A new preprint research paper posted to the medRxiv* server found changes to the lung microbiome during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection influence COVID-19 disease severity. Led by Ronald G. Collman from the University of Pennsylvania Perelman School of Medicine, they suggest a wide diversity in the microbiome is associated with less severe illness and the need for hospitalization.
Differences in the microbiome were observed in intubated patients who showed a higher prevalence for Staphylococcus. Greater amounts of Anelloviridae and Redondoviridae were also correlated with intubated patients with severe COVID-19 complications.
The researchers write:
“We report profound dysbiosis of the respiratory tract bacterial and viral microbiome in hospitalized COVID-19 patients, which differs from that of non-COVID patients, exhibits accelerated destabilization over time, and associates with disease severity and systemic immune profiles.
How they did it
The team collected oropharyngeal or nasopharyngeal swabs from 83 patients hospitalized for COVID-19 infection. Patients had a median of 64 years and included 39 women and 44 men. About 67% of patients were Black, followed by 24% of patients identifying as White. Except for five, all had comorbidities. The samples were obtained at a median of four days after being hospitalized. There were also 48% of participants who were intubated, with 24% dying. These patients also gave endotracheal aspirate samples.
Thirteen participants without COVID-19 but with an underlying condition were hospitalized but in the non-ICU. About 62% needed to be intubated, and of those, 46% died.
The severity of disease was measured using the WHO 11-point scale, with hospitalization being a level 4 and death labeled a level 10.
A total of 582 specimens for microbiome analysis was collected from COVID-positive patients and 75 from non-COVID.
Study controls consisted of 30 healthy individuals who provided swab samples and 12 samples that underwent bronchoscopy and bronchoalveolar lavage.
SARS-CoV-2 RNA levels
RNA extracted from patient samples was variable, and the viral load declined to undetectable in most patients during disease progression. However, some patients continued to exhibit SARS-CoV-2 RNA 3 weeks after symptom onset.
RNA levels did not correlate with clinical outcomes.
Genome sequencing from 26 patient samples showed SARS-CoV-2 fell under the B.1 lineage. This lineage contains the D614G mutation on the spike protein along with the P314L variant.
Less diverse lung microbiome in intubated patients with COVID-19
The respiratory microbiomes across intubated patients included common respiratory pathogens, including Staphylococcus, Klebsiella, and Stenotrophomonas. However, less diverse microbiomes were observed in patients with COVID-19.
Of the 24 intubated patients, 6 microbiomes showed a high prevalence for Staphylococcus. About 5 patients showed Staphylococcus dominance in the microbiome one week after culture testing, and only 3 had S. aureus. Three patients had Enterococcus.
Other pathogens present but in smaller quantities included Stenotrophomonas, Enterobacteriaceae, and Enterobacterales.
Researchers found stability in the microbiome for some patients while others showed changes over time. They conclude:
“Thus, the lower respiratory tract microbiome in critically ill intubated COVID-19 patients is low diversity, can be dominated by either pathogens or normal upper respiratory taxa, may have a predilection for Staphylococcus, and can be highly dynamic.”
Pathogens linked to greater disease severity
Disruptions in the microbiome also predicted immunity towards COVID-19 — a lower lymphocyte-to-neutrophil-ratio linked to less diverse airway microbiome communities. The decreased levels correlated with increased disease severity.
The team also looked at 193 individual cellular immune features from peripheral blood mononuclear cell phenotyping samples from 34 patients. Results showed the oropharyngeal microbiome is associated with systemic immune cell composition.
Early sampling showed Anelloviridae and Redondoviridae were one of the most excellent microbial indicators for requiring intubation in the hospital. The DNA viruses were also linked to a higher WHO score, which indicated greater disease severity.
Researchers used machine learning algorithms in two patients to find elevated levels of small circular DNA viruses predicted if a person would be intubated — although they were not as strong as bacteria in predicting COVID-19 disease severity. Prevotella and Mycoplasma in oropharyngeal samples were also associated with a greater risk of hospitalized intubation. This suggests bacterial lineages rather than DNA viruses correlated with higher disease severity.
“Our longitudinal analysis revealed greater destabilization of the oropharyngeal bacterial microbiome in COVID-19 than non-COVID patients. This finding is particularly striking given that non-COVID patients were overall sicker (all in the ICU; 40% mortality) than COVID-19 patients (both ICU and non-ICU patients; 24% mortality).”
Important Notice
*medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
How a ketogenic diet could reduce autoimmune disease severity through host-microbiome interactions