68  Respiratory Complications of
Down Syndrome
ANDREW P. PRAYLE, BMedSci, BMBS, PhD, and HARISH G. VYAS, DM, FRCP, FRCPCH
Introduction
Down syndrome (DS; trisomy 21) is the commonest chro-
mosomal abnormality compatible with live birth. There is
an incidence of approximately 1/800 live births, translating
to approximately 700 live born children in England and Wales
per year.1 In the United States the prevalence is 14/10,000
live births, with approximately 6000 births annually. However,
the overall population prevalence is somewhat lower, at
approximately 8.3 per 10,000.2
The phenotype is characterized by a characteristic facies
and stature, variable developmental delay and learning dif-
ficulties, and an increased incidence (over the general popu-
lation) of multiple specific diseases, including respiratory
disease, congenital heart defects, gastrointestinal malforma-
tions, autoimmunity, endocrine disease (in particular hypo-
thyroidism), hematologic malignancy, and orthopedic, vision,
and hearing disorders. Respiratory illness is highly prevalent
within the general pediatric population but even more so in
children with DS. Within this chapter we discuss the pertinent
complications of DS for the respiratory pediatrician.
The lifespan of individuals with DS is gradually improving
(Fig. 68.1). In 1983 median age at death was 25 years, sig-
nificant progress was made in the 1990s, and by 1997 it
was 49 years.3 More recent estimates suggest that a child
born in 2000 in Australia with DS had a life expectancy of
60 years.4 Part of this improved survival is likely related to
improved access to care, accompanied by a shift in public,
professional, and parental attitudes to care of children with
DS in the past few decades.5
Within this context of improving life expectancy, efforts
should be made to understand and improve the pulmonary
health of children with DS. Although some children with
DS will unfortunately have devastating illness in childhood
(often a combination of cardiac and respiratory disease),
much of the respiratory disease either improves with maturity
or is amenable to treatment. Therefore respiratory pediatri-
cians need to be vigilant for symptoms of respiratory disease,
judicious in investigation, and mindful that the consultation
involves careful explanation in a way that the patient and
carers can understand.
Children with DS are more likely to develop respiratory
disease than their peers without DS, and mortality from
respiratory disease in childhood in DS is higher than the
general population. Respiratory disease is the second leading
cause of death in children with DS, after cardiac disease.3
The rate of death of children with DS can be compared with
the general population with the standard mortality odds ratio
(SMOR). The SMOR in children under 10 with DS (compared
with children without DS) is 14 for cardiac disease, and 3.0
992
for a combination of respiratory pathologies including aspi-
ration, pneumonia, and influenza.
Not unexpectedly, children with DS are more likely to be
admitted to hospital than the general population. More than
half of children with DS have a respiratory related hospital-
ization, irrespective of presence of congenital heart disease
(CHD).6 Given the increased mortality, an increase in intensive
care admissions is also well recognized. Our own work based
on the United Kingdom national Paediatric Intensive Care
Registry (PICANet) estimates that 25% of children with DS
are admitted to pediatric intensive care units (ICUs) by 1
year of age, and approximately half of these admissions are
respiratory, although cardiac and respiratory disease often
coexist.
The common clinical manifestations of respiratory
disease in DS are summarized in Table 68.1. Respiratory
symptoms are exceedingly common in infants with DS;
however, because most studies of respiratory symptoms to
date have been retrospective in nature, the true scale of the
problem has not yet been fully characterized. A prospective
web-based parent-reported observational study is ongoing
in the Netherlands, which seeks to characterize the relation-
ship between respiratory symptoms, health care use, and
comorbidities.7 This study will provide useful information for
clinicians.
Given the multiple manifestations of respiratory disease
in DS, in this chapter we will elaborate on respiratory disease
in DS using an anatomically structured approach and cat-
egorize disease into that of the upper and lower airways.
However, it should be noted that frequently patients with
DS may have multiple disease processes of both the upper
and lower airways, and there is considerable overlap between
symptoms and disease. Therefore it is appropriate to take a
holistic “whole respiratory tract” approach to diagnosis and
management. In addition, it is important to note that disease
of other organ systems (chiefly cardiac, gastrointestinal,
immunologic, and neurologic) and obesity in DS can increase
the severity of respiratory disease (Table 68.2).
Upper Airway Disease and
the Trachea
ANATOMY OF THE UPPER AIRWAY IN
DOWN SYNDROME
In DS the upper airway is narrowed both above and below
the vocal folds. Narrowing above the trachea is due to rela-
tive macroglossia, midface hypoplasia, narrowed nasophar-
ynx, choanal stenosis, enlarged tonsils and adenoids, lingual
 68  •  Respiratory Complications of Down Syndrome 992.e1

ABSTRACT KEYWORDS
This chapter reviews the impact of trisomy 21 (the com- Down syndrome respiratory complications
monest trisomy) upon the respiratory tract, including its alveolar hypoplasia
impact upon the structure and function of the upper and
lower tract, the impact upon sleep, cardiorespiratory, and
gastrorespiratory interactions, typical radiologic findings,
and guidance for treatment.
 68  •  Respiratory Complications of Down Syndrome 993

70

60
Mean

Age at death among people with DS

Median
50 25th & 75th percentiles

40

30

20

10

0
1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Year
Fig. 68.1  Improvement in survival in people with Down syndrome (DS) in the United States. Presson and colleagues combined data from live births
of infants with DS from 1907 to 2007, published birth prevalence estimates of DS, and mortality data from death certificates to inform a Monte Carlo
model of survival over the past century. The improvement in survival commencing in the 1970s is striking. (Presson AP, Partyka G, Jensen KM. Current
estimate of Down syndrome population prevalence in the United States. J Pediatr. 2013;163(4):1163-1168.)

Table 68.1  Respiratory Disease Patterns in Down Table 68.3  Upper Airway Anomalies in Down
Syndrome Syndrome
Symptom Etiology Smaller midface and lower Shorter hard palate length
face skeleton Smaller mandible volume
Upper airway Stridor Shorter mental spine–clivus distance
obstruction Obstructive sleep apnea/sleep-disordered Soft tissues Smaller tonsils
breathing. Smaller adenoids
Postextubation stridor Smaller tongue
Recurrent respiratory Viral upper respiratory tract infections Relative impact of skeletal Higher tongue to skeletal size ratio
infections Lower respiratory tract infections (viral/ size upon soft tissue to Reduced upper airway size due to
bacterial) airway size ratio soft tissue crowding
Lobar pneumonia
Aspiration pneumonia Modified from Uong EC, McDonough JM, Tayag-Kier CE, et al. Magnetic
Wheeze Pulmonary edema/pulmonary hypertension resonance imaging of the upper airway in children with Down syndrome.
Asthma Am J Respir Crit Care Med. 2001;163(3 Pt 1):731-736 and Guimaraes CV,
Donnelly LF, Shott SR, et al. Relative rather than absolute macroglossia in
patients with Down syndrome: implications for treatment of obstructive
sleep apnea. Pediatr Radiol. 2008;38(10):1062-1067.

