Received: 8 April 2020 | Revised: 22 October 2020 | Accepted: 26 October 2020

DOI: 10.1111/apa.15641

REGULAR ARTICLE

Hospitalisations due to respiratory syncytial virus infection in

children with Down syndrome before and after palivizumab
recommendation in Japan

Keisuke Okamoto1 | Tomohiro Morio1 | Yoshikazu Nakamura2 | Hiroshi Hataya3 |

Koichi Mizuta4 | Masaaki Mori5

1
Department of Pediatrics and
Developmental Biology, Graduate School of Abstract
Medical and Dental Sciences, Tokyo Medical Aim: Down syndrome has been considered an independent risk factor for respiratory
and Dental University, Tokyo, Japan
2 syncytial virus (RSV) infection. Palivizumab, an anti-RSV humanised monoclonal an-
Department of Public Health, Jichi Medical
University, Shimotsuke, Japan tibody, was currently approved for all children with Down syndrome in Japan. To in-
3
Department of General Pediatrics, Tokyo vestigate the change in RSV-associated hospitalisation (RSVH) rates before and after
Metropolitan Children's Medical Center,
Tokyo, Japan
the universal approval of palivizumab in Japan in 2013, we conducted a nationwide
4
Department of Transplant Surgery, Jichi retrospective survey.
Medical University, Shimotsuke, Japan Methods: We conducted a nationwide, retrospective, questionnaire survey across
5
Department of Lifetime Clinical
paediatric institutions in Japan. The recruited children with Down syndrome were
Immunology, Graduate School of Medical
and Dental Sciences, Tokyo Medical and divided into two groups: those born April 2010 to March 2013 (2010–2012 cohort)
Dental University, Tokyo, Japan
and those born April 2013 to March 2016 (2013–2015 cohort).
Correspondence Results: Of the 664 institutions, 321 (48.3%) replied, and a total of 3929 children
Masaaki Mori, Department of Lifetime
with Down syndrome were registered. The percentage of children who received
Clinical Immunology, Graduate School of
Medical and Dental Sciences, Tokyo Medical palivizumab increased from 49.2% to 82.2%. The cumulative RSVH rate showed a
and Dental University, 1-5-45 Yushima,
decreased trend in the 2013–2015 cohort (OR, 0.83; 95%CI, 0.63–1.10), while the
Bunkyo-ku, Tokyo 113-8519, Japan.
Email: mori.phv@tmd.ac.jp rate of these children (without CHD and born at a gestational age ≥ 36 weeks) was
Funding information significantly decreased in the 2013–2015 cohort (OR, 0.56; 95%CI, 0.34–0.92).
This study was supported by a grant from
Conclusion: The cumulative RSVH rate tended to be decreased after approval for all
AbbVie (10286) Inc
children with Down syndrome although the result was not significant.

KEYWORDS

acute lower respiratory infections, Down syndrome, Japan, palivizumab, respiratory syncytial
virus

Abbreviations: RSV, respiratory syncytial virus; CHD, congenital heart disease; ALRI, acute lower respiratory infections; RSVH, RSV-associated hospitalisation; GA, gestational age; MV,
mechanical ventilation; ICU, intensive care unit; OR, odds ratio; CI, confidence interval; HR, hazard ratio.

