Paediatric Respiratory Reviews 26 (2018) 49–54

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

The evaluation and management of respiratory disease in children with

Down syndrome (DS)
Haya S. Alsubie a,⇑, Dennis Rosen b,c
a
Specialized Medical Center, Department of Pediatric Respiratory Medicine, Sleep Disorders Center, Box 84350, Riyadh 11671, Saudi Arabia
b
Harvard Medical School, Boston, MA, USA
c
Division of Respiratory Diseases, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA

Educational aim

 Respiratory disease in children with Down syndrome (DS) is often multifactorial, and may result from abnormalities in other organ
systems.
 Obstructive sleep apnea in children with DS is exceptionally common and, as in other children, poorly detected with history alone.
 The treatment of OSA with adenotonsillectomy in children with DS is less successful than in typical children, resulting in a greater
incidence of residual obstruction.

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

Keywords: Children with Down syndrome (DS) have wide range of respiratory problems. Although underlying
Upper airway obstruction abnormalities in the respiratory system are important causes of morbidity and mortality in children with
Adenotonsillectomy DS, particularly in the young, abnormalities in other organ systems may also impact respiratory function.
Congenital Heart Disease A comprehensive evaluation of the child with DS and respiratory disease may prevent short-term mor-
Gastroesophageal reflux
bidity and mortality, and reduce the incidence of complications in the long term. This review provides
Polysomnography
an overview of the various causes of respiratory disease, and insight into some of the newer therapies
Recurrent wheeze
available to treat obstructive sleep apnea, in this population.
Ó 2017 Elsevier Ltd. All rights reserved.

Introduction 29 in Kuwait [8], and 31 in Dubai [9]. Generally speaking, birth-

Trisomy 21, or Down syndrome (DS), has characteristic pheno-
typic features as well as varying degrees of developmental delay
and intellectual impairment. First described by John Langdon
Down in 1866, DS is the most common human chromosomal vari-
ance. The incidence of babies born with DS varies widely, and its
prevalence increases with maternal age [1]. Between 2004 and
2006 one out of every 772 babies born in the United States was
born with DS, or 14.47/10,000 live births [2].
In the Middle East, the prevalence of DS is relatively high, rang-
ing from 18/10,000 live births in Libya [3] to 20 in Qatar [4], 23.2 in
Arab citizens of Israel [5], 25.9 in Oman [6], 23 in Saudi Arabia [7],
⇑ Corresponding author.
E-mail address: haya392@hotmail.com (H.S. Alsubie).
rates in Arab countries are high, consanguineous marriages fre-
quent, childbirth at advanced maternal age common, and
pregnancy termination is rare. The higher prevalence of DS
reported in some Arab countries has been linked to a higher rate
of parental consanguinity [8,10–12].
Almost all studies reporting high incidences of DS in Arab coun-
tries suggest a possible link to high consanguinity. The Centre for
Arab Genomic Studies (CAGS) [13] reviewed overall incidence of
consanguinity in Arabs in the last decade, and found it to be pre-
sent in 56.3% of couples in Oman, 42.1–66.7% in Saudi Arabia and
22–54% in Qatar.
The provision of high-quality medical care to children with DS
requires an understanding of the multisystemic nature of this dis-
order, and this review will focus on the comprehensive evaluation
of respiratory care in children with DS. DS affects both the upper

