COVID-19: Zinc and Angiotensin-Converting Enzyme 2 (ACE2) Deficiencies as Determinants of Risk and Severity of Disease: A Narrative Review.

A growing body of evidence supports the premise that deficiencies of zinc and angiotensin-converting enzyme 2 (ACE2, a zinc enzyme) determine severity of coronavirus disease 2019 (COVID-19). ACE2 is part of the renin-angiotensin system (RAS) and acts as a feedback control system moderating blood pressure, keeping blood pressure within normal limits. For a virus to infect a person, the virus has to get inside the person's cells. The virus that causes COVID-19 uses ACE2 to get into the cell. Think of this like an invader from outer space attacking your car by getting in through your cruise control; the RAS is like the cruise control of your car. What happens next depends on how robust your cruise control is. If your cruise control is young and healthy perhaps very little happens; your car may slow down or speed up a bit. But if your cruise control is in poor condition the attack might disrupt the entire speed control system; your car may brake suddenly or speed out of control and crash. Feedback control systems (natural or man-made) are designed to keep dynamic systems in control, but under certain situations can drive the system completely out of control. The RAS is composed of two feedback loops: the ACE loop provides amplification, increasing pro-inflammatory cytokines and blood pressure; the ACE2 loop provides fine control and mitigates the vasoconstrictive, pro-inflammatory, and thrombotic actions of the ACE loop. Usually, there is balance, but in the setting of COVID-19, underlying deficiencies of zinc and ACE2 can lead to an imbalance. Exacerbated by the severe downregulation of ACE2 seen with viral entry, a "tipping point" is reached with loss of control of the RAS system resulting in increased angiotensin II (Ang II) causing downstream vasoconstriction, inflammation, and thromboses. These, in turn, lead to complications often seen in "severe COVID-19" such as acute respiratory distress syndrome (ARDS) or cytokine storm, often seen in high-risk patients in the second week of illness. This model suggests that supplemental zinc could replenish zinc in ACE2, stabilize the ACE2 axis, and prevent disruption of the RAS. This would prevent the vasoconstrictive, inflammatory, and thrombotic actions of Ang II, thus preventing the severe COVID-19 complications which cause the high morbidity and mortality seen in high-risk patients with underlying zinc deficiency. Zinc supplements are available, easy to use, and relatively safe. Randomized clinical trials are needed to confirm safety and efficacy of zinc supplementation to decrease severity of and morality from COVID-19 in high-risk patients. Since replenishment of zinc and active ACE2 in patients in whom these are deficient may take weeks, supplementation in high-risk populations prior to COVID infection may be required. Such supplementation should not replace vaccination but may be useful in populations for whom vaccination is not available or for populations exposed to viral variants to which available vaccines have insufficient coverage.