©2020 Foundation Acta Pædiatrica. Published by John Wiley & Sons Ltd

Acta Paediatrica. 2020;00:1–8.  wileyonlinelibrary.com/journal/apa | 1

2 |
1 | I NTRO D U C TI O N
Down syndrome is the most common chromosomal abnormality
among live-born infants and has an estimated annual prevalence of
22 per 10,000 births in Japan.1 The prevalence of Down syndrome
live births in Japan shows a slight increase which is higher than other
countries.1 Children with Down syndrome have anatomical and
physiological abnormalities which contribute to an increased sus-
ceptibility to respiratory infections. They are more likely to experi-
ence a severe course of respiratory-related illness which can even
lead to death. 2–4
Respiratory syncytial virus (RSV) is the most common viral
pathogen in young children, especially those younger than five years
of age, with acute lower respiratory infections (ALRI). 5,6 Respiratory
syncytial virus is associated with about 28% of ALRI episodes and
13%–22% of ALRI mortality in young children.5 The availability of
vaccines against bacterial pneumonia including Pneumococcus has
reduced child ALRI morbidity, which increased the proportional
contribution of viral pathogens such as RSV.6,7 However, there is no
available vaccine for RSV. The only prophylaxis for severe RSV in-
fection is palivizumab, an anti-RSV humanised monoclonal antibody.
This drug is administered once a month throughout the epidemic pe-
riod of RSV infection as a prophylactic measure, but initial approval
was limited to children with high-risk comorbidities such as prema-
turity and CHD.
The burden of RSV-associated ALRI in children with Down
syndrome aged two years or under has recently been identified
by several reports. 8–21 Thus, children with Down syndrome who
develop RSV-associated ALRI have a significantly higher risk of
hospitalisation and experience a severe course of illness with
attendant mortality. The children with Down syndrome without
CHD also have a higher risk of hospitalisation.17–21 However, the
current recommendations for palivizumab prophylaxis differ be-
22–25
tween countries. Outside Japan, the approval of palivizumab
is mainly limited to children with high-risk comorbidities such as
prematurity and CHD, administration of palivizumab to children
with Down syndrome without significant comorbidities is ap-
12,22–24
proved only in some provinces of Canada. Therefore, the
data on the use of palivizumab for children with Down syndrome
without significant underlying disorders are scarce. In Japan, na-
tional health insurance coverage for palivizumab was approved
in 2002 for RSV immune prophylaxis in preterm infants and chil-
dren with bronchopulmonary dysplasia and in 2005 for children
with CHD. In 2013, palivizumab was additionally approved for
children ≤24 months of age with Down syndrome or immuno-
compromised conditions. 25 To the best of our knowledge, this
is the first approval of palivizumab for all children with Down
syndrome at a national level, irrespective of underlying medical
conditions.
We conducted a nationwide retrospective survey in Japan to
determine the change in the RSV-associated hospitalisation (RSVH)
rate before and after the approval of palivizumab for all children with
Down syndrome in 2013.
OKAMOTO et al.
Key notes
• We retrospectively analysed whether the approval of
palivizumab in 2013 for all children with Down syn-
drome in Japan affected respiratory syncytial virus re-
lated hospitalisation (RSVH) rates.
• The cumulative RSVH rate in participants showed a de-
creased trend after palivizumab approval although the
result was statistically insignificant.
• The analysis of only children newly approved to receive
palivizumab (children without significant comorbidities)
showed a significant decrease in the RSVH rate.
2 | M E TH O DS
2.1 | Data collection
Questionnaires were sent to 664 medical institutions with paediatric
departments throughout Japan selected as previously reported. 26
The institutions mainly included teaching hospitals with paediatric
residency programmes. By questionnaire, we collected clinical data
on children with Down syndrome born between April 2010 and
March 2016.
Clinicians completed questionnaires retrospectively with ref-
erence to medical records (Table S1). Questionnaire items for each
child with Down syndrome were birth month and year, gestational
age (GA) at birth, presence of complications (CHD, haematological
disease, immunologic dysfunction, severe muscle hypotonia), his-
tory of recurrent ALRI, prophylaxis with palivizumab and RSVH. For
those children with Down syndrome who had a record of RSVH, we
obtained their age, length of hospital stay, and diagnosis at hospital-
isation, utilisation and duration of oxygen therapy, mechanical ven-
tilation (MV), intensive care unit (ICU) admission and outcome. The
answers to the questionnaire were based on the opinions of partic-
ipating doctors, and the definitions of each item were not included
in the questionnaire. We excluded data from children with Down
syndrome that lacked detailed information. The study protocol was
approved by the Institutional Review Board of Tokyo Medical and
Dental University (No. M2015-502, approved on January 29, 2016).
2.2 | Analyses and outcomes
To analyse the RSVH rate before and after approval of palivizumab
for all children with Down syndrome in 2013, we divided the partici-
pants into two groups: those born April 2010 to March 2013 (2010–
2012 cohort) and those born April 2013 to March 2016 (2013–2015
cohort).
We compared the characteristics of both groups. We also
compared cumulative RSVH rates in both groups up to two years
of age. For subgroup analyses, we analysed the same outcomes
OKAMOTO et al. | 3

among children with Down syndrome with CHD, born prematurely TA B L E 1 Characteristics of RSV-associated hospitalised children
(GA ≤ 35 weeks), or receiving palivizumab, respectively. We also an- with Down syndrome before and after the approval of palivizumab
for all children with Down syndrome
alysed cumulative RSVH rates among children with Down syndrome
newly approved to receive palivizumab in 2013 (without CHD and 2010–2012 2013–2015
born at GA ≥ 36 weeks). cohort cohort

