• Alpha-1 antitrypsin (AAT) is an enzyme produced by the liver that has activity against neutrophil-derived proteases and provides defence against protease-mediated tissue damage.
• AAT deficiency is common. About one in 5000 newborns of European descent will have the severe ZZ phenotype. This phenotype is associated with a marked (10-fold) reduction in enzyme activity.
• Between 60 and 80% of individuals with the ZZ phenotype will develop emphysema in adult life.
• Approximately 6% of affected babies will develop jaundice, of whom one-third will progress to cirrhosis. Up to 70% of affected babies have transient elevation of liver transaminases. AAT deficiency is the second commonest reason (after biliary atresia) for liver transplantation in childhood.
• Emphysema in individuals with the ZZ phenotype develops in adult life between the ages of 30 and 45 years, and up to 10 years earlier if these individuals are regular cigarette smokers. Management is the same as for other forms of emphysema, with the additional possibility of AAT replacement therapy for those with severe disease.
• One of the best studies of the effects of AAT deficiency on lung function in young people was carried out in Sweden. In 1972–1974, all newborns were screened for AAT deficiency, and 129 infants with severe PiZZ deficiency were identified. The majority of these underwent lung function testing at 16, 18, and 22 years of age. Lung function was normal at all ages, although there did appear to be a more rapid decline than normally expected (–1.2% FEV1/year).1
• AAT deficiency is not a risk factor for bronchiectasis. Since the ZZ phenotype is relatively common, the possibility of chance associations with bronchiectasis and other conditions is relatively high. Measuring AAT levels in children with bronchiectasis is not helpful, since it may result in a false attribution of their lung disease to AAT deficiency.
• Occasionally, referrals are made to paediatric respiratory specialists to ask advice about children with the PiZZ AAT deficiency. On the basis of the available evidence, it is fair to say that lung disease in childhood is not significantly more likely than in the general population. There is an ongoing increased risk of liver disease. Affected individuals should be advised that they must never smoke.
ACD is a developmental abnormality of the pulmonary vasculature, in which normal alveolar capillaries are absent and there is failure of the formation of the normal air–blood diffusion barrier. The cause is unknown. ACD usually affects term infants. There are often associated anomalies of the GI, genitourinary, or cardiovascular systems. There may be a family history of neonatal death. There are several reports linking ACD with FOX gene cluster defects on 16q24.1/24.2.
Histological examination of the lung
• Hypertrophy of the muscle coat of the small arteries.
• Paucity of capillaries adjacent to the alveolar epithelium.
• Branches of the pulmonary vein running with branches of the pulmonary arteries, rather than in the interlobular septa.
Most infants present within 6 h of birth with respiratory distress and cyanosis. Occasionally, the presentation is delayed, rarely for as long as 6 weeks. This is unlikely to represent any progression of the disease, but rather a redistribution of the blood flow within the lung, changes in pulmonary shunting, and the development of right heart failure. Clinically, these infants are indistinguishable from those with persistent pulmonary hypertension of the newborn (PPHN). The initial CXR is often normal but may show diffuse haziness or granularity.
This is the same as for PPHN, often a combination of high-frequency oscillatory ventilation and NO, or ECMO. Pneumothorax is common. In most cases, any improvement will be transient. It is very likely that those infants sick enough to need ECMO with ACD will die. A lung biopsy showing ACD could be considered as a contraindication to ECMO, since this treatment will be futile.
In most infants, the diagnosis is made at autopsy, suggesting that the condition is uniformly fatal. However, it is possible that milder forms of the disease, which may have a patchy distribution within the lungs, may occur. At least one case of long-term survival has been reported.
Al-Hathlol K, Phillips S, Seshia MK, Casiro O, Alvaro RE, Rigatto H (2000). Alveolar capillary dysplasia. Report of a case of prolonged life without extracorporeal membrane oxygenation (ECMO) and review of the literature. Early Hum Dev 57, 85–94.Find this resource:
Bishop NB, Stankiewicz P, Steinhorn RH (2011). Alveolar capillary dysplasia. Am J Respir Crit Care Med 184, 172–9.Find this resource:
Eulmesekian P, Cutz E, Parvez B, Bohn D, Adatia I (2005). Alveolar capillary dysplasia: a six-year single center experience. J Perinat Med 33, 347–52.Find this resource:
• Connective tissue diseases are rare in childhood, and, in most children, the lungs are not involved.
• Children with connective tissue disease may present with respiratory symptoms or may develop respiratory disease as part of their illness.
• Lung disease is usually of gradual onset and only slowly progressive, and it can therefore be missed.
• Occasionally, lung disease will present dramatically as an alveolar haemorrhage and acute respiratory failure.
Systemic lupus erythematosus
SLE is an autoimmune connective tissue disease, with a prevalence in children of around 1/10 000. It is commoner in African and Asian races than northern Europeans and is commoner in girls than boys (3:1), although this difference is less distinct in pre-pubertal children. In most individuals, the cause is not known, although genetic and environmental factors have been proposed. A variant of SLE can be induced by drugs such as hydralazine, nitrofurantoin, and quinolones. SLE can affect children of any age, including infants.
Signs and symptoms
Usual initial symptoms, which may be intermittent or persistent, include:
• joint pain;
• malar rash (which may be photosensitive);
• painful or painless ulcers in the nose or mouth.
Signs may include:
• joint inflammation;
During the course of the disease, respiratory involvement is seen in 20–40% of children with SLE and may be part of the presenting illness. Problems include the following.
• Pleuritis. Chest pain and breathlessness. Pleural effusion (exudates) may be present.
• Gradual onset of breathlessness on exertion, with a dry cough and inspiratory crackles on auscultation. CXR usually shows reticulonodular shadowing. Chest HRCT scan may show ground-glass attenuation and increased interstitial markings, reflecting non-specific interstitial pneumonitis, or patchy consolidation and bronchiectasis, reflecting the presence of OP. BO may occur but is uncommon.
• Acute pneumonitis: fever, cough, breathlessness, chest pain with bilateral infiltrates on CXR. The illness can be severe, occasionally leading to respiratory failure.
• Pulmonary haemorrhage. Although this is relatively rare in childhood SLE (only 5% of cases), it may be the presenting symptom. Presents with breathlessness, fever, and cyanosis and can progress to respiratory failure. Bilateral infiltrates on CXR. Haemoptysis is only seen in 50% of affected children with pulmonary haemorrhage.
• Increased risk of pulmonary infection, including Pneumocystis pneumonia, as a primary problem of the disease, but also as a consequence of immunosuppressive therapy.
Other organ involvement
• Renal tract. The renal tract is affected in 50–60% of patients at presentation. Nephritis in children appears to be more severe than in adults and usually requires aggressive treatment.
• CNS. Neuropsychiatric manifestations occur in 30–60% of children with SLE during the course of disease. The commonest problems are headache, behaviour disorder, memory problems, lethargy, and dizziness. Encephalopathy, seizures (generalized and focal), depression, hallucinations, and transverse myelitis can also occur.
• Cardiac disease:
• Musculoskeletal disease:
• Arthritis or arthralgia;
• Coagulopathy. There may be a prothrombotic tendency, associated with lupus anticoagulant or anticardiolipin antibodies. Although some of these antiphospholipid antibodies prolong the in vitro clotting tests (particularly the activated partial thromboplastin time, APTT) and are not corrected by adding normal plasma, they are associated with prothrombotic tendencies in vivo. They are associated with a number of collagen vascular diseases (also lymphomas and occasionally after viral infections), including SLE.
The following investigations will help determine if a child has SLE.
• Blood tests:
• ANA: elevated in most children with SLE, but not specific;
• anti-double-stranded (ds) DNA antibody: more specific and reflects disease activity;
• anti-Sm (Smith) antibody: very specific, not very sensitive;
• FBC: haemolytic anaemia, leucopenia, and thrombocytopenia are all consistent with SLE;
• complement levels: often reduced in SLE;
• tests of clotting: prolonged APTT may suggest the presence of lupus anticoagulant.
• CXR: findings have been described earlier in the chapter.
• Chest HRCT scan: findings as described earlier.
• Lung function testing: in chronic respiratory involvement, usually shows a restrictive pattern.
Requires four out of 11 specific criteria (Box 54.1).
Treatment depends on the severity and pattern of organ involvement. Symptomatic lung disease would usually be treated with systemic corticosteroids. Severe disease may require the addition of other immunosuppressants, either azathioprine or cyclophosphamide, or increasingly a monoclonal antibody such as rituximab. The treatment duration is several months to years. Frequent re-evaluation for disease progression or the development of new organ involvement is required. Serum markers, such as anti-dsDNA, complement levels, and ESR, can be used to monitor disease activity.
