ARTICLE IN PRESS

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ARTICLES
Hospitalization for Respiratory Syncytial Virus in Children with Down
Syndrome Less than 2 Years of Age: A Systematic Review
and Meta-Analysis
Souvik Mitra, MD, MSc, RCPC (Affiliate)1, Mohamed El Azrak, BSc2, Helen McCord, MN1, and Bosco A. Paes, FRCPC3

Objectives To compare the respiratory syncytial virus (RSV)-related hospitalization rate, hospital length of stay
(LOS), and need for assisted ventilation in children aged <2 years with Down syndrome and those without Down
syndrome.
Study design MEDLINE, Embase, and CINAHL databases were searched from inception up to December 2017.
Studies that provided data on RSV-related hospitalization in children aged <2 years with Down syndrome and those
without Down syndrome were included. Data were independently extracted in pairs by 2 reviewers and synthe-
sized with random-effects meta-analysis.
Results In 10 studies including a total of 1 748 209 children, 12.6% of the children with Down syndrome (491 of
3882) were hospitalized with RSV infection. The presence of Down syndrome was associated with a significantly
higher risk of RSV-related hospitalization (relative risk [RR], 6.06; 95% CI, 4.93-7.45; I2 = 65%; Grading of Rec-
ommendations, Assessment, Development and Evaluation [GRADE], moderate). RSV-related LOS (mean differ-
ence, 2.11 days; 95% CI, 1.47-2.75 days; I2 = 0%; GRADE, low), and the need for assisted ventilation (RR, 5.82;
95% CI, 1.81-18.69; I2 = 84%; GRADE, low). Children with Down syndrome without congenital heart disease (RR,
6.31; 95% CI, 4.83-8.23; GRADE, moderate) also had a significantly higher risk of RSV-related hospitalization. The
risk of RSV-related hospitalization remained significant in the subgroup of children aged <1 year (RR, 6.25; 95%
CI, 4.71-8.28; GRADE, high).
Conclusion RSV-related hospitalization, hospital LOS, and the need for assisted ventilation are significantly higher
in children with Down syndrome aged <2 years compared with those without Down syndrome. The results should
prompt reconsideration of the need for routine RSV prophylaxis in children with Down syndrome up to 2 years of
age. (J Pediatr 2018;■■:■■-■■).

R
espiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infection and hospitaliza-
tion in children aged <2 years.1,2 Certain high-risk groups, including premature infants, children with significant con-
genital heart disease (CHD), and infants with chronic lung disease, are at risk for severe RSV-related infection.3-5 Current
position statements from the Canadian Paediatric Society (CPS) and the American Academy of Pediatrics (AAP) routinely rec-
ommend prophylaxis against RSV in these children.6,7 However, the question exists as to whether children with Down syn-
drome are at increased risk for severe RSV infection. Several observational studies, systematic reviews, and nonsystematic expert
opinions suggest that Down syndrome, with or without additional risk factors such as prematurity and CHD, may increase the
risk of RSV-related hospitalization.8-10 A major limitation of previous systematic reviews has been the lack of quantitative data
synthesis or inclusion of studies with either possible high risk of bias or with probable use of immunoprophylaxis.9,10 Little
evidence also exists about the risk of RSV-related hospitalization in the subgroups of children aged <1 year and in children
with Down syndrome without CHD. In addition, no systematic reviews have used the Grading of Recommendations, Assess-
ment, Development, and Evaluation (GRADE) assessment for evaluating the quality
of assembled evidence. This lack of evidence is reflected in the current CPS6 and
AAP7 position statements that do not recommend routine RSV prophylaxis for
children with Down syndrome. Consequently, we conducted a comprehensive sys- From the 1Division of Neonatal Perinatal Medicine,
Department of Pediatrics, Dalhousie University and IWK
tematic review and meta-analysis to explore primarily the risk of RSV-related hos- Health Center, Halifax, NS, Canada; 2School of Dental
pitalization in children with Down syndrome aged <1 year and in those aged <2 Science, Trinity College Dublin, Dublin, Ireland; and
3
Department of Pediatrics, McMaster University, Hamilton,
ON, Canada
B.P. has served as an advisor and lecturer and has
received research funding and compensation from AbbVie
Corporation. The other authors declare no conflicts of
AAP American Academy of Pediatrics interest.
CHD Congenital heart disease Portions of this study were presented at the Pediatric
CPS Canadian Paediatric Society Academic Societies annual meeting, Toronto, May 5-8,
GRADE Grading of Recommendations, Assessment, Development, and Evaluation 2018, and at the Canadian Paediatric Society meeting,
Quebec City, May 30-June 2, 2018.
LOS Length of stay
RR Relative risk 0022-3476/$ - see front matter. © 2018 Elsevier Inc. All rights
RSV Respiratory syncytial virus reserved.
https://doi.org10.1016/j.jpeds.2018.08.006

