CYFRA 21-1 as a disease severity marker for autoimmune pulmonary alveolar proteinosis

Abstract

Background and objective: Serum markers, including Krebs von den Lungen (KL-6), surfactant protein (SP)-D, SP-A and carcinoembryonic antigen (CEA), are reported to reflect autoimmune pulmonary alveolar proteinosis (APAP) disease severity. We evaluated serum CYFRA21-1 levels as a marker of APAP.

Methods: In addition to KL-6, SP-D and CEA, we prospectively measured serum CYFRA 21-1 levels in 48 patients with APAP, consecutively diagnosed between 2002 and 2010. Diagnostic usefulness of CYFRA 21-1 was determined from 68 patients with interstitial lung diseases by receiver operator characteristic curve analysis. We evaluated the association between these serum markers and other disease severity markers, including pulmonary function parameters, alveolar-arterial oxygen gradient, British Medical Research Council score reflecting shortness of breath, and disease severity score. CYFRA 21-1 localization in the lung was examined by immunohistochemistry.

Results: Receiver operator characteristic curve demonstrated that CYFRA 21-1 effectively identified APAP. Serum CYFRA 21-1 levels at diagnosis were significantly associated with the measured disease severity parameters. Following whole lung lavage (n = 10) and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation (n = 20), serum CYFRA 21-1 levels were significantly decreased. Responders (n = 11) to GM-CSF inhalation revealed significantly higher serum CYFRA 21-1 levels than non-responders (n = 9). Serum CYFRA 21-1 appeared to be a significant predictor of effectiveness of GM-CSF based on regression analysis. Immunohistochemistry showed that CYFRA 21-1 was localized on hyperplastic alveolar type II cells and lipoproteinaceous substances in alveoli.

Conclusions: Serum CYFRA 21-1 is a sensitive and useful serum marker for diagnosis and evaluation of disease severity of APAP, and may predict the response to GM-CSF inhalation.

Keywords: alveolar epithelial hyperplasia; granulocyte-macrophage colony-stimulating factor; inhalation therapy; rare lung disease; whole lung lavage.