Signatures of COVID-19 Severity and Immune Response in the Respiratory Tract Microbiome

Abstract

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory tract, results in highly variable outcomes ranging from minimal illness to death, but the reasons for this are not well understood. We investigated the respiratory tract bacterial microbiome and small commensal DNA viruses in hospitalized COVID-19 patients and found that each was markedly abnormal compared to that in healthy people and differed from that in critically ill patients without COVID-19.

Severe COVID-19 Is Associated With an Altered Upper Respiratory Tract Microbiome

“…The SARS-CoV-2-induced URT microbiome dysbiosis itself, rather than consistent changes in specific bacterial taxa, could be associated with an increased risk of severe disease. However, while the overall antibiotic usage in our study was low, in other manuscripts examining the association of respiratory microbiome with COVID-19 severity, patient antibiotic use was either not reported ( Mostafa et al., 2020 ; Rueca et al., 2021 ; Ventero et al., 2021 ), reported as high in all groups ( Merenstein et al., 2021 ), or reported as highest in patients with the most severe COVID-19 ( Hernández-Terán et al., 2021 ; Li et al., 2021 ). Potentially, dysbiosis in some patients could be linked to administration of antibiotics rather than the SARS-CoV-2 infection.…”

“…An interpretation of these findings could be that we observed increasing microbiome dysbiosis or destabilization as disease severity increased. Other studies have similarly reported respiratory microbiome dysbiosis in patients with COVID-19 compared with controls ( Engen et al., 2021 ; Merenstein et al., 2021 ) and in those with the most severe disease ( Hernández-Terán et al., 2021 ). SARS-CoV-2-induced instability in the microbiome might make it challenging to identify specific taxa associated with disease severity as the changes could be stochastic and less likely to be shared among different patients, a finding also reported by Li et al., who found that patients with the most severe COVID-19 each had a distinct respiratory microbiome ( Li et al., 2021 ).…”

“…Previous studies have examined the association of SARS-CoV-2 infection with the respiratory microbiome ( De Maio et al., 2020 ; Mostafa et al., 2020 ; Shen et al., 2020 ; Zhang et al., 2020 ; Haiminen et al., 2021 ; Maes et al., 2021 ; Nardelli et al., 2021 ; Rosas-Salazar et al., 2021 ; Rueca et al., 2021 ; Ventero et al., 2021 ; Xu et al., 2021 ), focusing mostly on comparing SARS-CoV-2-infected and uninfected control patients, rather than on associations of the URT microbiome with disease severity among those with SARS-CoV-2. However, there have been studies that have examined the URT microbiome over a spectrum of different COVID-19 severities ( Mostafa et al., 2020 ; Hernández-Terán et al., 2021 ; Li et al., 2021 ; Merenstein et al., 2021 ; Rueca et al., 2021 ; Ventero et al., 2021 ). Similar to others, we found that overall URT community composition significantly differed among COVID-19 severity groups ( Mostafa et al., 2020 ; Rueca et al., 2021 ; Ventero et al., 2021 ).…”

“…However, understanding of the association of the URT microbiome with clinical outcomes related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)—the respiratory virus responsible for the ongoing coronavirus disease 2019 (COVID-19) pandemic—is limited, despite the URT being a major portal of entry for this virus ( Gallo et al., 2020 ). While previous research has focused mostly on comparing the respiratory microbiome during COVID-19 to uninfected controls ( De Maio et al., 2020 ; Shen et al., 2020 ; Zhang et al., 2020 ; Haiminen et al., 2021 ; Maes et al., 2021 ; Nardelli et al., 2021 ; Rosas-Salazar et al., 2021 ; Xu et al., 2021 ), studies examining the association between the URT microbiome and COVID-19 severity have been limited thus far ( Mostafa et al., 2020 ; Hernández-Terán et al., 2021 ; Li et al., 2021 ; Merenstein et al., 2021 ; Rueca et al., 2021 ; Ventero et al., 2021 ). To start filling this gap in knowledge, we compared the URT microbiome among uninfected adults and adults with mild, moderate, severe [but without the necessity for intensive care unit (ICU) admission], and very severe (admitted to the ICU) COVID-19.…”

The Upper Airway Microbiome and Lung Injury in COVID-19

“…A meta-analysis done by Morens and colleagues of 8,398 autopsies from 1918 to 1919 found that the vast majority had evidence of bacterial pneumonia ( 1 ) and concluded that most were from “common upper respiratory-tract bacteria.” Even as this was from the preantibiotic era, the findings have been foundational knowledge for bacterial–viral copathogenesis. In contrast to general agreement on the importance of bacterial superinfection in influenza infection, the role of bacterial copathogenesis in COVID-19 is less clear ( 2 – 5 ) and interactions may operate through indirect pathways.…”