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THE JOURNAL OF PEDIATRICS • www.jpeds.com
years both with and without CHD, compared with peers
without Down syndrome. The secondary objective was to
compare the hospital length of stay (LOS) and the need for
assisted ventilation between children with Down syndrome and
those without Down syndrome.
Methods
The study protocol was registered with the PROSPERO
database (CRD42017083527) (Supplement; available at
www.jpeds.com).
Eligibility Criteria
Prospective and retrospective observational studies (both cohort
and case-control designs) that compared RSV-related hospi-
talization data in children aged <2 years with and without Down
syndrome were included. Studies that confirmed routine use
of RSV prophylaxis in their respective samples or studies that
failed to report specific hospitalization details on children
aged < 2 years with respiratory tract infections were ex-
cluded from the quantitative synthesis. The exposure was clini-
cally and/or genetically confirmed Down syndrome. Children
born during the same period without Down syndrome served
as controls.
The primary outcome was RSV-related hospitalization and
was defined as any RSV-specific hospitalization. RSV infec-
tion was defined as either a laboratory-confirmed infection or
coded specifically as “RSV bronchiolitis” in the hospital/
population registry with or without laboratory confirma-
tion. Secondary outcomes included LOS for RSV-related
hospitalization and any requirement for assisted ventilation (in-
vasive or noninvasive).
Information Sources and Search Strategy
The MEDLINE, Embase, and CINAHL databases were searched
from inception until December 31, 2017 (Table I; available at
www.jpeds.com). Additional gray literature was sought through
personal communication from experts in RSV and by review-
ing abstracts and conference proceedings (European Society
for Pediatric Research and Pediatric American Societies, 1990-
2017). No language restrictions were applied.
Study Selection and Data Assembly. Retrieved titles, ab-
stracts, and full texts were screened by 2 independent review-
ers in duplicate to assess eligibility. The primary authors of 2
studies were contacted for further information during the
screening and data extraction process. Two reviewers ex-
tracted data, working independently in pairs and in dupli-
cate. Discrepancies were resolved in consultation with a third
reviewer.
Risk of Bias in Individual Studies
The risk of bias of eligible studies was assessed according to
the GRADE Working Group for assessment of risk of bias in
nonrandomized studies.11 Four criteria were used to assess limi-
tation in observational studies: failure to develop and apply
appropriate eligibility criteria (inclusion of control population),
2 Mitra et al
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Volume ■■ • ■■ 2018
flawed measurement of both exposure and outcome criteria,
failure to adequately control confounding, and incomplete or
inadequate follow-up.11 For each criterion, the risk of bias was
categorized as low, unclear, or high.
Synthesis of Results
The results were first described narratively, and when pos-
sible, the evidence was quantitatively pooled to obtain a
summary estimate using a random-effects model.12 Effect es-
timates and 95% CIs were estimated using relative risk (RR)
for binary outcomes and mean difference for continuous out-
comes. Statistical heterogeneity between studies was esti-
mated by the I2 statistic13,14 and interpreted using the Cochrane
Collaboration thresholds.15 Studies that presented LOS as
median (with IQR or range) were transformed to mean (and
SD) using the Hozo transformation method.16 All analyses were
performed with RevMan version 5.3 (The Nordic Cochrane
Centre Collaboration, Copenhagen, Denmark).
Risk of Bias Across Studies
Confidence in the estimates for each outcome across studies
was assessed using the GRADE approach.17 Two authors per-
formed an independent assessment using GRADEPro soft-
ware (GRADEPro guideline development tool; McMaster
University, Hamilton, Ontario, Canada).18 For any outcome,
failure to account for confounding in ≥50% of the included
studies was recorded as high risk of bias. An RR ≥2 was defined
as a large effect, and an RR ≥4 was defined as a very large effect
a priori. Publication bias was assessed for any outcome with ≥10
studies by visual inspection of the funnel plots and the Egger
test and Begg and Mazumdar test.15 Confidence in the esti-
mates was based on 4 levels: high, moderate, low, and very low.
Subgroup and Sensitivity Analyses
A subgroup analysis was planned a priori for the primary
outcome (RSV-related hospitalization) in children aged ≤ l year.
In addition, a post hoc sensitivity analysis was conducted for
RSV-related hospitalization including only studies with con-
clusive evidence that RSV prophylaxis was not used. Studies
in which there was definite use of prophylaxis or the use of
prophylaxis was unclear during the study period were excluded.
Results
A total of 426 potentially relevant articles were identified, 22
of which were excluded after full text screening (Table II; avail-
able at www.jpeds.com). Eleven studies including a total of 1
748 277 children met the study criteria and were included in
our quantitative analysis.19-29 The PRISMA study selection flow
diagram is shown in Figure 1.
Study Characteristics
The clinical profiles of the included children and method-
ological study characteristics are presented in Table III.19-29 All
but 1 study (that by Medrano López et al) was published in
English.28 All studies were published between 2004 and 2017
and included 8 retrospective studies, 20-26 1 combined
■■ 2018 ORIGINAL ARTICLES

Records identified through

Identification
electronic database search
(n = 426)

