Structural problems

Children with DS may have an abnormal or obstructed airway for a wide variety of reasons (table 2). The upper airway is often narrow in children with DS. This may result from a range of phenotypic features or associated conditions, including macroglossia, midface hypoplasia, choanal stenosis, a narrow nasopharynx, enlarged tonsils and adenoids, lingual tonsils and shortening of the palate.4 It has also been shown that the trachea is smaller in children with DS than in children without DS.5 This has important implications for clinicians who might intubate children with DS, and it is recommended that a smaller endotracheal tube is used than would be expected for the patient's weight.5

Tracheal bronchus is a congenital anomaly seen in DS consisting of an aberrant or accessory bronchus arising from the trachea.6 While this may be an incidental finding, it may also be associated with respiratory disease, particularly recurrent right upper lobe pneumonia.7

Additionally, these intrinsic structural problems may be exacerbated by hypotonia and obesity. Weight and obesity are potentially important factors for many children with DS, as a higher proportion of individuals with DS are overweight when compared with the general population, and appear to become overweight at a younger age.8 It is important to note that although DS specific growth charts suggest that for older children obesity is the norm, these charts do not indicate a desired standard, and excessive weight gain should be managed appropriately.3

Laryngomalacia, tracheomalacia and subglottic stenosis

Both laryngomalacia and tracheomalacia are associated with DS and may present with stridor. Laryngomalacia has been found to be the most common cause of airway obstruction in children with DS under the age of 2 years.9 In one study of patients with DS and respiratory symptoms undergoing fibreoptic bronchoscopy, laryngomalacia was found in 50% of subjects and tracheomalacia in 33%.6 These numbers are significantly higher than in children without DS who also underwent bronchoscopy for respiratory symptoms (19% and 7.4%, respectively). The majority (63%) of the children with DS in this study with laryngomalacia or tracheomalacia also had some form of CHD. As with laryngomalacia not associated with DS, the prevalence of laryngomalacia appears to decrease with increasing age, and other causes of airway obstruction become more important in children over the age of 2 years.9

In addition to the smaller trachea seen in patients with DS,5 there may be an increased incidence of subglottic stenosis. Miller et al10 felt that the relatively high proportion of patients with DS among those undergoing laryngotracheal reconstruction when compared with the overall incidence of DS suggested an increased incidence of subglottic stenosis in DS patients. However, in another series of findings at bronchoscopy in patients with respiratory symptoms, the incidence of tracheal stenosis was not significantly increased in patients with DS compared with those without.6

Congenital tracheal stenosis has been reported in patients with DS.10^–12 In patients with DS and congenital tracheal stenosis, the most common type appears to be segmental ‘hourglass’ stenosis.13 However, most cases of subglottic stenosis appear to be acquired postintubation; in one series of 17 patients with DS and subglottic stenosis, the stenosis was felt to be congenital in only four cases.10 It is not clear whether the suggested increase in incidence of subglottic stenosis in children with DS is due to an intrinsic increased risk of subglottic stenosis, or because children with DS are more likely to undergo surgery (eg, for heart or gastrointestinal defects) and, therefore, intubation.10 However, the incidence of postextubation stridor in patients with DS has been reported as 33%, much higher than in non-DS patients.12 This again emphasises the need for careful selection of endotracheal tube size in this cohort of patients,5 and careful management postextubation.

Sleep-related breathing disorders

There is an increased incidence of obstructive sleep apnoea in children with DS, although the actual incidence reported in studies varies and depends upon the definition and investigations used. For example, Stebbens et al14 used a combination of a questionnaire, overnight recordings of oxygen saturations, end tidal carbon dioxide, chest and abdominal wall movements, and clinical assessment to diagnose upper airway obstruction during sleep in 31% of children with DS. By contrast, Dyken et al15 examined a non-selected cohort of children with DS using full polysomnography (electroencephalography, electro-oculography, electromyography, electrocardiography, airflow measurement, chest wall movement and oximetry) and found obstructive sleep apnoea in 79% of subjects. Obstructive sleep apnoea, appears to arise most commonly in the second or third year of life.14 ,15

Important aetiological factors for development of sleep-disordered breathing in DS include the narrow upper airway, probable reduction in pharyngeal muscle tone in relation to generalised hypotonia, and tonsillar and adenoid hyperplasia.16 Sleep-related breathing disorders are associated with a wide range of symptoms, including developmental delay, behavioural difficulties, faltering growth, tiredness and pulmonary hypertension. However, because of the intellectual impairment and cardiac disease associated with DS, these manifestations may not be recognised, or may be dismissed as ‘just part of the DS’.3 ,16 Furthermore, it has been shown that reporting of sleep problems by parents is not a good predictor of abnormal sleep study results.17 It is therefore very important that careful consideration is given to the possibility of a sleep-related breathing disorder in all children with DS, and some have argued for screening of all patients.17 Obstructive sleep apnoea in DS is frequently effectively treated with tonsillectomy and adenoidectomy,9 ,14 and a trial of overnight mask continuous positive airways pressure should also be considered.18