• Juvenile dermatomyositis (JDM) is an inflammatory myopathy caused by a systemic vasculopathy.
• JDM typically presents with:
• The diagnosis is suspected on the clinical findings plus elevated creatine kinase and often positive ANA. MRI will show the affected muscle, and EMG, combined with muscle biopsy, confirms the diagnosis.
• Treatment is with immunosuppressive agents—corticosteroids, cyclophosphamide, methotrexate, and/or monoclonal antibodies.
• Oropharyngeal muscles may be involved in the disease, resulting in hoarseness, dysphagia, and difficulty handling secretions. Aspiration pneumonia may occur. Rarely, a tracheostomy may be needed for adequate airway toilet. Dysfunction of the oropharynx is associated with a poor prognosis and requires aggressive treatment.
• Weakness of the respiratory muscles can also occur, leading to a poor cough and an increased risk of infection, as well as hypoventilation. As with other forms of muscle weakness, hypoventilation may first become apparent during sleep.
• Direct involvement of the lungs is unusual in JDM. Diffuse interstitial pulmonary fibrosis is well documented in the adult form of dermatomyositis but has been reported only occasionally in children with JDM.
• There are case reports of association between dermatomyositis and PAP.
• Scleroderma is a rare chronic systemic disorder of unknown aetiology, characterized by:
• Raynaud phenomenon;
• skin fibrosis, ulceration, or atrophy, particularly affecting the face and hands;
• organ involvement, especially the lungs, kidneys, oesophagus, and heart.
• It is commonest in young adults but can affect teenagers and, rarely, children under the age of 10 years.
• Compared with adults, children are more likely to have localized scleroderma, rather than systemic sclerosis.
• Nailfold video-capillaroscopy is a simple test to distinguish simple Raynaud phenomenon from that associated with an underlying disease.
• The diagnosis is clinical, based on major and minor clinical criteria. ANA is often positive.
• There is no specific treatment, although immunosuppressant agents, such as pulsed IV cyclophosphamide and D-penicillamine have been tried, with variable and limited success for lung disease.
• When scleroderma is part of systemic sclerosis, lung involvement is common (90% of patients) in both adults and children.
• Aspiration lung disease, secondary to oesophageal dysmotility, can occur.
• Cardiac disease, such as cardiomyopathy, can present with respiratory symptoms or worsen pre-existing lung involvement.
• Pulmonary hypertension can occur and is usually a manifestation of the primary vasculopathy, rather than occurring as a result of hypoxia. Children with systemic sclerosis and pulmonary hypertension may have relatively little parenchymal lung disease.
• Lung fibrosis is very slowly progressive. Pulmonary hypertension can be more aggressive, resulting in right heart failure.
• There is an increased risk of lung malignancy in adults with systemic sclerosis.
Juvenile idiopathic arthritis
• Juvenile idiopathic arthritis (JIA) is defined as inflammation of one or more joints for at least 3 months in a child under the age of 16 years, in whom other known causes of arthritis have been excluded.
• It has an incidence of 10–20/100 000 children.
• Pauciarticular disease (50% of cases) affects four or fewer joints, mainly knees and ankles. It is commoner in girls and usually presents at 1–3 years of age. ANA may be positive and is associated with chronic uveitis. A later-onset form affects older boys and can be associated with acute uveitis.
• Polyarticular disease (30% of cases), affecting five or more small or large joints, is commoner in girls than boys, and, if RhF is positive, is the most likely form to cause joint deformity.
• Systemic-onset disease (20% of cases) has an equal sex incidence and may affect a variable number of joints, although sometimes joint involvement is not apparent for several weeks after the start of the illness. Systemic-onset JIA typically presents with high spiking fevers, a faint rash that comes and goes with the fever, lymphadenopathy, and hepatosplenomegaly. ANA and RhF are usually negative.
• First-line treatment is high-dose NSAID, followed by disease-modifying drugs (such as methotrexate) for resistant disease. Corticosteroids are used for episodes of intense inflammation or systemic illness.
• Lung involvement in JIA is rare and seen mainly in children with systemic-onset disease.
• During the acute phase of systemic-onset JIA, there may pleural inflammation with effusion, sometimes with an interstitial pneumonitis. Concurrent pericarditis is common and may contribute to pain and breathlessness. These acute inflammatory conditions usually respond well to NSAID therapy or systemic corticosteroids.
• Longer-term respiratory problems that have been reported to be associated with JIA include:
• There are no specific guidelines for the management of these rare lung diseases combined with JIA. It is possible that some may arise as a result of immunosuppressive therapies used for JIA. Each affected child needs to be investigated and treated, according to the findings. Investigations are likely to include CT scan, bronchoscopy, and, where the diagnosis remains unclear, lung biopsy.
• Atypical infection, including PCP, is an important differential in children with JIA on immunosuppressant therapy who develop lung disease.
• In asymptomatic children with JIA, lung function abnormalities may be found in up to 50%, including some with apparent small airways disease and others with restriction and decreased transfer factor.
• Sjögren’s syndrome is an idiopathic systemic autoimmune disorder.
• It is relatively common in middle-aged adult women, with usual symptoms of a dry mouth and dry eyes.
• It is rare in childhood; 75% of affected children are girls. Typical symptoms include:
• recurrent parotid swelling, often with fever;
• dry mouth (xerostomia), sometimes with oral ulcers;
• recurrent conjunctivitis with dry eyes (keratoconjunctivitis sicca);
• Investigation shows:
• positive ANA, anti-SSA, anti-SSB, or RhF in 80% of affected children;
• elevated amylase in 80%;
• elevated ESR in 80%;
• ocular examination may show keratoconjunctivitis and decreased tear production.
• Lung disease is reported in children with Sjögren’s syndrome, often presenting as an ILD, with breathlessness and dry cough.
• Lung function shows a restrictive defect.
• BAL can show increased numbers of neutrophils or lymphocytes.
• Lung biopsies from affected adults show interstitial fibrosis with lymphocytic infiltration.
• Treatment is usually with a combination of systemic corticosteroids, hydroxychloroquine, or azathioprine.
• BD is a multisystem vasculitis-like disorder, characterized by the triad of recurrent:
• mouth ulcers;
• genital ulcers;
• uveitis (less commonly seen in children).
• Other features include arthritis (large or small joints), erythema nodosum and other skin rashes, CNS involvement (meningoencephalitis and psychiatric or behavioural disorders), vascular lesions, including thrombosis (arterial and venous), and pulmonary arterial aneurysms.
• The cause is unknown, but there does appear to be neutrophil hyperfunction. This can be demonstrated clinically, using the pathergy test—a sterile 24-gauge needle is pricked under the skin. Neutrophil migration to the site results in the formation of a small nodule or pustule within 24–48 h.
• BD is a rare disease (1/100 000) and very rare in children. It is thought to be commoner in the Middle East and Turkey. When it does occur in children, it is nearly always in children >10 years of age.
• Oral ulceration is the hallmark of the disease. The ulcers are painful, usually occur in crops, and resolve without leaving a scar.
• Blood tests are non-specific. Inflammatory markers (ESR, CRP) are usually raised. Anticardiolipin is elevated in 30%, but other auto-antibodies (including ANA and ANCA) are negative.
• The diagnosis requires the presence of recurrent oral ulceration, plus two of the following:
• recurrent genital ulcerations;
• anterior or posterior uveitis or retinal vasculitis;
• erythema nodosum or other skin involvement, including pustular rash;
• positive pathergy test.
• The differential diagnosis for recurrent oral ulceration includes SLE, sarcoidosis, and Crohn’s disease or orofacial granulomatosis.
• Imaging of the head with MRI is indicated when there is CNS involvement. Vascular involvement (thrombosis or aneurysms) can be identified by angiography, CT with contrast, or magnetic resonance angiography (MRA). A history of haemoptysis should prompt this investigation to identify a pulmonary artery aneurysm (PAA).
• Cardiac evaluation, including echocardiography, may detect evidence of pulmonary hypertension associated with pulmonary thrombosis or emboli.
• Biopsy is often unhelpful, and the diagnosis is made clinically. Histology of the mouth or genital ulcers may show lymphocytic and plasma cell infiltration. Occasionally, there may be vasculitic necrosis.
• Treatment is usually a combination of colchicine (good for mouth ulcers), topical steroids, and systemic steroids. For more severe disease, azathioprine, cyclophosphamide, ciclosporin, methotrexate, and tumour necrosis factor (TNF) antagonists (e.g. infliximab) have all been tried.