Records after duplicates removed

(n = 329)
Screening

Records excluded
(n = 296)
Records (titles & abstracts) 39 Systematic review/expert
opinion/ editorial/ letter to the
screened
editor
(n = 329) 98 Duplicates
159 Not relevant population
/exposure/type of study

Full-text articles excluded

Eligibility

(n = 22)
Full-text articles assessed 8 Not relevant population
for eligibility 5 Not relevant outcome
(n = 33) 4 Systematic review/guideline
1 Not relevant exposure
4 Routine use of RSV
immunoprophylaxis

Studies included in
qualitative synthesis
Included

(n = 11)

Studies included in
quantitative synthesis
(meta-analysis)
(n = 11)

Figure 1. Literature search and study selection flow diagram.

retrospective and prospective cohort study,19 1 prospective
study,29 and 1 case-control study.27
All children included in the meta-analysis were aged ≤2 years.
Stagliano et al examined RSV-related hospitalization in chil-
dren with Down syndrome aged ≤3 years.20 However, on review,
the median age at admission was 9.8 months (IQR, 5.5-17.7
months) for the whole series and 3.5 months (IQR, 1.7-8.7
months) for children without Down syndrome. By consen-
sus, this study was included in our analysis. The lowest re-
ported median age at RSV-related hospitalization was 2 months
in the study by Zachariah et al and 3 months in the studies
reported by Bloemers et al and Murray et al.19,25,26 Grut et al
and Murray et al provided data on children aged ≤1 year and
were included in the respective subgroup analysis of RSV-
related hospitalization.23,25
RSV immunoprophylaxis was provided to some children in
3 studies. 24,28,29 Kristensen et al administered ≥1 dose of
Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age:
A Systematic Review and Meta-Analysis
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immunoprophylaxis to 118 of the 391 983 children in their
series.24 Sánchez-Luna et al recorded palivizumab use in
23.2% of their Down syndrome cohort and 0% of their no-
Down syndrome cohort.29 Medrano López et al reported
immunoprophylaxis in 83.4% of the children without Down
syndrome versus 39.9% of those with Down syndrome.28 All
these studies were excluded from the sensitivity analysis ex-
ploring RSV-related hospitalization in children with Down syn-
drome and those without Down syndrome without the use of
any prophylaxis.
Outcome Characteristics
RSV infection was confirmed by laboratory diagnosis for all
included cases in all studies except the study by Murray et al,
in which linked microbiological data to confirm RSV were not
available.25 In that study, only 28% of the bronchiolitis cases
had a confirmed diagnosis of RSV infection; however, the
3
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

authors grouped all bronchiolitis codes in children aged <1 year

RSV-related hospitalization, need for assisted ventilation

RSV-related hospitalization in infants aged ≤2 y and in
into a single “RSV bronchiolitis” code, because RSV was the

assisted ventilation, RSV-related hospitalization in

RSV-related hospitalization in children without CHD
most common cause of bronchiolitis in that particular age

RSV-related hospitalization, hospital LOS, need for

RSV-related hospitalization, hospital LOS, need for

RSV-related hospitalization in infants aged ≤1 y

group.25 Ten of the 11 studies reported on the primary outcome
of RSV-related hospitalization.19-26,28,29 Four studies reported

RSV-related hospitalization, hospital LOS

Outcome measures
on LOS following RSV-related hospitalization in children with
Down syndrome versus those without Down syndrome.18,20,25,26

children without CHD disease

Three studies reported the need for assisted ventilation fol-
RSV-related hospitalization

RSV-related hospitalization

RSV-related hospitalization
lowing RSV-related hospitalization.20,21,26 Three studies docu-
children without CHD

assisted ventilation
mented higher rates of RSV-related hospitalization in children
with Down syndrome without CHD compared with those
without Down syndrome.19,20,23

Hospital LOS
Risk of Bias within Studies
All the included studies had robust eligibility criteria, well-
defined exposure, and outcome criteria with adequate follow-
immunoprophylaxis

up. However, in 6 of the 11 studies, the extracted data were

not adjusted for potential confounders, such as age of admis-
used
RSV

Yes

Yes

Yes
No

No

No

No
No

No
No
No

sion and associated clinical conditions, which could inflate the

Study characteristics

effect estimate toward increased RSV-related hospitalization

in children with Down syndrome.19-21,24,25,28 Risk of bias for the
individual studies and the bias summary are provided in
Retrospective case-control

Figures 2 and 3 (available at www.jpeds.com). This was ac-

Retrospective cohort and
prospective cohort

counted for in the GRADE assessment for quality of evidence.