Table 68.2  Disease Complicating Respiratory Illness in tonsils, and a short palate (Table 68.3). Below the vocal folds,
Down Syndrome the trachea itself is considerably narrowed, with an internal
diameter approximately 2 mm narrower than the general
Organ System Manifestation
population in the pediatric age range.8 This narrowing likely
Cardiovascular Airway compression secondary to congenital contributes to the increased incidence of postintubation
heart disease stridor historically observed in children with DS.9
Pulmonary hypertension
Pulmonary edema (including high altitude
related) TRACHEOMALACIA AND LARYNGOMALACIA
Complications of cardiac surgery
Gastrointestinal Swallowing dysfunction Airway abnormalities contribute significantly to symptoms
Gastroesophageal reflux disease
Respiratory complications following repair of
in DS (Fig. 68.2), but this information is largely based on
esophageal atresia case series naturally representing groups of patients who
Immune system Recurrent respiratory tract infections have particularly serious symptoms. Without background
Increased severity of respiratory tract infections population data, case series can produce incorrectly elevated
Neurologic Hypotonia prevalence of diseases. In addition, case series are usually
Other Obesity
limited to small numbers of children, and so estimates
of prevalence of rarer conditions vary widely between
series.
994 SECTION 7  •  Miscellaneous Disorders of the Lung

Left
vocal
fold

Subglottic
stenosis

A B

C D
Fig. 68.2  Airway endoscopy abnormalities in Down syndrome. (A) Lower trachea appearance under general anesthesia, showing severe airway malacia.
(B) Appearance of subglottic stenosis immediately below the vocal fold. (C) Midtracheal stenosis due to previous intubation. (D) “Pinpoint” severe
tracheal stenosis. ([A–C] From Hamilton J, Yaneza MM, Clement WA, et al. The prevalence of airway problems in children with Down’s syndrome. Int J Pediatr
Otorhinolaryngol. 2016;81:1-4. [D] From Shapiro NL, Huang RY, Sangwan S, Willner A, Laks H. Tracheal stenosis and congenital heart disease in patients with
Down syndrome: diagnostic approach and surgical options. Int J Pediatr Otorhinolaryngol. 2000;54(2-3):137-142.)

Table 68.4  Endoscopic Findings in Down Syndrome is common in children with DS and usually presents in the
first months of life. Supraglottoplasty is uncommonly per-
Estimated Down formed for laryngomalacia and is reserved for complications
Syndrome
Population such as feeding failure, respiratory distress, and sleep-related
Prevalence (%) symptoms or apnea, often in the context of subglottic stenosis
Series Hamilton10 Bertrand11 (From Hamilton10) and cardiac surgery. However, surgical failure can occur in
Number studies 39 24 up to a third of patients, and in some patients tracheostomy
Subglottic stenosis 14 1 5.9 may be required.12 When undertaking surgery for laryngo-
Laryngeal cleft 2 0 0.8 malacia, the possibility of further surgical intervention should
Laryngomalacia 2 12 0.8 be considered and discussed with families.
Tracheomalacia 14 8 5.9
Bronchomalacia 10 5 4.2
Tracheal bronchus (wherein the right upper lobe bronchus
Tracheal stenosis 2 1 0.8 originates directly from the trachea rather than the right
main bronchus) can predispose to lower respiratory tract
Data from Hamilton J, Yaneza MM, Clement WA, et al. The prevalence of infection (LRTI).13 In a report on bronchoscopy findings in
airway problems in children with Down’s syndrome. Int J Pediatr children, 2 of 18 patients with a tracheal bronchus had DS,
Otorhinolaryngol. 2016;81:1-4 and Bertrand P, Navarro H, Caussade S, et al.
Airway anomalies in children with Down syndrome: endoscopic findings. which would suggest that the incidence in children with DS
Pediatr Pulmonol. 2003;36(2):137-141. is elevated. Where recurrent right upper lobe pneumonia
occurs in DS, a tracheal bronchus should be considered.
When associated with other airway anomalies such as ste-
In a series of 239 children with DS of whom 39 (16%) nosis, tracheal bronchus can cause significant management
underwent endoscopy for airway symptoms,10 the most challenges. This is especially so in the critical care setting
common finding was tracheobronchomalacia (Table 68.4). where distortion of the usual anatomy can lead to significant
In approximately half of patient with tracheobronchomalacia, hypoxic events in association with changes in the position
this affected both the trachea and bronchi.11 Laryngomalacia of the head and neck.14
 68  •  Respiratory Complications of Down Syndrome 995

SUBGLOTTIC AND TRACHEAL STENOSIS

Narrowing can occur at any point in the airways in DS.
However, subglottic stenosis deserves particular discussion.
The overall prevalence of congenital subglottic stenosis in
DS is approximately 1.3%.10,11 Most subglottic stenosis occurs
in the context of previous intubation, although this is not
always the case. Laryngotracheoplasty has a good success
rate and is presumably undertaken for patients on the more
severe end of the spectrum, of whom most have preen previ-
ously intubated.15
Despite the prevalence of subglottic stenosis, the diagnosis
should not be presumed in all cases of postoperative stridor.
In children with DS ventilated for cardiac surgery, up to 25%
develop postoperative stridor in the absence of subglottic
stenosis.16 These children tended to be less than the 10th
centile for weight and younger (with a mean age of 8 months,
compared with a mean age of 30 months in those without
postoperative stridor).
Tracheal stenosis (narrowing below the subglottic space
extending a varying length along the trachea) can be chal-
lenging to evaluate in DS. Tracheal stenosis in DS is associ-
ated with vascular rings and hypoplasia of the aortic arch.
At induction of general anesthetic, it may be that the extent
of the stenosis prevents the admission of even a narrow
Fig. 68.3  Sagittal magnetic resonance imaging of the head in Down
fiberoptic bronchoscope, especially if one or more complete syndrome. Note the apparent macroglossia caused by the small midface.
tracheal rings are present. When this occurs, a nonionic The tongue is in fact normal in size, and the midface is small. (Courtesy
tracheobronchogram or thin cut computerized tomogra- Prof. Lane F. Donnelly MD, Texas Children’s Hospital, Baylor College of
phy (CT) scan can be used to delineate the extent of the Medicine Texas Children’s Hospital.)
narrowing.17

CLINICAL PRESENTATION OF UPPER age- and sex-matched controls on magnetic resonance