https://doi.org/10.1016/j.prrv.2017.07.003
1526-0542/Ó 2017 Elsevier Ltd. All rights reserved.
50 H.S. Alsubie, D. Rosen / Paediatric Respiratory Reviews 26 (2018) 49–54
and lower respiratory tract in a variety of ways. Although respira-
tory disease is an important cause of morbidity and mortality in
children with DS, particularly in the young [14,15], abnormalities
in other organ systems may impact respiratory function as well.
The lower airway
A broad range of respiratory problems may be seen in children
with DS, either primary to the respiratory system or secondary to
abnormalities in other organ systems which adversely affect the
respiratory system. Because of this, it is essential to consider the
presence of multiple etiologies.
Congenital airway abnormalities
Children with DS have a high incidence of airway abnormalities.
The most common are laryngomalacia (50%) and tracheomalacia
(33%) [16] (Table 1), the majority of which (60%) are associated
with congenital heart disease (CHD) [16].Tracheomalacia and
bronchomalacia may result either from malformation of the intrin-
sic cartilage of the airway wall, or from external compression by an
abnormally-shaped heart or anomalous great vessels which can
form vascular rings or slings [17].
Congenital tracheal stenosis is more common in children with
DS [16,18–22]. A retrospective analysis of 40 cases with complete
tracheal rings found that seven (17.5%) occurred in children with
DS [20]. The most common form of congenital tracheal stenosis
is the segmental ‘‘hourglass” form [21].
Tracheal bronchus, a right upper-lobe bronchus arising directly
from the trachea proximal to the main carina, is much more com-
mon in children with DS (21%, according to one series) than in the
general pediatric population (2%) [23]. The presence of a tracheal
bronchus may predispose to recurrent right upper lobe pneumo-
nias or atelectasis because of aspiration and poor secretion clear-
ance [16,24]. It can also lead to persistent right-upper lobe
atelectasis in an intubated infant or child in whom the endotra-
cheal tube extends beyond the orifice of the right-upper-lobe
bronchus [24] (Table 2).
Table 1
Prevalence of common disorders in children with DS.
The cardiovascular system
Congenital heart disease: 54%
Complete atrial-ventricular canal: (CAVC) 42%
Ventriculoseptal defect: (VSD) 22%
Atrial septal defect: (ASD)16%
Airway Abnormalities
Laryngomalacia: 50%
Tracheomalacia: 33%
Complete tracheal ring: 17.5%
Tracheal bronchus: 21%
Obstructive sleep apnea: 50–97%
Lingual tonsil 30%
Table 2
Approach to upper-airway obstruction (UAO) in children with DS.
Presentation Stridor; snoring; dysphagia; witnessed apnea during sleep
Consider Laryngomalacia, tracheomalacia, subglottic stenosis, tracheal
stenosis, OSA, adenotonsillar hypertrophy, lingual tonsillar
hypertrophy
Investigations Pharyngolaryngoscopy, bronchoscopy, lateral neck x ray,
polysomnography, echocardiogram, cardiac catheterization
Therapy Conservative management for mild airway anomalies;
surgical intervention for severe airway anomalies; surgical
intervention for structural CHD; to treat OSA:
adenotonsillectomy, CPAP, BIPAP
Parenchymal abnormalities
Children with DS are predisposed to a variety of abnormalities
of the respiratory system which render them more susceptible to
infection and injury. Their lungs have fewer yet larger alveoli and
alveolar ducts with reduced surface area, a finding known as alve-
olar simplification [25]. The enlarged alveoli are more susceptible
to mechanical stress, already a concern because of the underlying
connective tissue abnormalities, especially during mechanical ven-
tilation. Children with DS have reduced ciliary-beat frequency and
movement, albeit with normal ciliary ultrastructure [26].
Sub-pleural cysts are a small cystic dilatations along the pleural
surface of the lung which communicate with the alveoli [27]. The
presence of sub-pleural cysts in DS was first reported in 1986
[28], and is a common finding in children with DS, with a preva-
lence ranging 20–36% [29], and higher in the presence of CHD
[30,29]. Although sub-pleural cysts are difficult to detect on regu-
lar chest radiographs, they are readily identified by chest computer
tomography and direct microscopy [29]. The clinical significance of
the sub-pleural cysts is unclear and hence their management and
treatment are usually conservative. However, it has been sug-