Retrospective cohort

Retrospective cohort

Retrospective cohort
Retrospective cohort

Retrospective cohort
Retrospective cohort
Retrospective cohort

Retrospective cohort
Type of study

Prospective cohort

Synthesis of Results
Among the children with Down syndrome, 12.6% (491 of 3882)
were hospitalized with RSV infection. Children with Down syn-
drome had a significantly higher risk of RSV-related hospi-
talization compared with those with Down syndrome (10
Down syndrome
children with
Number of

studies, 1 748 209 children: RR, 6.06 [95% CI, 4.93-7.45];

I2 = 65%; absolute risk difference, 127 more [95% CI, 99-162
395

93
842

52

196
814

399
182
630
25
279

more] per 1000 children; GRADE, moderate) (Figure 4, A and

Table IV). The LOS for RSV-related hospitalization was sig-
Population characteristics

nificantly higher in the children with Down syndrome (4

number of
children
671

161
633 200

58179

980
2442

391 983
296 618
362 890
68
1085

studies, 9853 children; mean difference, 2.11 days; 95% CI, 1.47-
Total

2.75 days; I2 = 0%; GRADE, low) (Figure 4, B). Similar results

were found regarding the need for assisted ventilation (3 studies,
26 147 children; RR, 5.82; [95% CI, 1.81-18.69]; I2 = 84%; ab-
9.8 [5.5-17.7] (median [IQR])

solute risk difference, 145 more [95% CI, 24-532 more] per
5 [0.5-25] (median [IQR])
Down syndrome, mo

4 [2-6.9] (median [IQR])

Age at admission

9 [1-20] (median [IQR])

6 [0-23] (median [IQR])

8 [4-12] (median [IQR])

7.4 ± 5.4 (mean ± SD)
of patients with

1000 children; GRADE, low) (Figure 4, C).

Table III. Characteristics of included studies

Subgroup Analysis
0-24 (range)

0-23 (range)

0-23 (range)

15.7 (mean)

*The median age of admission in preterm infants was 9 months.

RSV-related hospitalization was explored in the subgroup of

children with Down syndrome without CHD. Compared with
the children without Down syndrome aged <2 years, chil-
†

dren with Down syndrome without CHD in the same age group
†All children without Down syndrome had CHD.
publication

had a significantly higher risk of RSV-related hospitalization

Year of

2007

2017
2015

2004

2011
2017

2012
2014
2012
2016
2009

(3 studies, 635 115 children: RR, 6.31 [95% CI, 4.83-8.23];

I2 = 0%; absolute risk difference, 75 more [95% CI, 54-102
more] per 1000 children; GRADE, moderate) (Figure 4, D).
Medrano López et al28†
29

The rate of RSV-related hospitalization was also explored in

Sánchez-Luna et al

the subgroup of children aged ≤l year and found to be sig-

Kristensen et al24

Zachariah et al26
19

Stagliano et al20
Bloemers et al

Murray et al25
Gooch et al22
Fjaerli et al21

nificantly higher in children with Down syndrome (2 studies,

Ting et al27
Grut et al23

299 060 children: RR, 6.25 [95% CI, 4.71-8.28]; I2 = 0%; ab-
Authors
Source

solute risk difference, 126 more (95% CI, 89-175 more] per
1000 children; GRADE, high) (Figure 4, E).
4 Mitra et al

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 A Systematic Review and Meta-Analysis
Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age:

■■ 2018
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ORIGINAL ARTICLES
Low risk of bias

High risk of bias

Figure 4. Forest plots. A, RSV-related hospitalization in children with Down syndrome versus those without Down syndrome aged <2 years (all studies included). B, Hos-
pital LOS in children with Down syndrome vs those without Down syndrome aged <2 years. C, Need for assisted ventilation in children with Down syndrome vs those
without Down syndrome aged <2 years. D, RSV-related hospitalization in children with Down syndrome without CHD vs those without Down syndrome. E, RSV-related
hospitalization in infants aged <1 year with Down syndrome vs those without Down syndrome. F, RSV-related hospitalization in children with Down syndrome vs those
without Down syndrome aged <2 years in studies without the use of RSV immunoprophylaxis. G, RSV-related hospitalization in children with Down syndrome vs those
5

without Down syndrome aged <2 years in only high-quality studies without the use of RSV immunoprophylaxis.
 6

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Table IV. GRADE Summary of Evidence Profile for risk of RSVH in Down Syndrome

