Paediatric Respiratory Reviews 40 (2021) 65–72

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

Pulmonary complications in children with Down syndrome: A scoping

review
Mariska De Lausnay a,b,⇑, Kris Ides a,b,c, Mark Wojciechowski a, An Boudewyns d, Stijn Verhulst a,b,
Kim Van Hoorenbeeck a,b
a
Department of Pediatrics, Antwerp University Hospital, Drie Eikenstraat 655, 2650 Edegem, Belgium
b
Laboratory of Experimental Medicine and Pediatrics (LEMP), Antwerp University, Belgium
c
Cosys Lab, Flanders Make, Antwerp University, Belgium
d
Department of Otorhinolaryngology, Antwerp University Hospital, Drie Eikenstraat 655, 2650 Edegem, Belgium

Educational Aims

The reader will be able to:

 Be aware of the complicated interactions of pulmonary, cardiac and other anatomical / physiological abnormalities in children with
Down syndrome.
 Realize that some pulmonary problems that are relatively rare in the general pediatric population, are substantially more prevalent
in children with Down syndrome (e.g. combined airway malformations, pulmonary hypertension).
 Understand that the diagnostic work-up for children with Down syndrome will involve a lower threshold for airway endoscopy,
swallow studies, and imaging.

a r t i c l e i n f o a b s t r a c t

Keywords: Context: Down syndrome (DS) is a prevalent chromosomal disorder associated with a wide range of con-
Down syndrome genital anomalies and other health problems.
Pulmonary aspiration Objectives: To give a scoping overview of encountered lower airway problems (both infectious and non-
Airway abnormalities infectious) in DS children.
Lung complications
Data sources: We systematically searched the MEDLINE and PubMed databases for relevant publications.
Study selection: Studies were eligible if they were original studies about pediatric airway problems in DS
and were evaluated by the PRISMA guidelines.
Data extraction: Data concerning patient characteristics, study methods and outcomes were critically
reviewed.
Results: Sixty papers were included. These were reviewed and summarized by topic, i.e. airway anoma-
lies, dysphagia and aspiration, lower respiratory tract infections (and bronchiolitis in particular), pul-
monary hypertension and other. Respiratory problems are proven to be a frequent and a major health
burden in DS children. Airway anomalies (both single and multiple) are more prevalent and require a

Abbreviations: BPD, bronchopulmonary dysplasia; CHD, congenital heart disease; DS, Down syndrome; FEES, fiberoptic endoscopic evaluation of swallowing; GOR, gastro-
oesophageal reflux; GP, general practitioner; ILD, interstitial lung disease; IPH, idiopathic pulmonary hemosiderosis; LRTI, lower respiratory tract infection; mPAP, mean
pulmonary arterial pressure; NICU, neonatal intensive care unit; OR, odds ratio; OSA, obstructive sleep apnea; PAH, pulmonary arterial hypertension; PHT, pulmonary
hypertension; PICU, pediatric intensive care unit; PPHN, persistent pulmonary hypertension in the neonate; RSV, respiratory syncytial virus; RSVH, RSV hospitalization; RTI,
respiratory tract infection; SGS, subglottic stenosis; URTI, upper respiratory tract infection; VFSS, videofluoroscopic swallow study.
⇑ Corresponding author. Antwerp University Hospital, Drie Eikenstraat 655, 2650 Edegem, Belgium.
E-mail address: mariska.delausnay@uza.be (M. De Lausnay).

https://doi.org/10.1016/j.prrv.2021.04.006
1526-0542/Ó 2021 Elsevier Ltd. All rights reserved.
M. De Lausnay, K. Ides, M. Wojciechowski et al. Paediatric Respiratory Reviews 40 (2021) 65–72

specific approach. A large proportion of DS children have (often silent) aspiration, resulting in protracted
and difficult-to-treat symptoms. Respiratory tract infections are usually more severe and associated with
an increased need for (prolonged) hospitalization. Pulmonary hypertension, wheeze and some other rare
conditions are more commonly encountered in DS.
Limitations: Large number of studies and high levels of study heterogeneity.
Conclusions: Several lower airway problems are more frequent and more complex in children with DS.
These findings emphasize the need for a multidisciplinary approach by an experienced team allowing
for a prompt diagnosis, proper management and improved long term outcome.
Ó 2021 Elsevier Ltd. All rights reserved.

