recurrent wheezing (54% to 64% reduction in risk) compared with either the combined untreated group or the untreated, nonhospitalized group (Table IV). Greater gestational age was associated with a reduced risk of an adverse event in 3 of the 4 comparisons (13% to 21% reduction per 1 week increase in gestational age). In the model in which gestational age was not significant, higher birth weight was associated with a reduction in the risk of recurrent wheezing (39% reduction per kg increase in birth weight). In 3 of the 4 comparisons, a family history of asthma was associated with an approximate 2-fold increase in risk for recurrent wheezing or physician-diagnosed recurrent wheezing. In the assessment of recurrent wheezing compared with the combined untreated group, history of recurrent wheezing, history of RSV hospitalization, and presence of a wood-burning stove in the home were each associated with an increased risk of an event.

Table IV. Factors associated with time to onset of recurrent wheezing or physician-diagnosed recurrent wheezing by multivariable Cox proportional hazard regression

Variable	HR (95% CI)
	Recurrent wheezing		Physician-diagnosed recurrent wheezing
	Versus combined untreated groups	Versus untreated non-RSV hospitalized group	Versus combined untreated groups	Versus untreated non-RSV hospitalized group
Palivizumab treatment	0.46(0.27,0.78)	0.47(0.28,0.81)	0.36(0.19,0.66)	0.36(0.18,0.69)
Gestational age (per 1-week increase)	n/a	0.87(0.78,0.97)	0.84(0.75,0.94)	0.79(0.69,0.91)
Family history of asthma	1.94(1.23,3.07)	n/a	2.25(1.28,3.94)	2.30(1.20,4.40)
History of recurrent wheezing	1.93(1.01,3.66)	n/a	n/a	n/a
Birth weight (per kg higher)	0.61(0.38,0.99)	n/a	n/a	n/a
History of RSV hospitalization	1.86(1.07,3.22)	n/a	n/a	n/a
Wood-burning stove in home	1.80(1.04,3.10)	n/a	n/a	n/a

Variables shown are statistically significant at the .05 level. “n/a” indicates that the variable was not included in the final model.

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Discussion 

This study found that preterm infants without CLD who had received palivizumab before enrollment had a statistically significant lower incidence of recurrent wheezing and physician-diagnosed recurrent wheezing over a 2-year follow-up period compared with preterm infants who had not received palivizumab. The association between palivizumab treatment and improved respiratory outcomes remained statistically significant after adjusting for potential confounding variables. In addition, subjects previously treated with palivizumab had significantly longer time to onset of recurrent wheezing and physician-diagnosed recurrent wheezing even after adjustment for potential confounders. Furthermore, when the palivizumab-treated cohort was compared only with the untreated subjects with no previous history of RSV hospitalization, statistically significant differences in respiratory outcomes were still observed in all analyses. The significant differences in outcomes between treated and untreated subjects who were not hospitalized with RSV LRTI suggest that palivizumab exerted a protective effect by preventing RSV LRTI, not just by preventing hospitalization.

By design, the palivizumab-treated cohort did not have subjects who were hospitalized because of RSV. At the time of study initiation (2000-2001), palivizumab had just been introduced in Europe and Canada. Because palivizumab was expected to be 78% to 80% protective in this population, it would have been challenging to recruit a substantial conhort of palivizumab-treated, RSV hospitalized children. Thus, given the exploratory nature of the study, we chose to exclude RSV hospitalized subjects who had received palivizumab prophylaxis. However, in a secondary analysis, we compared the rates of recurrent wheezing and physician-diagnosed recurrent wheezing in a cohort of children who were not hospitalized (who had or had not received palivizumab) and found similar results. Ours is the first study of palivizumab prophylaxis to demonstrate a potential effect on RSV LRTI (because both cohorts were not hospitalized). RSVIG-IV is known to reduce RSV LRTI in high-risk infants,¹¹ so it is not surprising that palivizumab, a more potent and highly specific molecule would also reduce RSV LRTI.

