A93-09 Interstitial Lung Diseases Share Overlapping Immune Phenotypes Associated With Survival

Abstract Rationale Interstitial lung diseases (ILD) are a heterogeneous group of pulmonary syndromes with unpredictable disease progression and limited treatment options. Emerging data indicate distinct immunologic phenotypes in idiopathic and non-idiopathic pulmonary fibrosis. Our understanding of these immune subtypes is limited. Methods Bulk mRNA sequencing of whole blood was performed on patients enrolled in the Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Hierarchical clustering using Ward’s D linkage criterion was used to identify transcriptionally distinct sample clusters. The association between cluster membership and time to the composite end point of death or transplantation was assessed using a Cox proportional hazards model that included age, percent predicted forced vital capacity (ppFVC), sex, smoking history, and usual interstitial pneumonia (UIP) pattern. Because cluster membership, age, and ppFVC violated the proportional hazards assumption, we used a reference-patient approach to visualize the effect of cluster membership while using time-varying modeling to assess baseline hazard ratios for cluster membership. In the reference-patient approach, all covariates except the cluster were fixed at representative values (mean age, mean ppFVC, male sex, positive smoking history, and definite/probable UIP pattern). Results 899 patients were included in the analysis. Predicted survival curves for the reference patient demonstrated apparent differences across clusters. Median predicted survival in Cluster 1 was 34 months, compared to 24 and 19 months in Clusters 2 and 3, respectively (Figure 1-A). Clusters 2 and 3 demonstrated an increased baseline hazard ratio that attenuated over time (Cluster 2 HR = 3.99, p 0.001, 95% CI 1.78-8.94; Cluster 3 HR = 7.68, p 0.001, 95% CI 2.89-20.4) (Figure 1-B). Clusters were distinct with respect to sex distribution, baseline lung function, ILD subtype, and fibrosis pattern (Figure 1-C). Conclusion Hierarchical clustering of the whole blood captures crucial prognostic information beyond conventional risk factors. Further investigation into immunologic differences across clusters is encouraged. Funding Source: R01HL171918, HL145266, Three Lakes Foundation Acknowledgements: We thank all patients who participated in the Pulmonary Fibrosis Foundation (PFF) Patient Registry. We also thank the investigators, clinical research coordinators, and other staff at participating PFF Care Centers for providing clinical data; the PFF, which established and has maintained the Registry since 2016; and, lastly, the many generous donors. This abstract is funded by: NHLBI, Three Lakes Foundation