Approaching Clinical Trials in Childhood Interstitial Lung Disease and Pediatric Pulmonary Fibrosis

Abstract

Childhood interstitial lung disease (chILD) comprises a spectrum of rare diffuse lung disorders. chILD is heterogeneous in origin, with different disease manifestations occurring in the context of ongoing lung development. The large number of disorders in chILD, in combination with the rarity of each diagnosis, has hampered scientific and clinical progress within the field. Epidemiologic and natural history data are limited. The prognosis varies depending on the etiology, with some forms progressing to lung transplant or death. There are limited treatment options for patients with chILD. Although U.S. Food and Drug Administration-approved treatments are now available for adult patients with idiopathic pulmonary fibrosis, no clinical trials have been conducted in a pediatric population using agents designed to treat lung fibrosis. This review will focus on progressive chILD disorders and on the urgent need for meaningful objective outcome measures to define, detect, and monitor fibrosis in children.

Keywords: child; interstitial; lung diseases; rheumatologic; surfactant.

Figure 1.

Chest computed tomography (CT) findings in patients with childhood interstitial lung disease. (A) Axial CT image from a 10-year-old girl with systemic sclerosis, showing minimal areas of ground-glass attenuation, septal thickening, and peripheral honeycombing. (B) Axial CT images from a patient with juvenile systemic sclerosis. The left panel shows reticular and ground-glass opacities at the periphery when the patient was 12 years of age; the right panel shows that clusters of cysts have developed along the periphery in the same patient at 18 years of age. (C) Axial CT image from a 16-year-old girl with systemic lupus erythematosus, showing large areas of ground-glass attenuation superimposed on interlobular septal thickening (“crazy paving”). The right panel shows a high-resolution CT image from a 15-year-old girl with systemic lupus erythematosus and lupus pneumonitis showing a similar pattern. (D) CT scans from an 18-year-old with a genetic SPC (C460 + 1 G→A) showing reticular opacity, honeycombing, traction bronchiectasis, architectural distortion, and cystic opacity (without walls). This is not a typical adult pulmonary fibrosis pattern. A and C are reprinted from Reference by permission from the Radiological Society of North America. B is reprinted from Reference by permission from Elsevier.

Figure 2.

Epithelial injury hypothesis of idiopathic pulmonary fibrosis. Reprinted from Reference .

Figure 3.

(A) Mechanism of lung inflammation and remodeling in an SFTPC (surfactant protein C) BRICHOS mutant mouse model with cytokines from childhood interstitial lung disease (chILD) (54). A critical substitution at C121G (cysteine-to-glycine substitution at codon 121) in the SFTPC gene identified in a patient with chILD, when expressed in adult mice, resulted in an endoplasmic reticulum (ER)-retained proprotein and alveolar type 2 (AT2) cell ER stress. AT2-cell–derived cytokines in the mouse model were identified in BAL fluid (BALF) supernatants from patients with chILD, and STPF^C121G mice developed pulmonary fibrosis (54). (B and C) Histopathologic figure of lung specimens from two patients with SFTPC mutations at (B) 21 months of age, demonstrating chronic pneumonitis of infancy, and (C) 21 years of age with advanced fibrotic disease. ^aNon-AT2 source. ^bComp. UPR = unfolded protein response.