Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts

• Published in: American journal of respiratory and critical care medicine Vol. 210; no. 4; pp. 455 - 464
• Main Authors: Maddali, Manoj V, Moore, Andrew R, Sinha, Pratik, Newton, Chad A, Kim, John S, Adegunsoye, Ayodeji, Ma, Shwu-Fan, Strek, Mary E, Chen, Ching-Hsien, Linderholm, Angela L, Zemans, Rachel L, Moore, Bethany B, Wolters, Paul J, Martinez, Fernando J, Rogers, Angela J, Raj, Rishi, Noth, Imre, Oldham, Justin M
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 15.08.2024
• Subjects: Aged; Biomarkers - blood; Clinical outcomes; Cohort Studies; Female; Humans; Idiopathic Pulmonary Fibrosis - blood; Idiopathic Pulmonary Fibrosis - mortality; Latent Class Analysis; Male; Medical treatment; Middle Aged; Pathophysiology; Prospective Studies; Pulmonary fibrosis; idiopathic pulmonary fibrosis; latent class analysis; endotype; antifibrotic
• ISSN: 1073-449X; 1535-4970; 1535-4970
• DOI: 10.1164/rccm.202402-0339OC

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. To identify and validate biologically driven molecular endotypes of IPF. Latent class analysis (LCA) was independently performed in prospectively recruited discovery (  = 875) and validation (  = 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 (  = 555). LCA independently identified two latent classes in both cohorts (  < 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;  < 0.001; validation, HR, 1.95; 95% CI, 1.34-2.82;  < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (  = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45-0.93;  = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77-1.84;  = 0.422). 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.