Certainty assessment № of patients Effect

Number of
studies Study Risk of Other Children with Children without Relative Absolute
(References) design bias Inconsistency Indirectness Imprecision considerations Down Syndrome Down Syndrome (95% CI) (95% CI) Certainty
RSVH in DS versus non-DS children aged <2years (all studies included)
10 (19-26, observational serious* serious† not serious not serious Very strong association; 491/3882 (12.6%) 43900/1744327 (2.5%) RR 6.06 127 more per MODERATE
28,29) studies all plausible residual (4.93 to 7.45) 1000
confounding would suggest (from 99 more
spurious effect, while no to 162 more)
effect was observed
RSVH in DS versus non-DS children aged <2 years (studies without the use of RSV Immunoprophylaxis)
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7 (19,21,23, observational serious* serious† not serious not serious Very strong association; 381/3111 (12.2%) 32976/1351869 (2.4%) RR 6.39 131 more per MODERATE
25,26,28) studies all plausible residual (5.15 to 7.93) 1000
confounding would suggest (from 101 more
spurious effect, while no to 169 more)
effect was observed
RSVH in DS versus non-DS children aged <2 years (including only high quality studies without the use of RSV Immunoprophylaxis)
3 (21,26,28) observational not serious not serious not serious not serious Very strong association 226/1640 (13.8%) 16089/364672 (4.4%) RR 5.53 200 more per HIGH
studies (3.97 to 7.73) 1000
(from 131 more
to 297 more)
Length of hospital stay in DS versus non-DS children aged <2 years
4 (20,25,27,28) observational serious* not serious not serious not serious All plausible residual 105 9748 - MD 2.11 days LOW
studies confounding would suggest higher
spurious effect, while no (1.47 higher to
effect was observed 2.75 higher)
Need for assisted ventilation in DS versus non-DS children aged <2 years
3 (20,25,26) observational serious* very serious‡ not serious not serious Very strong association; 21/225 (9.3%) 780/25922 (3.0%) RR 5.82 145 more per LOW
studies all plausible residual (1.81 to 18.69) 1000
confounding would suggest (from 24 more
spurious effect, while no to 532 more)
effect was observed
RSVH in DS children without congenital heart disease (CHD) compared to non-DS children
3 (19,21,25) observational serious* not serious not serious not serious Very strong association 72/853 (8.4%) 8991/634262 (1.4%) RR 6.31 75 more per MODERATE
studies (4.83 to 8.23) 1000
(from 54 more
to 102 more)
RSVH in DS versus non-DS infants aged <1 year
2 (21,23) observational serious* not serious not serious not serious Very strong association; 88/996 (8.8%) 7181/298064 (2.4%) RR 6.25 126 more per HIGH
studies all plausible residual (4.71 to 8.28) 1000
confounding would suggest (from 89 more
spurious effect, while no to 175 more)
effect was observed

Volume ■■
Mitra et al

CI, confidence interval; MD, mean difference; RR, relative risk.