• Overall mortality in adult series is 15–20% at 5 years. Death is usually related either to pulmonary haemorrhage, thrombosis, or CNS disease.
• Lung disease affects 10–20% of adults with BD. A smaller proportion of children with BD seems to have lung disease, but this reduced incidence seems likely to be related to the duration of the disease, rather than any fundamental difference between adults and children.
• Most lung diseases in BD is caused by either PAAs or by pulmonary emboli. Symptoms include:
• Fatal pulmonary haemorrhage can occur, usually from the rupture of a PAA. The aneurysms are often on peripheral pulmonary vessels and ulcerate into adjacent bronchi.
• Very rarely, PAA may be the only manifestation of BD.
• In one series of adults and children with BD, 80% of those with PAA had extrapulmonary thrombosis or thrombophlebitis. Nearly all had episodes of haemoptysis. This suggests that, in the absence of these problems, PAAs are unlikely.
• Vascular inflammation can spread to the lung parenchyma and cause diffuse pulmonary haemorrhages, bronchiolitis, and OP.
• Pulmonary problems, such as fibrosis and alveolitis, that are not associated with vascular involvement are rare.
• Imaging usually reflects the consequences of thromboembolic disease or PAA. CXR may show pleural effusion, diffuse infiltrate, discrete densities, and hilar vessel prominence. HRCT may show pleural thickening, air trapping (on expiratory scans), bronchiectasis, and pulmonary nodules.
• Biopsy of the involved lung tissue may show a predominant lymphocytic pulmonary vasculitis.
• Familial dysautonomia, also known as Riley–Day syndrome, is an autosomal recessive disorder found almost exclusively in individuals of Ashkenazi Jewish descent. It occurs with an incidence of 1/4000 within the Ashkenazi Jewish population. It is caused by mutations in the IKBKAP gene.
• It is a progressive disease, affecting autonomic and some sensory nerves. It usually presents in the first year of life, with feeding difficulties, recurrent chestiness, lack of tears during crying, and autonomic crises, as described later in the chapter.
• Features of the autonomic dysfunction include:
• decreased tears—which can cause corneal drying and significant eye problems;
• abnormal sucking and swallowing;
• unstable and variable blood pressure, including postural hypotension;
• decreased sensitivity to hypoxia and hypercarbia, which can be associated with hypoventilation;
• syncope during vigorous exercise.
• Autonomic crises are common. The frequency of crises varies from child to child—from several per day to one per month. They can be precipitated by infection, tiredness, or emotional stress and result in:
• emotional lability;
• increased secretions;
• varying blood pressure (often hypertension);
• poor skin perfusion.
• Other neurological problems include:
• decreased tendon reflexes;
• hypotonia in infancy;
• seizures in 10%;
• decreased pain and temperature sensation;
• altered taste sensation;
• peripheral sensory neuropathy, with consequent increased injury.
• Renal disease, particularly glomerulosclerosis, occurs in 20% and may result in renal failure.
• Scoliosis is common in mid childhood and will worsen co-existing lung disease. Osteoporosis can also occur, which makes the management of the scoliosis more difficult.
• Most individuals have normal intelligence. Behavioural problems, including breath-holding episodes, are common.
• The commonest problem is aspiration lung disease, resulting in recurrent pneumonia, wheezing, and bronchiectasis.
• Night-time hypoventilation can also occur.
• The diagnosis is based on clinical suspicion, plus DNA test for IKBKAP mutations.
• Where there are persistent respiratory problems, CT chest may be helpful to determine the extent of the underlying lung disease.
• PSG should be carried out annually to identify any problems of respiratory control such as long respiratory pauses and blunted responses to hypoxia or hypercapnia.
Treatment and outcome
• Treatment is supportive. Eye care to maintain eye moisture is important.
• Most (80%) of affected children need a gastrostomy and fundoplication to reduce aspiration events.
• Chest physiotherapy and prophylactic antibiotics can be helpful in children with chronic lung disease and bronchiectasis. Full vaccination is recommended, including annual influenza vaccination.
• Although significant night-time hypoventilation is unusual, affected children may benefit from NIV during sleep.
• Decreased responses to hypoxia and hypercarbia mean that children with familial dysautonomia should avoid underwater swimming, and extra care should be taken with long-haul air travel, particularly in children with co-existing chronic aspiration lung disease.
• Respiratory disease is a major cause of morbidity and mortality. Median survival is 40 years of age. There is an undefined risk of sudden death.
Axelrod FB, Chelimsky GG, Weese-Mayer DE (2006). Pediatric autonomic disorders. Pediatrics 118, 309–21.Find this resource:
Maayan HC (2006). Respiratory aspects of Riley–Day syndrome: familial dysautonomia. Paediatr Respir Rev 7 (Suppl. 1), S258–9.Find this resource:
Norcliffe-Kaufmann L, Kaufmann H (2012). Familial dysautonomia (Riley-Day syndrome): when baroreceptor feedback fails. Auton Neurosci 172, 26–30.Find this resource:
Children with cirrhosis may develop a number of respiratory complications. These include hepatopulmonary syndrome, pulmonary hypertension, breathlessness due to restriction (caused by compression usually from ascites), right basal pneumonia, and pleural effusions.
• This condition is characterized by persistent hypoxia, the cause of which is not fully understood but which includes:
• functional intrapulmonary right-to-left shunting—sometimes due to vasodilatation of the pulmonary arterioles, leading to a rapid capillary transit time insufficient to allow full oxygenation. In other cases, there may be true pulmonary arteriovenous malformations;
• V/Q mismatch;
• reduced diffusion capacity.
• Intrapulmonary shunting may be demonstrated by perfusion scans, which will show deposition of the label in the brain and kidneys, indicating bypass of the pulmonary capillary bed. It can also be demonstrated by bubble contrast echocardiography.
• Clinically, the circulation appears to be hyperdynamic, because of the dilated pulmonary vascular bed.
• Cardiac catheterization does not usually show true arteriovenous shunts. The shunting arises as a result of dilatation of the pulmonary arterioles and capillaries.
• Occasionally, hepatopulmonary syndrome is caused by shunts that arise because of anastomoses between the pulmonary veins and systemic veins, usually either the portal or para-oesophageal veins.
• The severity of liver disease does not correlate with the likelihood of the presence of hepatopulmonary syndrome.
• It has been reported in children of all ages, including infants.
• The frequency of hepatopulmonary syndrome in children with cirrhosis ranges between 5% and 35% in different reported case series.
• Some children with hepatopulmonary syndrome will have no symptoms. Others will have breathlessness and exercise intolerance. Breathlessness and the degree of hypoxia are worse in the upright position; the opposite is the case in most cardiac causes of these problems.
• Low-flow oxygen is usually sufficient to correct the hypoxia. Since the most likely cause is right-to-left shunting, the situation is analogous to that of cardiac disease, and oxygen treatment needs only be given for symptom relief.
• This is occasionally seen in children with cirrhosis and may arise because of:
• pulmonary thromboemboli arising in the portal system;
• vasoactive substances bypassing the liver metabolism.
• Symptoms are similar to those of other causes of pulmonary hypertension and are predominantly breathlessness and exercise intolerance. There will usually be hypoxia, with evidence of RV strain or hypertrophy.
Idiopathic pulmonary haemosiderosis (IPH) is characterized by diffuse alveolar bleeding, in the absence of vasculitis or cardiac disease. As the name implies, the cause is not known. Links with milk allergy (Heiner’s syndrome) and fungal infection (with Stachybotrys chartarum) have been proposed but are not universally accepted and, in any case, only apply to a small proportion of children with IPH. The incidence of IPH is not known, but a large centre might see one case every 2 years. Minor epidemics of alveolar bleeding in infants have been described.
Symptoms and signs
• Seventy per cent are <6 years of age at presentation.
• Recurrent haemoptysis (common but not invariable).
• Dry cough is common.
• During active bleeds, there may be breathless and desaturation, either at rest or on exercise.
• Auscultation is often normal. There may be end-inspiratory crepitations.
• No signs of vascular disease (e.g. rash or arthritis). Although not well described in the literature, some patients with IPH have arthralgia.
• Pallor (anaemia variable, depending on recent bleeds).
• Children with Down’s syndrome appear to have susceptible pulmonary capillary beds and are more likely to bleed. The diagnosis of IPH in this group requires particularly careful exclusion of any cardiac cause (high pulmonary blood flow or raised pulmonary venous pressure).
The differential diagnosis for haemoptysis includes the following.
• Confusion with epistaxis or haematemesis.
• Inhaled foreign body.
