Patients with COVID-19 infection are at risk of acute respiratory disease syndrome (ARDS) and death. The tissue receptor for COVID-19 is ACE2, and higher levels of ACE2 can protect against ARDS. Angiotensin receptor blockers and statins upregulate ACE2. Clinical trials are needed to determine whether this drug combination might be used to treat patients with severe COVID-19 infection.

Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved.

The international community has responded to the Ebola outbreak in West Africa with a 'top down' approach. This has contributed to outbreak control, but has done much less to reduce the high mortality rate in individual patients. Ebola patients experience a breakdown in endothelial barrier integrity that leads to massive fluid losses and vascular collapse. Statins and angiotensin receptor blockers (ARBs) maintain or restore endothelial barrier integrity. Local physicians in Sierra Leone have treated approximately 100 consecutive Ebola patients with atorvastatin and irbesartan, and all but two inadequately treated patients have survived. The results of this experience have not been released and they need to be reviewed and validated. Unlike other treatments that target the Ebola virus itself, this 'bottom up' approach to treatment represents a paradigm shift by targeting the host response to infection. Treatment with these safe, inexpensive generic agents could be implemented readily throughout West Africa.

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W e thank Eftychios Siniorakis and colleagues for their thoughtful letter on how repurposing statins and angiotensin receptor blockers (ARBs) for coronavirus disease 2019 (COVID-19) treatment might affect patients with heart failure (1). Our understanding of the pathophysiology of COVID-19 disease has advanced rapidly in the past few months. The immunological dysregulation associated with the disease and the cardiovascular effects of infection (and especially the role of angiotensin converting enzyme 2 [ACE2]) have been comprehensively reviewed (2-7). Some patients who develop acute respiratory distress syndrome (ARDS) can be severely hypoxic and yet show relatively normal pulmonary compliance (8). Endothelial dysfunction and intense inflammation seem to be important contributors to their distress (9). In addition, pulmonary microvascular coagulopathy, sometimes associated with pulmonary or systemic embolization, has added a new dimension to clinical care (10-12). Many physicians have added anticoagulation to their treatments (13). Recently, van de Veerdonk and colleagues called attention to the contribution of the kallikrein-kinin system to COVID-19-induced ARDS (14, 15). Although much attention has been focused on the relationship between the renin-angiotensin system (RAS) and COVID-19 (5-7), there is considerable cross talk between the RAS and kallikrein-kinin systems (14-16). Experimentally, a reduction in ACE2 activity can impair inactivation of the B1 bradykinin receptor and this can be associated with an increase in inflammation-induced acute lung injury (17). This is the backdrop for the concern raised by Siniorakis et al.: some COVID-19 patients might have heart failure and be receiving combination treatment with an angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI). Neprilysin is known to degrade bradykinin, and ARB treatment can increase bradykinin levels (18). Thus, if bradykinin is involved in the genesis of the intense inflammation and microvascular coagulopathy seen in many COVID-19 patients (11, 14, 15), the increase in bradykinin levels that accompanies ARB and neprilyin inhibitor treatment might be harmful. (Angiotensin converting enzyme inhibitors [ACEIs] also upregulate bradykinin, and they are more commonly associated with acute episodes of angioedema than are ARBs.) To our knowledge, there have been no reports of COVID-19 patients who were treated with both ARNIs and ARBs or ACEIs. We believe that physicians should consider combination statin/ARB treatment of severely ill COVID-19 patients (19). Both drugs have beneficial effects on inflammation, coagulation abnormalities, and endothelial dysfunction. Recently published observational studies suggested that ACEIs, ARBs, and statins are associated with improved outcomes in COVID-19 patients (20, 21), although not all studies have shown this (22). Whether ARNI treatment of COVID-19 patients would be harmful remains to be