INTRODUCTION 1) Airway anomalies

Down syndrome (DS) or trisomy 21 is the most common human
chromosomal disorder with a live birth prevalence of approxi-
mately 1/700 to 980, depending on the geographical region [1].
Well-known characteristics of this condition are mental retarda-
tion, dysmorphic features and congenital anomalies such as heart
defects [1]. However, based upon our clinical experience we
observed that respiratory problems impose a morbidity that
should not be underestimated. This is probably due to anatomical,
functional and immunological problems. For instance, several
studies have investigated the microscopic structure and lung mat-
uration in DS subjects, suggesting a difference in the development
of epithelial and alveolar structures in DS compared to controls
[2,3].
The objective of this review is to systematically summarize the
evidence regarding lower airway problems (both infectious and
non-infectious) in pediatric DS patients.
METHODOLOGY
We conducted a systematic literature search in the MEDLINE
and Pubmed databases in November 2020 with the following
search terms: ‘‘Down syndrome or trisomy 21, respiratory or air-
way problems, not sleep apnea”. As the research population, we
selected pediatric DS patients (aged 0–18 years). Duplicates and
articles that were off-topic, reviews, meta-analyses, expert opin-
ions, case reports or in languages other than English, were
excluded. Publications about immunological and anesthesia prob-
lems were beyond the scope of this review. After initial screening
based on title and abstract by two independent reviewers (MDL
and KI) the remaining papers underwent full text evaluation
according to the PRISMA guidelines. A third researcher (KVH)
was consulted in case of discussion about inclusions. All screened
papers were listed systematically in a standardized Excel docu-
ment designed for reviewing.
RESULTS
The initial database searches resulted in 936 potentially rele-
vant papers. After primary review of titles and abstracts, 113 pub-
lications remained. After full text evaluation, another 58 were
excluded leaving 55 papers for inclusion. In the references of these
included articles, we retrieved 5 other relevant and valuable
papers, so that a total of 60 papers were reviewed in this study.
Fig. 1 shows this process according to the PRISMA study selection
flow chart. Given the heterogeneity of the covered topics, the
included studies were grouped and discussed according to the fol-
lowing subjects: airway anomalies, dysphagia and aspiration,
(lower) respiratory tract infections with a separate focus on
(RSV) bronchiolitis, pulmonary hypertension, miscellaneous.
66
We identified seven reports on airway anomalies in children
with DS. All of them were retrospective. Three described results
from laryngeal and bronchoscopy procedures in DS cohorts. Hamil-
ton et al. [4] performed endoscopic evaluations in 39 out of a birth
cohort of 239 DS children. Main indications for endoscopy were
failed or difficult extubation, stridor and croup syndrome. These
showed one or more airway anomalies in 33/39 (84.6% or 13.8%
of the total number of DS patients) [4]. About one third of these
patients needed surgery [4]. Bertrand et al. [5] conducted a similar
study in 24 out of a cohort of 119 DS children and compared the
results to a heterogeneous group of 324 controls (with other syn-
dromic conditions, immunodeficiencies) [5]. Indications for endo-
scopy in the DS patients were atelectasis, stridor and recurrent
pneumonia. There was a 75% prevalence of one or more anomalies
in the DS patients, compared to 35% in the control group [5]. Laryn-
gomalacia, tracheomalacia and tracheal bronchus were signifi-
cantly more common in DS. De Lausnay et al. [6] also compared
65 DS children to 150 controls (without significant underlying dis-
orders), with similar results: in the DS group, 71% had an airway
abnormality compared to 32% of the healthy controls [6]. Laryngo-
malacia and tracheomalacia were significantly more common in
the DS group. Multiple anomalies were present in 20% (DS) versus
5% (controls) [6]. Indications for bronchoscopy were mainly recur-
rent lower respiratory tract infections (LRTI), chronic cough and
stridor. Five (5/65 or 7.7%) needed surgery for symptom relief
[6]. Combining these three studies, a total of 97/128 or 75.8% of
endoscopic evaluations in DS children with chronic or recurrent
respiratory symptoms showed structural airway abnormalities.
Bravo et al. [7] described a case series of 40 pediatric patients
with tracheal stenosis due to complete tracheal rings over a period
of 20 years, with seven (17.5%) of them having DS. Six of these DS
children had an additional airway anomaly and all but one
required surgery [7].
Two studies looked at the prevalence of subglottic stenosis
(SGS). Miller et al. [8] reviewed the charts of their DS population
and found 17 children with a diagnosis of SGS. Of these, 13 were
considered acquired after intubations (mostly for cardiac surgery
and respiratory tract infections). The four other children had no
preceding risk factors and were considered congenital SGS [8]. At
the time of publication, 11/17 patients already had corrective sur-
gery [8]. Arianpour et al. [9] found 7981 hospitalizations with a
diagnosis of acquired SGS over a three-year period, making up
0.06% of all discharges. They subsequently compared comorbidities
and found an OR of 14.2 for DS (0.77% of total discharges in DS chil-
dren had a diagnosis of acquired SGS compared to 0.05% of all non-
DS discharges) [9].
Lastly, a multicenter study by Moreno et al. [10] identified 133
children with a diagnosis of tracheal bronchus. Eleven of them (or
8.3%) had DS. This study furthermore demonstrates the clinical rel-
evance of this airway abnormality, with a high prevalence of
M. De Lausnay, K. Ides, M. Wojciechowski et al. Paediatric Respiratory Reviews 40 (2021) 65–72

