Microbial Burden-associated Cytokine Storm May Explain Nonresolving Acute Respiratory Distress Syndrome in Patients with COVID-19

To the Editor:

We read with great interest the article reported by Kullberg and colleagues in the Journal on the association of lung microbiota of critically ill patients with coronavirus disease (COVID-19) with nonresolving acute respiratory distress syndrome (ARDS) (1). The study enrolled patients with COVID-19 under mechanical ventilation, and the primary clinical outcome was successful liberation from mechanical ventilation on Day 60 after starting mechanical ventilation (1). The authors showed that successfully extubated patients with COVID-19 have significantly less alveolar microbial burden in the lower respiratory tract and significantly less mortality than deceased or intubated patients on Day 60 after initiation of mechanical ventilation (1, 2). Unfortunately, how the enhanced microbial burden affected the clinical outcome of patients with COVID-19 remains unclear. Several studies have documented the importance of increased systemic and intraalveolar concentrations of inflammatory cytokines in the pathogenesis of COVID-19 or sepsis-associated ARDS (3–5). Thus, the significant correlation observed by the authors between the microbial burden and the bronchoalveolar lavage fluid concentration of inflammatory cytokines points to intraalveolar cytokines as the potential factors mediating the detrimental effects of enhanced microbial burden in patients with COVID-19 with ARDS. However, Kullberg and colleagues assessed correlations in all (extubated and deceased or intubated) patients and in all (first and followed-up) BAL fluid samples. The two groups were not separately evaluated. In addition, the difference in the BAL fluid concentrations of inflammatory cytokines between the two groups of patients was not evaluated. Therefore, it is difficult to determine whether inflammatory cytokines played some pathogenic role in the (deceased or intubated) group of patients with COVID-19 with poorer clinical outcomes.

To clarify the potential implication of excessive cytokine secretion as the process mediating the pathological effects of the enhanced lung bacterial or fungal burden in patients with COVID-19 with nonresolving ARDS, the BAL fluid concentrations of inflammatory cytokines and the strength of correlation of microbial burden with inflammatory cytokines should be separately evaluated and compared between the extubated and deceased or intubated groups. Addressing the above questions will provide important and original information on whether increased lung microbial burden–associated “cytokine storm” may explain nonresolving ARDS in critically ill patients with COVID-19.