RESPIRATORY TRACT DISEASE IN
DOWN SYNDROME
The clinical features of upper respiratory tract disease in DS
include cough and parental report of noisy breathing and
snoring. Sleep-disordered breathing in DS is discussed later.
Parents and carers describe a wide range of breathing-
associated sounds, with varying diagnostic utility. Snoring
should be specifically asked for because a history of snoring
is not always spontaneously volunteered. In more severe
disease, upper airway abnormalities can lead to increased
work of breathing and failure to thrive. Symptoms often
worsen with self-limiting (presumed viral) upper respiratory
tract infections and in LRTIs where the increased respiratory
rate unmasks previously asymptomatic upper airway disease.
A history of stridor, croup, chronic aspiration, and difficulty
in extubation should motivate careful assessment and
investigation.
Sleep-Related Breathing
Disorders
Sleep-disordered breathing, including obstructive sleep apnea
(OSA), is common in DS. There are multiple structural and
functional factors contributing to disordered and disturbed
sleep in DS, including midfacial hypoplasia, relatively large
tongue, small upper airway with superficial tonsils, increased
secretions, obesity, and hypotonia (Fig. 68.3).18 It is worth
noting that the tongue in DS is actually smaller than in
imaging (MRI) scans. The apparent macroglossia is actually
due to small craniofacial parameters, leading to relative
macroglossia for the size of the oral cavity.19 Similarly, adenoid
and tonsil volume is actually smaller in children with DS
without symptoms of OSA, but there is soft tissue crowding
within a smaller midface.20
Disturbed sleep behavior is frequently reported in DS.
Snoring occurs in half of school-age patients and is accom-
panied by parental report of restlessness, frequent waking,
bedwetting, delay in becoming alert after waking, and
challenging sleep behavior. However, there is little corre-
lation between polysomnography findings and parental
report.21
Sleep-disordered breathing is associated with neurocogni-
tive difficulties, including developmental delay, challenging
behavior, tiredness, pulmonary hypertension, and faltering
growth. Unfortunately, these are all also associated with DS,
and therefore the impact of sleep-disordered breathing may
be unrecognized.22 Sleep disturbance can be assessed with
a respiratory disturbance index; in children with DS, there
is a significantly higher respiratory disturbance index than
in controls (Fig. 68.4).23 In addition to OSA, the sleep of
children with DS demonstrates increased fragmentation,
numerous awakenings and arousals, and periodic leg move-
ments. These characteristics are to a certain extent indepen-
dent of the respiratory system and occur in the presence or
absence of OSA.
The reported incidence of OSA in DS depends to a certain
extent on the definition used and how aggressively patients
are investigated. In unselected consecutive patients with DS
996 SECTION 7  •  Miscellaneous Disorders of the Lung
15
Mean RDI
10
5 HISTOPATHOLOGY OF THE LOWER
0 contribute to reduced functional reserve in children with
DS Non-DS
Group
Fig. 68.4  Respiratory disturbance index (RDI) in children with and without
Down syndrome (DS). Comparison of RDI in children with and without
DS. 23 children with DS were compared with 13 children with primary
snoring. RDI, calculated as the number of obstructive or mixed apneas
and hypopneas per hour of sleep. (Data from Levanon A, Tarasiuk A, Tal
A. Sleep characteristics in children with Down syndrome. J Pediatr. 1999;
134(6):755-760.)
prospectively evaluated with polysomnography, there is evi-
dence of a high background rate of OSA, up to 80%. An
increased apnea index and elevated arousal index is found
in individuals with a high body mass index (BMI). This is
not always associated with snoring.24,25
Adenotonsillectomy is usually the first-line treatment for
OSA. However, the success rate of adenotonsillectomy is lower
in DS than in the general population,26 with only partial
improvement in polysomnogram parameters such as the
apnea-hypoxia index. Importantly, OSA is prevalent even
after surgery.27 Thus adenotonsillectomy may not be effective
alone in treating OSA in DS.
In addition to surgical management of OSA being less
effective in DS, tonsillectomy and adenoidectomy in DS are
associated with an increased risk of postoperative complica-
tions,28 and therefore careful postoperative monitoring is
required for these patients. For patients with severe OSA it
may be prudent that postoperative care takes place on the
ICU. In all DS cases, we advocate an inpatient (rather than
day case) procedure, to allow for monitoring on the night
after the surgery. If adenotonsillectomy is unsuccessful,
further therapeutic options can include home oxygen, con-
tinuous positive airway pressure (CPAP), further surgery, and
tracheotomy in extreme cases.
Central hypoventilation can occur in the absence of upper
airway anomalies, and higher rates of central apnea are
seen compared with other syndromes of developmental delay
such as fragile X.29 Sleep apnea in DS is multifactorial in
origin, and both airway abnormalities and a central mecha-
nism may play a role.
Lower Respiratory Tract
ETIOLOGY
Like the upper respiratory tract, the lower respiratory tract
has multiple recognized malformations in DS. Within this
context, even minor superimposed infection becomes more
severe than would be anticipated in a child without DS.
Pulmonary infection is multifactorial in origin, with con-
tributing factors including decreased pulmonary reserve due
to morphologic differences, poor immunologic function,
gastroesophageal reflux disease and aspiration, interactions
with CHD, and thoracic cage malformations.
RESPIRATORY TRACT IN DOWN SYNDROME
A number of morphologic differences in lung parenchyma
DS. The changes can be so severe that an experienced pedi-
atric pathologist may recognize that a sample of lung tissue
is from a patient with DS on external macroscopic evaluation
alone.
In DS the lung has a diffuse uniform porous pattern, with
increased size of alveoli and alveolar ducts.30 This pattern
occurs postnatally; the lung tissue has a more normal appear-
ance in prenatal life. These features are due to a failure of
alveolar multiplication within the acinus. The enlarged alveoli
and acinar hypoplasia (deficient alveolar multiplication) can
be formally characterized by radial count. In late gestation
fetuses the radial count in DS is higher than controls. However,
postnatally the radial count drops, and this reduction is
present throughout life (Fig. 68.5). This causes a reduction
in the number of alveoli and the overall lung surface area.
This acinar hypoplasia has been suggested to be due in part
to the complex interaction of the heart and lungs in patients
with severe CHD who undergo mechanical ventilation,
because radial counts are known to be low in CHD in the
absence of DS. However, acinar hypoplasia appears to occur
independently of CHD in children with DS.
Subpleural cysts are well recognized in DS (Fig. 68.6),
although the relevance of these to pulmonary disease has
not yet been fully elucidated.31,32 These cysts are approxi-
mately 1–2 mm in diameter and are lined by cuboidal epi-
thelium. Up to 20% of patients with DS have them at
postmortem, and they have been found in 36% of chest CT
scans.33 They are underrecognized and usually not apparent
on chest radiographs. Their development has been suggested
to occur secondary to reduced postnatal production of periph-
eral small airways and alveoli, which likely occurs in early
postnatal life.
EPIDEMIOLOGY OF LOWER RESPIRATORY
TRACT INFECTION IN DOWN SYNDROME
Children with DS are at high risk of early hospitalization in
the preschool age due to respiratory disease.6,34 In a cohort
of children with DS who survived to discharge from hospital
after birth, half were admitted again at least once in their
first 3 years of life, with a median number of two further
admissions. The most common reasons for admission (in
order of frequency) are CHD, pneumonia, acute bronchi-
tis, and bronchiolitis, with respiratory disease occurring in
approximately 50%. The length of stay for children with DS
is often 2–3 times longer than that of children without DS,
and respiratory support is more likely to be required.
The importance of even apparently mild respiratory tract
infections in DS should not be underestimated. Recurrent
respiratory tract infections can have implications for neu-
rodevelopment in DS.35 Children with DS whose parents report
 68  •  Respiratory Complications of Down Syndrome 997

14

12

10

Radial count
8

0
32 34 36 38 40 0 50 100 150 200 10 20 30 40 50 60 70
Weeks gestation Months post natal Years old
Fig. 68.5  Comparison of radial count in Down syndrome (DS), cardiac disease, and normal individuals. Points represent individuals with DS (solid circles)
or cardiac disease (hollow circles). Solid line indicates expected values for people without DS. (Modified from Cooney TP, Wentworth PJ, Thurlbeck WM.
Diminished radial count is found only postnatally in Down’s syndrome. Pediatr Pulmonol. 1988;5(4):204-209.)

