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Original Research Pediatrics

Short- and Long-term Pulmonary Outcome


of Palivizumab in Children Born Extremely
Prematurely
Dario Prais, MD; Eytan Kaplan, MD; Gil Klinger, MD; Huda Mussaf, MD; Meir Mei-Zahav, MD; Ephraim Bar-Yishay, PhD;
Patrick Staer, MD; Guy Steuer, MD; Lea Sirota, MD; and Hannah Blau, MBBS

Palivizumab reduces the severity of respiratory syncytial virus infection in


premature infants, but whether there is a protective effect beyond the preschool age is unknown. This study sought to assess the short- and long-term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born
extremely prematurely.

BACKGROUND:

Infants born before 29 weeks gestation in 2000 to 2003 were assessed at school age
by parental questionnaire, hospital chart review, and lung function tests. Children born
immediately before the introduction of routine palivizumab prophylaxis were compared with
age-matched children who received palivizumab prophylaxis during the rst respiratory
syncytial virus season.

METHODS:

Sixty-three children with a mean age 8.9 years were included: 30 had received
palivizumab and 33 had not (control subjects). The groups were similar in terms of
gestational age, birth weight, need for mechanical ventilation, and oxygen supplementation.
Fifty-three percent of the palivizumab group, compared with 39% of the control group, had
bronchopulmonary dysplasia (P .14). Wheezing occurred in the rst 2 years of life
in 27% of the palivizumab group and in 70% of control subjects (P .008); respective
hospitalization rates were 33% and 70% (P .001). At school age, rates of hyperresponsiveness (provocative concentration leading to a 20% fall in FEV1 < 1 mg/mL) were
33% and 48%, respectively (P .38). Spirometry, lung volumes, diffusion, and exhaled nitric
oxide were within normal limits, with no signicant differences between groups.

RESULTS:

Palivizumab prophylaxis was associated with reduced wheezing episodes and


hospitalizations during the rst 2 years of life in children born extremely prematurely.
However, it did not affect pulmonary outcome at school age. CHEST 2016; 149(3):801-808
CONCLUSION:

KEY WORDS:

bronchopulmonary dysplasia; pulmonary function test; respiratory syncytial

virus

ABBREVIATIONS: BPD = bronchopulmonary dysplasia; DLCO =


diffusing capacity of the lung for carbon monoxide; FENO = fraction of
exhaled nitric oxide; KCO = coefcient of diffusion; RSV = respiratory
syncytial virus; TLC = total lung capacity
AFFILIATIONS: From the Pulmonary Institute (Drs Prais, Kaplan,
Mussaf, Mei-Zahav, Bar-Yishay, Staer, Steuer, and Blau) and the
Department of Neonatal Intensive Care (Drs Klinger and Sirota),
Schneider Childrens Medical Center of Israel, Petach Tikva; the
Sackler Faculty of Medicine (Drs Prais, Kaplan, Klinger, Mussaf,
Mei-Zahav, Staer, Sirota, and Blau), Tel Aviv University, Tel Aviv;

journal.publications.chestnet.org

and the Faculty of Health Sciences (Dr Bar-Yishay), Ben Gurion


University of the Negev, Beer Sheba, Israel.
FUNDING/SUPPORT: This work was supported by an investigatorinitiated grant from Abbott.
CORRESPONDENCE TO: Dario Prais, MD, Pulmonary Institute,
Schneider Childrens Medical Center of Israel, Petach Tikva 49202,
Israel; e-mail: prais@post.tau.ac.il
Copyright 2016 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1378/chest.15-0328

