Lung microbiota predict invasive pulmonary aspergillosis and its outcome in immunocompromised patients
Abstract Rationale Recent studies have revealed that the lung microbiota of critically ill patients is altered and predicts clinical outcomes. The incidence of invasive fungal infections, namely, invasive pulmonary aspergillosis (IPA), in immunocompromised patients is increasing, but the clinical significance of variations in lung bacterial communities is unknown. Objectives To define the contribution of the lung microbiota to the development and course of IPA. Methods and measurements We performed an observational cohort study to characterise the lung microbiota in 104 immunocompromised patients using bacterial 16S ribosomal RNA gene sequencing on bronchoalveolar lavage samples sampled on clinical suspicion of infection. Associations between lung dysbiosis in IPA and pulmonary immunity were evaluated by quantifying alveolar cytokines and chemokines and immune cells. The contribution of microbial signatures to patient outcome was assessed by estimating overall survival. Main results Patients diagnosed with IPA displayed a decreased alpha diversity, driven by a markedly increased abundance of the Staphylococcus, Escherichia, Paraclostridium and Finegoldia genera and a decreased proportion of the Prevotella and Veillonella genera. The overall composition of the lung microbiome was influenced by the neutrophil counts and associated with differential levels of alveolar cytokines. Importantly, the degree of bacterial diversity at the onset of IPA predicted the survival of infected patients. Conclusions Our results reveal the lung microbiota as an understudied source of clinical variation in patients at risk of IPA and highlight its potential as a diagnostic and therapeutic target in the context of respiratory fungal diseases. ; This work was supported by the Fundação para a Ciência e a Tecnologia (FCT) (PTDC/SAU-SER/29635/2017 to CC and PTDC/MED-GEN/28778/2017 to AC). Additional support was provided by FCT (UIDB/50026/2020 and UIDP/50026/2020); the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023); the European Union's Horizon 2020 Research and Innovation Programme under grant agreement number 847507 (to AC); and the "la Caixa" Foundation (ID 100010434) and FCT under the agreement LCF/PR/HR17/52190003 (to AC). Individual support was provided by FCT (SFRH/BD/136814/2018 to SMG, CEECIND/03628/2017 to AC and CEECIND/04058/2018 to CC). The TG group acknowledges support from the Spanish Ministry of Science and Innovation for grant PGC2018-099921-B-I00, cofounded by the ERDF, the CERCA Programme/Generalitat de Catalunya, the Catalan Research Agency (AGAUR) SGR423, the European Union's Horizon 2020 Research and Innovation Programme under grant agreement ERC-2016-724173 and an INB Grant (PT17/0009/0023—ISCIII-SGEFI/ERDF). ; Peer Reviewed ; Postprint (author's final draft)