In addition, we conducted an analysis by the Cox proportional Characteristics (n = 1968) (n = 1961) p value
hazard model to estimate relationships between RSVH and potential
Gestational age
predictors, including GA, CHD, haematological disease, history of
≤28 weeks 15 (0.8) 17 (0.9) 0.83
recurrent ALRI and palivizumab use. To examine disease severity, we
29–31 weeks 38 (1.9) 20 (1.0) 0.01
analysed duration of hospitalisation and duration and rate of oxygen
32–35 weeks 159 (8.1) 179 (9.1) 0.49
therapy, MV and ICU hospitalisation in both groups.
≥36 weeks 1587 (80.6) 1670 (85.2) 0.75
Unknown 169 (8.6) 75 (3.8)
2.3 | Statistical analysis CHD 1150 (58.4) 1189 (60.6) 0.11
Haematological disease 164 (8.3) 162 (8.3) 0.93
We assessed the characteristics of children with Down syndrome, Recurrent ALRI 372 (18.9) 236 (12.0) <0.001
effects of palivizumab and severity of RSV infection using question- Palivizumab 968 (49.2) 1611 (82.2) <0.001
naires. To analyse the cumulative RSVH rate, we used the log-rank Hospitalisation (≤2 year) 113 (5.7) 104 (5.3) 0.55
test for Kaplan-Meier curves. The calculated odds ratio (OR) was
Note: Data are number (%). p values were obtained from chi-square test.
reported with 95% confidence intervals (95% CI). The Cox propor-
Abbreviations: ALRI, acute lower respiratory infection; CHD, Congenital
tional hazards analysis was used as multivariable analysis. The cal- Heart Disease; RSV, Respiratory syncytial virus.
culated hazard ratio (HR) was reported with 95% CI. To express the
disease severity of RSV infection for children with Down syndrome,
as previously reported, 27,28 total days were summarised per 100 (Table 1). The 2010–2012 cohort included more children born at
children. Continuous variables are presented as the mean ± stand- GA 29–31 weeks (p = 0.01), but the proportion of those born at
ard deviation and compared using the Mann-Whitney U test. The GA ≤ 35 weeks did not differ between each cohort (p = 0.81). The
chi-square test was used to analyse categorical variables presented 2010–2012 cohort included more children with a history of recur-
as frequency and percentage. Statistical significance was set at rent ALRI (p < 0.001) than the 2013–2015 cohort. The percentage of
p < 0.05. All data other than the Cox proportional hazards analysis children with Down syndrome receiving palivizumab increased from
were evaluated using GraphPad Prism v7.0 (GraphPad Software Inc, 968/1968 (49.2%) in the 2010–2012 cohort to 1611/1961 (82.2%) in
La Jolla, CA, USA). The Cox proportional hazards analysis was per- the 2013–2015 cohort (p < 0.001).
formed using JMP 15 (SAS Institute Inc, Cary, NC, USA). In the 2010–2012 cohort, the RSVH rate in children with Down
syndrome was 45/968 (4.6%) in those with palivizumab prophylaxis
and 58/812 (7.1%) in those without prophylaxis (p = 0.025), while in
3 | R E S U LT S the 2013–2015 cohort, the proportion was 86/1611 (5.3%) in those
with prophylaxis and 17/251 (6.8%) in those without prophylaxis
3.1 | Characteristics of participated children with (p = 0.36) (Table S2).
Down syndrome