Many previous epidemiologic studies², ³, ⁵, ⁷, ¹⁸, ¹⁹ have compared long-term outcomes in children hospitalized for RSV with controls not hospitalized for RSV or compared cohorts with and without serious RSV LRTIs.⁶, ²⁰ Therefore, we analyzed subgroups with both RSV-hospitalized and non-RSV hospitalized subjects in this study. RSV antibody levels were measured at study onset to determine RSV exposure. There were significant differences in RSV antibody levels at age 18 to 19 months (57% palivizumab-treated subjects with detectable antibody vs 70% in the untreated cohort, respectively). This was not surprising, because in the untreated cohort, a subgroup of subjects (1/3 of the whole) were hospitalized for RSV. However, when we examined just the untreated non-RSV hospitalized group, the proportion of subjects with detectable RSV antibody levels (61%) was comparable with the palivizumab-treated cohort (57%). Because the last palivizumab dose was given at a mean age of 7.5 months, and RSV-neutralizing antibodies were measured in these subjects at a mean age of 18.7 months, it is unlikely (given the monoclonal antibody half life of 17 to 20 days²¹) that these levels reflect residual neutralizing monoclonal antibody. Further, because the levels of RSV neutralizing antibody in the palivizumab treated cohort and the untreated, nonhospitalized subgroup were similar at enrollment, it is unlikely that even residual palivizumab would have had a direct effect on subsequent wheezing over the next 2 years.

This study has several limitations. First, the results of this study may not be generalizable to term infants, because there is evidence to suggest that the mechanisms determining recurrent wheezing are different in preterm and term babies.⁹, ¹⁰ Therefore, our findings do not support widespread use of palivizumab. Second, the follow-up of 24 months (to a mean age of 43 months at study completion) does not address longer-term outcomes of RSV LRTI. Additional follow-up of these subjects is planned with lung function assessment as a primary outcome. Third, the fact that parents and health care providers knew treatment group assignment may have influenced the outcomes of this study. However, we think this is unlikely because physicians who diagnosed wheezing events were not the study investigators. Further, the similarity between physician-diagnosed versus parent-diagnosed wheezing events argues against potential bias.

Because palivizumab had already been demonstrated to prevent RSV LRTI in premature babies without CLD (our study population), it was impossible to conduct a randomized placebo controlled trial to examine our hypothesis in this population of premature infants. A case-control study would have been retrospective and data collection would not have been complete (for the outcomes we studied), hence we designed this trial as a matched double-cohort study. The main disadvantage of this design is that results may reflect differences in study groups and the absence of randomization allows the possibility of imbalance of confounding factors. In our study, palivizumab was more frequently administered to infants with lower birth weight and gestational ages. This is expected as guidelines for palivizumab use favor treatment for smaller, more premature infants.²², ²³

Because palivizumab had just been introduced to the countries, mostly on a compassionate basis, its use in the first year was restricted mostly to children with CLD and very premature infants. Thus, though we matched infants by gestational age (±4 weeks) there was still a significantly lower mean gestational age in the palivizumab-treated group. These risk factors also would have increased the risk for recurrent wheezing in the palivizumab treated subjects compared with the untreated cohort.⁹, ¹⁰ In fact, the converse was the case. In our study, palivizumab was more frequently administered to infants with fewer siblings at home and fewer siblings in daycare, which could potentially decrease the relative risk for RSV acquisition and wheezing in the treatment group.²⁴ Multivariable analysis was used to take these factors into account; both the logistic and Cox regression models still showed a significant protective effect of palivizumab.

We specifically studied the prevention of RSV LRTI in young infants because the association between RSV LRTI and childhood recurrent wheezing disease appears to be greatest in those who develop RSV LRTI in infancy.³ Culley et al²⁵ demonstrated in a newborn mouse model that early infection with RSV biases airway immune responsiveness to a Th-2 phenotype, resulting in more severe inflammatory changes on reinfection. Although it is unclear whether Th-2–type immune responses play a role in the pathogenesis of post-RSV recurrent wheezing in humans,²⁶, ²⁷ it is known that the fetal Th-2 polarized state develops to the more balanced mature Th-1 dominant state throughout infancy and later childhood.²⁸ A second potential explanation for the association of RSV LRTI and recurrent wheezing comes from the observation that airway tissue damage in early life from viral infections and/or inhalant allergens causes interference in ongoing differentiation of lung tissue. This results in subsequent altered lung function and airway hyperresponsiveness.²⁹, ³⁰ Because palivizumab was administered only in the first year of life, we postulate that palivizumab substantially reduced subsequent recurrent wheezing by protecting susceptible infants against lower respiratory tract damage from RSV in their most vulnerable period. Finally, it has been demonstrated that preventing alterations in small airway neural networks caused by RSV in infancy is one mechanism by which palivizumab may prevent subsequent wheezing. This neural response to RSV also appears to be developmentally regulated.³¹ Piedimonte et al³² demonstrated that the administration of palivizumab to weanling rats resulted in reduced viral load and significantly decreased RSV-related neurogenic inflammation. They postulated that in this way, palivizumab use might prevent subsequent airway reactivity and recurrent wheezing.³² We demonstrated an approximately 50% lower incidence of recurrent wheezing in the infants who received palivizumab compared with controls. This could indicate that the attributable fraction of recurrent wheezing due to RSV could be as high as 50%. In the remainder, true atopic asthma may account for some proportion of cases.²⁰ Recently, rhinovirus infection in infants has been found to be a significant cause of subsequent recurrent wheezing in early childhood.³³ Other respiratory pathogens also have been implicated in the development of this recurrent wheezing.³³

