More Medical Issues in Down's Syndrome. A conference held under the auspices of the Royal Society of Medicine RESPIRATORY Forum on Learning Disability and The Down's Syndrome Medical Interest Group. Royal Society of Medicine, London, Thursday 26th April 2001 DISORDERS (GENERAL) Chaired by Dr Patricia Jackson, Edinburgh and Dr Liz Marder, Nottingham Respiratory disorders in Down's syndrome: overview with diagnostic and treatment options Summary of a presentation by Dr Iolo Doull Consultant Respiratory Paediatrician, Respiratory/Cystic Fibrosis Unit, University Hospital of Wales, Cardiff This overview mainly covers the portion of the respiratory tract distal to the epiglottis. Problems related to the Panel 1: Factors contributing to lower airway problems in Down's syndrome upper airway are covered in this series in the overview on sleep-related upper airway obstruction (srUAO). · Hypotonia · Relative obesity · Immune dysfunction Respiratory problems are a primary cause of mor- · Cardiac disease bidity and/or hospital admission particularly in young · Large airway compression children with Down's syndrome. Most textbooks do · Small lower airway volume not make reference to this and there is a lack of · Tracheobronchomalacia published research. There is an increased prevalence · Pulmonary hypoplasia of sleep-related upper airway obstruction and lower · Subpleural cysts · Gastro-oesophageal reflux airway disease, but the significance of symptoms is often under-recognised. Therefore, specialist investigation and treatment are often necessary Panel 2: Features associated with Down's but not often sought. syndrome which predispose to upper airway Studies suggest that up to 88% of children with disease Down's syndrome will be hospitalised at some stage · Hypotonia before their 16th birthday, and about 16% of these will · Obesity have more than four hospitalisations. In a teaching · Mid-face hypoplasia hospital in Australia, a retrospective chart review of 232 · Relative glossoptosis admissions of children with Down's syndrome over a · Small upper airway volume 6.5-year period gave over half the causes for admission · Increased secretions · as respiratory problems. Of the total admissions, 10% Nasal congestion · Tonsils and adenoids were ultimately admitted to the Paediatric Intensive Care Unit. Half of these PIC admissions were attributed to respiratory conditions. Lower airway problems Many factors contribute to the excess of lower Congenital abnormalities respiratory airway problems seen in children with In the general population, 7.5­20% of all congenital Down's syndrome (Panel 1). There is rarely one single anomalies are of the respiratory tract, and these are causative factor ­ the underlying pathology is often strongly associated with cardiovascular anomalies. They multifactorial. Furthermore, the lower airway cannot be can be divided broadly into stenotic or malacic (airway looked at in isolation; a lot of what appear to be lower collapse) anomalies, tracheo-oesophageal fistula and airway symptoms relate to upper airway problems. branching anomalies. It appears that congenital lower Panel 2 lists features associated with Down's syndrome airway problems are significantly more common in which predispose to upper airway disease. Determining children with Down's syndrome, particularly if there are the significance of different factors is critically associated cardiac defects. Unfortunately, there is a lack important for appropriate management. of published data. © Down's Syndrome Medical Interest Group · Children's Centre · City Hospital Campus · Nottingham NG5 1PB · www.dsmig.org.uk T: 0115 962 7658 ext 45667 · F: 0115 962 7915 · info@dsmig.org.uk Vascular compression of the large airways Immunoglobulin levels are normal until the age of The heart can cause vascular compression of the large about 5 years, but, thereafter, have increased levels of airways, either due to the heart chamber itself, or to IgA, IgM, IgG1 and IgG3 and decreased levels of IgG2 aberrant or distended vessels. The left atrium is and IgG4. particularly important, but vascular slings or rings and aberrant pulmonary or innominate arteries can cause respiratory problems. Panel 4: Tracheobronchomalacia management options In the absence of cardiac failure, it is easy to dismiss the heart and abnormalities of the blood vessels as · Observation ­ many children grow out of this causes of lower airway symptoms, but these must condition · Oxygen ­ a common approach for children with always be considered. Down's syndrome; may be adequate as sole therapy Tracheobronchomalacia · Continuous positive airway pressure (CPAP) In most groups of children prone to respiratory ­ quite high pressures may be needed problems, tracheobronchomalacia and bronchomalacia (20 cm H20) are most probably underdiagnosed. Part of the problem · Negative pressure ventilation · Surgery ­ aortopexy or, very rarely, a tracheal of diagnosis is that the presentation can be non-specific reconstruction and unless tracheobronchomalacia is specifically considered it probably will not be diagnosed. Panel 3 lists