title: Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase-7 (MMP-7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP-7 was predictive of mortality in an independent cohort of IPF patients.
  
  
  
  MMP-7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP-7 threshold of 12.1 ng/mL with all-cause mortality or transplant-free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m-PCMI).
  
  
  
  MMP-7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 ± 6.55 ng/mL vs 6.03 ± 2.51 ng/mL, P < 0.001). The plasma MMP-7 threshold of 12.1 ng/mL was significantly associated with both all-cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91-61.23 and 5.41-44.34, respectively, P < 0.001). MMP-7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP-7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DLCO) (r = -0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DLCO(r = 0.32, P = 0.001).
  
  
  
  This study confirms that MMP-7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied.
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Argyris
authors.initials: A
authors.lastname: Tzouvelekis
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jose D
authors.initials: JD
authors.lastname: Herazo-Maya
authors.affiliation: Department of Occupational and Environmental Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Slade
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jen-Hwa
authors.initials: JH
authors.lastname: Chu
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Deiuliis
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Changwan
authors.initials: C
authors.lastname: Ryu
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ibarra
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Pan
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Antin-Ozerkis
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
authors.affiliation: Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000097:blood* / Q000401:mortality* / Q000503:physiopathology / Q000601:surgery; D016040:Lung Transplantation; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000097:blood*; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011653:Pulmonary Diffusing Capacity; D015203:Reproducibility of Results; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D020783:Matrix Metalloproteinase 7
keywords: heparin plasma; idiopathic pulmonary fibrosis; matrix metalloproteinase-7; prognostic biomarker