gested that sub-pleural cysts may be associated with hypoxia
and contribute to increased pulmonary vascular resistance [33].
Recurrent wheeze
Recurrent wheeze has been reported in more than one-third of
children with DS [31,32] and many of these children are diagnosed
with asthma and treated accordingly [31], though often unsuccess-
fully. Indeed, relatively few children with DS meet the diagnostic
criteria of international asthma guidelines [33]. One case-control
study using the international study of asthma and allergy in child-
hood (ISAAC) questionnaire [34] for respiratory symptoms com-
pared parental response for 130 children with DS, 167 of their
siblings, and 119 age- and sex-matched typical controls. Wheeze
was more commonly reported in children with DS (18.5%) than
in their siblings (6.6%) or the typical controls (6.7%), with a relative
risk for recurrent wheeze in DS of 2.8 (95% CI, 1.42–5.51) relative to
their siblings, and 2.75 (95% CI, 1.28–5.88) relative to the typical
controls. However, a physician’s diagnosis of asthma was only
made in 3.1% of children with DS versus 4.2% of the siblings and
in 6.7% of the controls. Because of this, it is important to consider
that recurrent wheeze in patients with DS may be the result of con-
ditions other than asthma, as will be described in the coming sec-
tions of this review.
Children with DS tend to have worse lung disease than typical
children
Many children with DS have frequent upper respiratory tract
infections (URTI) in their early years, and these are often more sev-
ere and prolonged than similar infections in their typical peers
[35]. Children with DS have higher incidence of hospitalizations
because of RSV lower respiratory-tract infection, often associated
with longer and more complicated stays as well as with a higher
incidence of acute lung injury (ALI) and acute respiratory distress
syndrome (ARDS) [36–38].
A retrospective review of 232 hospital admissions of children
with DS during a 6.5 year period found acute lower respiratory dis-
ease to be the most common cause for acute hospital admission in
children with DS. The median length of stay and cost of admission
for children with DS with common respiratory conditions was two-
to three times greater than for typical children [35]. Children with
DS tend also to have a higher incidence of acute lung injury with
pneumonia relative to typical children. A retrospective study com-
 H.S. Alsubie, D. Rosen / Paediatric Respiratory Reviews 26 (2018) 49–54
pared 24 children with DS who were admitted to the PICU for
mechanical ventilation with 317 typical children also admitted to
the PICU for similar treatment. 58% (14/24) of the children with
DS met the criteria for acute lung injury (ALI) versus 13% (41 of
317) of the typical children. Likewise, 46% (11/24) children with
DS were diagnosed with acute respiratory distress syndrome
(ARDS) versus 7% (21 of 317) of the typical children [38]. Despite
the high incidence of ALI and ARDS in the children with DS, none
died in this study, whereas other studies have reported an almost
5% mortality rate of typical children who develop ARDS [39,40].
Upper airway abnormalities
Upper airway obstruction (UAO) in children with DS is common
and often multifactorial in nature. In one retrospective review, 71
(14%) of 514 children with DS followed over a 5-year period had
significant UAO [41]. 42% (30/71) had adenotonsillar hypertrophy,
and half of (39/71) those patients underwent pharyngolaryn-
goscopy and bronchoscopy in which multiple points of obstruction
were seen in 38% (15/71). Other findings included laryngomalacia
in 28%, macroglossia in 26%, subglottic stenosis in 23%, and con-
genital tracheal stenosis in 5% of the patients. 5 patients required
tracheostomy for persistent UAO. While the majority of the
patients (76%) who underwent surgical intervention had signifi-
cant or complete relief of obstructive symptoms, 24% had moder-
ate or severe residual symptoms postoperatively [41]. Younger
children were more likely to have more severe symptoms and less
likely to have complete resolution of their upper-airway obstruc-
tion following the airway surgery. It is important to recognize that
approximately 50% of patients with UAO had evidence of pul-
monary arterial hypertension (PAH) confirmed by cardiac catheter-
ization or echocardiogram; this improved in 91% of the patients
following their upper airway surgery. This finding underscores
