Abstract
Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the respiratory microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 respiratory microbiome studies by analyzing the upper (n = 58) and lower (n = 35) respiratory tract microbiome in well-phenotyped COVID-19 patients and controls combining microbiome sequencing, viral load determination, and immunoprofiling. We find that time in the intensive care unit and type of oxygen support, as well as associated treatments such as antibiotic usage, explain the most variation within the upper respiratory tract microbiome, while SARS-CoV-2 viral load has a reduced impact. Specifically, mechanical ventilation is linked to altered community structure and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomics of the lower respiratory tract of COVID-19 patients identifies specific oral bacteria in physical association with proinflammatory immune cells, which show higher levels of inflammatory markers. Overall, our findings suggest confounders are driving contradictory results in current COVID-19 microbiome studies and careful attention needs to be paid to ICU stay and type of oxygen support, as bacteria favored in these conditions may contribute to the inflammatory phenotypes observed in severe COVID-19 patients.
Highlights
1234567890():,; Understanding the pathology of COVID-19 is a global research priority
We longitudinally profiled the upper respiratory microbiota of 58 patients diagnosed with COVID-19 based on a positive qRT-PCR test or a negative test with high clinical suspicion based on symptomatology and a chest CT scan showing typical round glass opacities
We observed that the Shannon Diversity index (SDI) was significantly different across sampling moments (Kruskal–Wallis test, p value = 0.009; Supplementary Figure 1a), with significant differences between the swabs procured upon patient intensive care unit (ICU) admission and later timepoints, suggesting an effect of disease progression and/or treatment. We explored these differences further, and observed that SDI correlated negatively with the number of days spent in ICU at the Number of patients Type of sampling COVID-19 diagnosis (%) Patients admitted to ICU (%) Age Female sex (%) BMI Diabetic (%) Days in ICU Days in hospital
Summary
1234567890():,; Understanding the pathology of COVID-19 is a global research priority. While some studies report a low microbial diversity in COVID-19 patients[14,17] that rebounds following recovery[15], others show an increased diversity in the COVID-19 associated microbiota[16] These conflicting results could be due to differences in sampling location (upper or lower respiratory tract), the severity of the patients, disease stage, treatment, or other confounders. For the lower respiratory tract, we profiled microbial reads in cross-sectional single-cell RNA-seq data[18] from bronchoalveolar lavage (BAL) samples of 22 COVID-19 patients and 13 pneumonitis controls with negative COVID-19 qRT-PCR, obtained from the same hospital The integration of these data enabled us to (1) identify potential confounders of COVID-19 microbiome associations, (2) explore how microbial diversity evolves throughout hospitalization, (3) study microbe-host cell interactions, and (4) substantiate a link between the respiratory microbiome and SARS-CoV-2 viral load, as well as COVID-19 disease severity. These interactions may be driven by mechanical ventilation and its associated clinical practices, and could potentially influence COVID-19 disease progression and resolution
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