Respiratory Fungal Communities are Associated with Systemic Inflammation and Predict Survival in Patients with Acute Respiratory Failure

RATIONALE: Disruption of respiratory bacterial communities predicts poor clinical outcomes in critical illness; however, the role of respiratory fungal communities (mycobiome) is poorly understood. OBJECTIVES: We investigated whether mycobiota variation in the respiratory tract is associated with host-response and clinical outcomes in critically ill patients. METHODS: To characterize the upper and lower respiratory tract mycobiota, we performed rRNA gene sequencing (internal transcribed spacer) of oral swabs and endotracheal aspirates (ETA) from 316 mechanically-ventilated patients. We examined associations of mycobiome profiles (diversity and composition) with clinical variables, host-response biomarkers, and outcomes. MEASUREMENTS AND MAIN RESULTS: ETA samples with >50% relative abundance for C. albicans (51%) were associated with elevated plasma IL-8 and pentraxin-3 (p=0.05), longer time-to-liberation from mechanical ventilation (p=0.04) and worse 30-day survival (adjusted hazards ratio (adjHR): 1.96 [1.04–3.81], p=0.05). Using unsupervised clustering, we derived two clusters in ETA samples, with Cluster 2 (39%) showing lower alpha diversity (p<0.001) and higher abundance of C. albicans (p<0.001). Cluster 2 was significantly associated with the prognostically adverse hyperinflammatory subphenotype (odds ratio 2.07 [1.03–4.18], p=0.04) and predicted worse survival (adjHR: 1.81 [1.03–3.19], p=0.03). C. albicans abundance in oral swabs was also associated with the hyperinflammatory subphenotype and mortality. CONCLUSIONS: Variation in respiratory mycobiota was significantly associated with systemic inflammation and clinical outcomes. C. albicans abundance emerged as a negative predictor in both the upper and lower respiratory tract. The lung mycobiome may play an important role in the biological and clinical heterogeneity among critically ill patients and represent a potential therapeutic target for lung injury in critical illness.