• Bronchiectasis, including that caused by CF.
• Bleeding disorders, especially von Willebrand disease.
• Hereditary haemorrhagic telangiectasia—can be associated with tracheal telangiectasia.
• Pulmonary venous hypertension or high pulmonary blood flows.
• Pulmonary adenoma or carcinoid tumour.
• Goodpasture’s syndrome.
• Pulmonary vasculitis:
• microscopic polyangiitis, a variant of polyarteritis nodosa.
• Connective tissue disease: SLE.
Where there is no observed haemoptysis, the differential will be the same as for other forms of ILD (see Chapter 46).
• Blood tests:
• FBC and film (iron-deficient anaemia and reticulocytosis);
• ferritin, iron, and transferrin;
• renal function: should be normal in IPH;
• ESR: only mildly elevated in IPH;
• autoimmune tests: ANA (SLE), ANCA (WG and microscopic polyangiitis) should all be negative in IPH;
• for completeness, a RAST for milk protein should be done, at least in infants;
• standard tests for clotting (prothrombin time and activated thromboplastin time), plus tests for von Willebrand disease (factor VIII and VWB antigen).
• Lung function tests will show a restrictive pattern. kCO will be increased, because of the free Hb in the alveoli.
• Urine microscopy for red cells and white cells, indicating renal involvement: negative in IPH.
• CXR: in IPH, this may show diffuse alveolar shadowing, indicating alveolar haemorrhage.
• Echocardiography and ECG may be needed to exclude evidence of pulmonary hypertension.
• CT scan: usually shows a ground-glass appearance with alveolar infiltrates. The appearance can be patchy or mosaic.
• Bronchoscopy and BAL. The airways will usually appear normal. BAL will show haemosiderin-laden macrophages, with mild increase in neutrophils. Culture is usually negative. Haemosiderin-laden macrophages may also be seen in gastric aspirates or induced sputum.
• The numbers of haemosiderin-laden macrophages are expressed as the number of positive cells out of 300 counted. Haemosiderin appears in macrophages 36–48 h after alveolar bleeding, and the level of haemosiderin in macrophages peaks 6–8 days post-bleed. Levels fall below 50/300 by 6 weeks post-bleed.
• Lung biopsy is not usually necessary for the diagnosis, provided the clinical history and other investigations are typical for IPH. If performed, it will show alveolar blood with haemosiderin-laden macrophages, but no evidence of vasculitis. Alveolar septae may contain mild focal infiltrates of neutrophils, which can be seen to be within the capillary walls on EM. This may be reported as pulmonary capillaritis. It is not known whether the presence of pulmonary capillaritis affects the clinical course; however, careful collection of lung biopsy samples in national or multinational databases may lead to new insights into this and other rare lung diseases.
The diagnosis is usually based on a history of recurrent haemoptysis or recurrent episodes of breathlessness, plus an abnormal CXR and CT scan, plus iron deficiency anaemia, plus evidence (usually BAL) of pulmonary haemorrhage, in the absence of evidence (clinical or on investigation) of vasculitis.
• Despite the absence of marked inflammation, the main treatment for IPH is immunosuppression with systemic steroids. Most regimes will use prednisolone 2 mg/kg/day for 4 weeks, followed by a slow wean over 6 months. Weaning too quickly seems to be associated with recurrence. If breakthrough bleeds occur on prednisolone, a second-line agent should be added, either hydroxychloroquine or azathioprine, and prednisolone put back to 2 mg/kg/day, until bleeding has stopped. A slower wean should then be started. As for all children on long-term oral steroids, warnings about infection risk, particularly chickenpox, should be given.
• In children with severe hypoxic illness, a 3–5-day course of pulsed methylprednisolone can be used to try and control the bleeding. If no benefit is seen, cyclophosphamide can be tried. Cyclophosphamide can take up to 2 weeks to be effective, and supportive treatment should be maintained during this period, including mechanical ventilation, if necessary.
• Iron deficiency should be treated with a 3-month course of iron.
• Children should be monitored monthly for the first 6 months. FBC and reticulocyte count are sensitive measures of bleeding. Some units like to carry out repeat BAL to demonstrate that bleeding has stopped; however, there seems little benefit from this, and local tissue hypoxia that occurs during a lavage potentially increases the risk of rebleeding.
• CXR should be repeated during exacerbations.
• Treatment can be withdrawn when there has been no evidence of bleeding on low-dose therapy for 6 months.
With relatively aggressive immunotherapy, most children will now do well, and the disease will go into remission. Recurrence can occur and may be precipitated by lung infection, exposure to irritants (including cigarette smoke), and hypoxia. Where treatment is less successful, or the diagnosis is made after some years, there is a risk of pulmonary fibrosis, significant restrictive lung disease, and respiratory failure.
Taytard J, Nathan N, de Blic J, et al. (2013). New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare® cohort. Orphanet J Rare Dis 8, 161.Find this resource:
• LAM is a rare disorder, occurring almost exclusively in women of childbearing age, although it has been described in children (boys and girls) as young as 12 years of age.
• It is characterized by the progressive proliferation, migration, and differentiation of smooth muscle (SM)-like LAM cells in the lungs, kidneys, and lymphatic system. LAM cell proliferation is thought to obstruct small airways, giving rise to cysts and pneumothoraces. Obstruction of lymphatics can cause pleural effusions, and obstruction to pulmonary venules may cause haemosiderosis and haemoptysis.
• LAM occurs sporadically in association with mutations in the tuberous sclerosis complex genes TSC1 and TSC2 (sporadic LAM) and also in patients with tuberous sclerosis (TSC-LAM). It is associated with mammalian target of rapamycin (mTOR)-activating tuberous sclerosis gene mutations.
• Serum vascular endothelial growth factor (VEGF)-D (a lymphangiogenic growth factor that has a key role in tumour metastasis) is increased in most patients with LAM.
• Symptoms may include:
• chest pain;
• persistent cough;
• Pneumothorax is often the presenting problem and occurs in 65% of affected individuals at some time. Pleural effusions in 30% of affected individuals. The combination of a pneumothorax with pleural effusion in a young woman is suggestive of LAM.
• Physical findings are usually those of pneumothorax or pleural effusion. A search should be made for features of tuberous sclerosis:
• facial or nail bed fibromata;
• shagreen patch—rough, discoloured skin near the sacrum;
• café-au-lait spots;
• retinal hamartomas—usually white spots around the disc.
• CXR can be normal or can show:
• cystic changes;
• basilar reticulonodular changes;
• pleural effusions;
• hilar and mediastinal adenopathy;
• Lung biopsy. Histopathologically, the cysts are dilated distal airspaces and diffuse infiltration of atypical smooth muscle cells in the pulmonary interstitium, including spaces surrounding the airways, vessels, and lymphatics.
• Renal ultrasound. Renal angiomyolipomas, unusual hamartomas containing fat, smooth muscle, and blood vessels, are present in about 70–80% of patients with TSC-LAM and 50% of sporadic LAM.
There is no treatment with proven effectiveness. Often anti-oestrogen therapies are tried. A trial of sirolimus (rapamycin—an inhibitor of mTOR) showed stabilization of the lung function, reduction in symptoms, and improved quality of life. The disease is progressive. Recurrence has been reported after lung transplantation.
• Pelizaeus–Merzbacher disease (PMD) is a very rare neurodegenerative condition, with an incidence of about 1/500 000.
• It is an X-linked condition, only seen in boys; 70% have mutations in the proteolipid protein 1 (PLP1) gene.
• It is of relevance to the respiratory specialist, because it is a cause of neonatal and infant stridor. Combined with hypotonia, this often leads to recurrent respiratory infections, which is a frequent cause of death in these boys.
• Other characteristic features, usually present in the first few weeks or months of life, are:
• striking nystagmoid eye movements present from birth or soon after;
• neonatal hypotonia, but subsequent severe spasticity;
• ataxia and severe cognitive impairment.
• Affected boys do not walk or talk and have very limited purposeful movements.
• The stridor is caused by discoordinate laryngeal musculature.
• There is no effective treatment.
PAP is characterized by the accumulation of surfactant-like material in the alveoli. The presence of this material reduces lung compliance and interferes with gas exchange. The incidence of PAP in children is not known, but it is rare and most paediatric respiratory centres would not expect to see more than one affected child every 2–3 years. PAP comprises a heterogenous group of diseases which, in children, include:
• surfactant production disorders;
• autoimmune disorders;
• secondary to other diagnoses.
