Abstract
BackgroundCOVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19).MethodsBronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared.ResultsCOVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations.ConclusionCXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach.Trial registrationClinicalTrials.gov, NCT03955887
Highlights
COVID-19-related acute respiratory distress syndrome (ARDS) has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis
While demographic and comorbidity data were not statistically different, baseline severity according to the Sequential Organ Failure Assessment (SOFA) score in particular was found to be lower in COVID-19 ARDS patients (p = 0.045), with a trend toward less frequent septic shock (p = 0.120) and a marginally lower baseline arterial lactate levels (p = 0.079) at the onset of ARDS (Table 1)
We show that plasma CXCL2, CXCL10, CCL5, CD40 ligand, IL-10, and granulocytemacrophage colony-stimulating factor (GM-CSF) concentrations and epithelial lining fluid (ELF) CXCL1, CXCL10, granzyme B, TNF-related apoptosis inducing ligand (TRAIL), and epidermal growth factor (EGF) concentrations were found in greater concentrations in COVID-19 than in non-COVID-19 ARDS patients
Summary
COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs non-COVID-19). It has been established that the virus invades type 2 alveolar cells and ciliated epithelial cells that express ACE2 [5]. As they die, infected cells release virus particles and intracellular components including molecules likely to act as alarmins (i.e., danger signals), as reflected by rising lactate dehydrogenase (LDH) levels in the plasma [6]. Since most patients need to undergo mechanical ventilation in this context, ventilator-induced lung injury (VILI) could exacerbate tissue damage as well as local and systemic inflammation, acting as a “second hit.”. By promoting chemotaxis and activation of polymorphonuclear neutrophils (PMNs), mitochondrial alarmins are thought to represent proximal endogenous mediators of VILI and ARDS when they are released by injured alveolar cells [10, 11]
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