Secondary pulmonary alveolar proteinosis mimicking progression of interstitial lung disease during treatment for adult-onset still's disease: An autopsy case report.

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.