A B

C D
Fig. 68.6  Subpleural cysts in Down syndrome. (A) Histopathology sample showing cysts lined by a cuboidal epithelium along the pulmonary surface.
(B) Computerized tomography appearance of subpleural cysts, of approximately 3–5 mm in diameter. (C) Subpleural cysts can be unilaterally distrib-
uted, in this case in only the left hemithorax, and associated with pleural thickening. (D) Cysts can be diffusely spread over both hemithoraces in the
subpleural region.

frequent LRTI have lower developmental scores translating
to a 5-month drop in abilities when measured at 8 years
of age.
Viral infection is an important cause of respiratory disease
in DS, and respiratory syncytial virus (RSV) is particularly
troublesome. Between 10% and 15% of children with DS
without significant comorbidity are hospitalized due to
RSV.36,37 The odds of a child with DS being admitted with
RSV are 6 times higher than the general population, and of
those hospitalized approximately 10% require mechanical
ventilation. Children with DS and RSV are more likely to
have fever and consolidation on chest radiograph and more
frequently receive bronchodilators (implying an increased
rate of wheeze) compared with children without DS.
998 SECTION 7  •  Miscellaneous Disorders of the Lung
Guidelines regarding the use of palivizumab in children
with DS vary, and this remains a controversial area.38 Ran-
domized trials are lacking, but nonrandomized studies from
Canada and the Netherlands demonstrate some support for
the notion that palivizumab may be beneficial for all children
with DS39; however, a clinical trial is required.
In addition to increased risk of severe lung disease requir-
ing respiratory support, when receiving intensive care, there
is an increased risk of acute lung injury (ALI) and acute
respiratory distress syndrome (ARDS)40; surprisingly, the
overall mortality is not increased. It could be speculated that
ALI and ARDS occur in DS with less severe underlying disease,
and that it is the underlying disease that ultimately drives
mortality.
Overall mortality in DS is low in the pediatric intensive
care unit (PICU), with rates of approximately 6%41 and stan-
dardized mortality rates similar to children without DS.42
However, the scenario changes with sepsis, in which there
is an increased risk of mortality.43 Our interpretation of these
results is that respiratory infection in DS, even in critically
ill children, does not necessarily confer an increased risk of
mortality, although ALI and ARDS are more likely to occur.
However, if infection progresses to sepsis, this confers a much
poorer prognosis. We therefore aim to treat infection as early
as possible in respiratory disease, with the aim of preventing
sepsis.
Where standard intensive care is insufficient to rescue
patients from severe respiratory failure, extracorporeal mem-
brane oxygenation (ECMO) is an option. Cashen and colleagues
report on results from the international Extracorporeal Life
Support Organization Registry, which collects data from more
than 200 ECMO centers worldwide.44 They presented data
from 623 patients with DS who received ECMO. In keeping
with studies on ICU management of respiratory failure in
DS, they found no increased risk of mortality for children
with DS who received ECMO when compared with children
without. Over time the use of ECMO in DS has increased.
IMMUNE DYSFUNCTION AND SEVERITY OF
LOWER RESPIRATORY TRACT INFECTION
Children with DS are at an increased risk of infection. Often
this will present as more frequent upper respiratory tract
infections, although in general all respiratory infections
(including LRTIs) are increased. Mechanical factors, such
as the airway abnormalities and gastroesophageal reflux,
clearly play a part in this. In addition, there are well-described
abnormalities of immune cell function in DS, which are sum-
marized in Table 68.5.45–49 Research to characterize the
immune deficit is ongoing, but the deficit includes reduction
of multiple immune cell lines and antibody levels. A matu-
rational component of the immunodeficiency can normalize
with age. Studies investigating the correlation between the
immune deficit and rates of admission have given conflicting
results that appear to depend on which components of the
immune system are investigated.
After immunization, the specific antibody response for a
wide range of antigens in DS is reduced, including immu-
nization against important respiratory pathogens such as
pertussis and pneumococcus. In general, immunization does
induce a specific antibody response, albeit with reduced titers.
In addition to defects in adaptive immunity, children with
DS have abnormalities of innate immunity. These include
Table 68.5  Immune Function in Down Syndrome
Cell numbers Mild to moderate reduced T-cell counts
Mild to moderate reduced B-cell counts
Absence of normal lymphocyte expansion
Mild to moderate reduced naïve T-cell
percentages
Anatomic Reduced thymus size compared to age-
matched controls
Antibody production Suboptimal antibody response to
immunization
Decreased total and specific immunoglobulin
A in saliva
Innate immunity Decreased neutrophil chemotaxis
reduced neutrophil chemotaxis,50 and reduced killing of
Candida, but normal oxidative burst. In addition, absolute
levels of natural killer (NK) cells are reduced.51
Several underlying mechanisms for the immunodeficiency
in DS have been postulated, but a clear unifying genetic
mechanism has yet to be defined.45 Hypotheses that have
been considered include overexpression of genes on chromo-
some 21 (including SOD1, ITGB2, and RCAN1) and a sec-
ondary immunodeficiency caused by accelerated aging and
zinc deficiency. A better understanding of the immunodefi-
ciency in DS may be useful in the future in stratifying patients
according to risk of infectious disease and could help guide
therapy.
CLINICAL PRESENTATION OF LOWER
RESPIRATORY TRACT INFECTION IN
DOWN SYNDROME
Infections of the lower respiratory tract present in a similar
manner to those without DS. However, in our experience,
the onset of disease can be rapid. The hallmark symptoms
of cough and fever are accompanied by a varying degree of
increased work of breathing—elevated respiratory rate, sub-
costal and intercostal recession, with tracheal tug, grunting,
and use of accessory muscles in older children or head bob
in younger infants. Asymmetric chest expansion may be
visible. There are crackles sometimes accompanied by bron-
chial (tubular) breathing over the affected lobes, with or
without increased tactile vocal fremitus. Left untreated,
respiratory muscle fatigue will lead to respiratory failure.
Sputum may be produced or swallowed and vomiting is
common; it may be the most prominent feature. Fever may
be cyclic, especially in complicated pneumonia. The chest
radiograph demonstrates the expected consolidation, although
it should be noted that consolidation is common in viral
respiratory infections such as RSV. A key role of the chest
radiograph is in excluding complicated pneumonia.
WHEEZE IN DOWN SYNDROME APPEARS
INDEPENDENT FROM ATOPY
Children with DS are frequently reported to be “noisy breath-
ers,” and this may often be reported by their caregivers as
a wheeze. The parental report of wheeze can of course indi-
cate a wide variety of respiratory noises. It may well be the
case that many children reported to wheeze do not have
asthma.
Wheeze is diagnosed in up to 30% of children with DS
and appears independent from RSV infection, which is a