Clearly, the relationship between RSV and recurrent wheezing is complex. The interactions among developing immune and neural systems, as well as the genetic susceptibility to RSV and to subsequent recurrent wheezing after RSV, all contribute to the eventual phenotype. The results of our study suggest that palivizumab, by preventing RSV lower respiratory tract infection, may play a role in protecting against subsequent recurrent wheezing in premature infants without CLD.

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Appendix. 

The Palivizumab Long-Term Respiratory Outcomes Study Group 

Germany: Dr. V. Stephan, Department of Pediatrics, St. Josef Hospital, Ruhr University, Bochum; Dr. G. Munch, Dr. von Haunersches Children’s Hospital, Munich; Dr. R. Berner, University Children’s Clinic, Freiburg.

Spain: IRIS Study group. Coordinator: X. Carbonell Estrany, Hospital Clínic, Barcelona; Dr. J. Figueras, Hospital Clinic, Barcelona; Dr. C. Pedraz, Hospital Clinic, Salamanca; Dr. A. Remesal Escalero, Hospital Clínico, Salamanca; Dr. J. Fraga, Complejo Hospitalario Universitario de Santiago de Compostela; Dr. M. I. Martinez Soto, Complejo Hospitalario Universitario de Santiago de Compostela; Dr. J. Perez Frias, Hospital Materno-Infantil Carlos Haya, Málaga; Dr. J. Blasco Alonso, l Hospital Materno-Infantil Carlos Haya, Málaga; Dr. E. Narbona, Hospital Clínico San Cecilio, Granada; Dr. J. Maldonado Lozano, Hospital Clínico San Cecilio, Granada; Dr. V. Roques, Hospital La Fe, Valencia; Dr. M. Roques Escolar. Hospital La Fe, Valencia; Dr. S. Salas Hernandez, Hospital La Paz, Madrid; Dr. M. Tabeada Perianes, l Hospital Juan Canalejo, Coruna; Dr. J. L. Fernández Trisac, Hospital Juan Canalejo, Coruna; I. Echaniz, Hospital de Basurto, Bilbao, Dr. A. Aguirre Conde, Hospital de Basurto, Bilbao; Dr. S. Salcedo Abizanda, Hospital Valle de Hebron, Barcelona; Dr. J. Vinzo Gil, Hospital Valle de Hebron, Barcelona; Dr. J. Ortiz Tardio, Hospital Gral Jerez de la Frontera, Cádiz; Dr. A. Perez Sanchez, Hospital Virgen del Rocío, Sevilla; Dr. M. C. Macias Díaz, Hospital Virgen del Rocío, Sevilla; Dr. J. López Sastre, Hospital Central de Asturias, Oviedo; Dr. B. Fernández Colomer, Hospital Central de Asturias, Oviedo; Dr. J. Guzman Cabañas, l Hospital Reina Sofía, Córdoba; Dr. L. Garcia, Hospital Severo Ochoa, Leganes-Madrid; Dr. B. Jimenez Cobo, Hospital General de Alicante, Alicante; Dr. R. García Martínez, Hospital General de Alicante, Alicante.

Canada: Dr. K. Sankaran, Royal University Hospital, Saskatoon; Dr. A. Singh, Children & Woman’s Health Centre, Vancouver; Dr. I. Mitchell, Alberta’s Children Hospital, Calgary.

Sweden: Prof. H. Lagercrantz, Dept. of Neonatal Astrid, Stockholm; Dr. I. Tessin, Dept. of Neonatalogy Drottning Silvias Barn-och, Gotenborg.

Poland: Prof. J. Gadzinowski, Katedra I Clinic Neonatal, Poznan; Prof. J. Pietrzyk, Katedra Pediatric Amerykanskiego Institute, Krakow.

The Netherlands: Prof. J. L. L. Kimpen, Wilhelmina Children’s Hospital, Utrecht.

Abbott International: Dr Jessie Groothuis, Dr. P. Pollack, M. McCue, S. Williamsom, M. S. King, D. Morris.

Colorado: Dr. E. A. F. Simoes, The Children,s Hospital, University of Colorado School of Medicine, Denver.

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