Childhood Interstitial Lung Disease

Childhood interstitial lung disease is a heterogeneous group of more than 200 rare disorders that affect the lung parenchyma and impair gas exchange, with diffuse changes on imaging. Many arise in infancy, and they differ from adult forms in cause and course.

The prevalence is about 1 to 4 in 100 000 children, and the true frequency is uncertain because of underdiagnosis. Causes include disorders more specific to infancy (diffuse developmental disorders, growth abnormalities, neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis, and surfactant dysfunction from SFTPB, SFTPC, ABCA3 and NKX2-1 variants) and disorders in older children (hypersensitivity pneumonitis, connective tissue disease, aspiration, infection, drug reactions, sarcoidosis, vasculitis and histiocytosis).

Pathophysiology

Injury to alveolar epithelium or endothelium, abnormal surfactant metabolism, or abnormal lung growth leads to inflammation and fibrosis of the interstitium, thickening the gas exchange barrier.

Lung compliance falls, ventilation perfusion mismatch develops and hypoxaemia follows. Pulmonary hypertension and respiratory failure develop in advanced disease.

• Tachypnoea, increased work of breathing, chronic cough, and exercise intolerance.
• Hypoxaemia at rest or on exertion, crackles, and in infants poor feeding and failure to thrive.
• Digital clubbing, chest deformity and signs of pulmonary hypertension in advanced disease.

Red flags.

• Unexplained hypoxaemia or respiratory failure in a term newborn (surfactant protein disorders).
• Family history of interstitial lung disease or neonatal respiratory distress.
• Rapid deterioration, haemoptysis, or features of systemic disease (rash, arthritis, renal disease).

• Diagnosis is made when at least three of these four are present: respiratory symptoms (cough, rapid breathing, exercise intolerance), signs (tachypnoea, crackles, retractions, clubbing, failure to thrive, respiratory failure), hypoxaemia, and diffuse abnormalities on chest imaging, after exclusion of other disease.
• First exclude cystic fibrosis, primary ciliary dyskinesia, infection, immune deficiency, congenital heart disease (with echocardiography), aspiration and bronchopulmonary dysplasia.
• High resolution CT of the chest with controlled ventilation or sedation. Ground glass change, cysts, septal thickening or mosaic attenuation can suggest the diagnosis, for example central and right middle lobe and lingular ground glass in neuroendocrine cell hyperplasia of infancy.
• Bronchoalveolar lavage (cells, culture, siderophages), genetic testing for surfactant and other genes, autoimmune and vasculitis serology, precipitins, and lung function.
• Lung biopsy (thoracoscopic or open) if the diagnosis remains unclear and results would change management.

Differential diagnosis. Pulmonary infection, bronchopulmonary dysplasia, congenital heart disease with pulmonary oedema, aspiration, pulmonary haemorrhage syndromes, cystic fibrosis, immune deficiency and pulmonary vascular disease.

Supportive care.

• Oxygen to keep saturation 92% or over (higher in pulmonary hypertension), nutritional support, immunisation (including influenza and pneumococcal vaccines), prompt treatment of infection, and avoidance of smoke.
• Treat pulmonary hypertension and aspiration where present. Palliative care input for severe disease.

Disease directed therapy (evidence is limited and should be under specialist direction).

• Methylprednisolone IV pulses 10 mg/kg/day (maximum 500 mg) for 3 consecutive days each month, or oral prednisolone 1 to 2 mg/kg/day, tapered to the lowest effective dose.
• Hydroxychloroquine 10 mg/kg/day (maximum 400 mg) or azithromycin 10 mg/kg 3 times weekly as steroid sparing agents, with monitoring for retinal toxicity.
• Neuroendocrine cell hyperplasia of infancy is managed with supportive care. Steroids are not usually helpful, and most improve with age.
• Hypersensitivity pneumonitis: remove the antigen and give prednisolone 1 to 2 mg/kg/day, tapered.
• Lung transplantation for end stage disease, especially in surfactant protein B deficiency.

Monitoring. Oxygen saturation, growth, lung function, imaging, echocardiography and drug toxicity. Review every 3 months at first.

Referral and escalation. Early referral to a specialist centre for any suspected case, because diagnostic testing, genetic counselling and therapy need multidisciplinary expertise.