Identification
Records idenfied through
database searching
(n = 936 )

Duplicates removed
(n = 269)

Records aer duplicates removed

(n = 667 )
Screening

Exclusions (n = 554 ) due to

Records screened - Populaon: 127
(n = 667 ) - Subject: 296
- Design: 79
- Language: 14
- No abstract or full
Full-text arcles assessed text: 38
for eligibility
Eligibility

(n = 113 )
Exclusion (n = 58 ) due to:
- Populaon: 11
- Subject: 18
Relevant arcles added
- Design: 14
through references (n = 5)
- Language: 4
- No full text: 11
Included

Studies included in
qualitave synthesis
(n = 60 )

Fig. 1. PRISMA 2009 Flow Diagram.

recurrent pneumonia and atelectasis, mostly in the right upper
lobe [10].
These papers all emphasize the need for great attentiveness in
this population considering the prevalence of airway anomalies
and the associated consequences for airway management.
2) Dysphagia and aspiration
We identified four recent retrospective chart reviews, investi-
gating the presence of dysphagia and aspiration based on results
from videofluoroscopic swallow studies (VFSS) in cohorts of young
DS children [11–14].
Narawane et al. [11] found a very high prevalence of both oral
and pharyngeal dysphagia (89.8% and 72.4% respectively) in a
cohort of 127 DS infants who underwent VFSS. Furthermore, pha-
ryngeal penetration was present in 52% and tracheal penetration in
31.5%, mostly with thin liquids. When aspiration occurred, this was
mostly ‘‘silent” (in 67.5%) [11]. The study population however, was
very young with a mean age of 4 months, 30% being born prema-
turely (with a mean gestational age of 34 weeks) and 56% of chil-
dren already being fed by nasogastric or gastrostomy tube prior
to the VFSS [11]. This may partly explain the high percentages of
abnormal swallowing studies. Jackson et al. [12] examined older
DS children (n = 138) with a mean age of 2.1 years, and found oral
motor difficulties in 63.8%, pharyngeal dysphagia in 56.3% and
aspiration in 44.2%. Again, aspiration events were mostly ‘‘silent”,
despite the fact that most children were referred for VFSS because
of feeding symptoms [12]. There was no significant association
between the presence of oral and pharyngeal dysphagia, and
results were independent of age, sex and reason for referral.
Another study by Jackson et al. [13] compared the presence of deep
laryngeal penetration or aspiration (on VFSS or FEES) between a
group of 72 DS children younger than 6 months and a group of
39 DS children between 6 and 12 months old. The first group
showed abnormal results in 31.9%, compared to 51.3% in the older
group. There was no significant association with symptoms during
feeding. Risk factors for aspiration in this study were CHD, laryngo-
malacia and prior episode(s) of pneumonia [13]. Stanley et al. [14]
reviewed 174 charts of DS patients younger than 6 months. Results
from VFSS were available for 100 cases, 96% were abnormal. In
69%, the degree of pharyngeal dysphagia was severe enough to
warrant a modification of food consistency or switch to non-oral