major risk factor in children without DS.52 If asthma-related
wheezing is highly prevalent in DS, one might suspect that
markers of atopy such as positive skin prick testing would
be highly prevalent. However, this is not the case—the rates
of atopy are low in children with DS.53,54 Lung function tests
(especially spirometry) can be difficult to perform in DS, pre-
venting the accurate diagnosis of reversible bronchospasm.
However, these data on the discrepancy between the rates
of atopy, and rates of wheeze in DS raise the question of
whether this wheeze is in fact a manifestation of asthma,
or whether there are alternate explanations in many children
with DS. Therefore when given a history of wheeze, alternate
explanations other than asthma should be considered, includ-
ing intrathoracic airway malacia, muscle hypotonia with
upper airway collapse, and vascular malformations.
EFFUSIONS IN DOWN SYNDROME
Effusions (both pleural and pericardial) are frequently seen
in DS and can be pleural (chylous or nonchylous) or peri-
cardial. Fetal pleural effusion is a recognized sign of DS. It
is worth noting that pericardial and pleural effusions can
be presenting features of hematologic malignancy, which
have increased incidence in children with DS.55
Chylothorax has been associated with DS in several case
reports. It can occur spontaneously,56,57 after cardiac surgery,58
and in association with congenital pulmonary lymphangi-
ectasia (see later). Chylothorax often presents in the newborn
period or in infancy with signs of respiratory distress in the
absence of overt infection. Typical features are stony dullness
on percussion with reduced breath sounds and a pleural
effusion on the chest radiograph. Chylothoraces can be sig-
nificant and several hundred milliliters of fluid can be pro-
duced per day, even in relatively young children. Nonchylous
congenital pleural effusions are also described in DS but
appear to be uncommon.59,60
Cardiac effusions are well recognized in the context of DS
and can be clinically significant and cause tamponade. They
typically present with dyspnea, respiratory failure, and cya-
nosis and therefore should be included in the differential
diagnosis of respiratory failure in DS.61,62 The association
Fig. 68.7  Pulmonary Hemosidero-
sis in Down Syndrome. (A) Chest
radiograph of a 9-year-old girl with
Down syndrome showing bilateral
diffuse infiltrates. (B) The computed
tomography scan of the chest dem-
onstrated bilateral diffuse infiltrates
in the posterior aspects of the lungs.
(C) A cytospin of bronchoalveolar
lavage fluid stained with Prussian
blue revealed many hemosiderin
laden macrophages. (From Hiro-
fumi Watanabe, Mamoru Ayusawa
et al., Idiopathic pulmonary hemo-
siderosis complicated by Down
syndrome, Japan Pediatric Society,
Volume 57, Issue 5 October 2015,
Pages 1009–1012.) A C
68  •  Respiratory Complications of Down Syndrome 999
between effusion and hypothyroidism is described, and some
cases respond to thyroxine replacement therapy.63
RARE DISEASES OF THE LOWER RESPIRATORY
TRACT IN DOWN SYNDROME
DS is a common variant, and so there are numerous case
reports of rare diseases in patients who also have DS. When
a child with DS has an unusual respiratory presentation and
disease progression does not proceed as normal, this should
lead to consideration of a second diagnosis in addition to
DS. There are case reports of DS coexisting with idiopathic
pulmonary hemosiderosis (where the clue to diagnosis
may be recurrent anemia requiring transfusion coincident
with presumed pneumonia—Fig. 68.7),64 cystic fibrosis,65
primary ciliary dyskinesia,66 and several interstitial lung
diseases.
Childhood interstitial lung disease (ChILD) appears to be
more common in children with DS, although the increased
risk is difficult to quantify. Alveolar capillary dysplasia (ACD)
or congenital alveolar dysplasia (CAD) has been described
in a case series, but the overall frequency in DS is unknown.67
Given that lung alveolarization is known to be abnormal in
DS and that CAD and ACD are primary disorders of lung
development, it is tempting to speculate that the lung devel-
opment in DS is on a continuum with the developmental
disorder category of ChILD. Indeed, in their classification
scheme, Deutsch and colleagues categorized 46 cases as
“growth abnormalities reflecting deficient alveolarization,”
of which 15 were related to chromosomal disorders.68 Other
entities such as pulmonary interstitial glycogenosis (PIG)
(Fig. 68.8)69–71 and congenital pulmonary lymphangiectasia
(Fig. 68.9) are rare in children with DS.69
Imaging of the Lower Respiratory
Tract in Down Syndrome
Chest radiograph findings of pneumonia are similar to those
in children without DS, including lobar consolidation and
collapse. In RSV bronchiolitis, findings include the typical
B
1000 SECTION 7  •  Miscellaneous Disorders of the Lung

A B
Fig. 68.8  Histopathology of pulmonary interstitial glycogenosis (PIG). PIG is a recently described manifestation of childhood interstitial lung disease.
There is interstitial widening due to increased mesenchyme. (A) Hematoxylin and eosin (H&E) stain showing alveolar simplification and enlarged
and poorly septated airspaces. (B) Higher power H&E showing oval nuclei with clear cytoplasm in the interstitium typical of PIG. (From Popler J,
Lesnick B, Dishop MK, et al. New coding in the International Classification of Diseases, Ninth Revision, for children’s interstitial lung disease. Chest. 2012;
142(3):774-780.)

centers, 11 pairs of ribs, and a bell-shaped chest.70 If all

three of these are present, the probability of the infant having
DS approaches 60%.

Fig. 68.9  Histopathology in congenital pulmonary lymphangiectasia.
Immunohistochemistry (antibodies against podoplanin) highlighting
dilated lymphatic vessels in a child with trisomy 21 and congenital
pulmonary lymphangiectasia. (From Reiterer F, Grossauer K, Morris N,
et al. Congenital pulmonary lymphangiectasis. Paediatr Respir Rev. 2014;
15(3):275-280.)
hyperinflated lungs, bronchial cuffing, and streaky perihilar
regions (Fig. 68.10A). However, in DS, RSV bronchiolitis is
more likely to cause lobar consolidation. In patients with
chronic pulmonary disease, the radiograph can show changes
of diffuse disease. CT scans may show subpleural cysts, which
are typically less than 4 mm in diameter. In addition, CT
scans can delineate vascular and lung malformations, such
as an aberrant subclavian artery (Fig. 68.11) or a tracheal
bronchus (Fig. 68.12). A CT scan can also demonstrate a
complete cartilaginous tracheal ring, associated with tracheal
narrowing (see Fig. 68.10C). There can be pitfalls in using
plain films as the sole imaging modality, and a high index
of suspicion has to be maintained for alternate diagnoses—for
example diaphragmatic hernia can mimic lung consolidation
(Fig. 68.13).
Several features on the newborn chest radiograph are
predictive of trisomy 21 (see Fig. 68.10B). In particular,
infants with DS tend to have multiple manubrial ossification
Cardiorespiratory Interactions
and Pulmonary Vasculature
CONGENITAL HEART DISEASE IN
DOWN SYNDROME
Cardiovascular abnormalities occur in approximately 40%
of children born with DS. Overall mortality for CHD has
improved significantly over the past decades, and much of
the improvement appears to be due to a reduction in mortal-
ity in the first 2 years of life.
Within this context of better survival after significant
cardiac disease, many patients who are seen in the respira-
tory clinic have current or a past history of significant cardiac
morbidity. Thus care must be taken to consider both primary
lung disease and lung disease secondary to cardiac disease.
Cardiac surgery complications impacting the respiratory
system include chylothorax, recurrent laryngeal nerve palsy,
diaphragmatic paralysis, and subglottic stenosis. Patients
with DS appear particularly susceptible to pulmonary hyper-
tension. Secondary lung disease in patients following cardiac
surgery can result from airway compression, for example
from vascular anomalies, atrial enlargement, enlarged pul-
monary arteries, or cardiomegaly (see Upper Airway Disease
earlier).
The impact of cardiac surgery and postoperative venti-
lation on the lungs should not be underestimated. Histo-
logic findings of patients with DS, compared with patients
without DS, showed that 92% (22/24) of the patients with
DS had interstitial emphysema and 96% had overdistension
of peripheral air spaces. In contrast, the majority of control
patients (who had undergone cardiac surgery but did not
have DS) did not have interstitial emphysema or overdisten-
sion.71 Although ventilator technology and strategies have
improved significantly since this report, these data speak to
the fragility of the lungs in children with DS. Cardiovascular
disease can lead to pulmonary edema with a subsequent
 68  •  Respiratory Complications of Down Syndrome 1001

A B

C
Fig. 68.10  Imaging abnormalities in Down syndrome (DS). (A) Respiratory syncytial virus bronchiolitis in an infant with DS. (B) Chest radiograph that
is highly suggestive of an underlying diagnosis of DS due to abnormal heart shape (tetralogy of Fallot), esophageal atresia (note the coiled nasogastric
tube), and bowel gas in the abdomen (arrowhead) (indicating a tracheoesophageal fistula). Note also that there are 13 pairs of ribs. (C) Complete
tracheal ring (arrow) in a child with DS on computerized tomography. (From Radhakrishnan R, Towbin AJ. Imaging findings in Down syndrome. Pediatr
Radiol. 2014;44(5):506-521.)