Overall, 321 of 664 medical institutions (48.3%) replied to the ques-
tionnaire (Table S1). We originally collected data on 5031 children
with Down syndrome. After excluded the incomplete data and data
from children that did not match the study period, we analysed data
on 3929 children with Down syndrome born between April 2010
and March 2016. The 2010–2012 cohort comprised 1968 children
and the 2013–2015 cohort comprised 1961 children.
The mean GA at birth was 37.2 ± 2.0 weeks. In total, 59.5% had
CHD and 8.3% had haematological disease. A history of recurrent
ALRI was noted in 15.5%. Unfortunately, there were too few data
on immunologic dysfunction and muscle hypotonia for inclusion in
the analysis.
The proportion of children with Down syndrome with CHD
or haematological disease was similar between each cohort
3.2 | Comparison of cumulative RSV-associated
hospitalisation rate
To evaluate the effect of the introduction of palivizumab for the
expanded indication to include all children with Down syndrome,
we compared cumulative RSVH rates in both groups up to 2 years
of age. Although the difference between them was not significant,
the cumulative RSVH rate tended to be decreased in the 2013–
2015 cohort (OR 0.83; 95% CI 0.63–1.10) (Figure 1A). To examine
the effects of individual risk factors, we analysed children with
Down syndrome with CHD or premature birth (GA ≤ 35 weeks).
Children with these risk factors had been permitted to receive
palivizumab also in the 2010–2012 cohort and, therefore, there
was no significant difference in cumulative RSVH rates in those
4 |
A All children with Down syndrome included
B Childrenwith Down syndrome
without CHD and born at GA ≥36 weeks
F I G U R E 1 Epidemiologic features of children with Down
syndrome throughout childhood. A, Kaplan-Meier chart,
unadjusted for risk factors, depicting the RSV-associated
cumulative hospitalisation for all participating children with Down
syndrome by age; B, comparison of the cumulative hospitalisation
rate of the two cohorts of children with Down syndrome without
CHD and born at GA ≥ 36 weeks
with CHD (OR 1.06; 95% CI 0.73–1.54) (Figure S1A) or those
born prematurely (OR 0.92; 95% CI 0.40–2.13) (Figure S1B). We
also analysed only children with Down syndrome who received
palivizumab in these two groups where the cumulative RSVH
rates were not significantly different (OR 0.91; 95% CI 0.62–1.33)
(Figure S1C). Finally, when we analysed only children with Down
syndrome newly approved to receive palivizumab in 2013 (chil-
dren without CHD and born at GA ≥ 36 weeks), their cumulative
OKAMOTO et al.
RSVH rate was significantly decreased in this 2013–2015 cohort
(OR 0.56; 95% CI 0.34–0.92) (Figure 1B).
3.3 | Multivariable analyses using the Cox
proportional hazard model
Next, we conducted multivariable analyses using the Cox propor-
tional hazard model to estimate relationships between RSVH and
potential predictors, including GA, CHD, haematological disease,
history of recurrent ALRI and palivizumab use (Table 2). In the 2010–
2012 cohort, CHD was identified as an independent risk factor (HR
0.59; 95% CI 0.37–0.96), and history of recurrent ALRI was also an
independent risk factor (HR 5.47; 95% CI 3.55–8.42). However, pal-
ivizumab use was not significantly associated with a reduced risk of
RSVH (HR 0.91; 95% CI 0.56–1.49). In contrast, in the 2013–2015
cohort, palivizumab use was associated with a reduced risk of RSVH
(HR 0.54; 95% CI 0.30–0.98). History of recurrent ALRI was also an
independent risk factor (HR 8.80; 95% CI 5.66–13.68). Overall, his-
tory of recurrent ALRI (HR 6.86; 95% CI 5.06–9.32) and palivizumab
use (HR 0.71; 95% CI 0.51–0.99) were independent risk factors for
RSVH, respectively.
3.4 | Characteristics of hospitalised children aged
two years or under
In the 2010–2012 cohort, 113 children with Down syn-
drome ≤ 24 months of age were hospitalised; this was 104 in
the 2013–2015 cohort (Table 3). In both groups, the GA was
37.0 ± 2.2 weeks, and the number of haematological diseases was
about 10%. Approximately half of hospitalised children with Down
syndrome in both groups had a history of recurrent ALRI. The 2013–
2015 cohort included more children with Down syndrome with
CHD (p = 0.023) and who received palivizumab (p < 0.001) than the
2010–2012 cohort.
In both groups, age at hospitalisation was around 10 months, and
the diagnosis at admission was mainly pneumonia or bronchiolitis.
In Japan, RSV infections generally occur during autumn and winter
months (September-March). In both groups, about 80% of children
were admitted during the epidemic season (September-March).
3.5 | Disease severity and RSV-associated
hospitalisation
To examine disease severity, we analysed duration of hospitalisation
and duration and rate of oxygen therapy, MV and ICU hospitalisa-
tion (Table 3). The mean length of hospitalisation was 10.8 days in
the 2010–2012 cohort and 10.7 days in the 2013–2015 cohort.
The incidence and mean duration of oxygen therapy were 78.8%
and 7.8 days in the 2010–2012 cohort and 78.8% and 8.3 days in
the 2013–2015 cohort, respectively (not significant). There was no
OKAMOTO et al. | 5

TA B L E 2 Multivariable Cox proportional hazards analysis to estimate the risk of RSV-associated hospitalisation

2010–2012 cohort (n = 1968) 2013–2015 cohort (n = 1961) Overall (n = 3929)

Characteristics HR 95%CI p value HR 95%CI p value HR 95%CI p value

Gestational 1.01 0.52–1.99 0.97 1.13 0.58–2.21 0.72 1.00 0.62–1.59 0.99
age ≤ 35 weeks
CHD 0.59 0.37–0.96 0.03 1.12 0.70–1.80 0.64 0.83 0.60–1.15 0.27
Haematological disease 0.79 0.34–1.81 0.57 1.07 0.51–2.24 0.85 0.93 0.54–1.62 0.80
Recurrent ALRI 5.47 3.55–8.42 <0.001 8.80 5.66–13.68 <0.001 6.86 5.06–9.32 <0.001
Palivizumab 0.91 0.56–1.49 0.71 0.54 0.30–0.98 0.04 0.71 0.51–0.99 0.04

