Keywords respiratory syncytial virus - palivizumab - chronic lung disease
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory illness
among infants, resulting in annual epidemics worldwide. RSV infection is a significant
health care issue for infants in the early months of life, and especially in those
born prematurely. Hospitalizations and outpatient visits for community-acquired RSV
infections are associated with significant health care costs and resource usage. The
management of RSV-related illness has remained largely unchanged in the last decades,
and is mainly supportive. The monoclonal antibody palivizumab is the only agent marketed
and approved for RSV prophylaxis, but its use is restricted to high-risk children
(preterm-born infants, children with chronic lung disease [CLD] of prematurity, children
with hemodynamically significant congenital heart disease [HSCHD], and those with
neuromuscular disease).[1 ]
[2 ] A Cochrane's review published in 2013 concluded that palivizumab is effective in
reducing the incidence of RSV-related hospitalizations (RSVH) for severe lower respiratory
tract infections involving children with chronic lung disease or congenital heart
disease, or infants born preterm. It is worth noting that the Cochrane's review considered
all infants born preterm as a single group, irrespective of their gestational age
at birth.[3 ] Guidance for palivizumab prophylaxis from the American Academy of Pediatrics, updated
in 2014, did not include preterm infants born at > 29 weeks of gestation (wGA) in
the recommendations to receive that treatment, unless there were comorbidities involved.[4 ]
In Italy, palivizumab was administered to all premature infants born at < 32 wGA and
also to those born at 33 to 35 wGA if they had certain additional risk factors up
until 2016. Then the Italian Drug Agency (Agenzia Italiana del Farmaco [AIFA]) downgraded
palivizumab reimbursement to include only premature infants born at < 29 wGA. The
concomitant update on the scientific recommendations issued by the Italian Society
of Neonatology took a different approach, continuing to recommend palivizumab administration
for infants born between 29 and 32 wGA.[5 ] While it is hard to establish a definite gestational age “threshold” distinguishing
between high-risk and low-risk infants, current evidence in the literature indicates
that preterm infants born at 29 to 35 wGA are all at risk of severe RSV-related disease
than term-born infants, particularly in the early months of life.[6 ] Lanari et al demonstrated that the risk estimates for hospital admissions due to
bronchiolitis doubled for infants born at 33 to 34 wGA compared with those born at
term.[7 ] A recently-published observational cohort study, the SENTINEL study, investigated
the burden of severe RSV-related disease in infants born at 29 to 35 wGA who were
not given palivizumab; it showed that earlier GA and younger chronological age were
associated with the highest risk of severe RSV-related disease in terms of hospitalizations,
admission to intensive care units, and need for mechanical ventilation.[8 ] There is, therefore, a discrepancy between the scientific recommendations and the
rules governing eligibility for palivizumab reimbursement. The scientific societies
have encouraged the production of more data and further studies to clarify this conflicting
issue.
With this perspective, we designed a study to compare the incidence of RSVH among
infants born at 29 to 35 wGA in the season before (2015–2016) or after (2016–2017)
the introduction in 2016 of the AIFA's more restricted recommendations for palivizumab.
Materials and Methods
This retrospective observational cohort study was conducted at three neonatal intensive
care units (NICUs) in northern Italy. All Infants born at 29 to 35 wGA during two
consecutive epidemic seasons were identified from birth registries and health service
administrative data.
Season 1 included infants born at 29 to 35 wGA between March 15, 2015 and March 14,
2016. These infants would have received palivizumab based on the following criteria:
(1) prematurity < 326/7 wGA and < 12 months old; (2) birth at 33 to 35 wGA and additional risk factors (exposure
to smoke, treatment with surfactant, living with siblings < 10 years old, attendance
at daycare), and < 12 months old; (3) CLD and < 12 months old; (4) CLD and < 24 months
old when medical therapy was required at the start of the season; (5) HSCHD and < 12
months old; and (6) neuromuscular diseases, congenital abnormalities of the airways,
or immune deficiency, and < 12 months old.
Season 2 concerned infants born at 29 to 35 wGA between March 15, 2016 and March 14,
2017. This group would have received palivizumab in the case of: (1) prematurity < 296/7 wGA and < 12 months old; (2) CLD and < 12 months old; (3) CLD and < 24 months old
when medical therapy was required at the start of the season; (4) CHD and < 12 months
old; and (5) neuromuscular diseases, or congenital abnormalities of the airways, or
immune deficiency, and < 12 months old.
