Diagnostic and Prognostic Value of Serum Surfactant Protein D in Interstitial Lung Disease: A Systematic Review

Serum surfactant protein D (SP-D), secreted by alveolar type II pneumocytes, leaks into the circulation during alveolar epithelial injury, making it a candidate biomarker for interstitial lung disease (ILD). This systematic review appraises its contemporary diagnostic and prognostic value across ILD subtypes. PubMed, Scopus, Web of Science, and Embase were searched for original studies published from 2021 to 2025 reporting serum SP-D in adult ILD patients. Study selection, data extraction, and quality assessment (Newcastle-Ottawa Scale) followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Narrative synthesis was performed because of heterogeneity in populations, assay platforms, and outcomes. Ten studies enrolling 4,179 participants were included. Serum SP-D was significantly elevated in ILD versus controls in most studies, with diagnostic area under the curve values of 0.65-0.89. It correlated with forced vital capacity, diffusing capacity of the lungs for carbon monoxide, and radiological extent across phenotypes, and independently predicted progression in rheumatoid arthritis-associated ILD (hazard ratio = 1.003; p = 0.008). In acute exacerbation, SP-D uniquely correlated with coagulation markers, suggesting a distinct pathobiological role not captured by Krebs von den Lungen-6 (KL-6). Prognostic utility was limited in antifibrotic-treated idiopathic pulmonary fibrosis. KL-6 outperformed SP-D as a standalone marker, but SP-D provided complementary, non-redundant value in multi-biomarker strategies. Serum SP-D is a clinically relevant biomarker of alveolar injury in ILD, best utilised within multi-marker panels. Assay standardisation and prospective validation of SP-D-inclusive biomarker strategies remain priorities for future research.