Note: All data (HR, 95%CI, and p values) were obtained from analyses using the Cox proportional hazard model.
Abbreviations: ALRI, acute lower respiratory infection; CHD, Congenital Heart Disease; CI, confidence interval; HR, hazard ratio; RSV, Respiratory
syncytial virus.

significant difference between MV use and ICU admission. In the
2010–2012 cohort, one child required home oxygen therapy at dis-
charge. One child died in the 2013–2015 cohort.
27,28
As previously reported, we analysed total days of RSVH,
oxygen therapy, MV use and ICU stay per 100 children (Table S2,
Figure 2). In the 2010–2012 cohort, children receiving palivizumab
had significantly fewer total days of RSVH (52.8 days per 100 chil-
dren for those receiving palivizumab vs 60.6 days per 100 children
otherwise, p = 0.023). A similar non-significant trend favouring
palivizumab was observed in the 2013–2015 cohort. We could not
identify any significant changes between two cohorts (Figure 2A).
The total days of oxygen therapy per 100 children were similar
trends (Figure 2B).
4 | D I S CU S S I O N
This nationwide retrospective survey in Japan investigated the
change in RSVH rate before and after the approval of palivizumab
for all children with Down syndrome in 2013. We analysed 3929
children with Down syndrome who were born between April 2010
and March 2016. After the approval of palivizumab for all children
with Down syndrome in 2013, the cumulative RSVH rate of children
with Down syndrome ≤ 24 months of age tended to decrease al-
though the result was not significant. We confirmed that this was
especially the case in children with Down syndrome without signifi-
cant comorbidities (without CHD and born at GA ≥ 36 weeks) where
the decrease did achieve statistical significance. To the best of our
knowledge, this study was the first nationwide survey after palivi-
zumab prophylaxis approval for all children with Down syndrome at
a national level, irrespective of underlying medical conditions.
The projected number of live births with Down syndrome re-
mained around 2200 per year between 2010 and 2016 in Japan 1;
therefore, about 30% of them could be analysed in this study. Half
of the children with Down syndrome were known to have CHD with
8
or without abnormal haemodynamics, and similarly 59.5% had it
in this study. This data were believed to indicate the credibility of
this study. The proportion of children with Down syndrome receiv-
ing palivizumab increased from 49.2% in the 2010–2012 cohort to
82.2% in the 2013–2015 cohort. In Japan, health insurance began to
cover the cost of using commercial rapid test kits by immunochro-
matography in all paediatric inpatients in 2006. Through the period
of this study, the rapid antigen kits widely used by paediatricians in
clinical settings.
In the present survey, 113 children with Down syndrome (5.7%)
≤24 months of age were hospitalised in the 2010–2012 cohort; this
was 104 (5.3%) in the 2013–2015 cohort. In the previous reports,
the RSVH rate of children with Down syndrome ≤ 24 months of age
without receiving palivizumab was 9.9%–19.5% and that of healthy
controls was 0.7%–2.8%.8–11 In the previous large, well-known
palivizumab trials, that involved premature infants with or without
chronic lung disease or CHD, the RSVH rate was 4.8% and 5.3%,
respectively. 27,28 These results were similar to our study in children
with Down syndrome who received palivizumab after the approval,
indicating that prophylaxis was equally effective in the reduction
of RSVH. On the other hand, the RSVH rate of children with Down
syndrome ≤ 24 months of age with or without risk factors receiv-
ing palivizumab was reported as 1.2%–4.1%.12–16 A reduction in the
RSVH rate might be realised in future studies in this cohort of chil-
dren with Down syndrome.
Children with Down syndrome without significant risks such
as CHD and premature birth have also been considered as being at
higher risk for RSVH than healthy children. In a recent meta-analy-
sis, subgroup analysis revealed a significantly higher risk of RSVH in
children with Down syndrome without CHD (relative risk, 6.31; 95%
CI, 4.83–8.23).17 A study of nationwide inpatient hospital discharge
data in the USA between 1997 and 2012 reported that children with
Down syndrome without CHD had the highest RSVH rate among all
high-risk infants. 29 Previously, one prospective multicentre epide-
miological study in Spain reported that 35.5% (33/93) children with
Down syndrome without other significant risk factors had received
palivizumab prophylaxis, and the RSVH rate was 3.0% in those who
received prophylaxis but 15% in those who did not receive prophy-
laxis.13 In the present study, we showed that after the approval of
palivizumab for all children with Down syndrome in 2013, the cu-
mulative RSVH rate for those without risk factors such as CHD and
premature birth significantly decreased. We considered that paliv-
izumab prophylaxis is effective for children with Down syndrome
6 | OKAMOTO et al.