Types of disease
Neonatal disease due to surfactant protein B deficiency
Surfactant protein B (SPB) deficiency is an autosomal recessive disorder, caused by the loss of function mutations in the SPB gene. It has an incidence of around 1/1.5 million in children of northern European descent. The usual clinical presentation is of a term infant who develops severe neonatal respiratory distress in the first day of life, with CXR changes that resemble RDS. Most infants require mechanical ventilation. Occasionally, the initial presentation is with milder lung disease that progresses over the course of a few days. The disease is usually rapidly fatal. The only effective treatment is lung transplantation. Histological examination of lung tissue from infants with SPB deficiency shows large amounts of periodic acid–Schiff (PAS)-positive lipoproteinaceous material in the alveoli, much of which is a precursor protein for surfactant protein C. This suggests that SPB is important in the turnover of other surfactant proteins.
An increasing number of mutations in other surfactant genes and controlling genes (surfactant protein C, ABAC3 transporter deficiency, etc.) are being recognized, causing a spectrum of disease most commonly severe in the neonatal period, but milder forms appearing later in childhood (see Chapter 46).
Outside the neonatal period, PAP can present at any age, from infancy to adolescence. Later-onset disease can either be primary and related to disturbance of the function of granulocyte macrophage colony-stimulating factor (GM-CSF) or secondary.
Primary GM-CSF-related PAP can be due to either a genetic defect in the GM-CSF receptor or a related signalling gene, which usually results in symptoms in the first few years of life, or the presence of acquired anti-GM-CSF auto-antibodies, which usually presents in adolescence or adult life. High levels of neutralizing GM-CSF auto-antibodies block GM-CSF signalling, reduce macrophage surfactant catabolism, and impair pulmonary surfactant clearance. Without GM-CSF, alveolar macrophages internalize, but do not catabolize, surfactant, resulting in the development of large foamy, surfactant-laden macrophages and the accumulation of intra-alveolar surfactant.
Secondary disease can be associated with a wide range of conditions, including the following.
• Infections (especially Nocardia and Pneumocystis).
• Haematological malignancy (especially myeloid leukaemia).
• Lysinuric protein intolerance. This is a systemic disorder caused by a defect in the transport of cationic amino acids (lysine, arginine, ornithine). Features of the disease include hyperammonaemia, GI symptoms, failure to thrive, hepatosplenomegaly, renal disease, osteoporosis, haematopoietic abnormalities, pancreatitis, and lung involvement. Lung problems include pulmonary haemorrhage, symptomatic and asymptomatic interstitial fibrosis, as well as progressive and usually fatal alveolar proteinosis. The diagnosis is based on serum and urinary amino acid levels. Treatment with a low-protein diet and oral citrulline has limited benefit.
• Sideroblastic anaemia.
• progressive breathlessness during feeding or on exercise;
• dry cough;
• poor growth or weight loss.
Less commonly there is:
• chest pain;
The rate of disease progression is very variable, ranging from symptoms that come on over several months to those progressing to respiratory failure in a few weeks. Some children can have quite dramatic CT scan changes, with little in the way of symptoms.
Investigations for later-onset disease
• CXR shows bilateral diffuse airspace opacity.
• CT scan shows ground-glass opacification, often with interlobular septal thickening, giving the appearance of crazy paving.
• BAL returns a creamy pinkish fluid containing PAS-positive material and foamy macrophages. BAL fluid should be sent for culture and microscopy looking for Pneumocystis jiroveci.
• Lung biopsy is the gold standard diagnostic test.
• Other tests looking for the aetiology include:
• anti-GM-CSF antibodies;
• DNA for GM-CSF receptor defects;
• FBC and film;
• Ig levels and specific antibody levels to check the immune function;
• serum and urinary amino acids for lysinuric protein intolerance (plus DNA for SLC7A7 mutation analysis if high index of suspicion).
• Rarely, Niemann–Pick disease (NPD) type B can present with similar CT and BAL findings. There is nearly always hepatosplenomegaly (see ‘Niemann–Pick disease’, p. [link]).
When symptoms are mild, it is reasonable to watch and wait. In more severe disease, the treatment of choice is therapeutic lung lavage, using selective lung intubation and large volumes of pre-warmed saline to wash the lipoproteinaceous material out of the alveoli. The procedure may need to be repeated on multiple occasions to keep the disease under control. In patients with severe disease who have anti-GM-CSF antibodies, daily SC GM-CSF may lead to improvement.
Outcome for later-onset primary disease
The clinical course is variable. Some patients have mild to moderate stable disease, controlled with multiple lavage treatments; some have spontaneous remission, and some have disease with progression to respiratory failure.
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Suzuki T, Sakagami T, Young LR, et al. (2010). Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med 182, 1292–304.Find this resource:
Trapnell BC, Whitsett JA, Nakata K (2003). Pulmonary alveolar proteinosis. N Engl J Med 349, 2527–39.Find this resource:
• Pulmonary embolism (PE) is the term used to describe the arterial obstruction by a thrombus that has either arisen at a distant location or that has formed and extended within the pulmonary artery.
• Large central or bilateral PEs are life-threatening.
• The incidence of PE in children is around 1/100 000. It is commonest in the first 2 years of life.
• As with many rare conditions, the diagnosis is often delayed.
• Chronic recurrent small pulmonary emboli can cause pulmonary hypertension.
• Central venous lines.
• Congenital or acquired heart disease (risk of intracardiac clot formation).
• Inflammatory disease, including vasculitides.
• Prothrombotic disorder.
• Oral contraceptive pill.
• Sickle-cell disease.
• chest pain;
• cardiovascular collapse.
• pleural rub;
• a loud P2 heart sound suggests right heart strain;
• evidence of a peripheral thrombus.
• Measurement of serum D-dimers in adults is a highly sensitive test for excluding PE, with an elevated level found in 97% of cases. It seems to be less sensitive in children. Normal levels were found in five of 14 children with PE in one case series.
• Chest CT with contrast (sometimes called CT pulmonary angiogram) is usually the diagnostic test. Alternatives, such as MRA, radionuclide perfusion scans, and standard angiography can also be used, but their availability may be limited, particularly outside of the normal working day.
• Echocardiography will identify any embolic foci in the heart or associated with central lines and indicate if there is any RV dysfunction secondary to the PE.
• anti-thrombin III protein C and protein S levels;
• factor V Leiden;
• prothrombin gene mutations.
• When no cause is apparent, investigation for occult malignancy or inflammatory disorders should be considered.
• For most children, treatment with standard doses of SC fractionated heparin is appropriate. The effectiveness is judged by clinical improvement. For infants, where the absorption of fractionated heparin may be less reliable, IV heparin infusions, with monitoring of clotting times, may be required. Advice of a paediatric haematologist is essential.
• Thrombolytic therapy with tPa can cause bleeding. It is reserved for children with haemodynamic compromise associated with large central or bilateral clots. Recent surgery is a contraindication.
• Long-term anticoagulation with warfarin may be indicated, depending on the cause of the thrombus.
Pulmonary lymphangiectasia (PL) refers to a rare condition, in which there is dilatation of the normal lymphatic channels. The incidence is not known. Increased fluid in the lymphatic channels decreases the lung compliance and increases the work of breathing. Two forms of PL are recognized.
Primary pulmonary lymphangiectasia
Primary PL is thought to be an intrinsic abnormality of the lymphatic channels and may be associated with lymphoedema of other parts of the body, loss of intestinal lymph, and hemihypertrophy. Primary PL can be confined to the lung. The cause is not known. It may be found in association with genetic syndromes, including Down’s, Turner’s, and Noonan’s syndromes.
Secondary pulmonary lymphangiectasia
Secondary PL results from lymphatic obstruction (e.g. damage to the thoracic duct) or from increased lymph production, because of raised pulmonary venous pressure, such as that caused by pulmonary vein stenosis or mitral valve stenosis.
Primary PL will usually present in the neonatal period.
• Primary PL confined to the lung is particularly severe and may be fatal, despite intervention.
• More generalized lymphangiectasia can present prenatally as non-immune hydrops.
• Rarely, symptoms may not develop until later infancy or early childhood. Affected infants will have respiratory distress, usually with diffuse fine crackles.
• The diagnosis can be difficult. CXR will be abnormal, but non-specific, with increased interstitial markings and hyperinflation. Similar changes will be seen on CT scan. Fifteen per cent will have a pleural effusion that may be chylous.
• A lung biopsy is usually required to make a definitive diagnosis.
Secondary PL usually occurs where there is an easily recognized underlying condition.
There is no specific treatment for PL. Management is supportive. Large pleural effusions may need to be drained and may continue to reaccumulate for several days or weeks. Resolution may be speeded by using a medium-chain triglyceride diet or total parenteral nutrition (TPN) to decrease the volume of chyle. Pleurodesis may be helpful.