67
M. De Lausnay, K. Ides, M. Wojciechowski et al. Paediatric Respiratory Reviews 40 (2021) 65–72

feeding. Unlike the previous study, CHD was not a risk factor, bronchitis in 7 to 15.1% [20,22,23]. Asthma was the main diagnosis
whereas oxygen desaturation with feeding (OR = 15.8), functional in 5 to 6.9% [20,23]. Another retrospective study reviewed 66 DS
airway/respiratory anomalies (OR = 7.2), being underweight patients’ first admission at a pediatric intensive care unit (PICU)
(OR = 2.4) or premature (OR = 1.7) were associated with dysphagia [24]. Joffre et al. found that the primary reason for admission
[14]. was respiratory disease in 56/66 patients (84.8%) and cardiovascu-
In conclusion, all four of these studies retrospectively found oral lar disease in the 10 remaining patients (15.2%) [24] (note that
and/or pharyngeal dysphagia in a large proportion of DS infants there were no patients admitted for postoperative care immedi-
and young children, with aspiration often happening silently. An ately after a cardiac surgical procedure). There was a high mortal-
important limitation is that these papers only studied aspiration ity with 26 DS patients deceased; mortality was related to
by oropharyngeal motor problems and not considered in terms of respiratory failure (n = 14), multi-organ failure (n = 7) and refrac-
gastro-oesophageal reflux (GOR). Given the high prevalence rates, tory pulmonary arterial hypertension (n = 5). Forty-nine children
a low threshold for referral of these children for an assessment of (74%) required mechanical ventilation [24]. These studies all lack
swallowing (and/or GOR) studies is recommended. comparison to controls.
Bruijn et al. [25] studied a cohort of 24 DS patients, mechani-
3) Impact of (lower) respiratory tract infections cally ventilated for respiratory insufficiency at one PICU, and found
a large proportion of them meeting the criteria for acute lung
Healthcare utilization - Already in 1984, a prospective study was
injury and acute respiratory distress syndrome when comparing
published by Murdoch [15] about the increased need for general
them to 317 controls (with an OR of 9.4 and 11.9, respectively).
practitioner consults in DS children. These families consulted twice
Zhang et al. [26] studied risk factors for severe community
as often as controls and were prescribed more medication (such as
acquired pneumonia in 707 children admitted at a PICU and found
antibiotics). In both groups, respiratory problems such as respira-
that fatality was associated with the presence of DS (OR 6.8). Other
tory tract infections (RTI) comprised the largest category of illness,
risk factors were CHD, cerebral palsy and immune deficiency [26].
though these were even more frequent in DS [15]. These findings
Neonatal care - Admissions to neonatal intensive care units
were confirmed by many other researchers. Manikam et al. [16]
(NICU’s) were also studied with similar observations. Mann et al.
recently published a retrospective study comparing a large cohort
[27] performed a case control study with 725 DS infants and
of DS children (n = 992) to matched controls (n = 4874), and found
2175 controls. Infants in the DS group required more intensive care
an adjusted relative risk (RR) of 1.73 for RTI-related GP consulta-
compared to unaffected neonates (37% vs. 27%, p < 0.01) and stayed
tion and of 5.69 for RTI-related hospitalization. These disparities
longer in neonatal units (11 days vs. 5 days, p < 0.01) [27]. More DS
were most obvious for lower respiratory tract infection (LRTI).
infants required some form of respiratory support (31% vs. 22%,
Additionally, length of hospitalization was longer in DS patients
p < 0.001) with an OR of 1.4 for mechanical ventilation and of 1.8
(mean 5.2 days versus 2.4 days in controls, p < 0.0001) and they
for non-invasive ventilation (NIV). They also needed NIV signifi-
were also prescribed antibiotics more often for an RTI [16]. This
cantly longer and had oxygen need at discharge more often, both
research group used the same cohorts for another recent case-
irrespective of the presence of CHD [27]. McAndrew et al. [28] ret-
control study [17], where they investigated whether the prescrip-
rospectively examined NICU admissions of 1686 DS infants who
tion of antibiotics following an RTI-related GP consultation could
were born term without major anomalies and compared these to
reduce the risk of RTI-related hospitalization in the subsequent
227,706 controls. Although the most common clinical diagnoses
28 days. This was not the case for both the DS cohort and the con-
were similar in both groups, DS infants had a longer length of stay
trols (RR 0.699; 95% CI 0.471–1.036 in DS and similar numbers for
(median 10 versus 5 days in controls, p < 0.001) and were more
controls) [17]. However, these conclusions were based on rela-
likely to receive respiratory support (in over 75%) [28].