TA B L E 3 Characteristics of RSV-
2010–2012 cohort 2013–2015 cohort
associated hospitalised children with
(n = 113) (n = 104) p value
Down syndrome two years of age or
Gestational age (weeks) 37.0 ± 2.2 [28–40] 37.0 ± 2.2 [25–41] 0.53§ under in the 2010–2012 and 2013–2015
Number of CHD (%) 56 (49.6) 67 (64.4) 0.027* cohort groups

Number of haematological 8 (7.1) 11 (10.6) 0.36*

disease (%)
Number of recurrent ALRI 55 (48.7) 51 (49.0) 0.96*
(%)
Number of palivizumab (%) 45 (39.8) 86 (82.7) <0.001*
Age at hospitalisation 11.3 ± 6.8 [1–24] 10.2 ± 6.7 [0–24] 0.23§
(months)
Diagnosis at hospitalisation
Pneumonia (%) 50 (44.2) 40 (38.5) 0.39*
Bronchiolitis (%) 52 (46.0) 54 (51.9) 0.39*
Month of hospitalisation
April–August (%) 13 (11.5) 18 (17.3) 0.22*
September–March (%) 92 (81.4) 80 (76.9) 0.41*
Duration of hospitalisation 10.8 ± 12.2 [2–100] 10.7 ± 7.0 [1–49] 0.32§
(days)
Use of oxygen therapy (%) 89 (78.8) 82 (78.8) 0.99*
Duration of oxygen 7.8 ± 4.8 [1–29] 8.3 ± 6.2 [1–43] 0.89§
therapy (days)
Use of MV (%) 9 (8.0) 16 (15.4) 0.09*
Duration of MV (days) 13.8 ± 11.8 [5–43] 9.3 ± 7.0 [2–29] 0.43§
ICU hospitalisation (%) 6 (5.3) 13 (12.5) 0.06*
Duration of ICU admission 9.4 ± 2.9 [5–13] 10.6 ± 8.8 [2–35] 0.81§
(days)
Outcome
Suffering complication 1 (0.9) 0 (0)
(%)
Death (%) 0 (0) 1 (1.0)

Note: Data are number (%) or mean ± SD [range]. p values were obtained from chi-square test (*)
or Mann-Whitney U test (§). An annual epidemic of RSV infection in Japan is generally autumn to
winter, and the month of hospitalisation was stratified to whether epidemic (on season) or not (off
season).
Abbreviations: ALRI, acute lower respiratory infection; CHD, congenital heart disease; ICU,
intensive care unit; MV, mechanical ventilation; OR, odds ratio; RSV, Respiratory syncytial virus;
SD, standard deviation.

without significant comorbidities in a real-world setting. In addition,
by the Cox proportional hazard analysis, palivizumab use was sig-
nificantly associated with a reduced risk of RSVH in the 2013–2015
cohort, but not in 2010–2012 cohort.
A previous meta-analysis reported that children with Down syn-
drome had a significantly higher risk for severe RSV infection (higher
hospital admission rate, mortality, length of hospital stay, oxygen
requirement, ICU admission, need for MV and additional medica-
tion use) than children without Down syndrome. 20 However, the
effectiveness of palivizumab in the reduction of severe RSV infec-
tion has not been reported for children with Down syndrome in any
meta-analyses. Moreover, few studies determined this specific out-
come and small numbers of children with Down syndrome with se-
vere RSV infection were included in published reports.12,13 Here, we
found that children with Down syndrome receiving palivizumab had
fewer total days of hospitalisation and oxygen therapy compared
with those who had not received prophylaxis. However, we could
not identify any significant changes in the severity of RSV infection
in children with Down syndrome between the time before and after
the approval of palivizumab in 2013.
4.1 | Limitations of the study
This study had some limitations. First, since this was a retrospective
survey, the response rate may be inadequate to accurately determine
differences in the reported outcomes. Second, the indications for
RSVH may vary in each institution and between the children enrolled
OKAMOTO et al. | 7

F I G U R E 2 Total days of RSV A Total days of hospitali sation (per 100 children)
hospitalisation and oxygen therapy per
100 children with Down syndrome. A,
total days of RSV hospitalisation per 100
children before and after the approval of
palivizumab for all children with Down
syndrome in 2013. In each group (2010–
2012 cohort and 2013–2015 cohort), total
days of hospitalisation per 100 children
receiving palivizumab, not receiving
palivizumab or including all are shown.
B, total days of oxygen therapy per 100
children before and after the approval of
palivizumab for all children with Down
syndrome in the same way as A. Statistical
analyses were done by Mann-Whitney U
test

