• Laurens J De Sadeleer, Stijn E Verleden, Jonas C Schupp, John E McDonough, Tinne Goos, Jonas Yserbyt, Elena Bargagli, Paola Rottoli, Naftali Kaminski, Antje Prasse, and Wim A Wuyts.
• Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department CHROMETA, KU Leuven, Leuven, Belgium; Unit of Interstitial Lung Diseases, Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium. Electronic address: laurens.desadeleer@kuleuven.be.
• Chest. 2022 Jun 1; 161 (6): 157615881576-1588.

BackgroundGiven the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another.Research QuestionDo IPF endotypes exist and are they associated with outcome?Study Design And MethodsUsing a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples.ResultsOne hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes.InterpretationGene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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