tively small numbers of hospitalized patients (15 DS and 11 con-
Impact of LRTI on development - Two Dutch studies looked at the
trols). Subgroup analysis showed no protective effect of
influence of recurrent RTI on the development of DS children. Van
antibiotics in any type of RTI or age group, except for infants
Trotsenburg et al. [29] found that 42 out of 196 DS children had
younger than 1 year (OR 0.260 and NNT 11.9) [17].
recurrent lung or airway disease. This subgroup had a significantly
In a large cohort of children with birth defects (n = 13,316),
greater motor developmental age delay at the age of 2. There was
Jama Alol et al. [18] looked for associations between categories of
no significant difference in mental developmental age [29]. An
birth defects and the number of acute LRTI’s during the first two
observational study by Verstegen et al. [30] compared 8-year old
years of life. In this cohort, they identified 229 children with DS
DS children with and without parent-reported recurrent RTI’s.
and found an incidence rate ratio (IRR) of 8 for any acute LRTI
The group with recurrent RTI’s showed significantly lower mental
and of 13.6 for pneumonia [18]. Medrano et al. [19] prospectively
and motor development, more behavioral problems and lower
investigated the incidence of RTI-related hospitalization during
scores on health-related quality of life scales [30].
the first two years of life in a cohort of children with hemodynam-
In conclusion of these 16 articles, respiratory tract illness seems
ically significant congenital heart defect (CHD) (n = 760), of whom
to impose a great burden in DS children with more frequent need
73 had DS. They identified DS (and chromosomal disorders in gen-
of GP consulting, prescribed medication, hospitalization, longer
eral) as a risk factor for RTI-related hospitalization, (OR 2.12,
length of stay and need for respiratory support. Especially LRTI’s
p = 0.01) [19]. The most common diagnosis at admission was bron-
carry great morbidity and recurrent infections may have an
chiolitis [19].
adverse effect on development and wellbeing.
Four retrospective studies investigated the need for hospitaliza-
tion and admission diagnoses in DS cohorts. These cohorts com-
4) A focus on RSV bronchiolitis and prophylaxis
prised between 86 and 405 hospitalized DS patients, reviewed
over different time periods [20–23]. In these study populations,
Many studies have focused on bronchiolitis - and more specifi-
most DS children were already hospitalized before the age of 1
cally due to respiratory syncytial virus (RSV) - in DS children. In the
and had multiple admissions at a relatively young age. All of these
general population, about 1.5 to 3% of children are admitted to the
studies identified RTI’s as main reason for admission (in 26 to 54%
hospital because of RSV-LRTI, with higher prevalence in at risk
of all admissions reviewed), irrespective of the presence of CHD or
populations (such as prematurely born infants) [31–33]. In DS
other comorbidities [20–23]. Pneumonia was the most frequent
however, this proportion is even higher. Large cohorts of 52 to
LRTI in 17.1 to 24.7% of admissions, followed by bronchiolitis or
842 DS children have been investigated, with percentages of
68
M. De Lausnay, K. Ides, M. Wojciechowski et al.
admission varying from 9.6% to 19.5% [32,31,34,33,35–39]. Gener-
ally, these studies looked at hospitalization in the first 2 years of
life, with the exception of one using an age limit of 1 year [37]
and another one of 3 years [39]. Expressed differently, DS children
have an OR of RSV-related admission of 3.29 to 5.99 compared to
non-DS children [36,40,41]. Compared to children with other
chronic congenital conditions, DS children have an IRR of 2.18 for
RSV hospitalization [32]. Over the last decades, a decline has been
seen in RSV admissions among the high-risk patients with CHD and
chronic lung disease (probably due to the use of RSV prophylaxis)
but not in DS children without CHD [42]. Studies are also conclu-
sive that DS patients admitted for RSV, have a hospital stay that
is about twice as long as non-DS patients (median length of stay
4 to 10.9 days for DS groups, compared to 2 to 4.9 days for con-
trols) [32,34–36,38,41,39,43,44]. While controls are almost all
younger than 1 year old when admitted for RSV bronchiolitis, DS
children are older, with even a significant proportion around or
above the age of 2 [33,36,38,39,43]. This could have important con-
sequences for prophylaxis strategies. DS children admitted for RSV
bronchiolitis have higher severity scores [36], a higher need for
PICU admission and respiratory support [43,44] and a higher mean
cost of hospital stay [41]. Importantly, most of these findings
remain statistically relevant, even when correcting for additional
risk factors such as CHD or prematurity [40,33,36,39,44]. One study