The following information on the patient's neonatal characteristics and clinical course
while at the NICU was obtained from electronic medical charts: GA and birth weight,
need for mechanical ventilation, diagnosis of CLD or HSCHD, indications for palivizumab
prophylaxis, number of doses, mode of administration, and compliance. Infants with
major congenital anomalies other than HSCHD were excluded from the study.
Palivizumab (Synagis, AbbVie Srl, Aprilia, Italy) 15 mg/kg was administered in five
monthly courses over the epidemic seasons (from late November to late March) according
to existing protocols and guidelines.[5 ] The same timing and dosage were used for all infants, regardless of their GA and/or
underlying conditions. None of the infants were treated out of season.
Cases of bronchopulmonary dysplasia (BPD) were identified from the medical records
in compliance with the criteria stipulated by the consensus definitions of BPD.[9 ] The HSCHD was defined as uncorrected, or palliated cyanotic or acyanotic CHD with
pulmonary hypertension (systolic pulmonary arterial pressure > 40 mm Hg), or need
for medication to manage congestive heart failure, and the diagnosis was confirmed
by a pediatric cardiologist.[10 ]
Parents of eligible infants were interviewed by telephone through a questionnaire
to collect additional information about the number and age of siblings at home, daycare
attendance, breastfeeding, exposure to smoke, and hospitalizations for respiratory
infections during the 1st year of life. A risk factor score was calculated, scoring
one point for each of the following: (1) more than two siblings at home; (2) daycare
attendance; (3) no breastfeeding, or breastfeeding for less than 2 months; (4) parental
smoking; and (5) discharge from the NICU in the epidemic season. When hospital admissions
for respiratory infections were reported, parents were invited to provide all related
medical records. A thorough review of this clinical documentation was performed to
check whether these hospitalizations were related to RSV infection or not (as primary
and secondary outcomes, respectively).
RSVHs were defined as symptomatic admissions to hospital for deep or wet chest cough,
wheezing, hoarseness, stridor, or shortness of breath. RSV positivity was confirmed
by enzyme or immunofluorescent assay, polymerase chain reaction, or a positive viral
culture for RSV from nasopharyngeal secretions.[11 ]
For the purpose of this study, only the first episode of RSVH in each infant was considered.
The infants' age at the time of their RSVH, and the need for mechanical ventilation
or admission to the NICU were also recorded.
Informed consent for the collection of the infants' medical data was obtained from
parents shortly after birth and confirmed at the time of the telephone interview.
Statistical Analysis
The demographic and clinical data examined are reported as counts (percentages) for
categorical variables and mean ± standard deviation (SD) for normally-distributed
continuous variables. Proportions and continuous variables were compared using Fisher's
exact two-tailed test and the t -test, respectively. Specifically, the association between RSVH and season (classified
as a dichotomous variable: season 1/season 2) was assessed with Fisher's exact test.
RSVH risk ratios and corresponding 95% confidence intervals (CIs) were calculated
to compare between-group cumulative incidences, and odds ratios (ORs) were computed.
All tests were two-tailed, and a p < 0.05 was assumed to indicate statistical significance. All analyses were run using
the SPSS software, version 13.0 (SPSS Inc, Chicago, IL).
Results
[Fig. 1 ] shows the patient flow between 2015 and 2017. A total of 632 eligible infants identified
from the birth registries at the three centers, 314 in season 1 and 318 in season
2, were considered for this study. Data were unavailable for 96 patients (52 in season
1 and 44 in season 2) because parents could not be interviewed or contacted, or refused
consent. The sample included in the final analysis thus consisted of 536 infants (262
in season 1 and 274 in season 2).
Fig. 1 Study flow chart. wGA, weeks of gestational age.
[Table 1 ] shows the baseline characteristics and demographic features of the infants in the
two seasons. There were no significant differences between the two groups in terms
of mean gestational age, birth weight, multiple pregnancies, need for mechanical ventilation
during NICU stay, proportion of infants with HSCHD, or risk factor scores. The only
difference concerned the proportion of infants discharged with a diagnosis of BPD,
which was significantly higher in the second season.
