Host Transcriptional Signatures Associated with Etiology and Outcomes of Post-Hematopoietic Cell Transplant Lung Injury

Abstract

Background: Allogeneic hematopoietic cell transplant (alloHCT) is a potentially curative therapy for many hematologic disorders but is frequently complicated by infectious and noninfectious pulmonary injury. Differentiating these etiologies is challenging in clinical practice, and it remains unclear whether host response signatures can distinguish infectious from non-infectious lung injury following transplantation. Methods: We performed bulk RNA sequencing of whole-blood samples from 52 alloHCT recipients within 120 days of transplantation who developed lung injury due to bacterial, viral, or fungal pathogens as well as idiopathic pneumonia syndrome (IPS). We compared genes and host immune programs across etiologies of lung injury. In exploratory analyses, we evaluated associations between pathway enrichment and 30-day mortality after lung injury. Results: Distinct transcriptional programs were observed across etiologies. Viral pneumonia showed enrichment of interferon and adaptive immune signaling pathways. Bacterial pneumonia demonstrated enrichment of innate immune and heme metabolism pathways. Fungal pneumonia exhibited the strongest enrichment of cellular proliferation pathways. In contrast, IPS showed lower enrichment of immune signaling pathways than infectious etiologies. In exploratory analyses, enrichment of interferon and complement pathways were associated with increased 30-day mortality among patients with IPS, suggesting a maladaptive inflammatory response. Conversely, enrichment of these same pathways was associated with improved 30-day survival in infectious lung injury, potentially reflecting appropriate host immune activation to control infection. Conclusion: Host transcriptomic responses differ between infectious and noninfectious lung injury following alloHCT and show distinct associations with mortality. These findings highlight the potential utility of host transcriptomic profiling to support diagnosis, guide therapeutic management, and risk-stratify patients following transplantation.