Dear Editor,

As of August 31, 2020, there have been more than 25 million officially reported confirmed cases of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in the world (updated data available at https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6). Currently, the best strategies for mitigating the damage from COVID‐19 involve policies to encourage social distancing, contact tracing, and the wearing of masks to reduce the spread of the coronavirus. There is no effective treatment for symptomatic patients, with various forms of supportive care being an active area of research. However, certain disparities in the case loads of different ethnicities and different populations are beginning to emerge. Although there are many other factors that are intertwined, one hypothesis at the present moment is that vitamin D supplementation might hold promise as a preventive or therapeutic agent for COVID‐19 since the striking overlap between risk factors for severe COVID‐19 and vitamin D deficiency, including obesity, older age, and Black or Asian ethnic origin.

Vitamin D is a fat‐soluble vitamin that can regulate calcium and phosphorus metabolism, affecting bone growth and muscle health. It also plays significant role in the maintenance of immune homeostasis. Low vitamin D status is associated with many non‐communicable diseases. A variety of studies have shown that 1,25‐(OH)₂D, the active vitamin D metabolite, is involved in the development of several immune‐related diseases, such as psoriasis, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and so on.¹ Low levels of vitamin D is also associated with increased susceptibility to infectious disease. As a regulator of innate immunity, it could regulate the resistance to viruses, including induction of antimicrobial peptides and autophagy. Vitamin D can also be used as an adaptive immune regulatory factor. The active form 1,25(OH)₂D can inhibit inflammation reaction and inhibit inflammatory factor storms.¹ Vitamin D is related to the occurrence and development of many diseases. A recent meta‐analysis has showed that vitamin D supplementation has a protective effect on acute respiratory infections.²

Recent research found that compared with non‐infected people, patients with COVID‐19 have lower vitamin D levels. It suggests that insufficient vitamin D levels in the body increase the risk of COVID‐19 infection. However, another study found no association between vitamin D levels and COVID‐19 test results. Researchers further found that COVID‐19 mortality increases with northerly latitude after adjusting for age suggesting a link with ultraviolet and vitamin D. A study of 20 European nations found an association between the mean levels of vitamin D in various countries and the mortality caused by COVID‐19. However, this cross‐sectional study of the mean level for each country is limited. Also, the number of cases and COVID‐19 mortality for each country is affected by the different measures taken by each country to prevent the spread of infection.^3-5 A recent retrospective cohort study of 489 patients found an association between low vitamin D status (a year before COVID‐19 testing) and a positive COVID‐19 test result. For patients with deficient vitamin D status, the relative risk of testing positive for COVID‐19 was 1.77 times greater than patients with sufficient vitamin D status. Up to now, there is a lack of clinical trials and cohort studies in determining the preventing role of vitamin D in COVID‐19 severity and mortality. However, several retrospective studies have shown that vitamin D levels are related to the clinical outcomes of COVID‐19, such as increasing the appearance of severe respiratory dysfunction and the mortality risk. Low levels of vitamin D have also been reported in severe COVID‐19 patients.³ Some studies demonstrated the protective effects of combined vitamin D, Mg, and vitamin B12 against clinical deterioration of COVID‐19. Therefore, supplementation with vitamin D may play a role in prevention of infection as well as improve the disease outcomes. A recent quasi‐experimental study concluded that vitamin D3 supplementation taken during or just before COVID‐19 was associated with less severe COVID‐19 and better survival rate. However, it is important to note that some of the studies available online are not peer‐reviewed, or authors of some preprints do not have verifiable medical or scientific credentials. The mechanism may be that SARS‐CoV‐2 virus binds to angiotensin converting enzyme 2 (ACE2) receptors as a functional receptor to enter host cells. Subsequent dysregulation of the renin‐angiotensin system may lead to excess cytokine production resulting in prospective fatal acute respiratory disease syndrome. Down‐regulation of ACE2 in lung tissue leads to increased alveolar permeability, causing severe lung injury and lung failure. Vitamin D can upregulate ACE2 receptors in lung microvascular endothelial cells, which can bind the virus to inactivate it.^{3, 4} On the other hand, vitamin D plays an important role in innate and adaptive immune responses. It has an important role in inhibiting the cytokine storm by downregulating of pro‐inflammatory cytokines. It can also exert anti‐viral activities and modulates inflammatory response to viral infection by stimulating cathelicidin release, modulation of toll‐like receptor expression and natural killer (NK) cells function (Figure 1).

Although some clinical findings indicate that vitamin D may reduce the infection rates and mortality of COVID‐19, the evidence for vitamin D prevention and treatment of COVID‐19 is still insufficient. There are some ongoing clinical trials to explore whether vitamin D will affect the clinical outcome of COVID‐19, and whether vitamin D levels are related to SARS‐CoV‐2 infection. Pending results of such trials, people who are at higher risk of vitamin D deficiency including elderly, smokers, patients with chronic diseases, and excess uptake by adipose tissue in obesity should consider taking vitamin D supplements to maintain the circulating 25(OH)D. Although it is still debatable what level of serum 25(OH)D is optimal, guidelines for many countries consider 20 ng/mL (50 nmol/L) adequate. Public Health England updated its advice on vitamin D supplementation in April that everyone should consider taking a daily 10 μg vitamin D supplement. Even if vitamin D supplementation can be shown to provide a benefit in reducing cases or mortalities at the epidemiological level, it is unlikely that vitamin D alone can be a treatment or prevention for COVID‐19 infection. Until then, the only certainty is that vitamin D supplementation for individuals deficient in vitamin D is known to be safe, cost‐effective, and is of benefit for general immune system function and bone health.