B Total days of oxygen therapy (per 100 children)

in the two cohorts. Third, the RSV seasons in Japan varied by year,
and the number of RSV cases in the 2013–2015 period was 1.4-fold
higher than 2010–2012 (Figure S2). This may have influenced the
RSVH rate and severity of disease in children with Down syndrome;
thus, the change in RSVH rate between the period before and after
the expanded approval of palivizumab might be an underestimate.
Fourth, detailed information about palivizumab doses and inter-dose
intervals was unavailable which may have impacted the RSVH rate.
Several prospective studies previously reported that children with
Down syndrome received most of their planned doses during a given
RSV season.12–16,30 Finally, information on the immunologic status and
presence of hypotonia among the participating children with Down
syndrome was not available. Children with Down syndrome often have
compromised innate and adaptive immunity leading to an increased
susceptibility to respiratory infections.2,3 We found that a history of
recurrent ALRI was an independent risk factor, which might represent
a susceptibility factor for respiratory infections in these patients.
5 | CO N C LU S I O N
We showed that palivizumab administered to all children with
Down syndrome without comorbidities may significantly decrease
the cumulative RSVH rate. These findings need to be confirmed
in future, more robust, prospective clinical trials. A cost-effective
analysis of palivizumab for all children with Down syndrome is also
necessary prior to the implementation of this strategy.
AC K N OW L E D G E M E N T S
We would like to thank all the doctors and clerks from all over Japan
who cooperated in this study (show the details in Appendix S1).
C O N FL I C T O F I N T E R E S T
Dr Hataya received personal fees for lectures from Abbvie, inde-
pendent of the submitted work. Prof Mori received unrestricted
research grants to the Department of Lifetime Clinical Immunology
from AbbVie GK. The other authors have no conflicts of interest rel-
evant to this article to disclose.
ORCID
Keisuke Okamoto https://orcid.org/0000-0002-7195-902X
Masaaki Mori https://orcid.org/0000-0003-2130-4866
REFERENCES
1. Sasaki A, Sago H. Equipoise of recent estimated Down syndrome
live births in Japan. Am J Med Genet A. 2019;179:1815-1819.
8 |
2. Alsubie HS, Rosen D. The evaluation and management of respira-
tory disease in children with Down syndrome (DS). Paediatr Respir
Rev. 2018;26:49-54.
3. McDowell KM, Craven DI. Pulmonary complications of Down syn-
drome during childhood. J Pediatr. 2011;158:319-325.
4. Tenenbaum A, Hanna RN, Averbuch D, Wexler ID, Chavkin M,
Merrick J. Hospitalization of children with Down syndrome. Front
Public Health. 2014;2:22.
5. Shi T, McAllister DA, O'Brien KL, et al. Global, regional, and national
disease burden estimates of acute lower respiratory infections due
to respiratory syncytial virus in young children in 2015: a system-
atic review and modelling study. Lancet. 2017;390:946-958.
6. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneu-
monia requiring hospitalization among U.S. children. N Engl J Med.
2015;372:835-845.
7. Griffin MR, Zhu Y, Moore MR, Whitney CG, Grijalva CGUS. hospi-
talizations for pneumonia after a decade of pneumococcal vaccina-
tion. N Engl J Med. 2013;369:155-163.
8. Bloemers BL, van Furth AM, Weijerman ME, et al. Down syndrome:
a novel risk factor for respiratory syncytial virus bronchiolitis–a
prospective birth-cohort study. Pediatrics. 2007;120:e1076-e1081.
9. Kristensen K, Hjuler T, Ravn H, Simões EA, Stensballe LG. Chronic
diseases, chromosomal abnormalities, and congenital malforma-
tions as risk factors for respiratory syncytial virus hospitalization:
a population-based cohort study. Clin Infect Dis. 2012;54:810-817.
10. Fjaerli HO, Farstad T, Bratlid D. Hospitalisations for respiratory syn-
cytial virus bronchiolitis in Akershus, Norway, 1993–2000: a popu-
lation-based retrospective study. BMC Pediatr. 2004;4:25.
11. Grut V, Söderström L, Naumburg E. National cohort study showed that
infants with Down's syndrome faced a high risk of hospitalisation for
the respiratory syncytial virus. Acta Paediatr. 2017;106:1519-1524.
12. Yi H, Lanctôt KL, Bont L, et al. Respiratory syncytial virus prophy-
