# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 4 Comparisons to Other Etiologies
### Viral Respiratory Pathogens  
Despite its unprecedented global impact, SARS-CoV-2 is a relative newcomer among viruses known to induce ALI. Influenza virus, respiratory syncytial virus (RSV), and other coronaviruses have historically been the most impactful [131]. Similar to SARS-CoV-2, the ability of these pathogens to cause ALI is contingent upon infection of the lower respiratory tract, although as described below, resulting lung injury may differ in both mechanism and presentation [132]. COVID-19 is the third coronavirus of global significance to arise in little over two decades. SARS-CoV-1 and Middle East respiratory syndrome (MERS)-CoV emerged in 2002 and 2012, respectively, and combined have caused over 1500 deaths in the years since [133]. With 79.6% sequence homology to SARS-CoV-2, SARS-CoV-1 bears similarities including ACE2-mediated cell entry, which is similarly believed to induce RAAS derangement via the ang II-AT1 axis [134]. Indeed, many other features of SARS draw parallels to COVID-19 lung injury. For example, histological findings of DAD with monocytic and lymphocytic infiltrates, as well as systemic lymphopenia and thrombocytopenia, are consistent with COVID-19 pathogenesis [135]. Increased inflammatory cytokine release with reduced IFN-I production was associated with more severe ALI and may suggest a similar immunopathology, while high rates of pulmonary microthrombi (58%) and emboli (28%) suggest a similar degree of coagulpathy as in COVID-19 [136]. Notably, there is a higher mortality rate in SARS (10%), which may indicate more severe disease, although it is unclear what role evolving care practices may play in this [137]. MERS, on the other hand, is least similar among these three coronavirus diseases. MERS-CoV initiates cell entry via binding dipeptidyl-peptidase 4 (DPP4; a.k.a. CD26) [133]. Lung injury characterized by neutrophil and macrophage infiltrates is reported, and radiographic findings are consistent with viral pneumonia and ARDS. Additionally, MERS bears a high preponderance for renal injury, a feature which may be explained by direct infection, as kidney cells highly express DPP4 [137]. Similar to SARS and COVID-19, however, it is suggested severe disease involves a prolonged innate immune response and weaker adaptive response. The mortality rate for MERS has been reported at 40%, representing a massive increase relative to COVID-19 and SARS [137]. Inflenza viruses are negative-sense single-stranded RNA viruses responsible for seasonal epidemics and occasional pandemics such as the 2009 H1N1 pandemic [132]. Influenza A viruses (IAV) are responsible for the latter and other pandemics and will be the focus here. The pathophysiology of influenza lung injury is similar to COVID-19 in some respects. IAV tropism, mediated by viral hemagglutinin and host sialic acid residues, has been demonstrated to include AECs, endothelial cells, and leukocytes [132, 138]. In the early stage of infection, cell death (apoptosis, pyprotosis, and necroptosis have been observed) and IFN-I responses are induced in epithelial cells, while the virus employs several strategies to limit ISG activation and enhance replication [132, 139]. As with COVID-19, host innate responses are a double-edged sword. Elevated production of inflammatory cytokines promotes inflammatory monocyte infiltration and contributes to disruption of the alveolar-capillary barrier [140]. In both COVID-19 and IAV, neutrophil activity is directed towards NETosis within the pulmonary microcirculation, whereas direct infiltration of the alveoli is less frequent. Indeed, microvascular dysfunction is similarly involved in the pathophysiology of IAV. Endothelial cells are suggested to be a primary contributor to cytokine production and leukocyte recruitment, and direct infection by several IAV strains has been observed [140, 141]. Additionally, platelet activation and pulmonary thrombosis are a frequent finding in both experimental and clinical scenarios.