Congenital and structural abnormalities

A number of structural abnormalities have been noted to occur in DS. However, it is unclear to what degree these defects contribute to respiratory morbidity in children with DS. A particular pattern of pathological and histological abnormalities has been demonstrated in patients with DS, including macroscopic porous appearance and microscopically, enlargement of the alveolar ducts and alveoli, reduced numbers of alveoli and reduced acinar complexity.19 These findings appear to be related to a failure of alveolar multiplication in the postnatal period, as they were not observed in late gestation. A double capillary network was also commonly found in DS patients. The effect of these abnormalities on lung function has not been clearly established.

In addition to the general porosity of the lungs observed by Cooney et al,19 DS has been associated with subpleural cysts.20 These are often not recognised, since they are not normally apparent on a plain chest radiograph. They are generally felt to have limited or no clinical significance. However, there are reports of patients with DS and subpleural lung cysts who suffered adverse outcomes, including rapid development of severe pulmonary hypertension in one child with a coexisting atrioventricular canal defect and recurrent respiratory infections and bronchiectasis leading to respiratory failure in another.21 It has been suggested that subpleural lung cysts may alter lung mechanics and cause hypoxia, and may contribute to the development of pulmonary hypertension. It should be noted however, that these complications are seen in children with DS without subpleural lung cysts.

Respiratory tract infections and immunological defects

Children with DS appear to be more susceptible to respiratory tract infections.22 Importantly, they have a 30% increased risk of death from sepsis, even after adjusting for potential confounders.23 In one retrospective study of hospital admissions of children with DS, respiratory pathology was responsible for 54% of admissions, and was also the most common reason for admission to the paediatric intensive care unit (43%) and for ventilation (50%).24 Pneumonia was the most common diagnosis among both those hospitalised and admitted to paediatric intensive care. The length of admission for children with DS was shown to be two to three times longer than that for children without DS. This study was conducted in a centre that did not perform surgery for congenital heart disease. In a population-based study in Tennessee, the most common principal diagnosis for hospital admissions was congenital heart disease.2 However, as a group, respiratory illnesses were the most common principal diagnoses, accounting for 42% of all admissions, and 70.5% of admissions in children without CHDs. Pneumonia and acute bronchitis or bronchiolitis were the second and third most common principal diagnoses after CHDs. Respiratory infections are the second most common cause of mortality after CHDs in children under the age of 19.1 While CHD remains an important cause of morbidity and mortality, these data suggest that respiratory infections come at least a close second in terms of impact on the health of children with DS.

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection in children with DS. Children with DS are more likely to require hospital admission with RSV infection than children without DS.25 They also tend to have a more severe course and an increased length of stay.25 ,26 On this basis, some have advocated considering RSV prophylaxis for all children with DS, rather than only those who would routinely receive this because of CHDs.27

As well as increased frequency of respiratory infections, there is also an increased risk of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in children with DS admitted to intensive care.28 The cause of this increased incidence of ALI and ARDS has not been established, and it is not clear whether this may be related to the increased morbidity from respiratory infections.

The increased incidence of respiratory tract infections in children with DS is likely to be multifactorial. Structural abnormalities of the airways as described above are likely to play a role to a greater or lesser extent in any one patient. Patients with DS have increased mucus secretions and reduced ciliary beat frequency when compared with controls without DS.29 However, ciliary ultrastructure is normal, suggesting that the ciliary dysfunction is acquired and may be the result rather than the cause of increased respiratory infections. A number of immune defects have been identified in children with DS. These include reduced T and B lymphocyte subpopulations, decreased neutrophil chemotaxis and thymic abnormalities.30^–32 Abnormalities of B-cell function have been suggested, resulting in alterations of levels of immunoglobulin subclasses.31 ,32 Of particular clinical relevance are reported alterations in response to vaccinations,32 and it has been suggested that children with DS may benefit from pneumococcal polysaccharide vaccine.33 ,34 An alternative suggested approach is to check functional antibodies and repeat immunisations as necessary.3

Wheeze

Wheeze is commonly reported in children with DS. While they are frequently labelled as having asthma, few children with DS who wheeze meet international diagnostic guidelines.35 Although chronic rhinitis is often seen in children with DS, atopic diseases such as eczema or hayfever are diagnosed less commonly than in children without DS.35 Children with DS are also less likely to have positive skin prick tests than controls.36 These observations support the suggestion that wheeze in DS has an aetiology other than asthma.

