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.

越来越多的证据支持这样一个前提：锌和血管紧张素转换酶 2（ACE2，一种锌酶）的缺乏决定了 2019 年冠状病毒病（COVID-19）的严重程度。ACE2 是肾素-血管紧张素系统 (RAS) 的一部分，充当调节血压的反馈控制系统，将血压保持在正常范围内。病毒要感染人，就必须进入人的细胞内。引起 COVID-19 的病毒利用 ACE2 进入细胞。可以把这想象成一个来自外太空的入侵者通过你的巡航控制系统攻击你的汽车；RAS 就像汽车的巡航控制系统。接下来会发生什么取决于您的巡航控制系统的稳健程度。如果您的巡航控制系统年轻且健康，那么可能不会发生什么；您的汽车可能会减速或加速。但如果你的巡航控制系统状况不佳，攻击可能会破坏整个速度控制系统；您的汽车可能会突然刹车或失控并发生车祸。反馈控制系统（自然的或人造的）旨在保持动态系统受控，但在某些情况下可能会导致系统完全失控。RAS 由两个反馈环路组成：ACE 环路提供放大作用，增加促炎细胞因子和血压；ACE2 环路提供精细控制并减轻 ACE 环路的血管收缩、促炎和血栓形成作用。通常情况下是存在平衡的，但在 COVID-19 的情况下，锌和 ACE2 的潜在缺乏可能会导致失衡。随着病毒进入，ACE2 的严重下调会加剧这种情况，随着 RAS 系统失去控制，血管紧张素 II (Ang II) 增加，从而达到“临界点”，从而导致下游血管收缩、炎症和血栓形成。这些反过来又会导致“严重 COVID-19”中常见的并发症，例如急性呼吸窘迫综合征 (ARDS) 或细胞因子风暴，通常在患病第二周的高危患者中出现。该模型表明补充锌可以补充 ACE2 中的锌、稳定 ACE2 轴并防止 RAS 破坏。这将防止 Ang II 的血管收缩、炎症和血栓形成作用，从而防止严重的 COVID-19 并发症，这些并发症会导致潜在缺锌的高危患者出现高发病率和死亡率。锌补充剂是可用的、易于使用且相对安全的。需要进行随机临床试验来确认补锌的安全性和有效性，以降低高危患者的 COVID-19 严重程度和道德水平。由于缺乏锌和活性 ACE2 的患者补充锌和活性 ACE2 可能需要数周时间，因此高危人群可能需要在感染新冠病毒之前补充锌和活性 ACE2。