Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease

Abstract

Background: Childhood interstitial lung disease (chILD) encompasses a group of rare heterogeneous respiratory conditions associated with significant morbidity and mortality. Reports suggest that many patients diagnosed with chILD continue to have potentially progressive or fibrosing disease into adulthood. Over the last decade, the spectrum of conditions within chILD has widened substantially, with the discovery of novel entities through advanced genetic testing. However, most evidence is often limited to small case series, with reports disseminated across an array of subspecialty, clinical and molecular journals. In particular, the frequency, management and outcome of paediatric pulmonary fibrosis is not well characterised, unlike in adults, where clear diagnosis and treatment guidelines are available.

Methods and results: This review assesses the current understanding of pulmonary fibrosis in chILD. Based on registry data, we have provisionally estimated the occurrence of fibrosis in various manifestations of chILD, with 47 different potentially fibrotic chILD entities identified. Published evidence for fibrosis in the spectrum of chILD entities is assessed, and current and future issues in management of pulmonary fibrosis in childhood, continuing into adulthood, are considered.

Conclusions: There is a need for improved knowledge of chILD among pulmonologists to optimise the transition of care from paediatric to adult facilities. Updated evidence-based guidelines are needed that incorporate recommendations for the diagnosis and management of immune-mediated disorders, as well as chILD in older children approaching adulthood.

Keywords: Connective tissue disease associated lung disease; Drug induced Lung Disease; Interstitial Fibrosis; Paediatric Lung Disaese; Paediatric interstitial lung disease; Rare lung diseases; Surfactant protein; Systemic disease and lungs.

Figure 1. Findings of paediatric pulmonary fibrosis on lung histology. (A) Fibrotic NSIP with uniform expansion of alveolar septa by collagen (arrows) in a 20-month-old with an SFTPC mutation (H&E). (B) UIP pattern in an adolescent with an ABCA3 mutation consists of patchy dense fibrosis accentuated in the subpleural space with honeycomb cystic remodelling (*enlarged, irregular airspaces, H&E) and fibroblastic foci (insert (see arrow heads), Movat stain).(C) Focal dense periairway fibrosis (arrow) is present in a child with restrictive lung disease after bone marrow transplant (Movat stain). (D) Lobular remodelling in a child with NKX2.1 deficiency is characterised by cystic bronchiolar metaplasia (*) interspersed by bands of smooth muscle (arrows; H&E). ABCA3, adenosine triphosphate-binding cassette subfamily A member 3; NSIP, non-specific interstitial pneumonia; NKX2.1, NK2 homeobox 1; SFTPC, surfactant protein C; UIP, usual interstitial pneumonia.

Figure 2. Findings of paediatric pulmonary fibrosis on chest CT. (A) Reticular opacity consisting of mesh/net-like opacities associated with traction bronchiectasis with irregular bronchiolar dilation (yellow arrows) in an 11-year-old with a history of ARDS. (B) Honeycombing consisting of clustered enlarged airspaces with defined walls in a 15-year-old male with chILD of unknown aetiology. (C) Architectural distortion with deformation of the fissures, parenchymal bands consisting of irregular linear opacities, some of which extend to the pleural surface (yellow arrows) and traction bronchiectasis (red arrow) in a 19-year-old female with post-COVID-19 fibrosis. (D) Cystic lucencies with rounded areas of decreased density without defined wall (yellow arrows) in a 10-year-old patient with an ABCA3 mutation. ABCA3, adenosine triphosphate-binding cassette subfamily A member 3; ARDS, acute respiratory distress syndrome; chILD, childhood interstitial lung disease.

Figure 3. Lung histology findings of children with specific chILD entities. (A) Cellular and fibrotic NSIP seen in an adolescent later diagnosed with polymyositis (H&E).(B) Child with SAVI has dense interstitial fibrosis and occlusive airway fibrosis (Movat stain).(C) Peribronchiolar fibrosis with isolated multinucleated giant cells (arrows) in a child with hypersensitivity pneumonitis (H&E). chILD, childhood interstitial lung disease; NSIP, non-specific interstitial pneumonia; SAVI, stimulator of interferon genes-associated vasculopathy of infancy.

Figure 4. CT patterns of children with specific chILD entities. (A) SFTPC mutation in a 6-year-old with reticular opacities and cystic lucencies (yellow arrows) on axial CT image. (B) SAVI in a patient aged 7 years, with diffuse ground glass and reticular opacities with large cystic lesions on axial CT image. (C) COPA syndrome in a 13-year-old with diffuse reticular opacities and cystic lucencies (yellow arrows). (D, E) PPFE in a 15-year-old with papillary thyroid cancer with pleural thickening (red arrows), septal thickening, yellow arrows, traction bronchiectasis (green arrows) and pneumothorax (blue arrows) on (D) axial and (E) coronal images. COPA, coatomer protein subunit alpha; SAVI, stimulator of interferon genes-associated vasculopathy of infancy, SFTPC, surfactant protein C gene.