impact upon pulmonary function, causing a restrictive Table 68.6  Cardiac Disease Leading to Pulmonary
defect.72 Numerous cardiovascular diseases can lead to pul- Edema in Down Syndrome
monary edema (Table 68.6).
Pulmonary venous Pulmonary veno-occlusive disease
Cardiac surgery can result in trauma to the respiratory hypertension Pulmonary vein stenosis
system, causing chylothorax (due to direct injury to the tho- Cor triatriatum
racic duct, high central venous pressure, or central vein Supramitral ring
thrombosis) and recurrent laryngeal nerve injury (from direct Left ventricular dysfunction
trauma, stretching of the nerve or disruption of the blood Transposition of the great arteries
Hypoplastic left heart (with intact atrial septum)
supply) leading to diaphragmatic paralysis, and subglottic Decreased Lymphangiectasia
stenosis (Table 68.7). lymphatic flow Superior venacaval syndrome
Single ventricle physiology
Tricuspid valve stenosis
THE PULMONARY VASCULATURE AND Failing right ventricle
RESPIRATORY DISEASE IN DOWN SYNDROME Right ventricular outflow tract obstruction
Left-to-right heart Ventricular septal defect
In tandem with the alveolar growth disruption seen in DS, shunts Atrial septal defect
there is also disturbance of the pulmonary vasculature. Patent ductus arteriosus
Infants with DS who died in the first year of life demonstrated Partial anomalous pulmonary venous
connection
persistence of the double capillary layer from fetal develop- Systemic arteriovenous malformations
ment and thickened pulmonary arteries. All of these patients Aortopulmonary connections including surgical
had intrapulmonary bronchopulmonary anastomoses.73 shunts
Given the developmental anomalies of the pulmonary
vasculature, it is not surprising that there is a predisposition
for pulmonary hypertension in DS. Weijerman and colleagues
1002 SECTION 7  •  Miscellaneous Disorders of the Lung

A B

C D
Fig. 68.11  Aberrant right subclavian artery in Down syndrome. Chest computerized tomography series (proceeding caudally to cranially from panels
A–D) demonstrating an aberrant right subclavian artery. The artery traverses posteriorly behind the esophagus (indicated by the * in panel D). (From
Radhakrishnan R, Towbin AJ. Imaging findings in Down syndrome. Pediatr Radiol. 2014;44(5):506-521.)

Table 68.7  Pulmonary Complications of Cardiac

Surgery
Pulmonary Complication Etiology
Chylothorax Direct injury to the thoracic duct or
smaller vessels
High central venous pressure
Central vein thrombosis
Recurrent laryngeal nerve Surgery involving the ductus arteriosus,
palsy descending aortal, or left pulmonary
artery
Manipulation of right common carotid
artery or internal jugular vein for
extracorporeal membrane
oxygenation
Diaphragmatic paralysis Direct trauma to the phrenic nerve
Stretching of the phrenic nerve
Disruption of blood supply to the
phrenic nerve
Fig. 68.12  Tracheal bronchus. Coronal images from a chest computer- Subglottic stenosis Compression of the trachea by the
ized tomography in Down syndrome demonstrating a tracheal bronchus. endotracheal tube, in particular given
(From O’Sullivan BP, Frassica JJ, Rayder SM. Tracheal bronchus: a cause of the small size of the trachea in Down
prolonged atelectasis in intubated children. Chest. 1998;113(2):537-540.) syndrome

Modified from Healy F, Hanna BD, Zinman R. Pulmonary complications of

reported a recent series from the Dutch Paediatric Surveil-
lance Unit (DPSU). The overall population rate of CHD in
DS is 43%, within which the incidence of persistent pulmo-
nary hypertension of the newborn (PPHN) was 5.2%, com-
pared with 0.1% in the general population.74 Atrioventricular
septal defect is recognized to be particularly associated with
pulmonary hypertension.75
In DS, even in the absence of CHD, there is increased risk
of PPHN, which is present in up to 10% of admissions to
the neonatal ICU.76 Reassuringly, the majority of patients
demonstrate resolution of pulmonary hypertension. We
advocate treating comorbidities such left-to-right shunts,
congenital heart disease. Paediatr Respir Rev. 2012;13(1):10-15.
upper airway obstruction, and hypoxia to prevent the estab-
lishment of pulmonary hypertension. Treating upper airway
abnormalities is particularly helpful because adenotonsil-
lectomy can reduce the prevalence of pulmonary hyperten-
sion from 85% preoperatively to 5% postoperatively.77
It is speculated that the reduced alveolar count, the abnor-
mal fetal capillary network, and the reduced pulmonary
vascular bed seen in DS significantly increase the risk of
pulmonary hypertension.