laxis in Down syndrome: a prospective cohort study. Pediatrics.
2014;133:1031-1037.
13. Sánchez-Luna M, Medrano C, Lirio J. RISK-21 Study Group. Down
syndrome as risk factor for respiratory syncytial virus hospitaliza-
tion: a prospective multicenter epidemiological study. Influenza
Other Respir Viruses. 2017;11:157-164.
14. Paes B, Mitchell I, Yi H, Li A, Lanctôt KL, CARESS Investigators.
Hospitalization for respiratory syncytial virus illness in Down syn-
drome following prophylaxis with palivizumab. Pediatr Infect Dis J.
2014;33:e29-e33.
15. Manzoni P, Paes B, Lanctôt KL, et al. Outcomes of infants receiving
palivizumab prophylaxis for respiratory syncytial virus in Canada
and Italy: an international, prospective cohort study. Pediatr Infect
Dis J. 2017;36:2-8.
16. Simon A, Gehrmann S, Wagenpfeil G, Wagenpfeil S. Palivizumab use
in infants with Down syndrome-report from the German Synagis™
registry 2009–2016. Eur J Pediatr. 2018;177:903-911.
17. Mitra S, El Azrak M, McCord H, Paes BA. Hospitalization for respiratory
syncytial virus in children with Down syndrome less than 2 years of age:
a systematic review and meta-analysis. J Pediatr. 2018;203:92-100.
18. Chan M, Park JJ, Shi T, et al. The burden of respiratory syncytial
virus (RSV) associated acute lower respiratory infections in children
with Down syndrome: a systematic review and meta-analysis. J
Glob Health. 2017;7:e020413.
19. Manzoni P, Figueras-Aloy J, Simões EAF, et al. Defining the inci-
dence and associated morbidity and mortality of severe respiratory
OKAMOTO et al.
syncytial virus infection among children with chronic diseases.
Infect Dis Ther. 2017;6:383-411.
20. Beckhaus AA, Castro-Rodriguez JA. Down syndrome and
the risk of severe RSV infection: a meta-analysis. Pediatrics.
2018;142:e20180225.
21. Huggard D, Molloy EJ. Palivizumab for all children with Down syn-
drome? Arch Dis Child. 2019;104:94-97.
22. American Academy of Pediatrics Committee on Infectious Diseases
and Bronchiolitis Guidelines Committee. Updated guidance for
palivizumab prophylaxis among infants and young children at in-
creased risk of hospitalization for respiratory syncytial virus infec-
tion. Pediatrics. 2014;134:415-420.
23. Robinson JL, Le Saux N,Canadian Paediatric Society, Infectious
Diseases and Immunization Committee. Preventing hospitaliza-
tions for respiratory syncytial virus infection. Paediatr Child Health.
2015;20:321-333
24. Bollani L, Baraldi E, Chirico G, et al. Revised recommendations
concerning palivizumab prophylaxis for respiratory syncytial virus
(RSV). Ital J Pediatr. 2015;41:97.
25. Mori M, Morio T, Ito S, et al. Risks and prevention of severe RS virus
infection among children with immunodeficiency and Down’s syn-
drome. J Infect Chemother. 2014;20:455-459.
26. Mori M, Kawashima H, Nakamura H, et al. Nationwide survey of
severe respiratory syncytial virus infection in children who do
not meet indications for palivizumab in Japan. J Infect Chemother.
2011;17:254-263.
27. The IMpact-RSV Study Group. Palivizumab, a humanized respi-
ratory syncytial virus monoclonal antibody, reduces hospitaliza-
tion from respiratory syncytial virus infection in high-risk infants.
Pediatrics. 1998;102:531-537.
28. Feltes TF, Cabalka AK, Meissner HC, et al. Palivizumab prophylaxis
reduces hospitalization due to respiratory syncytial virus in young
children with hemodynamically significant congenital heart disease.
J Pediatr. 2003;143:532-540.
29. Doucette A, Jiang X, Fryzek J, Coalson J, McLaurin K, Ambrose CS.
Trends in respiratory syncytial virus and bronchiolitis hospitaliza-
tion rates in high-risk infants in a United States nationally represen-
tative database, 1997–2012. PLoS One. 2016;11:e0152208.
30. Kashiwagi T, Okada Y, Nomoto K. Palivizumab prophylaxis against
respiratory syncytial virus infection in children with immunocom-
promised conditions or Down syndrome: a multicenter, post-mar-
keting surveillance in Japan. Paediatr Drugs. 2018;20:97-104.
S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Okamoto K, Morio T, Nakamura Y,
Hataya H, Mizuta K, Mori M. Hospitalisations due to
respiratory syncytial virus infection in children with Down
syndrome before and after palivizumab recommendation in
Japan. Acta Paediatr. 2020;00:1–8. https://doi.org/10.1111/
apa.15641