Introduction
Acute respiratory distress syndrome (ARDS) requiring mechanical ventilation is the most severe manifestation of coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome – Coronavirus 2 (SARS-CoV-2). Mortality has varied since initial reports but remains consistently high, above 40%, even in the most recent publications (1). A significant debate concerning the existence and effects of hyperinflammation in severe COVID-19 is ongoing (2, 3) and most of the therapeutic trials have focused on dampening the systemic immune response. Immune modulation has become the therapeutic norm even after non-corticosteroid immunosuppressive trials registered only small effect sizes. Clinical and treatment effect heterogeneity persists and only recent reports have overlapped the recognized ARDS phenotypes – hyper- and hypo-inflammatory – onto COVID-19 (4, 5). Both these phenotypes seem to respond to corticosteroids, suggesting treatment heterogeneity within the phenotypes.
There is also a signal that the SARS-CoV-2 viral load may play a role in the therapeutic response and ultimately the survival of critically ill patients with severe hypoinflammatory COVID-19 (5). Autopsy studies have not definitively determined the direct cause of demise in patients with severe COVID-19 ARDS and confirm that the abnormal pulmonary response in fatal COVID-19 can be triggered by direct viral cytopathic damage, an exaggerated immune infiltrate and even ventilator-induced lung injury. (6–8). It remains unclear how to best differentiate and treat patients who succumb to the uncontrolled viral replication vs an exaggerated, virus-independent immune response.
The main objective for this study was to identify groups of patients with severe COVID-19 with similar viral loads and immune response intensities using prespecified measures of viral load and immune markers in bronchoalveolar lavage (BAL) and plasma. We hypothesized that using surrogates of semi-quantitative SARS-CoV-2 RT-PCR in BAL would better define COVID-19 ARDS phenotypes, and that lower airways samples would provide a more accurate window into viral infection and the triggered host immune response when compared with matched plasma samples.