Abstract
This chapter reviews the impact of trisomy 21 (the commonest trisomy) upon the respiratory tract, including its 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.
Keywords
Down syndrome respiratory complications, alveolar hypoplasia
Introduction
Down syndrome (DS; trisomy 21) is the commonest chromosomal 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. 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.
The phenotype is characterized by a characteristic facies and stature, variable developmental delay and learning difficulties, and an increased incidence (over the general population) of multiple specific diseases, including respiratory disease, congenital heart defects, gastrointestinal malformations, autoimmunity, endocrine disease (in particular hypothyroidism), 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, significant progress was made in the 1990s, and by 1997 it was 49 years. More recent estimates suggest that a child born in 2000 in Australia with DS had a life expectancy of 60 years. 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.
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 pediatricians 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. 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 for a combination of respiratory pathologies including aspiration, 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 hospitalization, irrespective of presence of congenital heart disease (CHD). 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 relationship between respiratory symptoms, health care use, and comorbidities. This study will provide useful information for clinicians.
| Symptom | Etiology |
|---|---|
| Upper airway obstruction | Stridor Obstructive sleep apnea/sleep-disordered breathing. Postextubation stridor |
| Recurrent respiratory infections | Viral upper respiratory tract infections Lower respiratory tract infections (viral/bacterial) Lobar pneumonia Aspiration pneumonia |
| Wheeze | Pulmonary edema/pulmonary hypertension Asthma |
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 categorize 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 ).
| Organ System | Manifestation |
|---|---|
| Cardiovascular | Airway compression secondary to congenital heart disease Pulmonary hypertension Pulmonary edema (including high altitude related) Complications of cardiac surgery |
| Gastrointestinal | Swallowing dysfunction Gastroesophageal reflux disease Respiratory complications following repair of esophageal atresia |
| Immune system | Recurrent respiratory tract infections Increased severity of respiratory tract infections |
| Neurologic | Hypotonia |
| Other | Obesity |
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 relative macroglossia, midface hypoplasia, narrowed nasopharynx, choanal stenosis, enlarged tonsils and adenoids, lingual tonsils, and a short palate ( Table 68.3 ). Below the vocal folds, the trachea itself is considerably narrowed, with an internal diameter approximately 2 mm narrower than the general population in the pediatric age range. This narrowing likely contributes to the increased incidence of postintubation stridor historically observed in children with DS.
| Smaller midface and lower face skeleton | Shorter hard palate length Smaller mandible volume Shorter mental spine–clivus distance |
| Soft tissues | Smaller tonsils Smaller adenoids Smaller tongue |
| Relative impact of skeletal size upon soft tissue to airway size ratio | Higher tongue to skeletal size ratio Reduced upper airway size due to soft tissue crowding |
Tracheomalacia and Laryngomalacia
Airway abnormalities contribute significantly to symptoms in DS ( Fig. 68.2 ), but this information is largely based on case series naturally representing groups of patients who have particularly serious symptoms. Without background population data, case series can produce incorrectly elevated prevalence of diseases. In addition, case series are usually limited to small numbers of children, and so estimates of prevalence of rarer conditions vary widely between series.
In a series of 239 children with DS of whom 39 (16%) underwent endoscopy for airway symptoms, the most common finding was tracheobronchomalacia ( Table 68.4 ). In approximately half of patient with tracheobronchomalacia, this affected both the trachea and bronchi. Laryngomalacia is common in children with DS and usually presents in the first months of life. Supraglottoplasty is uncommonly performed for laryngomalacia and is reserved for complications such as feeding failure, respiratory distress, and sleep-related symptoms or apnea, often in the context of subglottic stenosis and cardiac surgery. However, surgical failure can occur in up to a third of patients, and in some patients tracheostomy may be required. When undertaking surgery for laryngomalacia, the possibility of further surgical intervention should be considered and discussed with families.
| Series | Hamilton | Bertrand | Estimated Down Syndrome Population Prevalence (%) (From Hamilton ) |
|---|---|---|---|
| Number studies | 39 | 24 | |
| Subglottic stenosis | 14 | 1 | 5.9 |
| Laryngeal cleft | 2 | 0 | 0.8 |
| Laryngomalacia | 2 | 12 | 0.8 |
| Tracheomalacia | 14 | 8 | 5.9 |
| Bronchomalacia | 10 | 5 | 4.2 |
| Tracheal stenosis | 2 | 1 | 0.8 |
Tracheal bronchus (wherein the right upper lobe bronchus originates directly from the trachea rather than the right main bronchus) can predispose to lower respiratory tract infection (LRTI). In a report on bronchoscopy findings in children, 2 of 18 patients with a tracheal bronchus had DS, which would suggest that the incidence in children with DS 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 stenosis, tracheal bronchus can cause significant management challenges. This is especially so in the critical care setting where distortion of the usual anatomy can lead to significant hypoxic events in association with changes in the position of the head and neck.