the UAO as an important factor for PAH in children with DS [41].
The causes of upper airway obstruction in DS are age-related.
Laryngomalacia is the most common cause of upper-airway
obstruction in children with DS under the age of two years, and
is eclipsed by other causes such as adenotonsillar hypertrophy as
the children grow older [18].
Children with DS have smaller-than-normal airways than typi-
cal children and may require a smaller-than-usual endotracheal
tube relative to age-matched typical children to avoid potential
trauma to their airways [19]. The prevalence of subglottic stenosis
is thought to be higher in DS children, although it remains unclear
how much of this is congenital versus acquired [42,43].
UAO in children with DS rarely occurs in isolation [18], and many
be associated with significant gastroesophageal reflux disease (GERD)
which can cause upper airway inflammation leading to malacia and
further narrowing of the caliber of the upper airway [18].
Obstructive sleep apnea (OSA)
Children with DS are more susceptible to sleep-disordered
breathing. Anywhere from 50 to 97% of children with DS have
OSA [44,45], compared to 1–2% of the general pediatric population
[46,47]. Many of the characteristic anatomical abnormalities of
children with DS render them more susceptible to OSA, including:
midface and mandibular hypoplasia [48]; relative macroglossia; a
narrow nasopharynx; and a high-arched and narrow palate
[49,50]. The generalized hypotonia in children with DS can also
lead to increased UAW collapsibility during sleep.
Approximately 30–50% of patients with Down treated with ade-
notonsillectomy continue to have either persistent or recurrent
OSA [41,51,52]. One study of 27 patients with DS aged 4–19 years
51
(mean age 9.9 years) to evaluate the cause of persistent OSA despite
previous adenotonsillectomy using static and dynamic cine-MRI
studies of the upper airway (UAW) identified relative macroglossia
in 20 subjects (74%); glossoptosis in 17 (63%); regrowth of adenoid
and tonsillar tissue in in 17 (63%); enlarged lingual tonsils in eight
(30%); and hypopharyngeal collapse in six (22%).
A sleep history is helpful in identifying children with DS with
OSA. A history suggestive of OSA may include: snoring, gasping,
choking during sleep; breathing through an open mouth; sleeping
in a seated position or with the neck hyper-extended; night
sweats; restless sleep, witnessed apnea; and secondary nocturnal
enuresis. Children with OSA may also have daytime symptoms
including hyperactivity, emotional difficulties, decreased academic
performance, and attention deficit [53], [54]. Pulmonary hyperten-
sion [55], right sided heart failure, and cor pulmonale [56] are also
known complications of longstanding OSA in children with DS.
A general examination of children with DS suspected to have OSA
may reveal either failure to thrive or obesity. Proper assessment of
the craniofacial structures is necessary to detect abnormalities such
as mid-face hypoplasia, micrognathia or retrognathia. Likewise, it is
important to evaluate the oral cavity including the tongue, tonsillar
size, and the shape and position of the teeth, palate, and uvula. There
may also be evidence of longstanding upper-airway obstruction such
as pectus excavatum or Harrison sulci.
Although a complete history and physical examination are
important screening tools, one should have a low threshold for
obtaining a polysomnogram (PSG), as significant OSA may be pre-
sent despite an unremarkable history or physical examination [57].
While snoring is the most common symptom in children with OSA
and has been shown to be predictive of OSA in children with DS,
[44,58] it is important to stress that the absence of snoring does
not rule out OSA [59].The American Academy of Pediatrics cur-
rently recommends that all children with DS undergo polysomnog-
raphy by the age of four [60].
Adenotonsillectomy (AT) is generally the first line of treatment
for pediatric OSA [57]. Both the American Academy of Pediatrics
and the American Academy of Otolaryngology-Head and Neck Sur-
gery recommend close postoperative monitoring including over-
night oximetry for those at higher risk for respiratory
complications [57,61]. Included in this group are children with
craniofacial abnormalities, present in most children with DS.
Because upper airway obstruction (UAO) in children with Down
syndrome is often multifactorial, residual upper-airway obstruc-