801

Viral infections of the respiratory tract in infancy,


particularly by respiratory syncytial virus (RSV), are
associated with recurrent episodes of wheezing in
childhood.1 In addition, prematurity per se leads to
airway hyperresponsiveness,2 and low birth weight is
independently associated with asthma prevalence.3 Our
group reported previously that neurologically intact
extremely premature infants born in the postsurfactant
era had an encouraging pulmonary outcome at school age,
although airway hyperresponsiveness was common.4
Lung function in school-aged children born at term and
hospitalized for RSV infection in infancy was previously
reported.5-7 Sigurs et al7 found evidence of mild airway
obstruction at rest and after bronchodilation and slightly
more airway reactivity than in control subjects.
RSV prophylaxis with palivizumab, a humanized
monoclonal antibody, has been shown to reduce the severity
of RSV infection in premature infants during the rst year
of life.8 Moreover, there is cumulative evidence of a
persistent protective effect beyond the treatment period.
Several studies reported that palivizumab administration
to premature infants was associated with a reduction in

Materials and Methods


Subjects
A prospective cross-sectional study design was used. Participants
included children aged 7 to 10 years who were born at Schneider
Childrens Medical Center of Israel between 2000 and 2003 at a
gestational age below 29 weeks.
In Israel, routine RSV prophylaxis for infants born at < 29 weeks
gestation was introduced in 2001. The rst year of the program was
a transitional period, and implementation was partial. Therefore, for
the current study, we compared children born in 2000 and 2001
who did not receive palivizumab (control group) with children born
in 2001-2003 who received RSV prophylaxis (Synagis; AbbVie Ltd)
(palivizumab group). Clinically, all complied with the Ministry of
Health criteria for administering palivizumab prophylaxis because of
prematurity. Palivizumab was administered according to national
health policy at the time. The current study did not intervene in this
policy but recruited patients in midchildhood who had been
born before and after Synagis immunization had been instituted. A
small number of these patients were included in a previously
published study comparing extremely premature infants with and
without bronchopulmonary dysplasia (BPD) at school age.4 There
was no signicant change in the treatment protocol of the hospitals
neonatal ICU during the study period. To age match the groups,
patients in the control group, who were born earlier, were evaluated
in the rst year of the study, and children in the palivizumab group
were evaluated 1 year later. During the early years of the prophylaxis
program, palivizumab was centrally administered at the daycare
facilities of the discharging hospital. This made it possible for us to
corroborate the immunization status of the recruited subjects.
BPD in infancy was dened as lung disease requiring oxygen
supplementation at age 28 days. BPD severity was graded according
to the oxygen requirement at a corrected gestational age of 36 weeks,

802 Original Research

recurrent wheezing episodes during infancy9-11 and also


in early childhood, particularly in those without atopy.12
These ndings suggest that RSV infection predisposes
patients to ecurrent wheezing via an atopy-independent
mechanism, and this effect may be attenuated by
prophylaxis with palivizumab. On the other hand, the
complex relationship between genetic and environmental
factors has not been elucidated; there is some evidence that
genetic background predisposes to subsequent recurrent
wheezing episodes and asthma following viral infections,
independent of atopic sensitization.13
Whether palivizumab exerts a long-term protective
effect beyond the preschool period remains unknown.
A previous report suggested that RSV immune globulin
prophylaxis may improve airway function and decrease
asthma attacks at school age.14 However, there are no
reports of pulmonary function tests in children who
received RSV palivizumab prophylaxis during infancy.
The aim of the current study was to assess the shortand long-term effects of palivizumab prophylaxis on
respiratory morbidity and pulmonary function in
school-aged children born extremely prematurely.

as follows: mild, no oxygen; moderate, FIO2 0.22-0.30; severe, FIO2


> 0.30 or need for CPAP or mechanical ventilation.15,16
Patients unable to undergo pulmonary function testing for any reason,
including severe developmental delay, were excluded from the study, as
were patients with a severe systemic disease, including cardiac disease.
Patients who had had an intercurrent illness within 2 weeks before
their planned pulmonary function assessment were reassigned a later
date for testing.