presenting features. Tracheobronchomalacia can be There are normal numbers of CD4 cells but, on diagnosed both by bronchoscopy and bronchography average, decreased numbers of CD4/CD45RA cells which may show dramatic narrowing during expiration. (memory cells) and increased numbers of CD8 cells Management options are summarised in Panel 4. (killer cells). However, despite normal CD4 and increased CD8 there is decreased responsiveness on stimulation with phytohaemagglutinin (PHA) or con- Panel 3: Presenting features of tracheobroncho- canavalin A. Therefore, even though the numbers of malacia immune cells are increased, they are unable to function · Recurrent chest infections normally. There is also decreased production of inter- · Monophonic wheeze (a single note) leukin 2, interferon gamma and tumour necrosis factor · Stridor (with or without cough) · Failure to extubate alpha. (For more information, see Nespoli et al, 1993.) · Sudden collapse (death attacks) ­ children with tracheobronchomalacia may experience Airway size breathing difficulties as their airway can become In Down's syndrome, there is good evidence that the very floppy. If the child begins to panic they lower airway and lungs are smaller than normal. There increase their intrathoracic pressure, are documented problems with intubation and the risk compressing the airway and exacerbating respiratory distress. A vicious cycle develops of subluxation, and a number of reports that children which can lead to collapse with Down's syndrome require a smaller endotracheal · Disproportionate ventilatory requirement relative tube than expected ­ even correcting for age and height. to lung disease A significant decrease in both the coronal and sagital · Corticosteroid/2-agonist-resistant lung disease diameter of the trachea in adults with Down's syndrome has also been reported. Immune dysfunction Children with Down's syndrome have an increased risk Pulmonary hypoplasia of infection, autoimmune diseases and malignancy as a In children with Down's syndrome there is an increased result of immune dysfunction. Immune problems are risk of abnormalities of lung development. In a post- subtle and their contribution to the increased rate of mortem study of children with heart disease, six out of infection is as yet unclear. seven children with Down's syndrome had hypoplastic Children with Down's syndrome possess small lungs. All showed a decreased number of terminal lung cortical thymocytes, have altered intrathymic maturation units, the acini contained decreased number of alveoli, and decreased numbers of leucocytes and lymphocytes, the alveolar ducts were spacious and distended and which affect both cellular and humoral immunity. there was a decreased number of large alveoli. Pulmonary vascular disease Investigation of children with Down's It has been recognised for a number of years that the syndrome and lower airway symptoms risk of pulmonary hypertension and the development A child with Down's syndrome and lower airway of Eisenmenger heart disease in children with Down's symptoms should be investigated systematically (Panel syndrome is greater compared with children without 5). The first step is to refer the child to a cardiologist to Down's syndrome. This could be explained by pulmon- eliminate the possibility of the lower airway symptoms ary hypoplasia. The capillary bed in the lungs parallels being cardiac-related. The child should then be formally the alveolar surface area; with a decreased number of assessed for upper airway obstruction, as some lower alveoli the pulmonary vascular size is decreased, increa- airway symptoms in children with Down's syndrome sing the risk of pulmonary problems. In association with are a reflection of upper airway problems. sleep-related upper airway obstruction, this is what is now perceived to be the cause of accelerated pulmon- ary vascular disease in children with Down's syndrome. Panel 5: A recommended investigation strategy for children with Down's syndrome and lower Subpleural cysts airway symptoms Subpleural cysts are almost specific to Down's 1. Review cardiac status syndrome, where they have been well documented, 2. Assess for upper airway obstruction and may be related to the increased risk of pulmonary 3. Check immune status 4. Upper GI contrast series hypoplasia. The subpleural cysts can be detected by 5. 24-hour pH probe computed tomography but not by standard radiography. 