亲爱的编辑，

截至 2020 年 8 月 31 日，全球官方报告的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染确诊病例已超过 2500 万例（更新数据请访问 https://gisanddata.maps.arcgis .com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6)。目前，减轻 COVID-19 损害的最佳策略包括鼓励保持社交距离、追踪接触者和戴口罩等政策，以减少冠状病毒的传播。对于有症状的患者没有有效的治疗方法，各种形式的支持治疗是一个活跃的研究领域。然而，不同种族和不同人群的病例数量开始出现一定的差异。尽管还有许多其他因素相互交织，但目前的一个假设是，维生素 D 补充剂可能有望作为 COVID-19 的预防或治疗剂，因为严重 COVID-19 的危险因素与维生素 D 缺乏之间存在惊人的重叠，包括肥胖、老年以及黑人或亚洲人种。

维生素D是一种脂溶性维生素，可以调节钙磷代谢，影响骨骼生长和肌肉健康。它还在维持免疫稳态方面发挥着重要作用。维生素 D 水平低与许多非传染性疾病有关。多项研究表明，活性维生素 D 代谢物 1,25-(OH) ₂ D 参与多种免疫相关疾病的发生，例如牛皮癣、1 型糖尿病、多发性硬化症、类风湿性关节炎和很快。¹维生素 D 水平低也与感染性疾病的易感性增加有关。作为先天免疫的调节剂，它可以调节对病毒的抵抗力，包括诱导抗菌肽和自噬。维生素D还可作为适应性免疫调节因子。活性形式1,25(OH) ₂ D可抑制炎症反应，抑制炎症因子风暴。¹维生素D与多种疾病的发生、发展有关。最近的一项荟萃​​分析表明，补充维生素 D 对急性呼吸道感染具有保护作用。²

最近的研究发现，与未感染者相比，COVID-19 患者的维生素 D 水平较低。这表明体内维生素 D 水平不足会增加感染 COVID-19 的风险。然而，另一项研究发现维生素 D 水平与 COVID-19 检测结果之间没有关联。研究人员进一步发现，在调整年龄后，COVID-19 死亡率随着北纬度的增加而增加，这表明与紫外线和维生素 D 有关。一项针对 20 个欧洲国家的研究发现，不同国家的维生素 D 平均水平与 COVID 引起的死亡率之间存在关联。 ‐19。然而，这种对每个国家平均水平的横断面研究是有限的。此外，每个国家的病例数和 COVID-19 死亡率还受到每个国家为防止感染传播而采取的不同措施的影响。^3-5最近一项针对 489 名患者的回顾性队列研究发现，低维生素 D 状态（在进行 COVID-19 检测前一年）与 COVID-19 检测结果呈阳性之间存在关联。对于维生素 D 缺乏的患者，COVID-19 检测呈阳性的相对风险是维生素 D 充足的患者的 1.77 倍。到目前为止，还缺乏确定维生素 D 对 COVID-19 严重程度和死亡率的预防作用的临床试验和队列研究。然而，几项回顾性研究表明，维生素 D 水平与 COVID-19 的临床结果相关，例如增加严重呼吸功能障碍的出现和死亡风险。据报道，重症 COVID-19 患者的维生素 D 水平也较低。³一些研究证明维生素 D、镁和维生素 B12 联合使用对预防 COVID-19 临床恶化具有保护作用。因此，补充维生素D可能有助于预防感染并改善疾病结果。最近的一项准实验研究得出结论，在 COVID-19 期间或之前补充维生素 D3 与较轻的 COVID-19 严重程度和较高的生存率相关。然而，值得注意的是，一些在线研究没有经过同行评审，或者一些预印本的作者没有可验证的医学或科学证书。其机制可能是SARS-CoV-2病毒与血管紧张素转换酶2（ACE2）受体结合，作为功能性受体进入宿主细胞。随后的肾素-血管紧张素系统失调可能会导致细胞因子产生过多，从而导致致命的急性呼吸道疾病综合征。肺组织中ACE2的下调导致肺泡通透性增加，导致严重的肺损伤和肺衰竭。维生素D可以上调肺微血管内皮细胞中的ACE2受体，从而与病毒结合使其失活。^{3, 4}另一方面，维生素 D 在先天性和适应性免疫反应中发挥着重要作用。它通过下调促炎细胞因子在抑制细胞因子风暴中发挥重要作用。它还可以发挥抗病毒活性，并通过刺激抗菌肽释放、调节 Toll 样受体表达和自然杀伤 (NK) 细胞功能来调节对病毒感染的炎症反应（图 1）。

尽管一些临床研究结果表明维生素D可能降低COVID-19的感染率和死亡率，但维生素D预防和治疗COVID-19的证据仍然不足。目前正在进行一些临床试验，探讨维生素 D 是否会影响 COVID-19 的临床结果，以及维生素 D 水平是否与 SARS-CoV-2 感染有关。在等待此类试验结果之前，维生素 D 缺乏风险较高的人群，包括老年人、吸烟者、慢性病患者以及肥胖者脂肪组织过度摄取，应考虑服用维生素 D 补充剂以维持循环 25(OH)D。尽管血清 25(OH)D 的最佳水平仍存在争议，但许多国家的指南认为 20 ng/mL (50 nmol/L) 就足够了。英国公共卫生部门于 4 月份更新了关于补充维生素 D 的建议，即每个人都应考虑每天补充 10 微克维生素 D。即使维生素 D 补充剂可以在流行病学水平上证明有助于减少病例或死亡率，但单独使用维生素 D 不太可能治疗或预防 COVID-19 感染。在此之前，唯一可以确定的是，为缺乏维生素 D 的个体补充维生素 D 是安全的、具有成本效益的，并且有益于一般免疫系统功能和骨骼健康。