Secondary Pulmonary Alveolar Proteinosis Development during the Treatment for Anti-aminoacyl-tRNA Synthetase Antibody-positive Interstitial Lung Disease

Abstract

A 70-year-old woman with anti-aminoacyl-tRNA synthetase (ARS) antibody-positive interstitial lung disease (ARS-ILD) received daily medications and regular cyclophosphamide cycles for recurring exacerbations. Approximately four years after immunosuppression initiation, the patient was admitted for progressive dyspnea on exertion. Chest computed tomography (CT) findings were suggestive of acute exacerbation. Despite intensified immunosuppressive treatment, the radiographic findings worsened, and serum Krebs von den Lungen-6 (KL-6) levels increased. A bronchoalveolar lavage fluid (BALF) examination revealed amorphous globules and alveolar macrophages with eosinophilic granules. Owing to negative anti-granulocyte-macrophage colony-stimulating factor antibody tests, a diagnosis of secondary pulmonary alveolar proteinosis (PAP) was established.

Keywords: anti-aminoacyl-tRNA synthetase antibody-positive interstitial lung disease; immunosuppressants; secondary pulmonary alveolar proteinosis; steroid.

Figure 1.

Chest CT in June 2018 revealed bilateral lower lung-predominant peribronchovascular GGOs and consolidation (A). Approximately five months after initiating corticosteroid and immunosuppressive treatment, chest CT showed improvement (B). However, lower lung-predominant diffuse GGOs or reticular opacities with interlobular septa thickness were observed in June 2022 (C). CT: computed tomography, GGOs: ground-glass opacities

Figure 2.

Clinical course. After the diagnosis of ARS-ILD, prednisolone and tacrolimus were initiated. Although the ILD of the patient was temporarily exacerbated, the disease was controlled with high-dose PSL and monthly intravenous cyclophosphamide treatment. The DOE worsened after 47 months of treatment, and mPSL 1,000 mg was administered. However, her symptoms did not improve, and KL-6 levels increased markedly. Bronchoscopy was performed to diagnose secondary PAP. The PSL dose was gradually tapered to 6 mg, and the KL-6 levels decreased. She died of ILD exacerbation 10 months after the secondary PAP diagnosis. ARS-ILD: anti-aminoacyl-tRNA synthetase antibody-positive interstitial lung disease, DOE: dyspnea on effort, ILD: interstitial lung disease, KL-6: Krebs von den Lungen-6 (a biomarker for interstitial pneumonia), mPSL: methylprednisolone, PSL: prednisolone, SPAP: secondary pulmonary alveolar proteinosis

Figure 3.

Cytological findings of bronchoalveolar lavage fluid obtained in July 2022. A-C: A cytological examination showed D-PAS-staining-positive amorphous globules and macrophages phagocytizing granular material. D: In addition, foamy alveolar macrophages were detected. (A: D-PAS-staining ×1,000, B: D-PAS staining ×1,000, C: Papanicolaou staining ×400, D: Giemsa staining ×1,000). D-PAS: diastase-periodic acid-Schiff

Figure 4.

Autopsy findings of the lung. A: Most specimens were found to have hyaline membranes along alveolar septa, indicating the exudative phase of diffuse alveolar damage. B-D: A small portion of the left lower lobe specimen was found to have PAS-positive amorphous globules and macrophages with engulfed granular material [A: Hematoxylin and Eosin (H&E) staining ×200, B: PAS ×100, C: PAS ×2,000, D: H&E staining ×2,000].