compared risk factors for mortality in severe RSV cases admitted at
PICU and found an OR of 7.20 in the DS subgroup (p = 0.036) [45].
However, this was based on a small number of DS patients (9 DS
children on a total of 186 PICU patients, 2 DS patients deceased).
A retrospective case series of 53 DS patients who died from RSV-
related causes, showed no difference in age of death between DS
patients with or without comorbidities, or non-DS groups (median
age of death 6 months old) [46].
Usefulness of Palivizumab - A subgroup of children with DS
(those with congenital diaphragmatic hernia [CDH] or prematu-
rity) were eligible for monthly RSV prophylaxis (Palivizumab or
PVZ). However, given the substantial disease burden from RSV
infections, several research groups have investigated the useful-
ness of RSV prophylaxis in all DS children. The CARESS group
(Canadian RSV Evaluation Study of Palivizumab) compared chil-
dren immunized with PVZ because of prematurity to children with
underlying disorders (with 193 or 20.3% of them having DS) [47].
This second group was found to be hospitalized more frequently
for respiratory infections in general, but not for RSV [47]. The same
conclusion was made in another study by the CARESS group, com-
paring 600 DS patients who received PVZ to children immunized
because of prematurity, CHD and other underlying medical ill-
nesses: DS children have a higher hazard ratio for hospitalization
due to respiratory infections, but not for RSV after PVZ [48]. Later
on, they compared similar but larger groups of immunized chil-
dren, but this time they did find a significantly higher risk of RSV
hospitalization (RSVH) in the group with underlying conditions
such as DS [49]. In the DS subgroup, they calculated an OR of
1.83 for RSVH compared to prematurity and of 2.25 compared to
near-term infants [49]. A German study also found a higher RSVH
rate of 1.2% in 249 immunized DS children versus 0.71% in the total
group of 12,729 immunized children [50]. Two other studies com-
pared groups of DS children with and without PVZ prophylaxis and
found a significant reduction in RSV-related admission when PVZ
was administered in all DS children (from 6–9.8% without prophy-
laxis to 1.5–3% in DS children with PVZ) [51,52]. However, this
reduction was less convincing when excluding DS children with
additional risk factors [52]. A Japanese post-marketing surveillance
study found good tolerance of PVZ in a cohort of DS and immuno-
compromised children, with a low RSVH rate of 0.7% (2/304) [53].
In conclusion, (RSV) bronchiolitis imposes a significantly
greater disease burden in DS children than in the general popula-
69
Paediatric Respiratory Reviews 40 (2021) 65–72
tion but also than children with other comorbidities. A wide range
of studies demonstrates a much higher need for hospitalization
and respiratory support, a longer length of stay, and even a higher
mortality. Prophylaxis of all DS children with PVZ has a potential
benefit to reduce these health issues, though this effect is less clear
in patients without additional risk factors. Further studies are
required addressing the cost-benefit in this specific population.
The impact of viruses other than RSV is less well documented. A
study on hospitalizations related to human metapneumovirus
infection showed similar results to the RSV studies [54].
5) Pulmonary hypertension
Pediatric pulmonary hypertension (PHT) is an important condi-
tion that is described more frequently in DS. Untreated PHT leads
to irreversible pulmonary vascular changes with high mortality,
so attentiveness is mandatory. Our search contains four original
studies about PHT in DS children.
A prospective study by Berger et al. [55] enrolled 362 children
with PHT from 19 countries. They defined PHT by right-heart
catheterization measurements with a mean pulmonary arterial
pressure (mPAP) of 25 mmHg, a pulmonary vascular resistance
index of 3 WU/m2, and mean pulmonary capillary wedge pres-
sure of 12 mm Hg. Patients not meeting these criteria were
excluded, as were patients with (residual) left heart disease. If
right-heart catheterization could not be performed, patients could
exceptionally be enrolled based on echocardiography or
histopathology results. They found that 11.6% (42/362) of the total
number of patients with PHT were DS children [55]. Unsurpris-
ingly, DS was highly present in group 3 PHT (PHT associated with
respiratory conditions such as bronchopulmonary dysplasia, inter-
stitial lung disease or ILD, obstructive sleep apnea [OSA]) with 21%
(9/42), compared to 10% (32/317) of group 1 PHT (pulmonary arte-
rial hypertension of PAH). Of the latter, 26 patients had associated
CHD [55].
Bush et al. [56] conducted a retrospective cohort study, identi-
fying 1252 DS children with 28% (346/1252) of them meeting their
definition of PHT (mPAP > 25 mmHg, ratio PAP/SAP > 1/3, interven-
