Surfactant protein C dysfunction with new clinical insights for diffuse alveolar hemorrhage and autoimmunity

Abstract

Importance: Surfactant protein C (SP-C) dysfunction is a rare disease associated with interstitial lung disease. Early therapies may improve outcomes but the diagnosis is often delayed owing to variability of manifestations.

Objective: To investigate the manifestations and outcomes of SP-C dysfunction.

Methods: We retrospectively analyzed the records of five pediatric patients who were diagnosed with SP-C dysfunction between February 2014 and April 2017 at Beijing Children's Hospital.

Results: The five patients included two boys and three girls with a median age at diagnosis of 1.3 years. All patients presented with interstitial lung disease and had a heterozygous SFTPC mutation, including an I73T mutation in three patients, a V39L mutation in one patient, and a Y104H mutation in one patient. In addition to common respiratory manifestations, hemoptysis and anemia were observed in one patient with the I73T mutation. Elevated levels of autoantibodies and a large number of hemosiderin-laden macrophages in bronchoalveolar lavage fluid were found in two patients with the I73T mutation, suggesting the presence of diffuse alveolar hemorrage and autoimmunity. Chest high-resolution computed tomography features included ground-glass opacities, reticular opacities, cysts, and pleural thickening. Transbronchial lung biopsy was performed in one patient with the I73T mutation, which revealed the presence of some hemosiderin-laden macrophages in alveolar spaces. All patients received treatment with corticosteroids; two received combined treatment with hydroxychloroquine. During follow-up, the two patients who received hydroxychloroquine showed improved symptoms; of the remaining three patients, two died after their families refused further treatment, while the final patient was lost to follow-up.

Interpretation: This is the first report to describe a new phenotype of diffuse alveolar hemorrhage with autoimmunity in patients with I73T SFTPC mutation. Treatment with hydroxychloroquine should be considered for patients with SP-C dysfunction.

Keywords: Autoimmunity; Diffuse alveolar hemorrhage; Interstitial lung disease; Rheumatoid arthritis; Surfactant protein C.

Figure 1

Chest high‐resolution computed tomography (HRCT) of patients with surfactant protein C dysfunction. (A) HRCT of Patient 1 before treatment shows bilateral diffuse ground‐glass opacities. (B) HRCT of Patient 2 before treatment shows bilateral diffuse ground‐glass opacities. (C) HRCT of Patient 2 three years later after the treatment of prednisone and hydroxychloroquine shows bilateral reticular opacities and improvement of ground‐glass opacities. (D) HRCT of Patient 3 before treatment shows bilateral diffuse ground‐glass opacities. (E) HRCT of Patient 4 before treatment shows bilateral diffuse cysts and reticular opacities. (F) HRCT of Patient 5 before treatment shows bilateral diffuse ground‐glass opacities with cysts

Figure 2

Lung pathological findings of one patient with surfactant protein C dysfunction. (A) Transbronchial lung biopsy (Hematoxylin‐eosin stain; magnification ×20) of Patient 2 reveals thickened alveolar septum with mild infiltration of lymphocytes. (B) Transbronchial lung biopsy (Iron stain; magnification ×20) of Patient 2 reveals some hemosiderin‐laden macrophages in alveolar spaces (staining blue)