A B
Fig. 68.13  Unusual pathology in the lung masquerading as pneumonia in Down syndrome. (A) Chest radiograph shows apparent right lower zone
consolidation. (B) Barium swallow demonstrating a right-sided anterior diaphragmatic hernia. (From Picard E, Ben Nun A, Fisher D, et al. Morgagni hernia
mimicking pneumonia in Down syndrome. J Pediatr Surg. 2007;42(9):1608-1611.)
High-altitude pulmonary edema (HAPE) at moderate alti-
tudes appears more common in children with DS compared
with normal children.78 Intriguingly, it has been suggested
that HAPE could be an initial sign of developing pulmonary
hypertension.79
Gastrointestinal–Respiratory
Interactions in Down Syndrome
Gastrointestinal–respiratory interactions are particularly
important in DS. Within this, it is common to distinguish
between functional (dysmotility, reflux, and swallowing dys-
function) and structural (e.g., esophageal atresia) abnormali-
ties, recognizing that these often coexist. As research
progresses, the underlying pathogenesis of functional dis-
orders is gradually being elucidated. The role of the respira-
tory pediatrician is to minimize this impact on the pulmonary
health; so much of the work done in this domain is aimed
at assessing and treating functional disorders irrespective
of antecedent structural defects.
Congenital gastrointestinal defects are common in DS. In
a large US study of 1892 children with DS, gastrointestinal
malformations occurred in 6.7%.80 The most common mal-
formations were duodenal stenosis or atresia (3.9%), anal
stenosis or atresia (1.0%), Hirschsprung disease (0.8%),
esophageal atresia with or without tracheoesophageal fistula
(0.4%), and pyloric stenosis (0.3%).
Esophageal atresia is particularly associated with increased
respiratory problems long term postsurgery, even in children
without DS.81 Respiratory disease is multifactorial from tra-
cheomalacia, aspiration, gastroesophageal reflux disease,
tracheoesophageal fistula recurrence, and chest wall defor-
mities. Large case series of outcomes in children with DS
are lacking.
Functional disorders of gastrointestinal motility are par-
ticularly important in DS. DS is associated with disordered
development of the enteric nervous system, which is thought
to underlie the spectrum of functional disorders of the
68  •  Respiratory Complications of Down Syndrome 1003
gastrointestinal tract that are prevalent in DS.82 Animal
models of DS have shown evidence of disordered neuronal
migration and dendritic development. In people with DS,
there are reduced numbers of esophageal plexus ganglia
neurons, and this decreased ganglion cell population likely
extends over the complete length of the gut. In addition to
reduced neuronal cell numbers, there is also evidence of
altered physiology—differences in action potential and ion
channel kinetics have been identified.
Gastroesophageal dysmotility and reflux disease (GERD)
is common in the DS population.83 Approximately 50%
patients with DS are asymptomatic, but the other 50% have
symptoms such as dysphagia, regurgitation, and chest pain.
We suspect that GERD also occurs without reported symp-
toms, where the patient may not recognize the symptoms,
or it may be truly asymptomatic. Approximately 25% have
dysmotility and retention of food in the esophagus. In chil-
dren following major cardiac surgery, such as a VSD repair,
medical management of GERD has a high readmission rate
due to aspiration, failure to thrive, and poor feeding. However,
the outcomes of surgical management of GERD are also
unsatisfactory, with a significant rate of revision of fundo-
plication due to bloating. The choice of medical versus surgical
therapy is difficult and requires balancing the risk of inad-
equate medical therapy versus operative risk and the chances
of requiring further surgical procedures.
Swallowing dysfunction occurs in DS and causes aspira-
tion pneumonia.84,85 Pharyngeal dysfunction occurs com-
monly and is associated with cardiac surgery and failure to
thrive; it often requires a gastrostomy.
Obesity and Its Impact on the
Lung in Down Syndrome
Obesity is increasingly present in the general population. A
recent US series of 303 children with DS found that up to
50% of children have a BMI greater than the 95th percentile
for age and sex,86 whereas a Dutch study, which used
1004 SECTION 7  •  Miscellaneous Disorders of the Lung
different definitions, found a prevalence of overweight of
25%–32% and of obesity of 4%–5%.87 Obesity is not solely
due to changing demographics and increased obesity in the
general population, because in both studies children with
DS had higher BMI than the general population. In DS the
BMI is increased most in children over the age of 12 years,
and high BMI is a risk factor for OSA. Although obesity
prevalence varies from country to country, children with DS
are consistently more obese than the general population.
Both inactivity and overeating may contribute to this problem.
Overeating or hyperphagia can be assessed with standard
questionnaires such as those used in Prader-Willi syndrome.
When formally assessed, children with DS have hyperphagia
scores somewhat between children with lifestyle-related
obesity and children with Prader-Willi syndrome.88
In general, obesity has a negative impact on health, and
this is particularly the case for respiratory health in DS. In
children, obesity has a negative effect on pulmonary mechan-
ics, prevalence of asthma, and sleep-disordered breathing.89
In obesity, increased abdominal volume pushes the diaphragm
upward, reducing the functional residual capacity, and this
is made worse in DS by the effect of hypotonia on the chest
wall. Thus the combination of DS and obesity has a signifi-
cant impact on lung function, and obesity exacerbates the
already high rates of sleep-disordered breathing.
TREATMENT OF THE RESPIRATORY
COMPLICATIONS OF DOWN SYNDROME
Children with DS are frequently seen within the context of
pediatric respiratory/pulmonology clinics. The approach to
the history includes a focus on current and past symptoms,
including cough, wheeze, upper airway noises, and snoring.
The impact of current and previous comorbidities on pul-
monary health should be considered, along with the limita-
tions that respiratory disease causes to the patient’s lifestyle.
Specific points to consider include hospital admissions, respi-
ratory tract infections, daytime somnolence, and missed
school or other life opportunities. Growth should be monitored
carefully, with attention to faltering growth in infancy, and
obesity in later life. Multiple clinicians are often involved in
patients with DS, and it should be clear where responsibility
lies for routine surveillance, such as for thyroid disease. With
respect to respiratory symptoms, there is a fine line between
overinvestigating children and missing important symptoms
of treatable conditions such as airway malformation, sleep-
disordered breathing, and GERD. In particular, it is important
to carefully consider alternative diagnoses before making a
diagnosis of asthma. Success in being able to perform lung
function testing is variable. Many treatments for children
with DS are extrapolated from treatment of the same condi-
tion in children without DS, and this may not always be the
best approach.
CONSIDERATIONS WHEN TREATING
UPPER RESPIRATORY TRACT DISEASE IN
DOWN SYNDROME
Treatment of upper airway disease requires a close liaison
between the respiratory pediatrician, otolaryngologist, anes-
thesiologist, and intensive care team. One approach is to
undertake joint bronchoscopies (as rigid bronchoscopies are
Table 68.8  Size of Endotracheal Tube Diameter in
Down Syndrome
Down Non-Down
Age Syndrome Syndrome
Premature 2.0–2.5 2.5–3.0
Full-term newborn to 9 months 2.5–3.0 3.5–4.0
9–18 months 3.0–3.5 4.0–4.5
1.5–3 years 3.5–4.0 4.5–5.0
4–5 years 4.0–4.5 5.0–5.5
6–7 years 5.0 5.5–6.0
8–10 years 5.5 6.0–6.5
10–11 years 5.5 6.5–7.0
12–13 years 6.0 7.0–7.5
14 years and older 6.5 7.5–8.0
From Shott SR. Down syndrome: analysis of airway size and a guide for
appropriate intubation. Laryngoscope. 2000;110(4):585-592.
more frequently in the domain of the otolaryngologist and
flexible in the domain of the respiratory physician). The sur-
gical, ICU, and respiratory management of patients with
upper airway disease can be challenging.90
In intensive care and anesthetic practice, care must be
taken to use an endotracheal tube of appropriate diameter
(Table 68.8). Care should also be taken to ensure that after
intubation there is a leak around the endotracheal tube. The
presence of subglottic stenosis or a narrowed trachea also
has implications for the appropriate size of the pediatric flex-
ible bronchoscope if this is undertaken via an endotracheal
tube. Anecdotally, if severe airway anomalies are anticipated
(such as in children with DS who have noisy breathing, or
those who have previously had long periods of intubation),
it may be sensible to undertake flexible endoscopy prior to
intubation to look for airway anomalies such as subglottic
stenosis and to allow informed decisions regarding the size
of the endotracheal tube to use.90
AN APPROACH TO PREVENTION AND
TREATMENT OF LOWER RESPIRATORY TRACT
INFECTION IN DOWN SYNDROME
Much of the treatment of respiratory disease in DS is centered
on the treatment and prevention of LRTI. Frequent LRTIs
are an important source of morbidity and may well impact
developmental progress. Although LRTI does not usually
progress to sepsis, given the serious nature of sepsis when
it occurs, we advocate a general position of aiming to reduce
the risk of LRTI. The general approach consists of immuniza-
tion, parent and patient education for early signs of infection,
careful surveillance for modifiable risk factors, and early
treatment.
It should be ensured that patients are up to date with the
current immunization schedule at each clinic visit. Consid-
eration should be given to checking immunoglobulin levels,
functional antibodies, and lymphocyte subsets either as a
routine or for DS patients with frequent respiratory tract
infections. These should be checked in individuals who have
had an episode of sepsis or a history of four or more infec-
tions over 6 months, even if the patient was managed in the
community. Consultation with an immunologist is often
useful for individuals with specific functional antibody defi-
ciency, especially with respect to repeating the relevant

