| Autor: |
Maddali MV; Division of Pulmonary, Allergy, and Critical Care Medicine and.; Department of Biomedical Data Science, Stanford University, Stanford, California., Moore AR; Division of Pulmonary, Allergy, and Critical Care Medicine and., Sinha P; Division of Clinical and Translational Research, Washington University School of Medicine, St. Louis, Missouri.; Division of Critical Care, Department of Anesthesia, Washington University, St. Louis, Missouri., Newton CA; Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas., Kim JS; Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia., Adegunsoye A; Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois., Ma SF; Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia., Strek ME; Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois., Chen CH; Division of Pulmonary and Critical Care Medicine, University of California, Davis, Davis, California., Linderholm AL; Division of Pulmonary and Critical Care Medicine, University of California, Davis, Davis, California., Zemans RL; Division of Pulmonary and Critical Care Medicine., Moore BB; Division of Pulmonary and Critical Care Medicine.; Department of Microbiology and Immunology, and., Wolters PJ; Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, San Francisco, California; and., Martinez FJ; Division of Pulmonary and Critical Care Medicine, Cornell University, New York, New York., Rogers AJ; Division of Pulmonary, Allergy, and Critical Care Medicine and., Raj R; Division of Pulmonary, Allergy, and Critical Care Medicine and., Noth I; Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia., Oldham JM; Division of Pulmonary and Critical Care Medicine.; Department of Epidemiology, University of Michigan, Ann Arbor, Michigan. |
| Abstrakt: |
Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery ( n = 875) and validation ( n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement ( n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts ( P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64-2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34-2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes ( P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45-0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77-1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials. |
