LAUSR

Severe acute respiratory syndrome coronavirus 2 is the cause of the ongoing coronavirus disease-19 (COVID-19) pandemic. Mortality is mainly due to acute respiratory distress syndrome (ARDS) [1]. High blood pressure appeared to be an independent factor for severity in patients with COVID-19 [2, 3]. The renin–angiotensin system (RAS) is a hemodynamic and biological system that regulates blood pressure, plasma potassium, and the stability of pulmonary epithelial membranes (Fig. 1) [4]. In this system, two antagonistic pathways are balanced. The first is the angiotensinogen pathway that transforms angiotensinogen into angiotensin I (by renin), and then converts it into angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II attaches to angiotensin II type 1 receptor (AT1R) and activates the system to induce vasoconstriction, aldosterone secretion stimulation, hypokalemia, and pulmonary epithelium degradation [5]. The second way in which the angiotensin system is balanced involves a second angiotensin converting enzyme (ACE2) [6, 7]. This pathway transforms a part of angiotensin I [1–10] and angiotensin II [1–8] before it attaches to its AT1R receptor. The angiotensin I and II phosphorylation products are angiotensin 1–9 and angiotensin 1–7. They attach to the angiotensin II type 2 receptor receiver, inducing antagonist effects compared with AT1R [8]. In the infection phase (Fig. 2), COVID-19 virus uses the enzymatic receptor of ACE2 to penetrate the host cell [9, 10]. Coronavirus binding with ACE2 has been shown to lead to a downregulation of ACE2 [11], contributing to an increase in angiotensin 2 through ACE, as the decrease in ACE2 results in a lower conversion of angiotensin to angiotensin 1–7 vasodilator [12]. The lower the level of ACE2, the lesser angiotensin I [1–10] and angiotensin II [1–8] will be degraded; thus, their plasmatic concentration gradually increases. A US intensive care unit team demonstrated that an increase in angiotensin 1–10 and a decrease in angiotensin 1–9 (its ACE2 processing product) were correlated with a poor prognosis in ARDS [1]. Thus, elevations in angiotensin II concentrations and stimulation of AT1R lead to a decrease in the stability of the pulmonary endothelium and an aggravation of respiratory distress [13, 14]. The other effects are an increased secretion of aldosterone, hypokalemia induced by kaliuresis, and increased sodium reabsorption and inflammation [15]. Hypokalemia is frequently found in patients with COVID19. A Chinese team recently reported that hypokalemia was associated with a poor outcome (Wuhan’s experience) [16]. Conversely, RAS blockers can increase ACE2 and potentially promote virus loading into the cell [17]. We believe that major imbalance in RAS induced by the downregulation of ACE2 is an essential element of unfavorable evolution in patients with COVID-19. The biological marker of this imbalance appears to be hypokalemia. Several studies in influenza and Ebola lung infections have shown the beneficial role of AT1R blockers on lung damage, with a decrease in inflammation and cytokines [18–21]. In two animal studies, losartan demonstrated an increase in ACE2 expression [22, 23]. Losartan was also the molecule chosen in two trials recently started in the United States by the University of Minnesota to treat patients with COVID-19 (clinical trials. gov NCT04311177 and NCT 104312009). We began a preliminary study to document the kinetics of RAS in COVID+ patients (SAR-COV) before therapeutic evaluation (ISRA-COV). * François Silhol [email protected]