Bloemers et al37 investigated whether wheeze in children with DS is related to previous infection with RSV. While they demonstrated a high incidence of both parent-reported and physician-diagnosed wheeze in children with DS, this was not associated with previous RSV lower respiratory tract infection, in contrast with controls. A number of possible explanations have been suggested to explain the high incidence of wheeze in DS, including congenital lung abnormalities, tracheomalacia, upper airway collapse secondary to hypotonia or congenital heart disease.35 ,37

Congenital heart disease

Structural CHDs are found in just over 40% of infants with DS.38 ,39 The intimate nature of the relationship between the cardiovascular and respiratory systems means that a certain degree of respiratory morbidity might be expected in this group. However, children with DS seem to be more susceptible to pulmonary vascular problems than their counterparts with CHD and normal chromosomes. One manifestation of this pulmonary vascular fragility is seen in children with atrioventricular septal defect (AVSD), the most common CHD seen in children with DS.38 ,39 Children with DS and AVSD seem to develop higher degrees of increased pulmonary vascular resistance, and progress more quickly to pulmonary vascular occlusive disease than children with this defect who do not have DS.40 This phenomenon may be related to the abnormalities of lung structure seen in patients with DS, including reduced numbers of alveoli, enlargement of alveolar ducts and alveoli, and anomalies of pulmonary vasculature.19 However, pulmonary vascular disease does not appear to be an inevitable consequence of AVSD in DS, and other factors, such as the morphology of the defect, appear to play a role.41

Children with different types of CHD may also be at risk of compression of the airways. Airways compression from vascular anomalies is well recognised, however, airways compression and resulting malacia may also arise as a result of atrial enlargement, enlargement of the pulmonary arteries or massive cardiomegaly.42 This complication can result from lesions associated with a left to right shunt, such as ventricular septal defect, atrial septal defect or patent ductus arteriosus, all of which are commonly seen in DS.

Additionally, airway and respiratory function may be affected by complications of surgery for CHD. Surgical trauma affecting the respiratory system may include chylothorax, injury to the recurrent laryngeal nerve and diaphragmatic paralysis, in addition to the risk of subglottic stenosis as described above.42 It is therefore important to consider these possible effects of CHDs and their treatment in a child with DS and a CHD who presents with respiratory symptoms.

Pulmonary vascular problems without associated cardiac structural defects

Disorders of the pulmonary vasculature are not restricted to those with known CHD in DS. The increased susceptibility to pulmonary hypertension appears to extend to children with DS without structural cardiac lesions. This may initially manifest as persistent pulmonary hypertension of the newborn (PPHN). Estimates of the incidence of PPHN in infants with DS vary; Shah and colleagues observed that PPHN was present in 10% of infants with DS without serious structural cardiac malformations admitted to neonatal intensive care,43 while Weijerman et al39 studied a large cohort of children, all born with DS, and found an incidence of PPHN of 5.2%, out of whom 36% had no CHDs. By contrast, in studying 821 infants with DS born in the UK, Irving and Chaudhari found none who had presented with PPHN without an underlying cardiovascular anomaly.38

Pulmonary hypertension is a recognised complication of upper airway obstruction in children,44 and is an important consequence of chronic airway obstruction in those with DS.45 ,46 This further emphasises the importance of recognising and treating chronic airways obstruction and sleep-disordered breathing in children with DS. Additionally, investigation for, and treatment of, airway or respiratory disease forms an essential part of the management of pulmonary hypertension in children with DS.47

Another possible manifestation of the vulnerability of the pulmonary vasculature in DS is high-altitude pulmonary edema (HAPE). HAPE is defined by the presence of specific symptoms and signs of pulmonary oedema in the context of recent altitude gain.48 HAPE has been described as occurring in children with DS with CHD and left to right shunts and those with known chronic pulmonary hypertension, but also in children without any history of CHD or pulmonary hypertension.49 Indeed, HAPE may represent the first manifestation of pulmonary hypertension in DS.50

Congenital disorders of the gastrointestinal system

DS is associated with a number of congenital defects of the gastrointestinal system, including oesophageal atresia, duodenal atresia, ano-rectal malformations and Hirschsprung's disease. Of these, oesophageal atresia may impact upon pulmonary function. The incidence of oesophageal atresia in DS is 0.5–0.9%.51 Following surgical repair of oesophageal atresia, many patients continue to have respiratory problems beyond the initial postoperative period, including bronchitis, cough, pneumonia and wheezing.52 In one study of respiratory morbidity following repair of oesophageal atresia, 44% of patients were hospitalised with respiratory illnesses during the initial years following surgery, and approximately two-thirds of children had ongoing respiratory symptoms during the first 5 years.53 It is therefore perhaps to be expected that children with DS and oesophageal atresia might be particularly troubled by ongoing respiratory symptoms.