tricular septal flattening, and right ventricular dilatation or hyper-
trophy). The initial diagnosis of PHT was made in the first year of
life in 86% of patients (median age at initial diagnosis = 5 days,
reflecting the high incidence of persistent pulmonary hypertension
in the neonate or PPHN). Most patients had transient PHT (70%),
15% had persistent disease and 15% recurrent episodes of PHT
[56]. For initial diagnosis, 82% was classified as PHT group 1,
whereas recurrent episodes were mostly group 3 PHT. The most
important risk factors were CHD (with left-to-right shunt), OSA,
intermittent hypoxia, recurrent pneumonia, various airway
anomalies, reactive airway disease, and others [56].
A study by Hawkins et al. [57] prospectively included 25 pedi-
atric DS patients with PHT (defined as a tricuspid regurgitation
jet of 2.7 m/s in the absence of right ventricular outflow tract
obstruction) over a 4-year period. Patients with a large left-to-
right shunt and high pulmonary blood flow with low vascular
resistance were excluded. Median age in this study sample was
12.5 months. All children had some form of CHD. Furthermore,
the prevalence of respiratory disease was also significant (18/25
or 72% of patients), with polysomnography showing upper airway
obstruction in 12/18; endoscopy showing tracheomalacia or bron-
chomalacia in 8/16, laryngomalacia in 4/16, adenotonsillar hyper-
trophy in 8/16 and tracheo-oesophageal fistula in one; and CT-scan
showing ILD in one [57]. These children had lower mPAP at cardiac
catheterization than estimated from echocardiography (23 mmHg
compared to 34 mmHg in those without airway obstruction). The
authors suggested that this difference was attributable to the pro-
cedural intubation and subsequent relieve of airway obstruction
M. De Lausnay, K. Ides, M. Wojciechowski et al.
[57]. They emphasized the importance of thorough pulmonary
assessment in PHT patients, given the specific therapeutic
approach in case of concurrent respiratory problems.
A retrospective chart review by Shah et al. [58] identified 175
admitted DS infants of whom 17 were diagnosed with PPHN (de-
fined as hypoxemia refractory to oxygen therapy or lung recruit-
ment strategies and extrapulmonary right-to-left shunting
(ductal or atrial) in absence of severe pulmonary parenchymal dis-
ease). They excluded infants with CHD (n = 7), with other poten-
tially biasing congenital malformations and preterm babies.
PPHN was diagnosed in 13.7% of total DS admissions or in 10%
when excluding children with serious structural cardiac malforma-
tions. Of the 13 patients not lost to follow-up, 11 patients had nor-
malization of the right ventricular pressure with conservative
measures, whereas two infants required PDA closure and resolu-
tion of airway obstruction.
Despite the different definitions of PHT, all of these studies con-
firm the high incidence of this condition in (mostly very young) DS
children. They reflect the importance of adequate airway manage-
ment in PHT patients and, on the other hand, timely screening for
PHT in DS children with airway/lung disease.
6) Miscellaneous
Additionally, we found some noteworthy papers about other
pulmonary complications frequently associated with DS.
Wheeze - Given the high prevalence of LRTI and specifically
bronchiolitis as mentioned above, it could be assumed that post-
infectious wheeze is also a more common problem in DS children.
A combined retrospective and prospective study by Bloemers et al.
[59] compared four groups of children to investigate whether pre-
vious RSV LRTI is a risk factor for recurrent wheeze in DS. DS chil-
dren previously hospitalized for RSV-induced LRTI (n = 53) had a
36% prevalence of physician-diagnosed wheeze, compared to 30%
of DS children without RSV hospitalization (n = 110). In non-DS
children hospitalized for RSV (n = 48) this was 31% but in healthy
controls (n = 49) it was only 8% [59]. This means that recurrent
wheeze is very common among DS children and that RSVH did
not seem to significantly contribute to the risk of recurrent wheeze
in DS.
Another possibility is that the high prevalence of wheeze in DS
is attributable to atopy or allergic asthma. This was investigated by
Weijerman et al. [60] by questioning parents of 130 DS children. As
controls, they selected siblings of the DS children (n = 167) and
non-related children matched for age and sex (n = 119). Parents
reported significantly more wheeze in the past 12 months in the
DS children than in siblings (RR 2.8, p = 0.003) and controls (RR
2.75, p = 0.01), particularly in children below 4 years of age [60].
Conversely, DS children were less frequently diagnosed with
asthma (3.1%) than control children (6.7%; p = 0.04). The 24 DS
children who had been diagnosed with asthma in the past were
followed prospectively for 4 years by a single pediatrician. Based
on international guidelines, a diagnosis of asthma could not be