The outcome of primary PL is uncertain. With supportive care, the lung disease tends to improve with time. Lung function tests show a stable, predominantly obstructive pattern. There may be poor growth in the first 2 years and recurrent episodes of bacterial bronchitis. The presence of associated abnormalities may significantly affect the outcome. The prognosis of secondary PL depends on the nature of the lymphatic obstruction or venous hypertension.
• Lymphangiomatosis is a rare disease, characterized by diffuse or multifocal lymphangioma (abnormal proliferation of lymphatic vessels) that commonly affect the lung and mediastium and may also involve the liver, soft tissues, bones, and spleen.
• Lymphangiomatosis is differentiated from primary lymphangiectasia (see ‘Pulmonary lymphangiectasia’, p. [link]) by the increased number of complex anastomosing vessels with secondary dilatation, rather than the simple dilatation of pre-existing lymphatic capillaries. Primary lymphangiectasia usually presents in the neonatal period or early infancy. Lymphangiomatosis presents at any time throughout childhood (including infancy) and early adult life. Most reported cases are in children.
Signs and symptoms
• Lung involvement is found in the majority (80%) of affected children and typically presents with breathlessness and exercise intolerance.
• Splenomegaly is found in 20% of affected children.
• Bony involvement is common (75% of children) and may be the reason for the initial presentation, because of either deformity or pain from a pathological fracture. The axial skeleton, including the skull, ribs, shoulder girdle, spine, and pelvis, is most usually affected. After a fracture through an area of affected bone, there is typically failure of healing, followed by progressive reabsorption of bone around the fracture site. This condition is sometimes called Gorham’s vanishing bone disease.
• CXR may show unilateral or bilateral pleural effusions (chylothoraces), increased interstitial markings, and a widened mediastinum. Thickening of interlobular septa and the pleura is seen on CT scans.
• The typical radiographic appearance of the bony lesion is radiolucent cysts surrounded by a sclerotic rim.
• MRI will demonstrate mediastinal involvement.
• Biopsy of any masses present or the thickened pleura will usually be necessary to make the diagnosis
• Management of the pulmonary disease includes closed chest drainage of the chylothoraces; pleurodesis is often required. Involvement of the lung parenchyma can lead to progressive breathlessness, and systemic therapies with interferon-alpha and etoposide have been tried.
• The natural history of lymphangiomas is progressive enlargement. Where there is compression of surrounding structures or instability of bony structures, such as the cervical spine, surgical excision may be necessary. Pathological fracture of the ribs can lead to a sudden worsening of the respiratory status.
• Radiotherapy, electrical therapy, and bisphosphonates may be required to promote healing of fractures.
The prognosis in children is poor, with 40% 5-year mortality. Most children who die have extensive systemic disease, nearly always involving the lungs.
Alvarez OA, Kjellin I, Zuppan CW (2004). Thoracic lymphangiomatosis in a child. J Pediatr Hematol Oncol 26, 136–41.Find this resource:
Clement A, Nathan N, Epaud R, et al. (2010). Interstitial lung diseases in children. Orphanet J Rare Dis 5, 22.Find this resource:
Pfleger A, Schwinger W, Maier A, Tauss J, Popper HH, Zach MS (2006). Gorham–Stout syndrome in a male adolescent—case report and review of the literature. J Pediatr Hematol Oncol 28, 231–3.Find this resource:
• The lungs may be involved in several systemic vasculitic disorders. All the diseases are rare in childhood. In most, pulmonary involvement is unusual.
• Note that dermatomyositis (see ‘Dermatomyositis’, p. [link]) and BD (see ‘Behçet’s disease’, p. [link]) are both predominantly vasculitic diseases that can affect the lungs but are usually considered as connective tissue diseases.
• The clinical presentation depends on the size of the vessel involved.
• Medium to large arteritis can result in pulmonary infarction and necrosis. Granuloma formation may occur.
• Small-vessel disease can cause diffuse alveolar haemorrhage.
• Pulmonary symptoms and signs are non-specific (Box 54.2). Alveolar haemorrhage can cause rapid-onset respiratory failure with prominent hypoxia.
• CXR and CT scans will show diffuse alveolar shadowing when there is alveolar haemorrhage, and discrete abnormalities, such as nodules and areas of consolidation, usually due to tissue necrosis, when larger vessels are involved.
• Biopsy of an affected site is usually required for diagnosis. This will show inflammation of affected vessels, with associated tissue necrosis. There may be vessel thrombosis. Changes suggestive of diffuse interstitial pneumonitis are not associated with vasculitic conditions.
WG is an aggressive small-vessel vasculitis, characterized by the formation of necrotizing granulomata. It particularly affects the upper and lower respiratory tracts and the kidneys. Although an accurate incidence is not known, WG is occasionally seen in childhood and frequently presents with disease involving the respiratory tract. WG can affect children of any age, from infancy to adolescence.
Symptoms and signs
The usual symptoms at initial presentation include:
• mouth ulcers;
• nose bleeds;
• otitis and deafness;
Other symptoms may include:
• weight loss;
• skin rashes.
Examination may reveal:
• tachypnoea, with or without desaturation (suggesting alveolar haemorrhage);
• tender sinuses;
• oral or nasal granulomata, sometimes with nasal deformity;
• stridor (suggesting subglottic stenosis).
Possible organ involvement in Wegener’s granulomatosis
• Upper airway:
• granuloma formation;
• subglottic stenosis.
• Lower airway:
• granulomata with airway compression;
• alveolar haemorrhage;
• parenchymal granulomata.
• Renal: glomerulonephritis (10–20% at presentation; 60–70% in later disease).
• blanching or non-blanching macules and nodules in 50%;
• more rarely, massive necrotizing granulomata.
• arthralgia of the knees, hips, wrists, or ankles in 50%;
• objective evidence of arthritis is rare.
• conjunctival and corneal lesions;
• proptosis from orbital granuloma.
Investigations and diagnosis
• Blood tests:
• FBC and film: anaemia, leucocytosis, and thrombocytosis;
• ESR: always elevated;
• autoimmune tests: cytoplasmic ANCA (c-ANCA) is elevated in 80% of children with WG and is reasonably specific, but it may be increased in other conditions (such as CF and microscopic polyangiitis). p-ANCA is also elevated, but less specific, and is also elevated in Churg–Strauss disease. The diagnosis is made with tissue biopsy;
• Renal function.
• Urine analysis for evidence of glomerulonephritis.
• CXR: may be abnormal in the absence of symptoms. Findings consistent with WG are focal opacities of varying size, up to 10 cm, representing either nodules or atelectasis. Widespread diffuse infiltrates suggest alveolar haemorrhage. Hilar adenopathy and pleural effusion are less common.
• Chest CT scan: usually shows multiple focal opacities, sometimes with central necrosis. Diffuse opacity will be seen with bleeding. There may be evidence of airway stenosis or compression by granulomata.
• Sinus CT scan: may show sinus opacity with bone destruction.
• Biopsy. Histological examination of affected tissue, showing necrotizing granulomata, is the most certain method of diagnosis. Biopsy sites include the sinuses, lungs, kidneys, and skin. The diagnosis is usually based on biopsy findings.
Treatment usually involves a combination of high-dose prednisolone and cyclophosphamide. Methotrexate has also been used.
• CXR changes, usually a reticulonodular appearance, are found in 15% of children with Kawasaki disease. Atelectasis and pleural effusion are also reported.
• At post-mortem, evidence of pulmonary vasculitis has been seen in >50% of children who died as a consequence of Kawasaki disease.
• Pulmonary involvement seldom causes symptoms and, when present, usually resolves after the usual treatment with IVIg and salicylate.
• Also called allergic granulomatous angiitis.
• Three phases of the disease are recognized:
• a prodromal phase of allergic rhinitis and asthma that can last several years;
• a period of peripheral eosinophilia and eosinophilic tissue infiltration;
• a final phase of systemic vasculitis, which can be fatal, if not treated.
• The vasculitis is predominantly small vessel, including capillaries, and can involve the heart, kidneys, GI tract, brain, lungs, and eyes.
• Lung involvement may be associated with fever and breathlessness, and occasionally haemoptysis. There is usually a diffuse reticulonodular infiltrate on CXR. More rarely, there may be pleural disease or cavitating eosinophilic abscess formation.
• Treatment is immunosuppression, usually with systemic corticosteroids.
• This is a form of polyarteritis nodosa.
• It is associated with a rapidly progressive glomerulonephritis.
