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The evaluation and management of respiratory disease in children with Down syndrome (DS)
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 Harvard Medical School, Boston, MA, USA c Division of Respiratory Diseases, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA b
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
Keywords: Upper airway obstruction Adenotonsillectomy Congenital Heart Disease Gastroesophageal reflux Polysomnography Recurrent wheeze
a b s t r a c t Children with Down syndrome (DS) have wide range of respiratory problems. Although underlying abnormalities in the respiratory system are important causes of morbidity and mortality in children with DS, particularly in the young, abnormalities in other organ systems may also impact respiratory function. A comprehensive evaluation of the child with DS and respiratory disease may prevent short-term morbidity and mortality, and reduce the incidence of complications in the long term. This review provides an overview of the various causes of respiratory disease, and insight into some of the newer therapies available to treat obstructive sleep apnea, in this population. Ó 2017 Elsevier Ltd. All rights reserved.
Introduction Trisomy 21, or Down syndrome (DS), has characteristic phenotypic 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 variance. 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, ranging 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: [email protected] (H.S. Alsubie). https://doi.org/10.1016/j.prrv.2017.07.003 1526-0542/Ó 2017 Elsevier Ltd. All rights reserved.
29 in Kuwait [8], and 31 in Dubai [9]. Generally speaking, birthrates in Arab countries are high, consanguineous marriages frequent, 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 countries 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 present 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 disorder, and this review will focus on the comprehensive evaluation of respiratory care in children with DS. DS affects both the upper
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and lower respiratory tract in a variety of ways. Although respiratory 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 intrinsic 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 common 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 pneumonias or atelectasis because of aspiration and poor secretion clearance [16,24]. It can also lead to persistent right-upper lobe atelectasis in an intubated infant or child in whom the endotracheal 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 Consider
Investigations Therapy
Stridor; snoring; dysphagia; witnessed apnea during sleep Laryngomalacia, tracheomalacia, subglottic stenosis, tracheal stenosis, OSA, adenotonsillar hypertrophy, lingual tonsillar hypertrophy Pharyngolaryngoscopy, bronchoscopy, lateral neck x ray, polysomnography, echocardiogram, cardiac catheterization 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 alveolar simplification [25]. The enlarged alveoli are more susceptible to mechanical stress, already a concern because of the underlying connective tissue abnormalities, especially during mechanical ventilation. 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 prevalence ranging 20–36% [29], and higher in the presence of CHD [30,29]. Although sub-pleural cysts are difficult to detect on regular 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 suggested 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 unsuccessfully. 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 childhood (ISAAC) questionnaire [34] for respiratory symptoms compared 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 conditions other than asthma, as will be described in the coming sections 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 severe 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 disease 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 twoto 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-
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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 pharyngolaryngoscopy 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 congenital 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 significant or complete relief of obstructive symptoms, 24% had moderate 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 obstruction following the airway surgery. It is important to recognize that approximately 50% of patients with UAO had evidence of pulmonary arterial hypertension (PAH) confirmed by cardiac catheterization 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 typical 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 adenotonsillectomy continue to have either persistent or recurrent OSA [41,51,52]. One study of 27 patients with DS aged 4–19 years
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(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 hypertension [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 present 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 currently recommends that all children with DS undergo polysomnography 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 Surgery recommend close postoperative monitoring including overnight 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 obstruction is common after adenotonsillectomy. When present, positive airway pressure (PAP) therapy is generally the next line of treatment 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 retrognathia and DS, UAO found mandibular distraction to be successful 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 children 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 currently a pilot study underway exploring its use adolescents with DS and refractory OSA intolerant of CPAP [67].
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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 complete 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 disease 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 abortion 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 subglottic 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 expectancy of children with DS has risen to 60 years compared to 25 years in 1983 [70,71]. Most CHD is diagnosed in early childhood: 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 dislocations, 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 progressive 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 dysfunction, they should be reassessed clinically by the age of 18, especially prior to dental or surgical procedures including a screening 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].
have congenital anomalies in the gastrointestinal system, including: duodenal stenosis/atresia (1–5%), Hirschsprung disease (1– 3%), anal stenosis or atresia (<1–4%), esophageal atresia/tracheaesophageal 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, leading to persistent respiratory symptoms including bronchitis, pneumonia, cough and wheeze. One retrospective review of respiratory morbidity in 334 patients without DS age 1–37 years who had undergone 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 incidence of achalasia in children with DS which, too, can lead to frequent reflux and aspiration [84]. Autonomic differences leading to altered control of breathing Many children with DS exhibit differences in both parasympathetic and sympathetic autonomic nervous activity. This can manifest 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 abnormalities in their immune systems, including: mild-to-moderate Tand B-cell lymphopenia; mild-to-moderate reduced native T-cell percentages with corresponding reduction of T-cell excision circles; 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.