*50% or more of the included studies did not control for potential confounding.
†I2 value >50% on heterogeneity assessment.
‡I2 value >75% on heterogeneity assessment.
■■ 2018
Sensitivity Analysis
To account for the possible use of RSV immunoprophylaxis
in some children in 3 studies, a sensitivity analysis was con-
ducted for RSV-related hospitalization excluding these
studies.24,28,29 The risk of RSV-related hospitalization was mar-
ginally higher in children with Down syndrome without
immunoprophylaxis (7 studies, 1 354 980 children: RR, 6.39
[95% CI, 5.15-7.93]; I2 = 55%; absolute risk difference, 131 more
[95% CI, 101-169 more] per 1000 children; GRADE, moder-
ate) (Figure 4, F). Another sensitivity analysis was con-
ducted excluding studies with high risk of bias. In this analysis,
which included only high-quality studies with confirmed
nonuse of RSV immunoprophylaxis, Down syndrome re-
mained a significant risk for RSV-related hospitalization in chil-
dren aged ≤2 years (3 studies, 366 312 children: RR, 5.53
[95% CI, 3.97-7.73]; I2 = 44%; absolute risk difference, 200 more
(95% CI, 131-297] more per 1000 children; GRADE, high)
(Figure 4, G).
Risk of Bias Across Studies and Quality
Assessment
The quality of evidence on GRADE assessment was judged to
be moderate for RSV-related hospitalization in children with
Down syndrome compared with those without Down syn-
drome children aged <2 years (all studies included). Simi-
larly, the quality of evidence through sensitivity analysis without
the use of RSV immunoprophylaxis and the subgroup analy-
sis of children with Down syndrome without CHD was also
deemed moderate. The evidence was judged as high GRADE
for RSV-related hospitalization in the subgroup of children aged
<1 year and those aged ≤2 years, by sensitivity analysis of only
high-quality studies without RSV immunoprophylaxis. The
quality of evidence was judged to be low GRADE for LOS and
the need for assisted ventilation. No evidence of publication
bias was noted for the primary outcome (P = .81, Egger test;
.93, Begg and Mazumdar test) (Figure 5; available at
www.jpeds.com). The summary GRADE evidence profile is pre-
sented in Table IV.
Discussion
In this systematic review involving 1 748 277 children, chil-
dren with Down syndrome were found to have a signifi-
cantly higher risk of RSV-related hospitalization (GRADE,
moderate) and a significantly longer LOS (GRADE, low) and
need for assisted ventilation (GRADE, low) compared with chil-
dren without Down syndrome. On sensitivity analysis, the
results for RSV-related hospitalization remained significant
even after excluding studies with probable use of RSV
immunoprophylaxis (GRADE, moderate) and studies with a
high risk of bias (GRADE, high).
Down syndrome is characterized by a number of immu-
nologic abnormalities,30-32 congenital malformations,33-35 and
pulmonary hypertension,36 which may increase the suscepti-
bility to recurrent respiratory tract infections, including RSV.37-40
However, the current AAP and CPS position statements
Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age:
A Systematic Review and Meta-Analysis
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ORIGINAL ARTICLES
recommend RSV prophylaxis for children with Down
syndrome only if they have moderate-to-severe hyperten-
sion, significant CHD, or oxygen dependency or are severely
immunocompromised. 6,7 Both position statements cite
insufficient evidence precluding the routine use of RSV
immunoprophylaxis in children with Down syndrome.6,7
Systematic reviews, surveys, and nonsystematic expert opin-
ions have highlighted the heightened risk of hospitalization
and other complications related to RSV infection in children
with Down syndrome.9,10,41-44 Manzoni et al identified Down
syndrome as a significant risk factor for RSV-related hospi-
talization in early childhood (age <3 years) (rate ratio, 2.5-
12.6), even after excluding coexisting risk factors for severe
RSV disease, such as CHD and prematurity (rate ratio,
3.5-10.5).9 However, there has been no quantitative synthesis
of the evidence in a meta-analysis. The sole meta-analysis, by
Chan et al, which included data from a limited number of
observational studies, identified an RR of RSV-related hospi-
talization in children with Down syndrome of 6.8 (95% CI,
5.5-8.4) compared with those without Down syndrome.10
However, the authors failed to include data from large,
well-conducted, observational studies and to adjust for po-
tential confounders, such as the use of RSV immunoprophylaxis
in the analysis. Furthermore, no studies have provided quan-
titative synthesis on LOS, need for assisted ventilation, and
risk of RSV-related hospitalization in the subgroup of chil-
dren with Down syndrome age <1 year as well as those
without CHD.
This systematic review addresses the aforementioned gaps
in knowledge along with the respective quality of evidence
through GRADE assessment. These data will provide clini-
cians and policy makers with an evidence-based guide when
considering the risk of RSV-related hospitalization in chil-
dren with Down syndrome. The meta-analysis of all 10
included studies showed a significantly higher risk of RSV-
related hospitalization in children with Down syndrome. The
possible use of RSV immunoprophylaxis and risk of bias among
studies was also accounted for in the sensitivity and sub-
group analyses. Excluding all studies with high risk of bias and
those with possible use of RSV immunoprophylaxis, high
GRADE evidence revealed that for every 1000 children with
Down syndrome with RSV, there will be 200 more (95% CI,
131-297 more) hospitalizations compared with 1000 chil-
dren without Down syndrome with RSV (RR, 5.53; 95% CI,
3.97-7.73) (Table IV). This finding may have significant fi-
nancial and logistic implications for health care. Moreover, the
significantly increased LOS of RSV-related hospitalization and
need for assisted ventilation warrants a detailed health eco-
nomic evaluation regarding the possible benefits of routine RSV
immunoprophylaxis in these children. Interestingly, a Cana-
dian prospective observational registry of children who re-
ceived ≥1 dose of palivizumab during the 2006-2012 RSV
seasons showed no significant difference in RSV-related hos-
pitalization rates among children aged <2 years with Down syn-
drome and those without Down syndrome (RR, 1.03; 95% CI,
0.51-2.08). 37 The results of the latter study and of the
prospective cohort study by Yi et al suggest that routine RSV
7
THE JOURNAL OF PEDIATRICS • www.jpeds.com
immunoprophylaxis may significantly impact children
with Down syndrome, with a 3.6-fold reduction in the inci-
dence rate of RSV-related hospitalization.45 However, to date
there have been no randomized controlled trials on the effi-
cacy of RSV immunoprophylaxis in children with Down
syndrome.
Our study is not without limitations. Our data were drawn
overwhelmingly from retrospective studies. Even with our rig-
orous meta-analysis of the individual studies, there remains
some residual inherent heterogeneity that cannot be ac-
counted for statistically.
Regardless, the results of our meta-analysis challenge 2 rec-
ommendations from the AAP and CPS.6,7 First, one reason for
not providing prophylaxis in children with Down syndrome
<1 year as cited by both position statements is that the median
age of RSV-related hospitalization appears to be higher (1.3
years) in children with Down syndrome. Thus, prophylaxis
would minimally impact RSV-related hospitalization for chil-
dren with Down syndrome without other risk factors for RSV.6,7
However, in our subgroup analysis, the risk of RSV-related hos-
pitalization was significantly higher even in children with Down
syndrome aged <1 year (RR, 6.25; 95% CI, 4.71-8.28). Second,
the position statements recommend providing RSV
immunoprophylaxis to children with Down syndrome only if
there are other associated risk factors. Our subgroup analysis
revealed a significantly higher risk of RSV-related hospital-
ization even in children with Down syndrome without CHD
(RR, 6.31; 95% CI, 4.83-8.23).
This new evidence should encourage reconsideration of the
benefits and costs of RSV immunoprophylaxis in children with
Down syndrome up to 2 years of age. Furthermore, large ran-
domized controlled trials might be conducted to explore the
effectiveness of RSV immunoprophylaxis in children with Down
syndrome aged <2 years. This could prove challenging. Such
a study would require a large sample size of more than 900
subjects in a multicenter trial at significant cost over a pro-
longed duration, as reported by Yi et al. 45 Furthermore,
immunoprophylaxis reduces, but does not eliminate, the risk
of infection or bronchiolitis, and whether this benefit would
apply in children with Down syndrome, who may be hospi-
talized anyway because of a floppy airway, is unknown. In ad-
dition, further research should incorporate a detailed economic
evaluation of the cost-effectiveness of implementing routine
RSV immunoprophylaxis in children with Down syndrome at
the population level. Costs include not only hospitalization,
but also immunoprophylaxis. ■
We thank Dr Philip Zachariah, Assistant Professor of Pediatrics, Co-
lumbia University Medical Center, and Kim Kristensen, DMSc, Na-
tional University Hospital, Copenhagen for providing further clarification
of their published data.
Submitted for publication Apr 18, 2018; last revision received Jun 5, 2018;
accepted Aug 6, 2018
Reprint requests: Souvik Mitra, MD, MSc, RCPC (Affiliate), Department of
Paediatrics, Dalhousie University and IWK Health Center, G-2214, 5850/5980
University Ave, Halifax, NS, Canada B3K 6R8. E-mail: souvik.mitra@
iwk.nshealth.ca or souvik.mitra@dal.ca
8 Mitra et al
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Volume ■■
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9
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume ■■