• Lung involvement, particularly alveolar haemorrhage, is common.
• ANCA is usually positive (unlike other forms of polyarteritis nodosa).
• Diagnosis is usually by renal biopsy.
• Treatment is immunosuppression.
Sarcoidosis is an inflammatory granulomatous multisystem disease. It is found most often in young adults, particularly those of Irish, Scandinavian, or Afro-Caribbean descent. It is rare in children, with an estimated incidence of 0.6/100 000. It can occur at all ages of children, including infants, but is commonest in those >8 years of age. The cause is not known; clustering of cases can occur and suggests a combination of genetic and environmental factors, including viral infection and exposure to toxins. The following are the usual presenting symptoms and signs in children.
• General malaise.
• Weight loss.
• Skin involvement: painless nodules or plaques, especially around the eyes and nose. More rarely, erythema nodosum may occur.
• Eye involvement: redness, pain, photophobia caused by anterior uveitis. Conjunctival nodes and posterior uveitis may both be present.
• Oral mucosa: aphthous ulceration is reported.
• Arthritis: usually polyarticular, with large effusions and often painless.
• Lymphadenopathy: usually mobile and painless.
• Unilateral or bilateral parotid gland enlargement: non-tender, smooth.
Children <5 years of age typically present with arthritis, uveitis, and skin involvement. Older children are more likely to have lung involvement, uveitis, and lymphadenopathy. Other tissues that may be affected include:
• nervous system: cranial nerve palsies (especially facial nerve), aseptic meningitis, hydrocephalus, peripheral neuropathy, spinal cord involvement;
• endocrine system: central diabetes insipidus;
• heart: cardiomyopathy, heart block.
• muscles: muscle nodules and weakness.
In children >5 years of age, lung involvement is almost universal. Often, the children are asymptomatic, but there may be a dry cough, chest pain, or breathlessness. Examination is usually normal, but wheeze and crepitations have been described. Lung involvement is graded:
• stage 0, no involvement;
• stage I, bilateral hilar lymphadenopathy (BHL), paratracheal lymphadenopathy;
• stage II, BHL plus parenchymal infiltrate;
• stage III, parenchymal infiltrate without BHL;
• stage IV, extensive fibrosis with bullae, cysts, and emphysema.
Ninety-five per cent of those with lung involvement are stage I or II, so the finding of an infiltrate without BHL makes sarcoidosis a possible, but unlikely, diagnosis.
• CXR and chest CT scan: findings as per lung staging. Infiltrates are usually irregular, discrete lesions, surrounded by normal lung, and range in size, from a few mm to 2–3 cm. Nodules are often seen along bronchovascular bundles. Pleural thickening may also be seen.
• Lung function testing: may be normal or may show evidence of restriction. More rarely, there may be obstruction. kCO may be decreased.
• Bronchoscopy and BAL. Macroscopic appearances are usually normal; mucosal nodules with contact bleeding is described in adults. BAL reveals a moderate lymphocytosis (25–30% of cells present), with a 5:1 CD4+ to CD8+ ratio.
• FBC: leucocytes may be increased or decreased; eosinophils elevated in 50% of affected children;
• electrolytes: serum Ca elevated in 30%;
• urine electrolytes: hypercalciuria in up to 65% of children;
• liver function tests: mild elevation of transaminases is common;
• ACE levels: elevated in 80%, but not specific for sarcoidosis (also increased in lymphoma and TB, both of which may cause BHL);
• Igs: hypergammaglobulinaemia in 80%;
• ESR: elevated in 60–80%.
• Liver ultrasound: may identify nodules or evidence of cholestasis.
• Renal ultrasound: may identify nephrocalcinosis or nodules.
• 12-lead ECG, 24 h ECG, and echocardiography: heart block may occur, and nodules may be seen.
• Slit-lamp examination needed to fully evaluate eye involvement.
• Biopsy: the most easily available involved tissue should be selected (conjunctiva, skin nodule, salivary gland). If no peripheral site is available, hilar lymph nodes may need to be selected; fine-needle aspiration may be successful. Typical findings are well-formed, non-caseating granulomata, with varying degrees of fibrosis.
• TST or TB-Elispot to exclude TB.
There is no single diagnostic test, and making a firm diagnosis can be difficult. The American Thoracic Society (ATS) suggests a combination of:
• a compatible clinical picture;
• histological evidence of non-caseating granulomata;
• exclusion of other conditions, e.g. TB, neoplasm, HP.
• Asymptomatic children with hilar adenopathy caused by sarcoidosis do not need treatment.
• When there is loss of lung function, progressive radiological abnormality, or symptoms, treatment should be started.
• Standard treatment is immunosuppression with oral corticosteroids, usually at 1 mg/kg/day for 4–8 weeks, followed by a weaning regime over 3–6 months. Other immunosuppressants, such as hydroxychloroquine and azathioprine, have been tried in resistant disease.
In older children, the prognosis is usually good, with spontaneous remission in 70%. Ten to 20% have long-term respiratory or other organ impairment. Younger children tend to fare less well.
Storage diseases are a rare cause of lung disease in childhood, and most usually occur after the storage disease has been diagnosed. Occasionally, respiratory illness may be the first manifestation of the illness, e.g. in some cases of NPD.
• Gaucher’s disease (GD) is a multisystem lysosomal storage disease, caused by a genetic defect of the beta-glucosidase enzyme. This results in the accumulation of glucosylceramide in macrophages.
• GD is an autosomal recessive condition, particularly common in the Ashkenazi Jewish population where it has an incidence of 1/1000.
• Three types are recognized. Type 1 (>90% of cases) has no neurological involvement and can present in early childhood, but more often in adolescence. Type 2 disease is characterized by a rapid neurodegeneration, with death by 2 years of age. Type 3 is an intermediate form, with death usually by the age of 15 years.
• The diagnosis is made by the identification of typical Gaucher cells (macrophages filled with glucocerebroside) in the bone marrow or spleen, and by demonstrating a low beta-glucosidase enzyme activity in cultured fibroblasts or leucocytes.
• The typical presentation of type 1 GD includes:
• bruising due to hypersplenism;
• tiredness due to anaemia;
• bone pain;
• Seventy per cent of children and adults with type 1 GD have abnormal lung function tests, showing variable degrees of airways obstruction, reduced lung volumes, and diffusion defects.
• Clinically apparent lung disease is much less common, affecting <10% of patients. It is more common in children who present in early life and who have more severe systemic disease. It is also seen in children with type 2 disease.
• Lung disease can manifest as:
• exercise intolerance;
• hypoxia (sometimes with pulmonary hypertension);
• recurrent pneumonia.
• Respiratory problems may be due to direct lung involvement by GD, or due to hepatopulmonary syndrome, or due to mechanical compression of the lungs by massive hepatosplenomegaly.
• Direct lung involvement usually results in filling of the interstitial and alveolar spaces with Gaucher cells. CT scan of the chest shows diffuse ground-glass opacity, with increased interstitial markings. BAL fluid will contain Gaucher cells.
• The visceral, but not neurological, effects of GD can be reversed by enzyme therapy (recombinant human beta-glucosidase), given by IV infusion 2–4-weekly. The dose of enzyme required to treat lung involvement is higher than that required for other organ systems.
• Bone marrow transplantation is also effective.
• There is one case report of a 10-year-old with type 1 GD who developed progressive lung involvement and underwent successful bilateral lung transplantation, with no recurrence of GD in the graft 5 years after transplantation.2
• Mucopolysaccharidoses (MPS) are characterized by the abnormal tissue deposition of the mucopolysaccharides (now called glucosaminoglycans, GAGs) heparin sulfate, keratin sulfate, and dermatan sulfate. They arise as a result of genetic mutations in lysosomal enzymes that normally metabolize these substrates.
• Nine forms of MPS (MPS-I to MPS-IX) have been described, depending on the nature of the deposited material. A number of eponymous forms are also described, according to the clinical picture.
• Hurler’s syndrome is a severe form of MPS-I. Scheie syndrome is a milder form of MPS-I. Characteristic features include:
• normal appearance at birth; diagnosis between 6 and 24 months;
• coarse facial features and coarse hair;
• corneal clouding;
• developmental delay;
• enlarged tongue;
• skeletal abnormalities: dysostosis multiplex.
• Hunter syndrome is MPS-II and can be mild or severe. It is clinically similar to MPS-I, with the exception of corneal clouding.
• MPS-III, also known as Sanfillipo syndrome, is characterized by a progressive neurological involvement, with relatively mild somatic features.