There is an association between Hirschsprung's disease and congenital central hypoventilation syndrome, first described by Haddad in 1978.54 However, patients with Hirschsprung's disease and congenital central hypoventilation syndrome appear to be a separate group to those with DS and Hirschsprung's disease, as evidenced by differences in the length distribution of the aganglionosis and other associated abnormalities.55 This suggests that patients with DS and Hirschsprung's disease are not at increased risk of congenital central hypoventilation syndrome.

Functional disorders of the gastrointestinal system

Patients with DS may have abnormalities of swallow function, oesophageal dysmotility or gastro-oesophageal reflux. Problems with swallow function can give rise to aspiration, the inhalation of foreign material into the lower airway.56 Swallowing dysfunction resulting in aspiration has been shown to occur in children with DS, particularly with liquids.57 Often these children will aspirate ‘silently’, meaning that no cough or choking symptoms are observed at the time of aspiration. Oesophageal scintigraphy demonstrates significantly increased retention of liquid and semisolid boluses in the oesophagus by patients with DS, and an increased incidence of achalasia.58 Chronic recurrent aspiration secondary to swallow dysfunction may cause children to present with wheeze, chronic cough, recurrent pneumonia, pulmonary scarring or impaired lung function.56

Gastro-oesophageal reflux disease (GORD) has been defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and or complications.59 Gastro-oesophageal reflux is common in DS and is probably related to pathological changes in the nervous system.60 GORD in children with DS may result in a number of serious complications, including aspiration pneumonia.61 Since a wide range of conservative, pharmacological and surgical treatment options are now available for GORD, it is an important diagnosis to consider in any child with DS who encounters significant or recurrent respiratory problems.

Acute setting

For the child presenting acutely with respiratory problems, infection is the most likely cause, and careful management is required in view of the more severe course of common infections seen in children with DS. Consideration must be given to the most appropriate care setting, taking into account the severity of illness and any comorbidities. Those involved in intensive care of children with DS must be aware of their relatively narrow airway and risk of postextubation stridor. While infection is the most common cause of acute respiratory problems, other possible causes include airway obstruction, aspiration and pulmonary oedema.

Outpatient setting

In the outpatient setting, children with DS may present with persistent or recurrent respiratory symptoms, or be asymptomatic. A full history and examination is necessary, paying particular attention to both symptoms, including cough, wheeze, snoring and upper airway noises, as well as past medical history including associated comorbidities and any previous surgery. The impact of the symptoms on the child's life should be ascertained, including asking about development, daytime somnolence, hospital admissions and missed school or opportunities. This information can be used to guide investigations, which may be considered for gastro-oesophageal reflux, sleep-disordered breathing or airway abnormalities. While not subjecting children to unnecessary investigations, it is essential not to dismiss or overlook symptoms that may represent treatable conditions, such as reflux or sleep-disordered breathing, since treatment may have a significant effect on the child's quality of life. Specifically, in children presenting with wheeze, careful consideration of possible diagnoses and any appropriate investigations should be undertaken before making a diagnosis of asthma, since this is uncommon in DS. In addition, while all children with DS should have a general paediatrician (or general practitioner) overseeing their care, referral to a specialist in respiratory medicine, cardiology, gastroenterology or ear, nose and throat should be made whenever the severity or complexity of child's problems falls outside the capabilities of the generalist.

Management will largely be guided by specific conditions identified, for example, antireflux medication for GORD or adenotonsillectomy for sleep-disordered breathing. Respiratory symptoms may be multifactorial and, therefore, an approach is needed which identifies all the contributory factors or conditions and treats each one. Additionally, there are also a number of general considerations. Growth and body mass index should be monitored, and weight management addressed in children who are overweight or obese. All children with DS should be immunised according to the national schedule of immunisations. Children with DS may benefit from polysaccharide pneumococcal vaccine (PPV)33 and indeed, many would fall into the ‘at-risk’ groups who should receive it after their second birthday, on account of their respiratory or cardiovascular disease.62 The Down Syndrome Medical Interest Group suggests that there is a ‘strong case’ for both PPV and influenza vaccination in children with DS.63 Experience suggests many children benefit from a combination of these measures, plus prophylactic antibiotics (especially during winter) and physiotherapy.3

With recent improvements in management of CHD in DS, respiratory problems are an increasingly important cause of morbidity and mortality. This is an area in need of ongoing research and inclusion in local and national guidelines.