# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 4 Comparisons to Other Etiologies
### Non-Pulmonary Sepsis  
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, and non-pulmonary sepsis is among the most common risk factors associated with development of ARDS [11; 166]. Conceptually, sepsis-induced ALI differs from pneumonia-induced ALI in that the endothelial barrier is affected prior to the epithelium [167]. However, the severe endothelial disruption observed in COVID-19 lung injury raises questions as to whether its pathophysiology might closely resemble that of sepsis-induced ALI.  
Both sepsis and severe COVID-19 demonstrate an exacerbated innate inflammatory response that contributes to the development of ALI. In sepsis, these responses are characterized by elevated plasma levels of an array of pro-inflammatory mediators including IL-1, IL-6, IL-8, and TNF-\(\alpha\), a similar profile reported in COVID-19 [168; 169; 10; 69]. These cytokines and chemokines stimulate the activation of immune cells, especially neutrophils and monocytes which further contribute to inflammation through interacting with the endothelium, releasing antimicrobial agents and, in the case of neutrophils, undergoing NE-Tosis [79; 169]. In terms of immune cells infiltrating the lungs, unlike COVID-19, neutrophils are the predominant effector in sepsis, and alveolar neutrophil presence is associated with worse outcomes [167]. The acute hyper-inflammatory phase of sepsis is generally followed by a state of immune exhaustion characterized by severe lymphopenia with associated activation of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) signaling [170]. Indeed, lymphopenia associated with elevated PD-1 is well reported in severe and critical COVID-19 [81]. Thus, there are important shared trends of innate and adaptive immune activation in sepsis and COVID-19. However, it should be emphasized that these trends have potential to be more heterogeneous in non-pulmonary sepsis due to multiple possible causative agents.  
Endothelial activation is observed in both sepsis and COVID-19 but may be driven primarily by different mechanisms. Activation of TNF receptors and PAR-1, as well as decreased shear stress due to septic shock, are proposed to be key events in sepsis driving the shift to a pro-inflammatory and pro-coagulative state [171]. While these are also contributing factors in COVID-19, some reports suggest that direct infection by SARS-CoV-2 may be the most important factor. Nonetheless, ensuing barrier permeability and pro-inflammatory cytokine transcription in both cases point towards a similar phenotype of widespread endothelial activation. In keeping with this, both sepsis and severe COVID-19 are characterized by extensive coagulopathy [122]. Patients in both groups present with elevated D-dimer and PAI-1, the levels of which are correlated with poor outcomes [172; 173; 122]. In either case, NETosis plays a central role in coagulation through the exposure of histones, nucleic acids, and tissue factor, which promote platelet aggregation and clot formation [78; 174]. Disseminated intravascular coagulation (DIC) is described as intravascular activation of coagulation with loss of localization and has been well reported in sepsis as a contributing factor to organ dysfunction and death [172]. DIC has been suggested to occur in COVID-19; however, some suggest that the latter represents a different phenotype due to significant contributions of intra-alveolar fibrin deposition [122]. Indeed, a novel definition for \"COVID-19-associated coagulpathy\" is a current area of focus. Differences aside, coagulation within the pulmonary microcirculation prompts the formation of capillary microthrombi and ensuing perfusion defects, worsening gas exchange.