Table 1
Infant baseline characteristics and hospital admissions for respiratory infections
proportions
Season 1
2015–2016
n = 262 (%)
Season 2
2016–2017
n = 274 (%)
OR
95% CI
p -Value
Gestational age (days), mean (±SD)
229 (±10.9)
228 (±11.6)
–
–
0.54
Birth weight (grams), mean (SD)
1,803 (±441.4)
1,768 (±492.9)
–
–
0.39
Mechanical ventilation during NICU stay (at least 24 hours)
101/262 (38.5)
106/274 (38.6)
–
–
0.98
CLD
0/262 (0)
12/274 (4.4)
–
–
< 0.001
HSCHD
6/262 (2.3)
8/274 (2.92)
–
–
0.37
Multiple pregnancies
87/262 (33.2)
92/274 (33.6)
–
–
0.92
Patients not exposed to palivizumab
167/262 (63.7)
221/274 (80.6)
–
–
< 0.001
Risk factor score[a ]
–
–
0.85
0
28/262 (10.7)
29/274 (10.6)
–
–
–
1
83/262 (31.7)
95/274 (34.7)
–
–
–
2
91/262 (34.7)
95/274 (34.7)
–
–
–
3
51/262 (19.5)
44/274 (16.1)
–
–
–
4
9/262 (3.4)
11/274 (4.0)
–
–
–
RSVH among all infants
5/262 (1.91)
14/274 (5.11)
2.77
0,98–7.80
0.045
RSVH among infants not exposed to palivizumab
3/167 (1.80)
13/221 (5.88)
3.42
0.96–12.20
0.045
RSVH among infants exposed to palivizumab
2/95 (2.10)
1/53 (1.88)
1.09
0.67–1.35
0.88
Hospitalizations for bronchiolitis unrelated to RSV
11/262 (4.20)
14/274 (5.11)
–
–
0.63
Abbreviations: CI, confidence interval; CLD, chronic lung disease; HSCHD, haemodynamically
significant congenital heart disease; NICU, neonatal intensive care unit; OR, odds
ratio; RSV, respiratory syncytial virus; RSVH, hospitalization due to RSV; SD, standard
deviation.
Note: Data are unless otherwise stated as n (%).
a Risk factor score was calculated, scoring one point for each of the following: (1)
more than two siblings at home; (2) daycare attendance; (3) no breastfeeding, or breastfeeding
for less than 2 months; (4) parental smoking; and (5) discharge from the NICU in the
epidemic season.
The proportion of infants was not exposed to palivizumab increased significantly from
63.7% in season 1 to 80.6% in season 2 (p -value < 0.0001). Similarly the proportion of infants hospitalized for confirmed RSV-related
respiratory infections rose from 5 (1.9%) of 262 infants in season 1 to 14 (5.1%)
of 274 infants in season 2 (OR = 2.77; 95% CI: 0.98–7.78; p -value = 0.045). When only the infants not exposed to palivizumab were considered,
a similar increase emerged from 3 (1.8%) of 167 infants in season 1 to 13 (5.9%) of
221 infants in season 2 (OR = 3.42; 95% CI: 0.96–12.20; p -value = 0.044).
In contrast, there was no significant difference between the two seasons in the incidence
of hospital admissions for low respiratory tract infection caused by respiratory viruses
other than RSV.
In accordance with AIFA and scientific society recommendations, all infants with BPD
in either season were given palivizumab. Only one episode of RSVH occurred among these
infants, and it happened in season 1. This clearly means that there was no impact
on the above-mentioned results attributable to the increase in the number of BPD patients
in season 2, as previously reported.
It is worth noting that the 14 episodes of RSVH occurring in season 2 affected infants
with gestational ages of 31 weeks (three cases), 32 weeks (two cases), 33 weeks (two
cases), 34 weeks (two cases), and 35 weeks (five cases), whereas the five episodes
occurring in season 1 involved infants with gestational ages of 31 weeks (one case),
33 weeks (three cases), and 34 weeks (one case).
Discussion
The present study assessed the burden of RSVH for infants born at 29 to 35 wGA and
discharged from three NICUs in northern Italy during two consecutive seasons in which
two different palivizumab prophylaxis allocation policies were adopted following changes
to AIFA's reimbursement policies. It emerged that the overall incidence of RSVH increased
significantly in the season 2, when eligibility for prophylaxis with palivizumab free
of charge was restricted to infants born < 29 wGA and denied to those with gestational
ages between 29 and 35 weeks.