Clinical and Demographic Data


Perinatal data were obtained from the Department of Neonatal
Intensive Care. Relevant clinical and demographic data were
extracted from the medical records. The parents of the children
participating in the study completed a questionnaire covering
respiratory symptoms and medical history, and the children were
examined by a physician on the day of lung function testing. The
parental reports regarding hospitalizations during the rst 2 years of
life were conrmed against the electronic medical records at
hospitals within the region.
Measurements
Pulmonary function was measured in the lung function laboratory of
the hospitals Pulmonary Institute according to the American
Thoracic Society guidelines.17,18 Spirometry was performed with a
ZAN100 ow sensor (ZAN Messgerte GmbH), and plethysmography
and measurement of the diffusing capacity of the lung for carbon
monoxide (DLCO) were performed with a constant-volume body
plethysmograph and a DLCO unit (ZAN500; ZAN Messgerte GmbH).
Carbon dioxide diffusion was corrected for alveolar volume, indicated
as KCO. Spirometry and lung volumes were expressed as percent of
predicted normal values using the equations of Polgar and Varuni19 ;
KCO % predicted was calculated as described by Weng and Levison.20

149#3 CHEST MARCH 2016

Methacholine challenge tests were performed with a KoKo spirometer


equipped with a dosimeter (Pulmonary Data Services, Inc) and triple
doses of fresh methacholine solutions in normal saline,21 according to
American Thoracic Society recommendations.22 The fraction of
exhaled nitric oxide (FENO) was measured with a chemiluminescence
analyzer (CLD 77 AM; ECO MEDICS AG) according to the American
Thoracic Society/European Respiratory Society recommendations.23
Statistical Analysis
A sample size of 30 subjects in each group was determined presuming the
following difference in % predicted FEV1 between the groups: 95% 
10.0% vs 85%  10%. A given sample size of 20 infants in each group
and an a of 0.05 (two-tailed) would have a power of 0.87. This means
that 87% of studies would be expected to have a signicant effect,
rejecting the null hypothesis that the two populations means are

Results
Background Characteristics

Sixty-three children aged 8.9 (0.68) years, mean (SD),


were included in the study. The attrition of the index
study group is described in Figure 1. Thirty children
had received palivizumab in infancy and 33 had not.
The background characteristics of the two groups are
presented in Tables 1 and 2. At enrollment, there
were no signicant between-group differences in
demographic parameters. Concerning perinatal
characteristics, it should be noted that in the group
who received palivizumab, there was a higher percentage
of infants with BPD and this was more severe, as
expressed by oxygen requirement, although these
differences did not reach statistical signicance. The
groups were similar in terms of the need for antenatal

equal. Because of possible drop-out, we decided to enroll 30 patients in


each group.
All analyses were performed using BMDP software,24 Data were
described as mean and SD or value and percent. Discrete variables
were compared between groups using the Pearson c2 test or Fisher
exact test, as appropriate. For variables that did not have a Gaussian
distribution, we used the nonparametric Mann-Whitney U test.
Continuous variables were compared across groups using the
Student t test. A P value of # .05 was considered signicant.
Ethics
The institutional review board of Rabin Medical Center approved the
study (approval number 4858). Written informed consent was
obtained from the parents of all subjects.

and postnatal steroid therapy, maternal smoking


during pregnancy, passive exposure to smoke, and
family or personal history of asthma or atopy.
Clinical and Respiratory Symptoms

Short-term Outcome: As shown in Table 3,


palivizumab prophylaxis had a major protective
inuence on short-term respiratory outcomes. In
particular, it was associated with a signicant reduction
in the rate of hospital admissions for respiratory disease
during the rst 2 years of life, from 70% in the control
group to 33% in the palivizumab group (P .001).
Furthermore, all 10 hospitalized patients in the
palivizumab group had a single admission, whereas in
the control group, of the 23 hospitalized patients, 14 had
a single admission and nine had repeated admissions

210 Infants born <28 weeks


2000-2003
57 died
153 discharged

118 suitable

35 excluded
Major congenital malformations (n = 5)
Neurological disorders (intraventricular
hemorrhage 3-4, post-hemorrhagic
hydrocephalus, periventricular leukomalacia)
(n = 30)
19 not located

99 contacted
36 not enrolled
Neurologically handicapped (cerebral palsy,
convulsions, pervasive developmental disorder) (n = 7)
Declined to participate (n = 29)
63 enrolled
Palivizumab group (n = 30)
Control group (n = 33)
Figure 1 Recruitment of subjects in mid-childhood.