The gastrointestinal system
In summary
DS is associated with a number of congenital and functional defects of the gastrointestinal system. 4–10% of children with DS
Children with DS are prone to wide range of respiratory problems that may originate at any level of respiratory tract, as well
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as in other organ systems. A comprehensive evaluation of is necessary to identify the underlying causes, to prevent short-term morbidity and mortality, and long-term morbidity in these children.
Future directions Further studies are needed to define the optimal approach to reducing, and management of the pulmonary complications in children with DS status-post CHD repair. Long-term studies are needed to better define specific risk factors, outcomes, and evidence-based treatment approach for OSA in children with DS.
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Pediatr Infect Dis J 2010;29:672–3. https://doi.org/10.1097/ INF.0b013e3181d7ffa5. [38] Bruijn M, van der Aa LB, van Rijn RR, Bos AP, van Woensel JBM. High incidence of acute lung injury in children with Down syndrome. Intensive Care Med 2007;33:2179–82. https://doi.org/10.1007/s00134-007-0803-z. [39] Randolph AG, Meert KL, O’Neil ME, Hanson JH, Luckett PM, Arnold JH, et al. The feasibility of conducting clinical trials in infants and children with acute respiratory failure. Am J Respir Crit Care Med 2003;167:1334–40. https://doi. org/10.1164/rccm.200210-1175OC. [40] Curley MA, Thompson JE, Arnold JH. The effects of early and repeated prone positioning in pediatric patients with acute lung injury. Chest 2000;118:156–63. [41] Jacobs IN, Gray RF, Todd NW. Upper airway obstruction in children with Down syndrome. Arch Otolaryngol Head Neck Surg 1996;122:945–50. [42] Irving CA, Chaudhari MP. Cardiovascular abnormalities in Down’s syndrome: spectrum, management and survival over 22 years. Arch Dis Child 2012;97:326–30. https://doi.org/10.1136/adc.2010.210534. [43] Weijerman ME, van Furth AM, van der Mooren MD, van Weissenbruch MM, Rammeloo L, Broers CJM, et al. Prevalence of congenital heart defects and persistent pulmonary hypertension of the neonate with Down syndrome. Eur J Pediatr 2010;169:1195–9. https://doi.org/10.1007/s00431-010-1200-0. [44] Fitzgerald DA, Paul A, Richmond C. Severity of obstructive apnoea in children with Down syndrome who snore. Arch Dis Child 2007;92:423–5. https://doi. org/10.1136/adc.2006.111591. [45] Marcus CL, Keens TG, Bautista DB, von Pechmann WS, Ward SL. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991;88:132–9. [46] Brunetti L, Rana S, Lospalluti ML, Pietrafesa A, Francavilla R, Fanelli M, et al. Prevalence of obstructive sleep apnea syndrome in a cohort of 1,207 children of southern Italy. Chest 2001;120:1930–5. [47] Gislason T, Benediktsdóttir B. Snoring, apneic episodes, and nocturnal hypoxemia among children 6 months to 6 years old. An epidemiologic study of lower limit of prevalence. Chest 1995;107:963–6. [48] Fink GB, Madaus WK, Walker GF. A quantitative study of the face in Down’s syndrome. Am J Orthod 1975;67:540–53. [49] Shapiro BL, Gorlin RJ, Redman RS, Bruhl HH. The Palate and Down’s Syndrome. N Engl J Med 1967;276:1460–3. https://doi.org/10.1056/ NEJM196706292762603. [50] Guimaraes Carolina VA, Donnelly Lane F, Shott Sally R, Amin Raouf S, Kalra Maninder. Relative rather than absolute macroglossia in patients with Down syndrome: implications for treatment of obstructive sleep apnea. Pediatr Radiol 2008;38:1062–7. https://doi.org/10.1007/s00247-008-0941-7. [51] Donaldson JD, Redmond WM. Surgical management of obstructive sleep apnea in children with Down syndrome. J Otolaryngol 1988;17:398–403.
