Background
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and can result in organ dysfunction including acute respiratory distress syndrome (ARDS), severe acute kidney injury (AKI), and death [
1‐
3]. While only a minority of COVID-19 patients will become critically ill, these patients take up a disproportionate share of intensive care unit (ICU) resources and experience high mortality [
1,
3]. Our previous work has defined markers of endothelial dysfunction as critical determinants of organ failure and mortality among ICU patients, but it is unclear whether COVID-19 shares this pathophysiology [
4‐
6]. A clear understanding of the shared and unique characteristics of COVID-19-related critical illness could help to inform the development of novel therapeutics and the repurposing of existing interventions.
Previous reports have suggested that severe COVID-19 is characterized by derangements in inflammatory, endothelial and epithelial cell injury pathways [
7]. However, comparisons to other critically ill populations are under-reported. For example, comparisons of plasma biomarkers of endothelial function have largely focused on COVID-19 alone [
8], comparisons between COVID-19 and healthy controls [
9], and comparisons between patients with increasing severity of COVID-19 [
10]. While these studies have advanced our knowledge, the findings are conflicting and the study designs prevent discriminating differences specific to the host response to severe SARS-CoV-2 infection versus a general signature of critical illness. Thus, it is unknown whether inflammatory, endothelial and epithelial cell injury pathways are an early marker of the host response to SARS-CoV-2, and, in turn, if therapies that target these pathways to modulate the host response should be preferentially tested in COVID-19.
To address this knowledge gap, we developed the COVID-19 Host Response and Clinical Outcomes (CHROME) study enrolling a prospective cohort of patients admitted to an ICU as persons under investigation (PUIs) for COVID-19. Blood was collected within 24 h and again 3 days after ICU admission. We hypothesized that biomarkers of the host response would be different early after ICU admission in COVID-19 compared to a matched cohort of ICU patients without COVID-19.
Discussion
The pathophysiology of severe COVID-19 has been reported to be characterized by severe inflammation and vascular injury. However, the extent to which these findings are specific to COVID-19 as opposed to critical illness in general is unclear [
19]. To our knowledge, this is the first study of a cohort of ICU patients admitted as PUI in which circulating biomarkers have been compared between patients that ultimately ruled in or out for COVID-19. We found distinct differences in the relationship of biomarkers based on COVID-19 status. For example, in non-COVID-19, inflammatory and endothelial biomarkers were highly correlated and consistent with our prior work [
5]. In contrast, in COVID-19 inflammatory and endothelial pathways seemed to be uncoupled. Moreover, in COVID-19, there was a lower correlation between coagulation (INR and platelets) and endothelial markers compared to non-COVID-19.
In adjusted comparisons between COVID-19 and non-COVID-19 patients, we found that circulating markers of endothelial dysfunction and inflammation (Ang-2:1 ratio, Ang-2 and sTNFR-1) were lower in COVID-19 compared to non-COVID-19 patients. In contrast, acute phase proteins (SAA), and markers of epithelial cell injury/innate immune activation (sRAGE) were significantly greater in COVID-19, independent of demographics and ICU severity of illness. While mortality rates were similar between groups, dysregulation of Ang-2:1 ratio were only associated with hospital mortality in the non-COVID-19 population. In contrast, SAA was associated with ARDS only in COVID-19 patients. Despite higher sRAGE concentrations in COVID-19 patients, higher sRAGE concentrations were associated with ARDS only in the non-COVID-19 population. These findings suggest that, unlike previously studied causes of critical illness, endothelial dysfunction may not be a distinct signature of the host response to COVID-19 infection, and, in contrast, epithelial cell injury/innate immune activation and inflammation may be a pathway for future study and targeting of therapeutics in COVID-19.
We found that rates of hospital mortality and organ dysfunction were similar in critically ill patients with and without COVID-19. These findings differ from previous studies reporting extremely high rates of AKI, thrombosis and death in patients with COVID-19 [
20]. However, the study designs used in these prior reports comparing COVID-19 clinical outcomes to historical cohorts rather than within a contemporaneous cohort may result in significant confounding. Comparison of clinical outcomes between COVID-19 and a contemporaneous cohort mitigates, though does not eliminate, confounding due to differences in processes of care, differences in practice patterns due to system strains and allocation of limited resources. An additional factor differentiating our study from multiple prior studies is that while shortages of medical resources and ICU beds occurred in a number of other cities and countries, our center did not experience a limitation of resources, staff, or ICU beds and never approached crisis standards of care [
21]. In addition, enrollment in the CHROME study occurred from April to September allowing for a broader representation of demographics and comorbidities among both the COVID-19 and non-COVID-19 admissions [
22]. In contrast to similarities in mortality and organ dysfunction, COVID-19 patients experienced increased LOS, a very important factor that have strained ICU resources across the globe as a result of the COVID-19 pandemic.