6. Flexible bronchoscopy 7. Repeat steps 1 and 2 Gastro-oesophageal reflux Gastro-oesophageal reflux disease (GORD) is a very important problem in Down's syndrome. In many The next step is gastrointestinal imaging to exclude children with Down's syndrome, GORD is vascular slings and rings and compression of the trachea, misdiagnosed as asthma and remains untreated. as well as to detect GORD. A 24-hour pH probe can be Common presenting symptoms are: also be performed to check for GORD. If necessary, a · vomiting, which may cause failure to thrive flexible bronchoscopy can investigate upper and lower · oesophagitis, which may or may not be associated airway compression. Immune dysfunction can be with chest pain, anaemia and irritability examined by a full blood count and immunoglobulin · respiratory symptoms ­ apnoea, coughing, wheeze check, but this rarely affects management. and aspiration pneumonia. If no underlying cause is found following these investigations, it is worth reviewing the cardiac status A simplistic view of GORD is that the gastric and the possibility of upper airway obstruction again contents rise up the oesophagus and spill into the as these are the two major contributors to lower airway trachea and cause aspiration pneumonia. There is now problems in children with Down's syndrome. substantial evidence that spilling of gastric contents As already mentioned it is important to remember into the lungs is not the only cause of respiratory that asthma is over-diagnosed in children with Down's symptoms. syndrome. It should be, therefore, a diagnosis of A study in rabbits looked at the effects on exclusion. respiratory conductance of intra-oesophageal acid and oesophageal distension. Both decreased conductance Approaches to treatment and management compared with baselines, making it harder for the rabbit of lower airway symptoms to breathe. In both situations, this was reversed by · Treat cardiac disease aggressively vagotomy. This is only part of an increasing body of ­ If there is no evidence of respiratory failure evidence that in humans simply having acid in the secondary to tissue fluid, investigate further to oesophagus may affect respiratory status, whether or not ensure that the heart size is normal and not it spills over into the lungs. compressing large airways. DSMIG is indebted to the Down's Syndrome Association who have met all the production costs for this summary. · Treat GORD aggressively ­ For the treatment of mild cases of GORD, Summary of treatment and management positioning is of limited use. Antacids and milk approaches thickeners can help in mild to moderate cases. A · Treat cardiac disease aggressively cow's-milk-free diet may be considered if there are · Treat GORD aggressively symptoms suggesting cow's milk protein · Treat upper airway disease aggressively · intolerance. Prokinetics are useful ­ cisapride Treat lower airway disease · Consider physiotherapy during relapse seems to be more effective than domperidone, · Consider supplementary oxygen although it is currently unavailable in the UK. · Non-invasive ventilation rarely needed ­ In moderate GORD, H2-receptor antagonists have limited success. Omeprazole has been shown to be a more effective treatment. ­ Severe GORD with significant symptoms is an · Non-invasive ventilation indication for fundoplication. ­ A large number of children may simply require Note: It may be months before any respiratory benefit oxygen, even if they have large airway problems. is seen following commencement of treatment, but Non-invasive ventilation is relatively uncommon. thereafter improvement tends to be progressive. Summary · Treat upper airway disease aggressively · Children with Down's syndrome have significant respiratory morbidity which is under-recognised and · Treat lower airway disease accounts for a large number of hospitalisations. ­ The mainstays of management are continuous · Contributory factors include hypotonia and obesity, prophylactic antibiotics and regular inhaled both of which can affect the other contributory glucocorticosteroids. factors. Other factors include cardiac disease, both ­ A once-daily regimen of prophylactic antibiotics failure and the compression effect on airways and is very useful for children with Down's syndrome lungs, immune dysfunction and GORD. and lower airway problems. The choice of · The causes are often multifactorial. Treating one antibiotic is influenced by a number of factors: factor alone is often unsuccessful. It is therefore - Whether a particular respiratory pathogen is important that treatment aims to optimise all the identified from cough, swab or sputum samples contributory factors. - Septrin (co-trimazole) is often used, unless there are abnormal blood counts. Alternatives include Further reading Augmentin (amoxycillin with clavulanic acid) or Nespoli L, Burgio GR, Ugazio AG, Maccario R. cefixime. Immunological features of Down's syndrome: a review. - Patient preference is very important. J Intellect Disabil Res 1993;37:543­51. ­ Ideally, a metered dose inhaler with a large volume spacer should be used to administer inhaled A complete transcript of this presentation, together with glucocorticosteroids, with a mask for younger references, is available at www.dsmig.org.uk. children. Compliance, especially in children, is an important issue and, although the guidelines do not recommend it, nebulised corticosteroids can be useful. · Physiotherapy ­ Regular physiotherapy is not popular with children, especially those with lower airway problems. However, it may be useful to teach parents how to perform physiotherapy so that it can be used when their child is unwell, and so may tolerate it better. © 2002 Down's Syndrome Medical Interest Group. Produced by Oxford PharmaGenesisTM Ltd, UK