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803

TABLE 1

] Perinatal Characteristics of Children Born Extremely Prematurely, by Palivizumab Prophylaxis

Characteristics

Palivizumab Group (n 30)

Male sex

17 (56)

Gestational age, mean (SD), wk

Control Group (n 33)


16 (48)

P Value
.62

26.5 (1.2)

26.7 (1.2)

889 (167)

944 (205)

.25

Surfactant treatment

23 (79)

28 (87)

.49

Maternal antenatal steroids

20 (71)

27 (82)

.37

7 (28)

7 (25)

.98

Birth weight, mean (SD), g

Postnatal steroids
Mechanical ventilation, d

.52

16 (0-58)

8 (0-81)

.17

3 (0-18)

3 (0-44)

.70

O2 support, d

54 (0-540)

33 (2-120)

.07

BPD

16 (53)

13 (39)

.14

9 (31)

4 (13)

.11

.47

CPAP, d

Oxygen support at PCA 36 wk


Discharged home on oxygen, No.

Data are given as No. (%) or median (range) unless otherwise indicated. BPD bronchopulmonary dysplasia; O2 oxygen; PCA postconceptional age.

(total, 32 admissions) (P .001). In addition, the mean


length of stay was shorter for the palivizumab group:
4.6  1.8 days vs 6.4  2.3 days (P .03).
Analysis of the parental response to the questionnaire
revealed that 11 of the children (27%) in the palivizumab
group had had a wheezing episode during the rst 2 years
of life, as opposed to 23 (70%) of the control subjects
(P .008). A diagnosis of asthma by a physician was
reported in 10 children in the palivizumab group (33%)
and in six in the control group (18%) (P .25). A family
history of asthma was found in six children (20%) and
nine children (27%), respectively (P .56).
Long-term Outcome: Wheezing episodes during the
year preceding study enrollment were documented in four
children (13%) in the palivizumab group and six children
(18%) in the control group (P .73). However, the
TABLE 2

number of episodes of upper respiratory tract infection


was lower in the palivizumab group: nine children
(27%) as opposed to 23 children (70%) in the control
group (P < .005). The use of bronchodilators and inhaled
corticosteroids during the year before enrollment was
similar for the two groups: three (10%) vs ve (15%) and
one (3.3%) vs two (6%) respectively, without signicant
difference between the groups (P .71).
Pulmonary Function Tests at School Age

No signicant differences were found at school age


between the palivizumab and control groups in any of
the lung function parameters (Tables 4, 5) or in the
rates of abnormal spirometry tests at rest, positive
methacholine tests, signicant reversibility after
bronchodilation, or FENO levels. The similar lung
function in the two groups also held true on separate

] Demographic Characteristics of Children Born Extremely Prematurely, by Palivizumab Prophylaxis at


Enrollment

Characteristics

Palivizumab Group (n 30)

Male sex
Age,a mean (SD), y

Control Group (n 33)

17 (56)

16 (48)

8.87 (0.6)

8.84 (0.8)

P Value
.62
.85

Weight,a mean (SD), kg

26.7 (5.7)

26.6 (6.1)

.92

Height,a mean (SD), cm

128.6 (6.6)

129.8 (8.2)

.52

BMI-SDS,a mean (SD)

0.32 (1.04)

0.63 (1.36)

.32

Passive smoker
Family history of eczema or allergic rhinitis
Personal history of eczema or allergic rhinitis
Physician-diagnosed asthma
Wheezing episodes during last year

11 (37)

10 (30)

.42

9 (30)

14 (42)

.43

9 (30)

4 (12)

.12

10 (33)

6 (18)

.25

4 (13)

6 (18)

.73

Data are given as No. (%) unless otherwise indicated. SDS SD score.
a
At enrollment for pulmonary function testing.