immunizations and consideration of further immunologic
workup. Yearly influenza immunization is recommended
unless contraindicated. Due to the increased risk of pneu-
mococcus, in addition to administering the pneumococcal
conjugate vaccine in infancy, we recommend the administra-
tion of pneumococcal polysaccharide vaccine after the second
year of life. Functional antibodies (such as pneumococcal
and Haemophilus) should be undertaken, with reimmuniza-
tion considered where necessary.
For children with frequent infections, we consider pro-
phylactic antibiotics. Strategies include administering them
throughout the year or for the winter months only. One
approach is to use the frequency of symptomatic infections
to guide when to stop, and we generally consider a trial off
antibiotics in the late spring.
There is an extensive differential diagnosis of respira-
tory disease in DS, especially when the patient’s course is
unusual. Treatment of gastroesophageal reflux disease (see
Gastrointestinal–Respiratory Interactions in Down Syndrome),
and swallowing disorders leading to aspiration can lead to
a resolution of respiratory symptoms. Where respiratory
symptoms are chronic or recurrent, consider pulmonary and
airway malformations, external compression of the airway,
and rarer parenchymal disorders and organize appropriate
radiologic investigation and bronchoscopy.
Liaison between the respiratory clinic and emergency
department (ED) is useful. Some institutions are able to put
an “alert” on patient’s case notes informing the ED of the
diagnosis of DS and emphasizing the need for prompt and
aggressive therapy on arrival to the ED. One approach to an
episode of infection is to increase (usually double) the dura-
tion of the course of antibiotics. For individuals who present
with respiratory failure or sepsis, early consultation with
pediatric intensive care is essential, especially given the overall
excellent prognosis from respiratory failure but poor prognosis
in sepsis.
TREATMENT OF GASTROINTESTINAL
DISORDERS IN DOWN SYNDROME—THE
PULMONOLOGISTS VIEW
Given the increased prevalence of swallowing dysfunction,
dysmotility, and GERD, careful assessment for functional
gastrointestinal disorders should be undertaken. Involvement
of speech and language therapists is often helpful. Initial
treatment of reflux disease is usually medical, proceeding
Table 68.9  Rare Syndromes Associated With Alveolar Simplification
Syndrome Cause
Patau Trisomy 13
Edwards Trisomy 18
Arthrogryposis multiplex congenital AMCN (5q35)
OMIM %208100
(though is genetically heterogeneous)
Spondyloepiphyseal dysplasia COL2A1 (12q13.11)
congenital OMIM #183900
Autosomal dominant
Larsen syndrome FNLB Mutation (3p14)
Autosomal dominant
OMIM #150250
68  •  Respiratory Complications of Down Syndrome 1005
to surgical management if there is failure of medical
management.
Careful counseling of parents with regard to the risks of
surgical management is important but should be put into
the context of the risks of untreated chronic aspiration.
Treatment of gastroesophageal reflux is undertaken with
the expectation that this will prevent episodes of pulmonary
infection and reduce the chance of significant pulmonary
hypertension.
At present there are no clinical trials to guide the best
approach to management of GERD in DS. In young infants,
milk thickeners are a first step, with elevation of the thorax
as much as possible during and after feeds. Pharmacologic
therapies include antacids, prokinetics, H2 blockers, and
proton pump inhibitors. Surgical management includes Nissen
fundoplication (positioning the distal esophagus intraab-
dominally, hiatus hernia repair, and a fundal wrap). It can
be undertaken with varying degrees of fundal wrap and can
be performed laparoscopically. Alternatives to fundoplication
include gastrojejunal tube feeding and jejunostomy; these
procedures reduce food reflux but do not prevent reflux of
swallowed saliva and stomach contents.
Conclusions
Providing respiratory care for children with DS requires a
long-term approach to lung disease throughout the pediatric
period, with different pathologies presenting at different ages.
Given the intellectual impairment that is often present, there
are challenges throughout in terms of managing disease, in
ensuring that children are able to understand and adhere
to a treatment program, and that parents are supported in
undertaking this treatment.
Other Genetic Anomalies
Several other genetic disorders can be associated with sig-
nificant pulmonary manifestations, and these are mostly
associated with pulmonary hypoplasia. Table 68.9 lists
selected genetic syndrome known to be associated with
pulmonary hypoplasia. The chromosomal abnormalities
Edwards (trisomy 18) and Patau syndrome (trisomy 13) are
recognized to have pulmonary hypoplasia. Page reported on
a series of more than 700 postmortem examinations and
Survival Reference
Death in neonatal period early infancy 91
Death in neonatal period and early infancy 91
Heterogeneous prognosis—survival to 91
adulthood has been described for those
without significant pulmonary or cardiac
involvement.
Wide clinical variability, survives to 91
adulthood
Variable severity—adult cases reported. 92
Continued
1006 SECTION 7  •  Miscellaneous Disorders of the Lung

Table 68.9  Rare Syndromes Associated With Alveolar Simplification—cont’d

Syndrome Cause Survival Reference
Lethal pterygium syndrome Autosomal recessive Lethal in the fetal stage of development 93
CHRNG, CHRND, CHRNA1 (2q)
OMIM 253290
Roberts syndrome/SC phocomelia Autosomal recessive Survival poor after the neonatal period. 94
syndrome ESCO2 (8p21.1)
OMIM #269000
Pulmonary hypoplasia associated Preterm rupture of membranes, or renal Survival depends on extent of hypoplasia. 95
with oligohydramnios agenesis.
Fetal akinesia deformation sequence Autosomal recessive Lethal congenital syndrome 95
(FADS), Pena Shokeir syndrome DOK7 (4p16.3)
MUSK (9q31.3)
RAPSN (11p11.2)
Asphyxiating thoracic dystrophy/ WDR34 (9q34.11) Lethal in neonatal period. The SRTD of which 95
short-rib thoracic dysplasia 11 Autosomal recessive Jeune syndrome is a well-known member
(SRTD)/Jeune syndrome of the group, are a group of autosomal
recessive skeletal dysplasias, and within
this group there is phenotypic variability.
Some forms are less severe with survival to
later life.
Thanatophoric dysplasia FGFR3 (4p16.3) Fatal in early infancy 95
Autosomal dominant
OMIM #187600
Spondylocostal dysotosis 1 The spondylocostal dysostoses are a The prognosis is variable within the group, 95
group of usually autosomal recessive with some forms having normal lifespan,
disorders which include Jarco-Levin and others dying early in infancy.
syndrome. Rib abnormalities are
common leading to pulmonary
hypoplasia.
Autosomal recessive
Mutation in Notch signaling gene DLL3 at
19q13.1
Cerebrocostomandibular syndrome Autosomal dominant, autosomal recessive Rib gaps are associated with pulmonary 96
SNRPB (20p13) hypoplasia.
OMIM #117650
Pulmonary agenesis/dysgenesis/ Autosomal recessive Usually die shortly after delivery, although 97
hypoplasia, micropthalmia/ STRA6 (15q24.1) some survival to early childhood occurs.
anopthalmia and diaphragmatic OMIM #601186 Not all cases show pulmonary hypoplasia.
defect (PDAC) syndrome (also There is genetic heterogeneity.
termed Spear syndrome and
Matthew-Wood syndrome

AMCN, Arthrogryposis multiplex congenita; CHRNA1, cholinergic receptor, nicotinic, alpha polypeptide1; CHRND, cholinergic receptor, nicotinic, delta
polypeptide; CHRNG, cholinergic receptor, nicotinic, gamma polypeptide; COL2A1, collagen Type II; Alpha-1; DLL3, delta-like 3; DOK7, downstream of
tyrosine kinase 7; ESCO2, establishment of cohesion 1, S. Cerevisiae, Homolog of, 2; FGFR3, fibroblast growth factor receptor 3; FNLB, filamin B; MUSK, muscle,
skeletal, receptor tyrosine kinase; OMIM, online mendelian inheritance in man; RAPSN, receptor-associated protein of the synapse; SNRPB, small nuclear
ribonucleoprotein polypeptides B and B1; STRA6, stimulated by retinoic acid 6; WDR34, WD repeat-containing protein 34.
The reader is directed onwards to the references within the table.

identified multiple cases of pulmonary hypoplasia on his- Suggested Reading

topathologic grounds, of which three had trisomy 13, one
trisomy 18, and one deletion of the long arm of chromosome
13.91 In this series of pulmonary hypoplasia, there were also
cases of arthrogryposis multiplex, osteogenesis imperfecta,
thanatophoric dysplasia, and spondyloepiphyseal dyspla-
sia congenita. Pulmonary hypoplasia is also recognized to
occur in Larsen syndrome,92 lethal pterygium syndrome,93
and Roberts-SC phocomelia syndrome.94 Unfortunately,
the outcome of major syndromic malformations associ-
ated with pulmonary hypoplasia is very poor, with death
occurring either in utero, in the neonatal period, or in early
infancy.
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