To the Editor:I read with interest the article by Kapandji and colleagues (1) arguing in favor of the early intense lung alveolar epithelial injury as the predominant pathophysiology of coronavirus disease (COVID-19)–associated acute respiratory distress syndrome (CARDS) based on marked elevation in the s-RAGE (soluble form of the receptor for advanced glycation end-products) levels among patients with CARDS. I concur with the authors’ conclusion that plasma levels of s-RAGE correlate with CARDS severity and that the higher average plasma s-RAGE level in patients with CARDS in comparison with non-CARDS (1) strongly implies key differences in the early pathophysiological process in these subsets of ARDS. However, despite significantly greater average baseline s-RAGE levels observed in CARDS in comparison with non-CARDS, a closer look into the data produced by Kapandji and colleagues revealed that a higher proportion of patients in the non-CARDS group had severe ARDS (45% vs. 26%) and a higher ventilatory ratio. Furthermore, the average PaO/FiO ratio was significantly lower in the non-CARDS group than in the CARDS group. Thus, the higher baseline s-RAGE levels may not simply imply more severe lung epithelial injury in the CARDS group versus the non-CARDS group. Based on this argument, I believe, an alternate source for higher plasma s-RAGE levels early in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could be a possibility. Considering the fact that a higher proportion of patients in the CARDS group had systemic disorders such as hypertension, diabetes, and at least one cardiovascular risk factor, the greater Day 90 mortality observed in the CARDS group (1) may be secondary to the nonpulmonary causes. Importantly, COVID-19 is a multisystem disorder with histopathological evidence in favor of early endothelial injury even before any significant epithelial injury (2, 3). So, an important question that arises is whether an early endothelial injury is responsible for higher baseline s-RAGE levels observed in the CARDS group and thus describes a pathophysiological phenomenon unique to the atypical CARDS.It has been postulated that RAGE plays a role in the SARS-CoV-2–mediated inflammatory response in the lungs (2, 4, 5). When healthy, the lung epithelial cells, apart from skin, are the only cell types known to express RAGE (5). However, in inflammatory disorders, increased expression of RAGE may occur on the immune cells such as monocytes and dendritic cells as well as on the endothelial cells (4, 5). Upregulation of RAGE on the endothelial cells is known to play an important role in the pathophysiology of vascular dementia, uncontrolled diabetes, coronary artery disease, and obesity, the known risk factors for COVID-19 (5). Ang II (angiotensin II), tumor necrosis factor-α, and IL-1β levels can induce expression of RAGE on the endothelial cells (5), and an increase in these inflammatory mediators was hypothesized as the cause of the complex clinical picture of COVID-19 (2, 4, 5). Thus, activation of the ACE (angiotensin-converting enzyme)/Ang II/AT1R (Ang II type 1 receptor) pathway after the binding of SARS-CoV-2 to ACE2 via its S-protein (spike protein) to invade host cells can result in RAGE activation (3) on the pulmonary epithelial as well as endothelial cells. Furthermore, activation of ADAM 17 (a disintegrin and metalloprotease 17), directly after SARS-CoV-2 S-protein binding to ACE2 (6), and indirectly by Ang II–p38-MAPK (p38 mitogen-activated protein kinase) axis (7) and RAGE–p38-MAPK pathway (8), can result in excessive ectodomain shedding of RAGE, resulting in high plasma s-RAGE levels in early COVID-19. Interestingly, in a study by Kehribar and colleagues, the serum s-RAGE level was significantly higher in the asymptomatic COVID-19 group than in the control group (9). In addition, after adjusting for age, serum s-RAGE level was higher in the patients with lung involvement than in the control group and the asymptomatic COVID-19 group. Based on the above arguments and from Kapandji and colleagues’ observation of differences in baseline s-RAGE levels between COVID-19 and non–COVID-19 pneumonia, I postulate that early dysregulation of the renin–angiotensin system and ADAM-17 overactivation are the processes distinct to the early phase of SARS-CoV-2 infection that can result in transactivation of RAGE axis and early increase in s-RAGE. This phenomenon may not simply mirror the severity of lung epithelial injury; instead, it may suggest indirect endothelial dysfunction. I further propose Kapandji and colleagues perform subgroup analysis of their data to compare the plasma s-RAGE levels in patients with mild COVID-19 disease, patients with mild non-CARDS, and healthy control subjects as this could further help in understanding the phenomenon of epithelial–endothelial cross-talk in COVID-19 (2).Much evidence suggests that endothelial injury augments RAGE expression and the amount of circulating s-RAGE reflects RAGE expressed on injured endothelial cells (10). In severe sepsis, the serum level of s-RAGE was strongly associated with that of vascular cell adhesion molecule-1, an early marker of endothelial activation related to systemic inflammation (10) and COVID-19 (11). Importantly, the histopathological findings of distinctly higher incidence of pulmonary microthrombi, as high as 73% in COVID-19 as compared with H1N1 influenza (24%), emphasizes the importance of extensive endothelial dysfunction in COVID-19 (12).In conclusion, early ADAM-17–mediated ectodomain shedding of RAGE, endothelial activation, and inflammation may be contributory to the high baseline s-RAGE levels in patients with CARDS in the study of Kapandji and colleagues. Finally, measurements of specific markers for alveolar epithelial cell injury (human-type I cell 56-kD protein and cytokeratin 18), marker of alveolar capillary barrier disruption (surfactant protein D), and endothelial injury such as angiopoietin 2 may provide distinct temporal characteristics of circulating alveolar epithelial and endothelial injury markers in COVID-19.