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149#3 CHEST MARCH 2016

TABLE 3

] Wheezing Episodes and Hospital Admissions Because of Respiratory Illness During the First 2 Years of
Life, by Palivizumab Prophylaxis

Outcome Parameters

Palivizumab Group (n 30)

Subjects with wheezing episodes


Subjects hospitalized
Hospital admissions, No.

Control Group (n 33)

P Value

8 (26.7)

23 (69.7)

.008a

10 (33.3)

23 (69.7)

.001a

10

32

.001a

RSV-positive admissions

2 (20.0)

19 (59.3)

.033a

Subjects hospitalized during RSV season

5 (16.6)

21 (63.6)

.001a

Length of stay, mean (SD), d

4.6 (1.8)

.03b

6.4 (2.3)

Data are given as No. (%) unless otherwise indicated. RSV respiratory syncytial virus.
a
Fisher exact test.
b
Student t test.

analysis of the children born before 26 weeks gestation


(n 16 in the palivizumab group, n 14 in the control
group) or with severe BPD (requiring oxygen support
at postconceptional age 36 weeks) (n 9 in the
palivizumab group, n 4 in the control group). No
signicant difference was found between BPD and
non-BPD subjects within the palivizumab group. There
was also no signicant difference in late lung function
between children with or without a family or personal
history of eczema or allergic rhinitis (Table 6).

Discussion
The current study investigated the impact of palivizumab
prophylaxis on the short- and long-term pulmonary
TABLE 4

outcome of infants born extremely prematurely. To


the best of our knowledge, this is the rst study of
palivizumab to include pulmonary function assessment
at school age. It is unique because of the opportunity
provided to enroll children who had been born extremely
prematurely with similar perinatal management, who
were born immediately before or after national
implementation of routine RSV prophylaxis.
The short-term results showed a marked protective effect
of palivizumab on pulmonary morbidity during the rst 2
years of life, as demonstrated by a signicant reduction in
hospital admissions and wheezing episodes. However, by
the time the children reached school age, no signicant

] Spirometry and Bronchial Responsiveness at School Age


Palivizumab Group

Parameters

Control Group

P Value

FVC % predicted, mean (SD)

30

89 (12)

32

89 (11)

.94

FEV1 % predicted, mean (SD)

30

84 (13)

32

84 (11)

.87

Subjects with FEV1 % predicted < 80%, No. (%)

30

8 (27)

32

6 (19)

.54

FEV1/FVC ratio, mean (SD)

30

0.9 (0.1)

32

0.9 (0.1)

.75

% change in FEV1 after bronchodilation,


median (range)

26

0 (20 to 40)

30

3.6 (4 to 20)

.43

Subjects with signicant reversibility,a No. (%)

26

4 (15)

30

4 (13)

1.00

FEF50% % predicted, mean (SD)

30

78 (27)

32

78 (27)

1.00

FEF25%-75% % predicted, mean (SD)

30

78 (28)

32

76 (29)

.79

% change in FEF25%-75% after bronchodilation,


median (range)

26

15 (11 to 115)

30

22 (6 to 79)

.70

PC20, median (range), mg/mL

24

2.95 (0.24 to 16)

23

2.5 (0.15 to 16)

.72

Subjects with positive methacholine


test,b No. (%)

24

15 (62)

23

15 (65)

.84

PC20 < 1 mg/mL, No. (%)

24

8 (33)

23

11 (48)

.38

FEF25%-75% forced expiratory ow at 25% to 75% of FVC; FEF50% forced expiratory ow at 50% of FVC; PC20 provocative concentration leading to a
20% fall in FEV1.
a
> 10% change in FEV1 after bronchodilation.
b
Positive methacholine test: PC20 < 4 mg/mL.