Low risk of bias

High risk of bias

Figure 2. Risk of bias assessment of included studies. Low

risk of bias. High risk of bias.

9.e1 Mitra et al

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■■ 2018 ORIGINAL ARTICLES

Figure 3. Assessment summary across the risk of bias items. Risk of bias (RoB) assessment items: failure to develop and
apply appropriate eligibility criteria, flawed measurement of both exposure and outcome criteria, failure to adequately control
confounding, incomplete or inadequately short follow-up. RoB categories: low; unclear, and high. The horizontal axis repre-
sents the percentage of included studies.

Figure 5. Funnel plot for the primary outcome, RSV-related hospitalization in children with Down syndrome vs those without
Down syndrome aged <2 years, showing a nonsignificant small study effect on the Egger test (P = .81) and the Begg-
Mazumdar test (P = .93).

Table I. Electronic search strategies

MEDLINE Embase CINAHL
1. Infant/ #1 “infant”/exp OR “infant” Query Limiters/expanders
2. Child/ or child*.mp. #2 child S4 (Respiratory syncytial virus OR respiratory syncytial virus
3. 1 or 2 #3 children bronchiolitis in children OR respiratory syncytial virus
4. Down syndrome/ or Down syndrome.mp. #4 #1 OR #2 OR #3 infection in children OR bronchiolitis) AND (S1 AND S2
5. trisomy 21.mp. #5 “trisomy” AND S3)
6. Trisomy/ #6 “trisomy 21” S3 Respiratory syncytial virus OR respiratory syncytial virus
7. Respiratory syncytial virus infections/ or #7 “Down syndrome” bronchiolitis in children OR respiratory syncytial virus
respiratory tract infections/ or respiratory #8 #5 OR #6 OR #7 infection in children OR bronchiolitis
syncytial viruses/ or respiratory syncytial #9 “human respiratory syncytial virus” S2 Down syndrome or trisomy 21
virus.mp. or bronchiolitis/ #10 “respiratory syncytial virus infection” S1 infant OR children
8. 4 or 5 or 6 #11 “respiratory tract infection”
9. 3 and 7 and 8 #12 “lower respiratory tract infection”
#13 “bronchiolitis”
#14 #9 OR #10 OR #11 OR #12 OR #13

Hospitalization for Respiratory Syncytial Virus in Children with Down Syndrome Less than 2 Years of Age: 9.e2
A Systematic Review and Meta-Analysis
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Table II. List of excluded studies

