In conclusion, Ang II-mediated heterogenous pulmonary vasoconstriction with microthrombotic perfusion defects but not pulmonary vasodilation is likely the predominant mechanism for silent hypoxemia in early COVID-19 pneumonia. Our hypothesis is supported by the fact that the patients with precapillary pulmonary hypertension and hypoxia often demonstrate significant intrapulmonary arteriovenous shunt with increase in alveolar-arterial PaO2 gradient [33]. This hypothesis is further supported by the high incidence of raised PVR and right ventricular dysfunction in early COVID-19 disease [34] and reports of lung perfusion deficits that do not overlap with ground-glass opacities or consolidation and are not associated with major vessel occlusion [10, 35]. Based on this model, we have previously advocated the beneficial role of steroids and anticoagulant in the early to late stages of COVID-19 [10] and this recommendation is now supported by more clinical evidence [36, 37]. We strongly believe determining the predominant pathophysiology ─ heterogenous pulmonary vasoconstriction versus pulmonary vasodilation ─ has an important treatment implication: early pulmonary vasoconstrictors versus vasodilators. Disappointingly, no study has yet evaluated the role of NO therapy at an early stage of COVID-19 disease and our recommendation on the use of early NO therapy in the treatment of symptomatic high risk COVID-19 patients [10] is still under debate [38, 39], the issue certainly warrants high quality randomized clinical trials. Nonetheless, a recent multicentric retrospective study comparing the outcome of COVID-19 disease in the elderly population on antihypertensive with those who were not on any antihypertensive therapy, authors identified significant benefits of ACE inhibitors (ACEIs), AT1R blockers (ARBs) as well as calcium channel blockers in reducing the severity and mortality of COVID-19 [40]. Our hypothesis of “epithelial-endothelial cross-talk” further raises interest in the possible therapeutic role of ACEIs or ARBs in COVID-19.
Conflict of interest statement: None