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[73] Geggel RL, O’Brien JE, Feingold M. Development of valve dysfunction in adolescents and young adults with Down syndrome and no known congenital heart disease. J Pediatr 1993;122:821–3. [74] Sylvester PE. Aortic and pulmonary valve fenestrations as ageing indices in Down’s syndrome. J Ment Defic Res 1974;18:367–76. [75] Goldhaber SZ, Rubin IL, Brown W, Robertson N, Stubblefield F, Sloss LJ. Valvular heart disease (aortic regurgitation and mitral valve prolapse) among institutionalized adults with Down’s syndrome. Am J Cardiol 1986;57:278–81. [76] Perloff JK, Child JS. Clinical and epidemiologic issues in mitral valve prolapse: overview and perspective. Am Heart J 1987;113:1324–32. [77] Wilcken DE, Hickey AJ. Lifetime risk for patients with mitral valve prolapse of developing severe valve regurgitation requiring surgery. Circulation 1988;78:10–4. [78] Cohen WI, Patterson B, editors. Health care guidelines for individuals with Down syndrome: 1999 revision (Down syndrome preventive medical checklist). Down Syndrome Medical Interest Group, 4. Down Syndrome Quarterly; 1999. p. 1–15. [79] Pueschel SM, Annerén G, Durlach R, Flores J, Sustrová M, Verma IC. Guidelines for optimal medical care of persons with Down syndrome. International League of Societies for Persons with Mental Handicap (ILSMH). Acta Paediatr 1995;84:823–7. [80] Weijerman ME, de Winter JP. Clinical practice. The care of children with Down syndrome. Eur J Pediatr 2010;169:1445–52. https://doi.org/10.1007/s00431010-1253-0. [81] Moore SW. Down syndrome and the enteric nervous system. Pediatr Surg Int 2008;24:873–83. https://doi.org/10.1007/s00383-008-2188-7. [82] Chetcuti P, Phelan PD. Respiratory morbidity after repair of oesophageal atresia and tracheo-oesophageal fistula. Arch Dis Child 1993;68:167–70. [83] Frazier JB, Friedman B. Swallow function in children with Down syndrome: a retrospective study. Dev Med Child Neurol 1996;38:695–703. [84] Zárate N, Mearin F, Hidalgo A, Malagelada JR. Prospective evaluation of esophageal motor dysfunction in Down’s syndrome. Am J Gastroenterol 2001;96:1718–24. https://doi.org/10.1111/j.1572-0241.2001.03864.x. [85] Ferri R, Curzi-Dascalova L, Del Gracco S, Elia M, Musumeci SA, Pettinato S. Heart rate variability and apnea during sleep in Down’s syndrome. J Sleep Res 1998;7:282–7. [86] Telakivi T, Partinen M, Salmi T, Leinonen L, Härkönen T. Nocturnal periodic breathing in adults with Down’s syndrome. J Ment Defic Res 1987;31(Pt 1):31–9. [87] Clark RW, Schmidt HS, Schuller DE. Sleep-induced ventilatory dysfunction in Down’s syndrome. Arch Intern Med 1980;140:45–50. [88] Ferri R, Curzi-Dascalova L, Del Gracco S, Elia M, Musumeci SA, Stefanini MC. Respiratory patterns during sleep in Down’s syndrome: importance of central apnoeas. J Sleep Res 1997;6:134–41. [89] Wong W, Rosen D. Isolated mild sleep-associated hypoventilation in children with Down syndrome. Arch Dis Child 2017. https://doi.org/10.1136/ archdischild-2016-311694. archdischild-2016-311694. [90] de Hingh YCM, van der Vossen PW, Gemen EFA, Mulder AB, Hop WCJ, Brus F, et al. Intrinsic abnormalities of lymphocyte counts in children with down syndrome. J Pediatr 2005;147:744–7. https://doi.org/10.1016/j. jpeds.2005.07.022. [91] Cocchi G, Mastrocola M, Capelli M, Bastelli A, Vitali F, Corvaglia L. Immunological patterns in young children with Down syndrome: is there a temporal trend? Acta Paediatr 2007;96:1479–82. https://doi.org/10.1111/ j.1651-2227.2007.00459.x. [92] Loh RK, Harth SC, Thong YH, Ferrante A. Immunoglobulin G subclass deficiency and predisposition to infection in Down’s syndrome. Pediatr Infect Dis J 1990;9:547–51. [93] Nuorti JP, Whitney CG. Centers for Disease Control and Prevention (CDC). Prevention of pneumococcal disease among infants and children – use of 13valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine – recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2010;59:1–18.
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 Harvard Medical School, Boston, MA, USA c Division of Respiratory Diseases, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA b
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
Keywords: Upper airway obstruction Adenotonsillectomy Congenital Heart Disease Gastroesophageal reflux Polysomnography Recurrent wheeze
a b s t r a c t Children with Down syndrome (DS) have wide range of respiratory problems. Although underlying abnormalities in the respiratory system are important causes of morbidity and mortality in children with DS, particularly in the young, abnormalities in other organ systems may also impact respiratory function. A comprehensive evaluation of the child with DS and respiratory disease may prevent short-term morbidity and mortality, and reduce the incidence of complications in the long term. This review provides an overview of the various causes of respiratory disease, and insight into some of the newer therapies available to treat obstructive sleep apnea, in this population. Ó 2017 Elsevier Ltd. All rights reserved.