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805

TABLE 5

] Lung Volumes, Diffusion, and Exhaled Nitric Oxide at School Age


Palivizumab Group

Parameters

Control Group

P Value

TLC % predicted, mean (SD)

28

101 (14)

29

104 (13)

.30

RV % predicted, mean (SD)

28

128 (45)

29

145 (38)

.13

RV/TLC ratio, mean (SD)

28

FRC % predicted, mean (SD)

28

136 (32)

29

129 (22)

.36

KCO % predicted, mean (SD)

17

93 (8)

26

90 (12)

.42

FENO, median (range), ppb

28

Subjects with FENO > 8 ppb, No. (%)

28

0.28 (0.08)

9.4 (2.0-33.2)
7 (25)

29

0.31 (0.06)

33

8.0 (3.0-64.7)

33

9 (27)

.10

.75
1.00

FENO fraction of exhaled nitric oxide; FRC functional residual capacity; KCO coefcient of diffusion; ppb parts per billion; RV residual volume;
TLC total lung capacity.

differences were found in pulmonary function between


the groups, indicating that palivizumab had an early but
not a long-term protective effect on this population. Our
study population included very premature infants, and
our data cannot be extrapolated to the potential effect of
palivizumab given to term babies.
RSV infection has severe implications for the
extremely premature lung, including epithelial cell
necrosis, ciliary destruction, submucosal inammation
and edema, mucus secretion, and bronchiolar plugging,
leading to airway obstruction.24 Considering these
pathophysiologic effects of RSV in prematurely born
children, recurrent wheezing episodes in these infants
should not be considered asthma. Beyond its immediate
pathogenicity, RSV infection in mice was also associated
with long-term airway hyperresponsiveness,25 which
was probably a consequence of the direct insult to the
airway rather than an indirect effect of atopy.5 The latter
assumption was supported by a large clinical study
wherein palivizumab treatment reduced subsequent

TABLE 6

recurrent wheeze in children aged 2 to 5 years without a


family history of atopy, but not in infants with a family
history of atopy.12 Furthermore, in a recent randomized,
double-blind, placebo-controlled trial, palivizumab
prophylaxis given to late-premature infants led to a
signicant decrease in the total number of wheezing
days and RSV-infection-related hospitalizations during
the rst year of life.10 Our ndings are compatible
with those of these earlier studies, showing a marked
protective effect of palivizumab extending over the rst
2 years of life, regardless of family history of atopy.
Thus, palivizumab may act by preventing the direct
airway insult caused by RSV infection that provokes
hyperresponsiveness and wheezing.
We did not nd differences between the palivizumab
and control groups at school age regarding pulmonary
function at review or respiratory symptoms or use of
bronchodilators during the year before enrollment.
Thus, there did not appear to be a difference in the
development of asthma at this time. It appears from the

] Pulmonary Function Tests at School Age in Patients With a Family History of Atopy, Eczema, or
Allergic Rhinitis
Palivizumab Group

Parameters

Control Group

P Value

FVC % predicted, mean (SD)

10

94.7 (10.2)

15

91.9 (10.1)

.56

FEV1 % predicted, mean (SD)

10

92.1 (10.9)

15

88.8 (8.4)

.68

2.9 (20 to 15)

14

2.7 (2.4 to 12)

.26

87.3 (30.2)

15

84.8 (30.4)

.87

% change in FEV1 after bronchodilation,


median (range)
FEF25%-75% % predicted, mean (SD)

8
10

% change in FEF25%-75% after


bronchodilation, median (range)

24.6 (5 to 46)

14

18.9 (6 to 53)

.51

FENO, median (range), ppb

9.0 (4.7 to 17.4)

15

17.2 (3.0 to 64.7)

.15

PC20, median (range), mg/mL

4.1 (1.7 to 12.9)

13

4.62 (0.2 to 15)

.96

See Tables 4 and 5 for expansion of abbreviations.

