Interstitial lung disease biomarkers: a systematic review and meta-analysis

High-resolution CT and pulmonary function tests remain the standard for diagnosing fibrotic interstitial lung diseases (ILDs) butare limited by radiation exposure, access, and inter-observer variability. Blood-based biomarkers could enable earlier, less invasive diagnosis and monitoring. We therefore evaluated the diagnostic accuracy of biomarkers, specifically Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D), in distinguishing fibrotic ILDs from healthy individuals or non-fibrotic respiratory conditions.

A systematic review and bivariate random-effects meta-analysis were conducted, comparing serum or bronchoalveolar lavage fluid levels of KL-6, SP-A, or SP-D against histopathology or high-resolution computed tomography (HRCT). Diagnostic accuracy was assessed using sensitivity, specificity, and heterogeneity (I²). Subgroup analyses examined disease subtypes, control groups, and biomarker cutoffs.

Nineteen studies involving 3,320 participants were included. KL-6 (16 studies, 3,006 participants) had a pooled sensitivity of 0.74 (95 % CI: 0.67-0.80) and specificity of 0.90 (95 % CI: 0.85-0.93). SP-D (11 studies, 1,167 participants) showed a sensitivity of 0.73 (95 % CI: 0.66-0.79) and specificity of 0.78 (95 % CI: 0.69-0.86). SP-A (five studies, 671 participants) had a sensitivity of 0.71 (95 % CI: 0.51-0.85) and specificity of 0.91 (95 % CI: 0.67-0.98). Subgroup analysis showed significantly reduced diagnostic performance in autoimmune-associated ILDs versus idiopathic interstitial pneumonia (e.g., KL-6 specificity 0.87 vs. 0.98; P = 0.015).

KL-6 and SP-A demonstrated high specificity and moderate sensitivity, supporting their use to rule in fibrotic ILDs. Diagnostic accuracy was lower in autoimmune interstitial lung diseases (ILDs), suggesting that tailored thresholds or combined testing may be necessary.