tion is common after adenotonsillectomy. When present, positive
airway pressure (PAP) therapy is generally the next line of treat-
ment for OSA in children, with and without DS.
Significant mandibular retrognathia in children with DS may
cause UAO and OSA. A retrospective study of 35 patients with ret-
rognathia and DS, UAO found mandibular distraction to be success-
ful in all who underwent it [62,63]. Likewise, in children with
narrow, high-arched palates, rapid maxillary expansion (RME)
has also been demonstrated to be an effective treatment option.
One study of 24 children with DS who underwent RME found that
this yielded reductions in hearing loss, rates of ENT infections, and
parentally-assessed symptoms of UAO [63]. A systematic review
and meta-analysis of sleep study outcomes in non-syndromic chil-
dren who had undergone RME as treatment for obstructive sleep
apnea (OSA) revealed an improvement in the apnea-hypopnea
index (AHI) and oxygen desaturation nadir, especially in the short
term (<3-year follow-up) [64].
Hypoglossal nerve stimulation is an effective treatment of OSA
in selected adults by dynamically advancing the position of the
tongue in synchronization with inspiration [65,66]. There is cur-
rently a pilot study underway exploring its use adolescents with
DS and refractory OSA intolerant of CPAP [67].
52 H.S. Alsubie, D. Rosen / Paediatric Respiratory Reviews 26 (2018) 49–54
Other treatments for OSA may include tongue reduction, tongue
hyoid advancement, uvulopalatopharyngoplasty, and maxillary or
midface advancement [68].
Other organ systems affecting respiratory health
The cardiovascular system
Congenital Heart Disease (CHD) is present in 54% of children with
DS [69]. Most is amenable to complete surgical correction in infancy
[42]. The most common forms of CHD in this population are com-
plete atrial-ventricular canal (CAVC), ventriculoseptal defect (VSD),
and atrioseptal defect (ASD), accounting for 42%, 22%, and 16% of
CHD in this population, respectively. Complex congenital heart dis-
ease is becoming less common in infants with DS, and there has been
an annual reduction in the incidence by about 2% annually since
1992. Although atrioventricular septal defect (AVSD) was far more
common than VSD in the three-year period between 1992 and
1994, their incidence was equivalent in the years 2010–2012 [69].
This phenotypic shift may either be the result of the selective abor-
tion of fetuses with DS or the result of improved antenatal diagnosis
of complex congenital heart defects which, in turn, has resulted in
the termination of these pregnancies. Post-operative complications
from CHD repair may include: thoracic duct injury and chylothorax;
recurrent laryngeal nerve injury resulting in vocal cord paralysis;
phrenic nerve injury leading to diaphragmatic paralysis; and sub-
glottic stenosis secondary to intubation.
The surgical treatment of CHD has significantly reduced the
overall mortality in children with DS. One study, for example,
found that whereas between the years 1985–1995, 101/163
(62%) infants undergoing heart surgery had a mortality of 30%,
between the years1996-2006, 129/180 (72%) underwent the same
surgery with only a 5% mortality [42]. Most of these children now
survive into adulthood. In recent years, the estimated life expec-
tancy of children with DS has risen to 60 years compared to
25 years in 1983 [70,71]. Most CHD is diagnosed in early child-
hood: according to one study, 74% were diagnosed in infancy and
18% between 1 and 4 years of age.
Acquired heart disease is more common in adults with DS than
in the general population, with mitral-valve prolapse, aortic-valve
regurgitation, and tricuspid-valve prolapse occurring in 57%, 17%,
and 17% respectively, according to one study [72,73]. The cause
of valve dysfunction in DS is not completely understood. People
with DS in general have a higher incidence of subluxations and dis-
locations, and aortic valve fenestrations, too, tend to develop with
advancing age [74]. This points to an underlying primary collagen
or elastic-tissue defect [75,76]. Alternatively, variations in chordal
support and valve structure may produce valve injury and lead to
weakening of the valve structure [76]. Finally, the endocardial
cushions contribute to mitral and tricuspid valve formation, and
these are frequently abnormal in DS.
Mitral valve prolapse is associated with an increased risk of pro-
