BAL Cell Gene Expression is Indicative of Outcome and Airway Basal Cell Involvement in IPF
Prasse A, Binder H, Schupp JC, Kayser G, Bargagli E, Jaeger B, Hess M, Rittinghausen S, Vuga L, Lynn H, Violette S, Jung B, Quast K, Vanaudenaerde B, Xu Y, Hohlfeld JM, Krug N, Herazo-Maya JD, Rottoli P, Wuyts WA, Kaminski N.
Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a variable and unpredictable course.
Objective: We designed this study to determine whether bronchoalveolar lavage (BAL) cell gene expression is predictive of survival in IPF.
Methods: Retrospective study analyzing the BAL transcriptome of three independent IPF cohorts: Freiburg (Germany), Siena (Italy) and Leuven (Belgium) including 212 patients. BAL cells from 20 healthy volunteers, 26 patients with sarcoidosis stage III or IV, and 29 patients with COPD were used as controls. Survival analysis was performed by Cox models and component-wise boosting. Presence of airway basal cells was tested by immunohistochemistry and flow cytometry.
Measurements and main results: 1582 genes were predictive of mortality in the IPF derivation cohort in univariate analyses adjusted for age and sex at FDR < 0.05. A nine-gene signature, derived from the discovery cohort (Freiburg), performed well in both replication cohorts, Siena (p < 0.0032) and Leuven (p = 0.0033). nCounter® expression analysis confirmed the array results (p < 0.0001). The genes associated with mortality in BAL cells were significantly enriched for genes expressed in airway basal cells. Further analyses by gene expression, flow cytometry and immunohistochemistry showed an increase in airway basal cells in BAL and tissues of IPF compared to controls, but not in COPD or sarcoidosis.
Conclusions: Our results identify and validate a BAL signature that predicts mortality in IPF and improves the accuracy of outcome prediction based on clinical parameters. The BAL signature associated with mortality unmasks a potential role of airway basal cells in IPF.