B107-09 Cachexia Is Associated With Distinct Lower Airway Transcriptomic Profile in Bronchiectasis

Abstract Rationale Cachexia is characterized by inflammatory dysregulation, weight loss, and sarcopenia. While cachexia is a marker of poor prognosis and treatment failure in chronic diseases, including bronchiectasis and non-tuberculous mycobacterial (NTM) lung disease, its role in disease pathogenesis remains unclear. Transcriptomic profiling of the lower airway provides a means to uncover host pathways underlying this systemic phenotype. We hypothesize that cachexia contributes to bronchiectasis pathogenesis, and to evaluate this hypothesis, we investigated the lower airway host transcriptome of patients with bronchiectasis/NTM with and without cachexia. Methods We recruited subjects in the NYU Bronchiectasis and NTM Research Registry (IRB s14-01950) who had lower airway and blood samples with and without NTM lung disease. We divided subjects into two groups: 1) cachexia (5% weight loss over 6 months, 2% weight loss with BMI20 over 6 months, or BMI18.5) and 2) non-cachexia. We excluded patients without sufficient weight measurements to determine cachexia status. We evaluated host gene expression with RNA sequencing of lower airway samples. Results We identified 144 subjects, 55 with cachexia and 89 with non-cachexia. 68/144 had NTM lung disease (NTM+, 28/68 with cachexia). We identified a higher rate of cavitary lung disease in the cachexia group versus the non-cachexia group (25.5% vs 10.1%, p = 0.027, Chi-squared). We isolated oral commensals in clinical culture more frequently in the non-cachexia versus the cachexia group (52.8% vs 30.9%, p = 0.017, Mann-Whitney). We then explored changes in the lower airway transcriptome. We found 4,286 differentially enriched genes (DEGs) in NTM+ participants between the cachexia and non-cachexia groups (Fig 1A). Ingenuity Pathway Analysis showed that the cachexia group had upregulated canonical pathways related to immune checkpoints PD-1 and PD-L1, TNF, cytotoxic T-cell mediated apoptosis, granzyme signaling, and IL-10, and downregulated pathways involving IL-1 and IL-15 (Fig 1B). We identified multiple DEGs in the NTM- group with cachexia (n = 78, 27/78 with cachexia) including downregulation of neutrophil degranulation pathways (Fig 1C-D). Gene set enrichment analysis using the Hallmark dataset across all subjects demonstrated upregulation of signaling pathways related to interferon, TGF-beta, Pi3k Akt mTOR, and TNF-alpha in those with cachexia (Fig 1E-F). Conclusions Cachexia represented a distinct host-response endotype in bronchiectasis and NTM lung disease with altered inflammatory signaling. The enrichment patterns suggested that NTM infection may potentiate immune dysregulation, raising the possibility that host-pathogen interactions modulate cachexia biology. Future directions include targeted pathway analyses for mechanisms of cachexia development in this population and potential effects on treatment response. This abstract is funded by: NIH