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149#3 CHEST MARCH 2016

data that RSV prophylaxis has no effect on long-term


airways reactivity. Almost all values were within the
clinically normal range in both groups, although both
showed reversibility of mild small-airway obstruction
and some air trapping. There are several possible reasons
for the lack of a difference between the groups. First,
others have found that the deleterious effect of RSV on
long-term wheezing appears to be nonsignicant by age
13 years5 and may already be receding by age 7 to 10
years. If this is correct, palivizumab would not be
expected to effect a change. Second, the generally good
pulmonary outcome of our extremely preterm
population may make that population less susceptible to
long-term impairment caused by RSV infection despite
signicant early RSV-related morbidity. Finally, the
palivizumab group tended to have a lower birth weight
and more BPD and oxygen requirement at baseline,
although this did not reach signicance. Possibly,
palivizumab provided some form of protective effect in
these infants with BPD because their lung function was
not lower than that of the control group. In contrast to
our ndings, another study suggested that RSV
prophylaxis was associated with a mild protective effect
on airway obstruction at school age as expressed by
FEV1/FVC.14 However, that study was performed a
decade earlier, prior to the introduction of routine
surfactant therapy, and it included children with worse
lung disease who could have been more susceptible to an
RSV insult. Furthermore, those children had received
RSV-enriched immune globulin, and not palivizumab,
which is a monoclonal antibody. That preparation
contained additional immunoglobulins that exerted
other anti-infective or antiinammatory effects, as
suggested by the reduction in episodes of otitis media.26
As demonstrated in our previous study,4 children born
with extreme prematurity display increased airway
hyperresponsiveness at school age, although without
evidence of eosinophilic inammation, as indicated by

journal.publications.chestnet.org

the normal FENO measurements. In the current study,


palivizumab neither prevented nor reduced this
hyperresponsiveness. It is possible that bronchial
hyperactivity in such premature infants is related to the
extreme prematurity of the lung itself rather than to
ongoing inammation. Lung immaturity per se can result
in excessive shortening of airway smooth muscle, changes
in the elastic or tethering forces of the surrounding lung
parenchyma, and changes in the airway epithelium.27,28
As such, it is not surprising that palivizumab prophylaxis
against RSV infection had no effect on this outcome.
The limitations of the current study include the
relatively small group of enrolled subjects from a single
tertiary center. As a result, we recruited the maximal
number of subjects available and did not attempt to
achieve matching beyond the criteria of gestational age
and age at enrollment. An additional limitation was
our use of retrospective recall questionnaires as a source
of data on some of the early effects of palivizumab.
However, the parental hospitalization reports were
veried against the electronic medical database. It is
likely that parents of prematurely born infants well
remember every hospital admission during the rst
years of life. Last, we lacked data on overall RSV
infection rates in our cohort. However, this study was
not focused on the efcacy of palivizumab in preventing
early RSV infection, and there is no reason to infer that
either of the groups would have been underexposed to
RSV, thereby skewing the results.

Conclusions
Palivizumab prophylaxis was associated with reduced
hospital admissions and wheezing episodes during the
rst 2 years of life in children born with extreme
prematurity. However, it did not change the long-term
pulmonary outcome, including airway hyperreactivity, as
measured by pulmonary function testing at school age.

807

Acknowledgments
Author contributions: D. P. and H. B. had
full access to all the data in the study and take
responsibility for the integrity of the data and
the accuracy of the data analysis, including
and especially any adverse effects. D. P. and
H. B. contributed to the study conception and
design, patient recruitment, data collection,
analysis and interpretation of the data,
drafting of the initial manuscript, and
approved the nal manuscript as submitted.
E. K. contributed to patient recruitment, data
collection, analysis and interpretation of the
data, and revision of the manuscript, and
approved the nal manuscript as submitted;
E. B.-Y. contributed to data collection,
analysis and interpretation of the data, and
revision of the manuscript, and approved the
nal manuscript as submitted; G. K., H. M.,
M. M.-Z., P. S., G. S., and L. S. contributed
to interpretation of the data and revision
of the manuscript, and approved the nal
manuscript as submitted.
Financial/nonnancial disclosures: None
declared.
Role of sponsors: The sponsor had no role in
the design of the study, the collection and
analysis of the data, or the preparation of the
manuscript.
Other contributions: We thank the children
and their families for participating in a long
day of lung function testing. We thank Pearl
Lilos, BSc, for her dedicated statistical
analysis, Yelena Matyashuk and Nassrin
Gabarra for the meticulous performance of
the pulmonary function tests, and Ruthy
Erelboim for her secretarial assistance.

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