Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis.
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course.


OBJECTIVE
The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF.


METHODS
Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested.


RESULTS
High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort.


CONCLUSIONS
Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.
The Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh Medical Center, NW 628 MUH, 3459 5th Avenue, Pittsburgh, PA 15261, USA.
Thomas J
TJ
Richards
Naftali
N
Kaminski
Fred
F
Baribaud
Susan
S
Flavin
Carrie
C
Brodmerkel
Daniel
D
Horowitz
Katherine
K
Li
Jiin
J
Choi
Louis J
LJ
Vuga
Kathleen O
KO
Lindell
Melinda
M
Klesen
Yingze
Y
Zhang
Kevin F
KF
Gibson
D000368:Aged; D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000097:blood*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood* / Q000401:mortality*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000097:blood; D020783:Matrix Metalloproteinase 7 / Q000097:blood; D020782:Matrix Metalloproteinases / Q000097:blood*; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D009418:S100 Proteins / Q000097:blood*; D000067616:S100A12 Protein; D016019:Survival Analysis; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016209:Interleukin-8; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D020782:Matrix Metalloproteinases; D020783:Matrix Metalloproteinase 7; D020781:Matrix Metalloproteinase 1