Greater bacterial, fungal lung microbiota burden linked to nonresolving ARDS in COVID-19
A higher bacterial and fungal lung microbiota burden in patients with COVID-19 was linked to nonresolving acute respiratory distress syndrome, according to a study published in American Journal of Respiratory and Critical Care Medicine.
Robert F. J. Kullberg, MD, a PhD candidate in the center for experimental and molecular medicine at Amsterdam University Medical Centers, and colleagues conducted the observational cohort study to assess the relationship between lung microbiota and clinical outcomes of COVID-19-related ARDS, hypothesizing that increased lung bacterial and fungal burdens were associated with nonresolving ARDS and mortality.
The study included 114 mechanically ventilated patients (median age, 64 years; 84% men) with COVID-19 and ARDS who underwent bronchoscopy with bronchoalveolar lavage (BAL).
Researchers profiled lung microbiota via 16S rRNA gene sequencing, using quantitative polymerase chain reaction to quantify bacterial burden via the 16S rRNA gene and fungal burden via the 18S rRNA gene. They evaluated key features of lung microbiota — including bacterial and fungal burden, alpha-diversity and community composition — as predictors.
Successful extubation adjudicated 60 days after intubation served as the study’s primary endpoint.
Of the total cohort, 94.7% of patients received systemic antibiotics between ICU admission and first sampling, and 53.5% died during ICU stay. Sixty-day mortality was 52.6%.
After analyzing BAL samples, researchers reported that extubation was less likely among patients with increased lung bacterial (per log10 increase, subdistribution HR [SHR] = 0.64; 95% CI, 0.42-0.97) and fungal (per log10 increase, SHR = 0.59; 95% CI, 0.42-0.83) burden.
When categorizing patients by tertiles, researchers found that patients with the highest bacterial (SHR = 0.46; 95% CI, 0.21-0.98) and fungal (SHR = 0.34; 95% CI, 0.16-0.72) burdens had significantly lower likelihood of extubation and survival than patients in the lowest tertile.
Mortality was also higher in patients with increased bacterial (P = .012) and fungal (P = .0498) burden.
In addition, when comparing the community composition of lung bacterial microbiota between patients who were and were not extubated by day 60, researchers found what they called a “small difference” in community composition between these groups (P = .0045), with bacterial burden significantly linked to beta-diversity (P = .003). However, researchers were not able to identify individual bacterial gena that were definitively associated with successful extubation.
Additional analyses showed that higher bacterial DNA and fungal burden were associated with increased alveolar concentrations of proinflammatory cytokines (eg, tumor necrosis factor-alpha).
“Critically ill patients with COVID-19 with increased lung bacterial and fungal burden had higher mortality and lower incidences of liberation from invasive mechanical ventilation,” the researchers concluded.
They added, “Our findings confirm the importance of the lung microbiome in ARDS and COVID-19 and highlight the significance of the — often overlooked — pulmonary fungal burden in critically ill patients. The lung microbiome has an important role in the heterogeneity in clinical outcomes of COVID-19-related ARDS.”
In a related editorial, Clea R. Barnett, MD, and Leopoldo N. Segal, MD, MSc, both of the division of pulmonary and critical care medicine at New York University Grossman School of Medicine, wrote that these results and others suggest that “it is not just uncontrollable SARS-CoV-2 infection that kills patients with COVID-19, though that’s likely one big part of it.”
However, there are several challenges in conducting studies in critically ill patients, Barnett and Segal wrote, including the timely collection of samples; the use of appropriate time-dependent outcomes, as patients with COVID-19 can succumb long after the first month of treatment; the ability to capture confounders, such as use of antibiotics and immunosuppressants; and the identification of secondary bacterial pneumonias.
“Bottom line, we need more studies including early time points, longitudinal samples and detailed consideration of all possible confounders,” they wrote. “Why? Disentangling this web of microbial, pathogen and host dynamics is the only way we will be able to risk-stratify patients and identify treatable traits.”