3c. Secondary pulmonary Infection.
Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury with a high mortality rate and pneumonia; infections such as COVID and sepsis are predisposing factors together with aspiration (summarised in 17). Twenty years before COVID, it was suggested that the RAS had a role in the pathogenesis of ARDS and demonstrated that angiotensin converting enzyme insertion/deletion polymorphism was associated with susceptibility and outcome in ARDS (49). This has been shown in human data with COVID, mortality disproportionally affecting Blacks who commonly have DD mutation. Even back in 2002 this team suggested that that ACE inhibitors may lower the risk of developing ARDS or reduce the severity of the disease. Subsequently in animal experiments in acute lung injury angiotensin II is upregulated and mediates acute lung failure by way of the AT1 receptor and that ACE2 and the AT2 receptor are protective against this injury (16). Consistent with theses findings Yan et al using influenza A H5N1 virus infection in mice showed that the ARB losartan improved animal survival and ameliorated acute lung injury (6).
Based on a retrospective cohort non COVID pneumonia study Mortensen et al 2012 (50) examined the influence of statins and inhibitors of the RAS on outcomes. They concluded that statins and to a lesser extent ACE inhibitors and ARBs improved these outcomes. The potential benefits of the pulmonary effects of ARBs aware seen, and he speculated that having increased ACE2 expression with pre-existing ARB treatment may be of benefit in the course of SARS-CoV-2 infection (13). In a similar fashion in a recent review on COVID-19 (11) concluded that with patients with lower respiratory tract infections ACEIs and ARBs may be associated with improved outcomes. From a repurposing standpoint the prevailing view would be that inhibitors of RAS may be of benefit in lower respiratory tract infections.
3d . Intubation. Severe gas exchange problems requiring mechanical ventilation can occur with COVID-19 disease. As indicated by Kim et al 2017 acute respiratory distress syndrome (ARDS) is refractory hypoxemic respiratory failure with a high mortality rates, which have been reported to range from 30% to 70% (51). Animals studies of Jerng et al 2006 have suggested a link between mechanically induced proinflammatory responses and the RAS. In particular the observation that mechanical ventilation can produce a proinflammatory response in the lungs (52). Moreover, they demonstrated that RAS is involved in the pathogenesis of the ventilator induced lung injury. Of particular importance was the observation that pre-treatment with captopril or concomitant infusion of losartan attenuated the lung injury and inflammation (52). A role of Angiotensin 1-7 in improving key responses in an experimental model of ARDS was described by Zambelli et al 2015 (53). They demonstrated that Angiotensin 1-7 reduced the severity of lung injury and inflammation following pulmonary acid aspiration and high stretch mechanical ventilation.
Subsequently Kim et al. (52) examined the medical records of patients admitted to a medical intensive care unit for mechanical ventilation support. They concluded that an ACE inhibitor or ARB may have beneficial effect on ARDS patients. From the standpoint of repurposing what is important is the observation that inhibition of RAS is implicated in ventilation proinflammatory response in the lungs, that COVID-19 is a disease of RAS dysregulation and that observational data with RAS inhibitors suggests they may be beneficial.