• MPS-IV, also known as Morquio syndrome, has a predominant involvement of the skeleton. Patients are often very short, but with normal intelligence. Instability of the odontoid process, which is found in most forms of MPS, is particularly severe in MPS-IV and may require stabilizing surgery to prevent a fatal atlanto-axial subluxation, which can, for example, occur as the neck is extended during intubation.
• MPS-V is no longer used. MPS-VI to IX are rare.
The diagnosis is by spot urine analysis for GAGs, followed by lysosomal enzyme assay using fibroblasts or white cells. The clinical severity and life expectancy are variable in all forms of MPS and now also dependent on enzyme replacement where available. MPSs are autosomal recessive, apart from MPS-II (Hunter), which is X-linked.
The respiratory consequences of MPS include the following.
• Upper airway obstruction secondary to the deposition of GAGs in the upper airway and tongue. This is predominantly a problem in children with Hurler’s syndrome and may result in OSA. PSG should be used to identify OSA in at-risk children.
• Restrictive lung deficit. Again this is most marked in children with Hurler’s but can also be seen in severe Hunter syndrome. The restriction can be severe (FVC <40%) and result in exercise intolerance. The cause of the restriction is multifactorial and includes:
• hepatosplenomegaly, which affects diaphragmatic excursion;
• restricted movement at costovertebral joints (GAGs are deposited in joints);
• rib abnormalities;
• deposition of GAGs in the lung interstitium, reducing lung compliance.
• Recurrent respiratory infection. This is predominantly a problem in children with an upper airways obstruction or a restrictive lung disease, or both. It probably represents secondary effects of these conditions on the reduced ability to clear airway secretions. These problems will be compounded, if there is significant neurodisability.
• Children with MPS-I and MPS-II frequently have cardiomyopathy, which can present as acute cardiac failure. The presence of cardiac dysfunction can contribute further to a decreased lung compliance and risk of respiratory infection.
• Night-time nasal CPAP is usually effective in the treatment of OSA. Adenotonsillectomy may be helpful, although great care should be taken to avoid atlanto-axial subluxation during intubation and surgery. Occasionally, a tracheostomy may be required when the upper airway obstruction is severe.
• Cardiac disease should be screened for and treated appropriately.
• Children with recurrent respiratory infection may be helped by chest physiotherapy and prophylactic antibiotics, especially during the winter months. Pneumococcal and influenza vaccination should be used routinely.
• Bone marrow transplant can improve survival in severe Hurler’s syndrome, especially if carried out before the age of 2 years.
• Enzyme replacement is now available for MPS-I and II and results in small improvements (10–15%) in the restrictive lung defect of children with MPS-I.
• NPD is a rare autosomal recessive lysosomal storage disorder that results in the deposition of sphingomyelin and cholesterol in affected tissues, particularly affecting the brain and the reticuloendothelial system.
• Six forms of NPD are recognized. Type A accounts for 85% of cases.
• NPD arises because of a decreased activity of the lysosomal enzyme sphingomyelinase, either directly, because of mutations in the sphingomyelinase gene SMPD1 (NPD type A and B), or indirectly through the effects on enzyme processing as a result of mutations in the NPC1 gene (NPD type C).
• Neurological involvement is seen in types A and C, but not in type B.
• Infants with type A do not develop much beyond the skills of a 10-month-old, have progressive neurodegeneration, and usually die within 5 years, often with bronchopneumonia.
• Children with type B disease have significant hepatosplenomegaly, like children with type A disease, but without neurological impairment.
• Type C disease often presents in school-aged children with ataxia and progressive intellectual impairment.
• The diagnosis of NPD types A and B is made by assaying the sphingomyelinase activity in white blood cells or cultured fibroblasts. Type C disease is diagnosed by studying the cholesterol metabolism in cultured fibroblasts.
• Pulmonary parenchymal involvement can be seen in all forms of NPD but is particularly prominent in type B disease.
• Lung disease usually occurs in the context of an older child or adult who has already been diagnosed with NPD, usually because of hepatosplenomegaly. Rarely, lung disease may occur earlier, sometimes in the first year of life, before hepatosplenomegaly has developed. Thus, NPD should be included in the differential for children who present with ILD.
• The clinical presentation of lung involvement includes breathlessness, recurrent episodes of pneumonia, cough, and haemoptysis. Clinically, type B NPD disease is similar to type 1 GD. Lung disease in NPD can cause progressively worsening hypoxia and respiratory failure.
• Extensive bronchial casts have been described in NPD lung disease, and, when these are combined with interstitial changes, NPD should be considered as a possible diagnosis.
• CT scan may show ground-glass opacities in the upper lung zones, possibly due to partial filling of the alveoli with ‘Pick cells’ and thickening of the interlobular septa.
• If lung function can be measured, it may be normal or, more typically, show a restrictive defect. There is usually a reduced transfer factor, consistent with a diffusion defect.
• BAL will show foamy macrophages.
• Open lung biopsy will show foamy macrophages and thickened alveolar walls. The presence of foamy macrophages may raise the possibility of alveolar proteinosis.
• The main differential for type B NPD disease is type 1 GD, which can have a similar presentation and histological findings.
• Pulmonary involvement in type B NPD is a significant cause of morbidity and mortality.
• Case reports in adults with severe pulmonary involvement suggest that whole-lung lavage may be of benefit in removing large numbers of lipid-laden cells. Bronchial casts may also be cleared by this process. Lung lavage may be less successful in children.
• Hypoxia can develop, requiring long-term supplemental oxygen therapy to prevent cor pulmonale.
• No specific therapy is available for NPD. Bone marrow and liver transplants have been tried for type B disease, with little success.
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Uyan ZS, Karadag B, Ersu R, et al. (2005). Early pulmonary involvement in Niemann–Pick type B disease: lung lavage is not useful. Pediatr Pulmonol 40, 169–72.Find this resource:
• Transfusion-related acute lung injury (TRALI) has a reported incidence rate of 1.8 per 100 000 transfusions in children3 which is lower than that reported in adults (1 in every 2000 transfusions). The serious hazards of transfusion (SHOT) data from the UK and Ireland identified only five cases of TRALI reported in children from 1996 to 2003.
• TRALI is characterized by an ARDS-like illness. There is a rapid onset of respiratory distress, hypoxia, and non-cardiogenic pulmonary oedema during or soon after (within 6 h) a blood transfusion. The diagnosis requires the absence of fluid overload or other identifiable cause of acute lung injury.
• TRALI is probably immune-mediated, possibly related to anti-HLA or anti-granulocyte antibodies in the donor blood. These antibodies are thought to activate host neutrophils within the lung capillaries, leading to capillary leak.
• Donor blood associated with TRALI is usually derived from multiparous women who will have had several exposures to paternal HLA and leucocyte antigens. This group makes up 30% of the donor population. There has been a reduction of immune-mediated TRALI in the UK, following the implementation by the UK Blood Services of a policy of using male donors, as far as possible, for FFP and the plasma contribution to platelet pools.
• CXR shows bilateral pulmonary infiltrates.
• Pulmonary oedema fluid has a high protein content (almost the same as plasma); this test can be used to demonstrate that fluid arises as capillary leak, not because of high left atrial pressure (cardiogenic oedema).
• Cardiac echocardiography can be used to identify evidence of left atrial overload and hence distinguish cardiogenic from non-cardiogenic oedema.
• There may be transient leucopenia, perhaps reflecting the sequestration of white cells in the lung. The WBC count recovers within 24 h of onset.
• Treatment is supportive, including the use of mechanical ventilation.
• It is important to recognize early that the cause is non-cardiogenic. Inappropriate use of diuretics can worsen associated hypotension.
• Systemic steroids are sometimes used, but there is no evidence of benefit, and their use is controversial.
• TRALI usually resolves after 3–4 days.
• Mortality approximately 1–5% in adults. No mortality data available for children.
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Church GD, Price C, Sanchez R, Looney MR (2006). Transfusion-related acute lung injury in the paediatric patient: two case reports and a review of the literature. Transfus Med 16, 343–8.Find this resource:
Serious Hazards of Transfusion. Available at: <http://www.shotuk.org>.
1 Piitulainen E, Sveger T (2002). Respiratory symptoms and lung function in young adults with severe alpha(1)-antitrypsin deficiency (PiZZ). Thorax 57, 705–8
2 Rao AR, Parakininkas D, Hintermeyer M, Segura AD, Rice TB (2005). Bilateral lung transplant in Gauchers type-1 disease. Pediatr Transplant 9, 239–43.
3 Gauvin F, Robillard P, Hume H, et al. (2012). Transfusion-related acute lung injury in the Canadian paediatric population. Paediatr Child Health 17, 235–9