evidence: What Causes Hypoxemia in COVID-19? (Part I) The FLARE Four - Critical COVID-19 is characterized by hypoxemic respiratory failure - The perceived discordance between severity of hypoxemia and both the extent of radiographic disease and level of clinical distress has led many to propose novel and unlikely mechanisms of hypoxemia in COVID-19 - Distinguishing between hypoxemia and true hypoxia is essential to understanding the phenomenon of so-called "happy hypoxics" in COVID-19 - Fundamental mechanisms of hypoxemia are shared by all pulmonary diseases, including COVID-19. The most common causes of severe hypoxemia are low V/Q and its extreme, pulmonary shunt [...] The canonical presentation of severe COVID-19 is hypoxemia and, often, ARDS (April 10 FLARE). Early studies of gas exchange in ARDS emphasized the predominant contribution of shunt, which is thought to be secondary to continued perfusion of collapsed and/or fluid-filled alveolar units (Albert and Jobe, 2012). The observation of severe hypoxemia in COVID-19 despite only mild parenchymal involvement (Gattinoni et al., 2020) has led some to speculate (Leisman et al., 2020) that novel mechanisms must underlie the hypoxemia. These speculations have been the subject of intense debate both in the scientific literature (Leisman et al., 2020) and in non-peer reviewed forums. Proposed novel mechanisms of hypoxemia include endotheliitis, failure of hypoxic pulmonary vasoconstriction (Archer et al., 2020; Lang et al., 2020) and/or macro- or microvascular thrombosis (Klok et al., 2020).