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%. 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 previously intubated.
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. 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 challenging to evaluate in DS. Tracheal stenosis in DS is associated 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 fiberoptic bronchoscope, especially if one or more complete tracheal rings are present. When this occurs, a nonionic tracheobronchogram or thin cut computerized tomography (CT) scan can be used to delineate the extent of the narrowing.
Clinical Presentation of Upper 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 ). It is worth noting that the tongue in DS is actually smaller than in age- and sex-matched controls on magnetic resonance imaging (MRI) scans. The apparent macroglossia is actually due to small craniofacial parameters, leading to relative macroglossia for the size of the oral cavity. 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.
Disturbed sleep behavior is frequently reported in DS. Snoring occurs in half of school-age patients and is accompanied by parental report of restlessness, frequent waking, bedwetting, delay in becoming alert after waking, and challenging sleep behavior. However, there is little correlation between polysomnography findings and parental report.
Sleep-disordered breathing is associated with neurocognitive 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. 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 ). In addition to OSA, the sleep of children with DS demonstrates increased fragmentation, numerous awakenings and arousals, and periodic leg movements. These characteristics are to a certain extent independent 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 prospectively evaluated with polysomnography, there is evidence 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.
Adenotonsillectomy is usually the first-line treatment for OSA. However, the success rate of adenotonsillectomy is lower in DS than in the general population, with only partial improvement in polysomnogram parameters such as the apnea-hypoxia index. Importantly, OSA is prevalent even after surgery. 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 complications, 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, continuous 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. Sleep apnea in DS is multifactorial in origin, and both airway abnormalities and a central mechanism 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 contributing factors including decreased pulmonary reserve due to morphologic differences, poor immunologic function, gastroesophageal reflux disease and aspiration, interactions with CHD, and thoracic cage malformations.
Histopathology of the Lower Respiratory Tract in Down Syndrome
A number of morphologic differences in lung parenchyma contribute to reduced functional reserve in children with DS. The changes can be so severe that an experienced pediatric 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. This pattern occurs postnatally; the lung tissue has a more normal appearance 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. These cysts are approximately 1–2 mm in diameter and are lined by cuboidal epithelium. Up to 20% of patients with DS have them at postmortem, and they have been found in 36% of chest CT scans. They are underrecognized and usually not apparent on chest radiographs. Their development has been suggested to occur secondary to reduced postnatal production of peripheral 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. 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 bronchitis, 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 neurodevelopment in DS. Children with DS whose parents report 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. 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.
Guidelines regarding the use of palivizumab in children with DS vary, and this remains a controversial area. Randomized 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 DS ; however, a clinical trial is required.
In addition to increased risk of severe lung disease requiring respiratory support, when receiving intensive care, there is an increased risk of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) ; 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% and standardized mortality rates similar to children without DS. However, the scenario changes with sepsis, in which there is an increased risk of mortality. 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 membrane 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. 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 summarized in Table 68.5 . Research to characterize the immune deficit is ongoing, but the deficit includes reduction of multiple immune cell lines and antibody levels. A maturational 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.
| 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 |
After immunization, the specific antibody response for a wide range of antigens in DS is reduced, including immunization 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 reduced neutrophil chemotaxis, and reduced killing of Candida, but normal oxidative burst. In addition, absolute levels of natural killer (NK) cells are reduced.
Several underlying mechanisms for the immunodeficiency in DS have been postulated, but a clear unifying genetic mechanism has yet to be defined. Hypotheses that have been considered include overexpression of genes on chromosome 21 (including SOD1, ITGB2, and RCAN1) and a secondary immunodeficiency caused by accelerated aging and zinc deficiency. A better understanding of the immunodeficiency 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, subcostal 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 bronchial (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 breathers,” and this may often be reported by their caregivers as a wheeze. The parental report of wheeze can of course indicate 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. 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. Lung function tests (especially spirometry) can be difficult to perform in DS, preventing 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, including 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 pericardial. 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.
Chylothorax has been associated with DS in several case reports. It can occur spontaneously, after cardiac surgery, and in association with congenital pulmonary lymphangiectasia (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 significant and several hundred milliliters of fluid can be produced per day, even in relatively young children. Nonchylous congenital pleural effusions are also described in DS but appear to be uncommon.
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 cyanosis and therefore should be included in the differential diagnosis of respiratory failure in DS. The association between effusion and hypothyroidism is described, and some cases respond to thyroxine replacement therapy.
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 ), cystic fibrosis, primary ciliary dyskinesia, and several interstitial lung diseases.