No. Reference Reason for exclusion
1 Jama-Alol KA, Moore HC, Jacoby P, Bower C, Lehmann D. Morbidity due to acute lower respiratory Reported outcomes were not specific to RSV.
infection in children with birth defects: a total population-based linked data study. BMC
Pediatr. 2014;14:80.
2 Zhang Q, Guo Z, Langley JM, Bai Z. Respiratory syncytial virus-associated intensive care unit Included children up to age 14 years; data on relevant
admission in children in Southern China. BMC Res Notes. 2013;6:447. population not provided.
3 American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Expert Committee guidelines
Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants
and young children at increased risk of hospitalization for respiratory syncytial virus infection.
Pediatrics. 2014;134:415-20.
4 Afghani B, Ngo T. Severe respiratory syncytial virus infection in term infants with genetic or other Included children up to age 5 years; data on relevant
underlying disorders. Pediatrics. 2008;121:868; author reply, 868-9. population not provided.
5 Bloemers BL, van Furth AM, Weijerman ME, Gemke RJ, Broers CJ, Kimpen JL, et al. High incidence of Not a relevant outcome
recurrent wheeze in children with Down syndrome with and without previous respiratory syncytial
virus lower respiratory tract infection. Pediatr Infect Dis J. 2010;29:39-42.
6 Bloemers BL, Broers CJ, Bont L, Weijerman ME, Gemke RJ, van Furth AM. Increased risk of Review article
respiratory tract infections in children with Down syndrome: the consequence of an altered
immune system. Microbes Infect. 2010;12:799-808.
7 Broers CJ, Gemke RJ, Weijerman ME, Kuik DJ, van Hoogstraten IM, van Furth AM. Frequency of lower Reported outcomes were not specific to RSV.
respiratory tract infections in relation to adaptive immunity in children with Down syndrome
compared to their healthy siblings. Acta Paediatr. 2012;101:862-7.
8 Chaushu S, Yefe Nof E, Becker A, Shapira J, Chaushu G. Parotid salivary immunoglobulins, recurrent Not a relevant population or outcome
respiratory tract infections and gingival health in institutionalized and non-institutionalized
subjects with Down's syndrome. J Intellect Disabil Res. 2003;47(Pt 2):101-7.
9 Robinson JL, Le Saux N; Canadian Paediatric Society, Infectious Diseases and Immunization Expert Committee guidelines
Committee. Preventing hospitalizations for respiratory syncytial virus infection. Paediatr Child
Health. 2015;20:321-33.
10 Doucette A, Jiang X, Fryzek J, Coalson J, McLaurin K, Ambrose CS. Trends in respiratory syncytial Specific data on exposure and outcomes were not
virus and bronchiolitis hospitalization rates in high-risk infants in a United States nationally available.
representative database, 1997-2012. PLoS One. 2016;11:e0152208.
11 Yi H, Lanctôt KL, Bont L, Bloemers BL, Weijerman M, Broers C, et al; CARESS investigators. Effect of RSV immunoprophylaxis was evaluated in
Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. children with Down syndrome.
Pediatrics. 2014;133:1031-7.
12 Hilton JM, Fitzgerald DA, Cooper DM. Respiratory morbidity of hospitalized children with trisomy 21. Not a population of interest; lack of control group
J Paediatr Child Health. 1999;35:383-6.
13 Megged O, Schlesinger Y. Down syndrome and respiratory syncytial virus infection. Pediatr Infect Dis Comparison group data not provided.
J. 2010;29:672-3.
14 Mori M, Morio T, Ito S, Morimoto A, Ota S, Mizuta K, et al. Risks and prevention of severe RS virus Review article
infection among children with immunodeficiency and Down's syndrome. J Infect
Chemother. 2014;20:455-9.
15 Paes B, Mitchell I, Yi H, Li A, Lanctôt KL; CARESS Investigators. Hospitalization for respiratory syncytial Effect of RSV immunoprophylaxis was evaluated in
virus illness in Down syndrome following prophylaxis with palivizumab. Pediatr Infect Dis children with Down syndrome
J. 2014;33:e29-33.
16 van Beek D, Paes B, Bont L. Increased risk of RSV infection in children with Down's syndrome: clinical Article on RSV immunoprophylaxis implementation; not
implementation of prophylaxis in the European Union. Clin Dev Immunol. 2013;2013:801581. related to our research question.
17 Verstegen RH, van Gameren-Oosterom HB, Fekkes M, Dusseldorp E, de Vries E, van Wouwe JP. Did not report RSV-specific outcomes.
Significant impact of recurrent respiratory tract infections in children with Down syndrome. Child
Care Health Dev. 2013;39:801-9.
18 Galleguillos C, Galleguillos B, Larios G, Menchaca G, Bont L, Castro-Rodriguez JA. Down's syndrome Included children up to age 14 years; data on relevant
is a risk factor for severe lower respiratory tract infection due to respiratory syncytial virus. Acta population not provided.
Paediatr. 2016;105:531-5.
19 Vizcarra-Ugalde S, Rico-Hernández M, Monjarás-Ávila C, Bernal-Silva S, Garrocho-Rangel ME, Ochoa- Not a relevant population
Pérez UR, et al. Intensive care unit admission and death rates of infants admitted with respiratory
syncytial virus lower respiratory tract infection in Mexico. Pediatr Infect Dis J. 2016;35:1199-203.
20 Lee YI, Peng CC, Chiu NC, Huang DT, Huang FY, Chi H. Risk factors associated with death in patients Not a relevant outcome
with severe respiratory syncytial virus infection. J Microbiol Immunol Infect. 2016;49:737-42.
21 Manzoni P, Paes B, Lanctôt KL, Dall'Agnola A, Mitchell I, Calabrese S, et al. Outcomes of infants Evaluated effect of RSV immunoprophylaxis in children.
receiving palivizumab prophylaxis for respiratory syncytial virus in Canada and Italy: an
international, prospective cohort study. Pediatr Infect Dis J. 2017;36:2-8.
22 Pisesky A, Benchimol EI, Wong CA, Hui C, Crowe M, Belair MA, et al. Incidence of hospitalization for Included children up to age 3 years; data on a relevant
respiratory syncytial virus infection amongst children in Ontario, Canada: a population-based study population not provided.
using validated health administrative data. PLoS One. 2016;11:e0150416.

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