confirmed in any of these 24 patients. The researchers also found
no sensitization to inhalation allergens [60].
Despite wheezing being frequent in DS, these two papers con-
clude that neither prior (RSV) bronchiolitis nor asthma seems to
contribute a great deal to this phenomenon in contrast to the gen-
eral pediatric population.
Subpleural cysts - Biko et al. [61] reviewed DS children with
prior CT imaging of the lungs to determine the prevalence of sub-
pleural cysts. These are benign small cystic dilatations along the
subpleural surface of the lungs of unknown etiology, frequently
seen in DS patients and rarely in other persons. In this study, sub-
pleural cysts were observed on scans from 9/25 (36%) DS children
(age range 3 months to 6 years old with a mean age of 5.5 years)
70
Paediatric Respiratory Reviews 40 (2021) 65–72
[61]. Some of them also had cysts along the lung fissures and bron-
chovascular bundles, but not parenchymal. Given the very small
number of cases, it is not possible to make any assumptions about
associated risk factors. In any case, the authors found no clear cor-
relation with CHD, need of extracorporeal membrane oxygenation
or chronic ventilator support. However, both patients from the
study cohort that were born <34 weeks, had subpleural cysts, sug-
gesting a possible association with prematurity [61].
Idiopathic pulmonary hemosiderosis (IPH) - This is an extre-
mely rare condition that is seen relatively frequently in DS. It is
defined by a triad of iron deficiency anemia, respiratory symptoms
(including dyspnea, cough and hemoptysis) and pulmonary infil-
trates on chest imaging. The diagnosis is confirmed by the presence
of hemosiderin-laden macrophages in broncho-alveolar lavage
fluid and/or on lung tissue specimens. A publication from the
French RespiRare group (the French Reference Center for Rare Lung
Diseases) retrospectively found a cases series of 25 IPH patients
over a 16-year period, with 5 (20%) of them having DS [62]. A pos-
sible link with autoimmune diseases and autoantibodies is sug-
gested. Although most IPH patients had a favorable outcome, one
of the DS children had a fatal pulmonary hemorrhage [62]. A
follow-up paper a few years later compared data from pediatric
IPH patients with and without DS [63]. They included 34 patients,
nine (26%) presented with DS. Children in the DS group presented a
more severe form of the disease with an earlier onset, frequent sec-
ondary pulmonary hypertension, and an increased risk of fatality
[63].
LIMITATIONS
Although we have tried to make our search as broad as possible,
we had no access to other databases such as Embase and we also
limited our search to articles published in English. Most studies
were retrospective and often, a comparison to controls is lacking.
Nevertheless, we found 60 relevant articles that were of relatively
good quality and that came to coherent conclusions about the dis-
cussed topics.
CONCLUSIONS
Pulmonary complications are frequent and a major health bur-
den in children with DS. Airway anomalies (both single and multi-
ple) are prevalent in DS children and require a specific approach.
There is a remarkable proportion of DS children with aspiration
(often silent), which sometimes results in protracted and
difficult-to-treat symptoms. Respiratory tract infections are often
more severe and associated with a greater need for hospitalization
and a prolonged stay, a well-known example of this is the high
prevalence rate and severity of RSV bronchiolitis in DS. Prophylaxis
with PVZ could benefit all patients with DS, even without addi-
tional risk factors such as CHD. Pulmonary hypertension and other
(sometimes rare) conditions are much more common in DS.
Increased awareness and a low threshold for investigation of pul-
monary complications in children with DS are required. A multidis-
ciplinary approach for the diagnosis and management of
respiratory problems in this population may ultimately result in
lower morbidity and mortality with an improvement in develop-
ment, wellbeing and quality of life of patients and their caregivers.
DIRECTIONS FOR FUTURE RESEARCH
 Explore the impact of airway anomalies e.g. on the prevalence
or severity of obstructive sleep apnea in DS children.
 Investigate the role of GOR in pulmonary aspiration.
M. De Lausnay, K. Ides, M. Wojciechowski et al.
 Determine the cost-effectiveness of PVZ in DS patients without
CHD or prematurity.
 Optimize the management of PHT in DS patients with pul-
monary problems.
 Investigate the etiology and optimal treatment of frequent
wheeze in DS.
CONFLICT OF INTEREST
The authors have no conflicts of interest relevant to this article
to disclose.
FUNDING
The authors did not receive any funding related to this
manuscript.
APPENDIX A. SUPPLEMENTARY DATA
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.prrv.2021.04.006.
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