Plasma Surfactant Protein-D, Matrix Metalloproteinase-7, and Osteopontin Index Distinguishes Idiopathic Pulmonary Fibrosis from Other Idiopathic Interstitial Pneumonias

Am J Respir Crit Care Med. 2016 Nov 15;194(10):1242-1251. doi: 10.1164/rccm.201505-0862OC.


Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs.

Objectives: To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD.

Methods: We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes.

Measurements and main results: Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002).

Conclusions: A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.

Keywords: biomarker; fibrosis; plasma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biomarkers / blood
  • Cohort Studies
  • Diagnosis, Differential
  • Female
  • Humans
  • Idiopathic Interstitial Pneumonias / blood
  • Idiopathic Pulmonary Fibrosis / blood*
  • Male
  • Matrix Metalloproteinase 7 / blood*
  • Middle Aged
  • Osteopontin / blood*
  • Pulmonary Surfactant-Associated Protein D / blood*
  • ROC Curve
  • Sensitivity and Specificity


  • Biomarkers
  • Pulmonary Surfactant-Associated Protein D
  • Osteopontin
  • Matrix Metalloproteinase 7