Studies have suggested that COVID-19 is a hyperinflammatory syndrome or “cytokine storm”. The presumed elevations in IL-6 concentrations have been hypothesized as causal in severe COVID-19 and this has led to interventional trials testing therapies that block IL-6 [
23,
24]. Of note, in our study, plasma concentrations of IL-6 and IL-8 were consistently elevated but similar between ICU patients with and without COVID-19 suggesting that there is heterogeneity in the inflammatory response and sub-groups of patients regardless of COVID-19 status may have elevated IL-6 concentrations. Another key inflammatory biomarker measured in our study was sTNFR-1. sTNFR-1 is the circulating form of the membrane-bound receptor which is essential for TNF signaling that results in both inflammation and endothelial dysfunction [
25,
26] and we and others have shown that sTNFR-1 is highly associated with organ dysfunction and death in sepsis and other forms of ARDS [
16]. Counter to what we had hypothesized, we found that sTNFR-1 was lower in COVID-19 relative to non-COVID-19, but our findings are consistent with results from Sinha et al. showing that sTNFR-1 concentrations were lower in patients with COVID-19-associated ARDS compared to a historical cohort of patients with ARDS [
27].
In contrast to these prototypical inflammatory cytokines, chemokines, and cytokine receptors we found that the acute phase protein, SAA, was markedly elevated in COVID-19. Our results extend a prior report from China that demonstrated that SAA concentrations were associated with severity of respiratory failure and mortality in hospitalized patients with COVID-19 [
28]. Finally, levels of sRAGE, a marker of alveolar type 1 cell-injury that is associated with risk for ARDS and related mortality, were significantly greater in COVID-19 patients [
29,
30]. Our findings suggest that SAA and sRAGE may be useful indications of COVID-19 pathophysiology.
Considerable interest has focused on the potential role for vascular pathology in the development of severe COVID-19 [
7]. However, in our survey of multiple markers of endothelial function/dysfunction and injury, we only observed significantly lower Ang-2 and Ang-2:1 ratio in COVID-19 relative to non-COVID-19 patients. We also found a trend toward lower sTie-2 and higher concentrations of Ang-1 in COVID-19. Previous studies have demonstrated that Ang-1 and 2 concentrations are associated with mortality in community acquired pneumonia and sepsis [
6,
31]. However, the majority of studies examining Ang-1 and Ang-2 in critical illness were likely to have had had an underlying bacterial (as opposed to viral) etiology [
31,
32]. Our results suggest that endothelial dysfunction is not a dominant contributor to severe COVID-19 and, more generally, that the findings of a dysregulated Ang-Tie-2 axis in bacterial sepsis may not be extrapolated to viral pneumonia. These findings also suggest that therapeutic targeting of the Ang-Tie-2 axis early in COVID-19 critical illness as has been proposed [
33,
34] may not be optimal. The increasing trajectory of Ang-2 concentrations from days 1 to 3 in COVID-19 patients are intriguing and may suggest that endothelial dysfunction may be a later finding in COVID-19.
This study had a number of strengths. First, the comparison of critically ill COVID-19 patients to contemporaneous critically ill patients with symptoms clinically suggestive of COVID-19 but who tested negative for SARS-CoV-2 reduces confounding due to differences in clinical management and resource allocation due to the COVID-19 pandemic. Second, all ICU blood samples were collected with uniform handling to minimize any bias due to sample handling issues. All biomarker measurements were completed using the same assay and laboratory procedures. Third, clinical outcomes were ascertained using a detailed electronic case report form by trained research coordinators and all patients had complete hospital follow up.
Limitations of this study include the small sample size which may have compromised our ability to detect minor differences in biomarker concentrations between critically ill patients with and without COVID-19. Nonetheless, we had adequate power to exclude the large effect sizes that have been observed in prior studies of inflammatory biomarkers such as IL-6 in COVID-19 and the Ang-Tie-2 axis in sepsis and ARDS. We were able to identify several significant novel associations in spite of this limitation. Another general limitation of our study as with many COVID-19 studies in the critically ill is that the limitations to imaging and lab evaluation due to the respiratory isolation mandated for those who tested positive for SARS-CoV-2 could lead to biases for outcomes such as diagnosis of VTE or initiation of RRT in the COVID-19 patients. However, this is unlikely to have affected the biomarker measurements of the main comparison between COVID-19/non-COVID-19. Another limitation is that corticosteroids or anti-inflammatory agents may have influenced plasma biomarker concentrations between COVID-19 and non-COVID-19 groups. To account for this, we adjusted for known corticosteroid use but residual confounding may still exist.
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