Introduction Trisomy 21, or Down syndrome (DS), has characteristic phenotypic 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 variance. 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, ranging 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: [email protected] (H.S. Alsubie). https://doi.org/10.1016/j.prrv.2017.07.003 1526-0542/Ó 2017 Elsevier Ltd. All rights reserved.
29 in Kuwait [8], and 31 in Dubai [9]. Generally speaking, birthrates in Arab countries are high, consanguineous marriages frequent, 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 countries 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 present 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 disorder, and this review will focus on the comprehensive evaluation of respiratory care in children with DS. DS affects both the upper
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and lower respiratory tract in a variety of ways. Although respiratory 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 intrinsic 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 common 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 pneumonias or atelectasis because of aspiration and poor secretion clearance [16,24]. It can also lead to persistent right-upper lobe atelectasis in an intubated infant or child in whom the endotracheal 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 Consider
Investigations Therapy
Stridor; snoring; dysphagia; witnessed apnea during sleep Laryngomalacia, tracheomalacia, subglottic stenosis, tracheal stenosis, OSA, adenotonsillar hypertrophy, lingual tonsillar hypertrophy Pharyngolaryngoscopy, bronchoscopy, lateral neck x ray, polysomnography, echocardiogram, cardiac catheterization 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 alveolar simplification [25]. The enlarged alveoli are more susceptible to mechanical stress, already a concern because of the underlying connective tissue abnormalities, especially during mechanical ventilation. 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 prevalence ranging 20–36% [29], and higher in the presence of CHD [30,29]. Although sub-pleural cysts are difficult to detect on regular 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 suggested 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 unsuccessfully. 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 childhood (ISAAC) questionnaire [34] for respiratory symptoms compared 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 conditions other than asthma, as will be described in the coming sections 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 severe 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 disease 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 twoto 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-
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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 pharyngolaryngoscopy 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 congenital 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 significant or complete relief of obstructive symptoms, 24% had moderate 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 obstruction following the airway surgery. It is important to recognize that approximately 50% of patients with UAO had evidence of pulmonary arterial hypertension (PAH) confirmed by cardiac catheterization 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 typical 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 adenotonsillectomy continue to have either persistent or recurrent OSA [41,51,52]. One study of 27 patients with DS aged 4–19 years
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(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 hypertension [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 present 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 currently recommends that all children with DS undergo polysomnography 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 Surgery recommend close postoperative monitoring including overnight 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 obstruction is common after adenotonsillectomy. When present, positive airway pressure (PAP) therapy is generally the next line of treatment 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 retrognathia and DS, UAO found mandibular distraction to be successful 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 children 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 currently a pilot study underway exploring its use adolescents with DS and refractory OSA intolerant of CPAP [67].
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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 complete 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 disease 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 abortion 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 subglottic 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 expectancy of children with DS has risen to 60 years compared to 25 years in 1983 [70,71]. Most CHD is diagnosed in early childhood: 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 dislocations, 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 progressive 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 dysfunction, they should be reassessed clinically by the age of 18, especially prior to dental or surgical procedures including a screening 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].
have congenital anomalies in the gastrointestinal system, including: duodenal stenosis/atresia (1–5%), Hirschsprung disease (1– 3%), anal stenosis or atresia (<1–4%), esophageal atresia/tracheaesophageal 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, leading to persistent respiratory symptoms including bronchitis, pneumonia, cough and wheeze. One retrospective review of respiratory morbidity in 334 patients without DS age 1–37 years who had undergone 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 incidence of achalasia in children with DS which, too, can lead to frequent reflux and aspiration [84]. Autonomic differences leading to altered control of breathing Many children with DS exhibit differences in both parasympathetic and sympathetic autonomic nervous activity. This can manifest 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 abnormalities in their immune systems, including: mild-to-moderate Tand B-cell lymphopenia; mild-to-moderate reduced native T-cell percentages with corresponding reduction of T-cell excision circles; 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.
The gastrointestinal system
In summary
DS is associated with a number of congenital and functional defects of the gastrointestinal system. 4–10% of children with DS
Children with DS are prone to wide range of respiratory problems that may originate at any level of respiratory tract, as well
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as in other organ systems. A comprehensive evaluation of is necessary to identify the underlying causes, to prevent short-term morbidity and mortality, and long-term morbidity in these children.
Future directions Further studies are needed to define the optimal approach to reducing, and management of the pulmonary complications in children with DS status-post CHD repair. Long-term studies are needed to better define specific risk factors, outcomes, and evidence-based treatment approach for OSA in children with DS.
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