gressive mitral regurgitation [77] and endocarditis, as well as with
arrhythmias and cerebral embolism [76]. Because adults with DS
without underlying cardiac disease may also develop valve dys-
function, they should be reassessed clinically by the age of 18,
especially prior to dental or surgical procedures including a screen-
ing echocardiogram [78]. In situations in which adults with Down
syndrome who have not undergone an echocardiogram are at risk
for endocarditis, some recommend they be given prophylactic
antibiotics [79].
The gastrointestinal system
DS is associated with a number of congenital and functional
defects of the gastrointestinal system. 4–10% of children with DS
have congenital anomalies in the gastrointestinal system, includ-
ing: duodenal stenosis/atresia (1–5%), Hirschsprung disease (1–
3%), anal stenosis or atresia (<1–4%), esophageal atresia/trachea-
esophageal fistula (0.3–0.8%). All are more frequent in children
with DS than in typical children [80].
Esophageal atresia and tracheo-esophageal fistula can directly
affect the respiratory system by means of recurrent aspiration, lead-
ing to persistent respiratory symptoms including bronchitis, pneu-
monia, cough and wheeze. One retrospective review of respiratory
morbidity in 334 patients without DS age 1–37 years who had under-
gone repair of esophageal atresia and tracheo-esophageal fistula
revealed that 147 (44%) were hospitalized with respiratory illness
in the initial years following surgery, two-thirds before the age of 5.
Children with DS are more prone to gastroesophageal reflux
(GER) because of their reduced muscle tone, specifically in the
lower esophageal sphincter, and perhaps because of differences
in their enteric nervous system [81]. Patients with underlying
GER are more likely to be hospitalized with respiratory illness
[82]. Aspiration pneumonia may be a presenting diagnosis of GER
and should be considered in children with chronic cough, wheeze
or recurrent pneumonia. GER can easily be confused with asthma
and remain untreated.
Dysphagia is common in children with DS and can lead to silent
aspiration, especially of liquids [83]. There is also an increased inci-
dence of achalasia in children with DS which, too, can lead to fre-
quent reflux and aspiration [84].
Autonomic differences leading to altered control of breathing
Many children with DS exhibit differences in both parasympa-
thetic and sympathetic autonomic nervous activity. This can man-
ifest as altered heart rate variability [85] and respiratory instability
with the occurrence of frequent periodic breathing and central
sleep apnea [86–88]. Children with DS have also been found to
have mildly elevated baseline end-tidal carbon-dioxide levels
while sleeping relative to typical children [89].
The immune system
Children with DS have been frequently reported to have abnor-
malities in their immune systems, including: mild-to-moderate T-
and B-cell lymphopenia; mild-to-moderate reduced native T-cell
percentages with corresponding reduction of T-cell excision cir-
cles; impaired mitogen-induced T-cell proliferation; suboptimal
antibody response to standard immunizations, including tetanus,
pneumococcus, haemophilus influenza type-B, and diphtheria;
and decreased neutrophil chemotaxis [90,91]. Children with DS
presenting with recurrent respiratory-tract infections should be
investigated for possible immunodeficiency, including testing of
serum immunoglobulins, immunoglobulin G subclasses, vaccine
titers, T- and B-cell subsets, and complement levels [92].
Children with DS should be vaccinated according to the national
schedule for immunization, including the influenza vaccine. The
Advisory Committee on Immunization Practices (ACIP) has also
recommended the administration of the 23-valent pneumococcal
polysaccharide vaccine in children over 2 years of age with a
higher risk of pneumococcal disease, such as those with chronic
underlying diseases or who are immunocompromised [93], and
so this should be strongly considered in children with DS. Children
with DS and congenital heart disease or prematurity who meet the
criteria for RSV prophylaxis should receive palivizumab.
In summary
Children with DS are prone to wide range of respiratory prob-
lems that may originate at any level of respiratory tract, as well
 H.S. Alsubie, D. Rosen / Paediatric Respiratory Reviews 26 (2018) 49–54 53

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