Secondary pulmonary alveolar proteinosis mimicking progression of interstitial lung disease during treatment for adult-onset still’s disease

Rationale: Secondary pulmonary alveolar proteinosis (sPAP) is a rare disorder caused by impaired surfactant clearance due to alveolar macrophage dysfunction and is often associated with hematologic disorders or immunosuppressive therapy. In patients with connective tissue disease–associated interstitial lung disease (CTD-ILD), worsening respiratory findings are frequently interpreted as progression of the underlying ILD, which may delay recognition of sPAP, particularly when anti–granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies are negative. In the present case, preexisting ILD and repeated bronchoscopic findings of organizing pneumonia further obscured the development of sPAP, making the diagnosis particularly challenging. Patient concerns: A 68-year-old woman with adult-onset Still’s disease (AOSD)–associated ILD developed progressive respiratory deterioration during immunosuppressive therapy. Despite apparent control of AOSD-related systemic inflammation, serum Krebs von den Lungen-6 (KL-6) levels increased markedly, and new diffuse ground-glass opacities appeared on chest computed tomography. Diagnoses: Repeated bronchoscopic examinations demonstrated organizing pneumonia without features suggestive of PAP, supporting the interpretation of progressive CTD-ILD. However, KL-6 levels progressively increased to 19,333 IU per liter despite treatment, raising suspicion of PAP. Anti–GM-CSF antibody testing was negative, and a definitive diagnosis could not be established during life. Autopsy ultimately revealed sPAP with periodic acid–Schiff–positive intra-alveolar material and myelodysplastic syndrome (MDS). Hematologic abnormalities had initially been attributed to systemic inflammation, and subsequent bone marrow examination showed MDS-like dysplasia without establishing a definitive diagnosis of MDS. Interventions: The patient received escalating immunosuppressive therapies, including a Janus kinase inhibitor, under the assumption of progressive CTD-ILD, with the aim of minimizing glucocorticoid exposure. Outcomes: Respiratory failure progressed despite treatment, and bronchoscopy was not feasible in the terminal stage. The patient died of respiratory failure. Postmortem examination confirmed sPAP and MDS. Lessons: In patients with CTD-ILD receiving immunosuppressive therapy, marked and progressive elevation of KL-6 should prompt reconsideration of the diagnosis, even when bronchoscopy does not demonstrate PAP and anti–GM-CSF antibodies are negative. Early recognition is essential to avoid inappropriate intensification of immunosuppression and further impairment of alveolar macrophage function.