Our results confirm and reinforce similar reports from other countries and health
care settings. In the U.S.A., Rajah et al found a significant increase in the number
of RSVH involving infants up to 6 months old born at 29 to 346/7 wGA after the implementation of the 2014 recommendations of the American Academy
of Pediatrics, as well as an increased morbidity (in terms of the need for oxygen
supplementation, admission to pediatric intensive care units, mechanical ventilation,
and length of hospital stay) in 29 to 34 6/7 wGA in < 3 months old infants.[12 ] Likewise, in a single-center study from Italy that retrospectively reviewed the
records for children ≤12 months old admitted to hospital for RSV-induced lower respiratory
tract infections from 2014 to 2017, there was a higher proportion of admissions for
infants born < 36 wGA, and a greater need for high-flow nasal cannula ventilation
in the 2016 to 2017 epidemic season (after more restrictive palivizumab allocation
policies had been implemented) than in the previous two seasons.[13 ] In Italy, the birth rate is approximately 450,000/year, and it is estimated that
some 5% of infants are born at between 29 and 35 wGA, that is, approximately 22,500
newborns. Assuming a 3.2% increase in RSVH, as suggested by the results of our analysis,
we should expect an increase of approximately 720 admissions in a year in this subgroup
of premature infants. Though a thorough economic analysis goes beyond the scope of
this study, our findings indicate that it is mandatory to consider the health care
costs resulting from excessively restrictive rules covering the prescription of palivizumab.
Our conclusion is consistent with the report from Zuccotti and Fabiano, who performed
an economic impact analysis on RSV-related hospitalization and clinical examinations
for infants < 3 years old, and concluded that extending the prophylaxis to infants
born at 29 to 32 wGA up until they are 6 months old is a cost-effective strategy.[6 ] Besides there is the indirect burden of RSV-related infections to consider, including
social costs, parental burden,[14 ] and long-term respiratory sequelae. It is well known that RSV infection, especially
when severe, is a risk factor for recurrent wheezing, asthma, and overall lung function
impairment. The multicenter, randomized controlled MAKI trial performed by the Dutch
RSV Neonatal Network showed a 61% relative reduction in the number of wheezing days
during the 1st year of life in infants born at 33 to 35 wGA who were exposed to palivizumab
as opposed to placebo.[15 ] Mochizuki et al also documented a significant reduction in the prevalence of wheezing
at 6 years of age in a group treated with palivizumab versus placebo (15.3 and 31.6%).[16 ] These data point to the real advisability of preventing severe RSV-related infections
in infants (especially those at high risk) to limit late negative outcomes of early
exposure to this pathogen.
It is worth emphasizing that the restrictions on eligibility for palivizumab reimbursement
in season 2 led to a significant increase in RSVH, but had no impact on hospital admissions
for other respiratory viruses. This is important in that it rules out the possible
influence, for instance, of other environmental conditions relating to respiratory
viruses circulating in the community, or of an overall higher risk of respiratory
disorders in the study population in season 2, to justify the excess number of RSVH.
Limitations
We acknowledge that our study has some limitations. Due to the small size of the samples
of infants, who experienced an episode of RSVH, it was impossible to stratify the
risk by gestational age at birth. In addition, data collection was based on a search
for birth data and telephone interviews, so the study is prone to recall bias. We
are, nonetheless, convinced that a hospital admission is a memorable event for an
infant's parents and unlikely to be overlooked by the questionnaire that we administered
to parents, whose compliance in answering the interview questions and coming to the
center in the event of hospitalization was generally good.
Conclusion
In conclusion, the results of our study confirm previously-published evidence, and
underscore the fact that all preterm-born infants, regardless of their gestational
age, are highly vulnerable to severe RSV-related infections. In addition, this study
shows that the incidence of RSVH increases significantly when eligibility for palivizumab
prophylaxis is restricted. Clinicians and policy-makers should carefully consider
the cost-benefit balance concerning palivizumab prophylaxis, and be aware that a limited
coverage is likely to bring a surge in RSVH for infants not receiving it.
