Clinical practices underlie COVID-19 patient respiratory microbiome composition and its interactions with the host

Abstract

Understanding the pathology of COVID-19 is a global research priority. Early evidence suggests that the microbiome may be playing a role in disease progression, yet current studies report contradictory results. Here, we examine potential confounders in COVID-19 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 found that time in the intensive care unit and the type of oxygen support explained the most variation within the upper respiratory tract microbiome, dwarfing (non-significant) effects from viral load, disease severity, and immune status. Specifically, mechanical ventilation was linked to altered community structure, lower species- and higher strain-level diversity, and significant shifts in oral taxa previously associated with COVID-19. Single-cell transcriptomic analysis of the lower respiratory tract of ventilated COVID-19 patients identified increased oral microbiota compared to controls. These oral microbiota were found physically associated with proinflammatory immune cells, which showed 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.

Dysbiosis and structural disruption of the respiratory microbiota in COVID-19 patients with severe and fatal outcomes

“…A common feature in MADs is that commensal/neutral bacteria can become pathogenic at the face of disease 21 . That is the case of bacteria such as g_ Prevotella , g_ Veillonella , g_ Streptococcus , g _Actinomyces , or g_ Megasphaera , which have been found as opportunistic pathogens in other studies characterizing COVID-19 microbiota 12,19–21 and that were also found in this work (severe and fatal associated microbiota (Fig. 2B)).…”

“…For mild COVID-19, we found some microbial groups associated with disease or bacteremia like g_ Prevotella melaninogenica , g_ V. parvula and g_ Neisseria subflava 7,28 . For the case of severe COVID-19, we found g_ Megasphaera that has been associated with the risk of ventilator-associated pneumonia (VAP) in other studies characterizing COVID-19 microbiota 12 . Additionally, we found g_ Rothia dentocariosa highly abundant in deceased patients.…”

Alterations in the respiratory tract microbiome in COVID-19: current observations and potential significance

“…A major confounding factor is that therapeutic interventions may influence the microbiome in COVID-19 [48], with treatments such as antibiotics and mechanical intervention co-occurring with more severe disease (see Table 1). Bradley et al sought to avoid this by sampling the oropharyngeal microbiome at hospital admission and predicting the future need for respiratory support [49].…”

“…Studies profiling patients prior to treatment avoid this effect (i.e., Bradley et al [49]). Other studies with both COVID and non-COVID-19 patients receiving antibiotics can identify the effect of specific antibiotics, which can then be separated from the effects of COVID (i.e., Lloréns-Rico [48])…”

Bacterial and fungal communities in tracheal aspirates of intubated COVID-19 patients: a pilot study

“…Overall, they confirmed predominance of multiple pathobionts and oral commensal bacteria in lower respiratory tract samples 5 – 9 , the latter supporting the idea of micro-aspiration of oral microbes as a source of lung colonization and infection. Some studies have already linked the composition of microbial communities with COVID-19 disease severity 8 , 10 , 11 . Most of these studies confirm similar patterns in COVID-19 patients compared to patients diagnosed with community-acquired pneumonia in the pre-pandemic era 6 .…”