Previous research has shown that zinc can interfere with proteolytic processing of polyproteins in RNA viruses,¹ and the RNA polymerase of SARS‐CoV‐1.² Coronaviruses frequently cause the common cold. A recent meta‐analysis of seven randomized controlled trials showed that zinc lozenges shortened the mean duration of the common cold by 33% (95% confidence interval: 21%–45%).³ Hospitalized COVID‐19 patients taking supplemental zinc in addition to standard therapy were reported to have lower death rates,⁴ and patients with lower zinc levels on admission had higher mortality.⁵ We recently reported that four outpatient COVID‐19 patients taking high dose oral zinc appear to recover shortly after initiation of zinc.⁶

We retrospectively reviewed consecutive cases of laboratory confirmed COVID‐19 (26 cases), or CDC case definition (two cases), who were started on zinc gluconate/citrate lozenges (23 mg of elemental zinc, 21 patients) or zinc acetate lozenges (15 mg of elemental zinc, seven patients), at a total dosage of 2–2.5 mg/kg/day. Patients were instructed to place one lozenge on their tongue q2–4 h while awake, for a minimum of 10 days. Depending on weight, patients took between 6 and 12 lozenges daily. Written or verbal consent was obtained before treatment. The median number of days between symptom onset and initiation of zinc was 4 days, ranging from 1 to 21 days after onset of symptoms. The mean age was 40: 17 female, 11 male, 3 Hispanic, 3 Asian, 1 African‐American, and 21 Caucasian. Patients were contacted daily for symptom evaluation, and for side effects.

Ten symptoms were scored according to a COVID‐19 symptom checklist, categorized on a 3‐point scale: 0 = no symptoms, 1 = mild, 2 = moderate, 3 = severe. Fever and shortness of breath were further defined as follows: Fever 0 = ≤98.6, 1 = ≥98.6–100.0, 2 = ≥100.0–102.0, 3 = ≥102.0. Shortness of breath (SOB) 1 = moderate intensity exercise, 2 = with walking on flat surface, 3 = with any movement or at rest.

Cough, nausea/vomiting, diarrhea, sore throat, headache, muscle/body aches, fatigue and loss of smell/taste were also assessed.

All 28 patients were improved after 7 days of zinc. Symptomatic improvement began a mean of 1.6 days after zinc treatment. Patients 40 or older took an average of 2.1 days to improve versus 1.4 days for those under 40 (p < .05, t test). The mean COVID score at 7 days was not different for more than 40 aged patients, versus less than 40. The time to improvement did not correlate with the number of days since the onset of symptoms. Nine patients were symptomatic with fever, cough and SOB, before zinc. The mean COVID‐19 symptom score pretreatment was 8.6, versus 1.6 posttreatment, p ≤ .001, Wilcoxon signed‐rank test. No patients were hospitalized after zinc treatment. A comparison of COVID‐19 checklist scores before and after 7 days of zinc is seen in Table 1. Three weeks after zinc two patients were still fatigued: otherwise, all were aymptomatic.

The clinical course of Case 18 is seen in Figure 1. After 2 days of zinc symptoms began to improve.

Four patients complained of nausea after taking zinc (three with acetate, one with gluconate). Zinc acetate was associated with vomiting in two patients when ingested on an empty stomach; thereafter only zinc gluconate was used, after food.

In this retrospective review, initiation of zinc lozenges was followed by symptomatic and objective improvement in 28 consecutive COVID‐19 patients. Zinc gluconate or acetate were initially chosen because they have the most theoretical and experimental effectiveness in the treatment of the common cold,⁷ and zinc gluconate was found to be better tolerated than zinc acetate in our patients. The frequent and high dose regimen was chosen for three reasons. First, zinc may directly inhibit SARS‐Cov‐2 replication; this may require frequent dosing. Second, 2 weeks of 200 mg zinc daily has negligible toxicity. Third, trials of zinc for the common cold that failed were underdosed.⁷ Our use of zinc differs significantly from the previous retrospective report⁴ in frequency (q2–4 h vs. once daily), length of dosage (>10 vs. 5 days), and type of zinc salt (zinc gluconate/acetate vs. sulfate).

The mechanisms by which zinc may help COVID‐19 patients are unknown, but include direct inhibition of viral replication, improvement of mucociliar clearance of SARS‐Cov‐2, reduction of secondary bacterial infection, improvement of lung and kidney tissue healing after ischemia, modulation of T and B lymphocytes, and restoration of interferon‐alpha production.^{8, 9} Zinc supplementation reduces the incidence of pneumonia,¹⁰ and improves outcomes in diarrhea.¹¹ In addition, mild zinc deficiency is often present in those groups at highest risk from COVID‐19; namely, the elderly, diabetic, obese, and hypertensive.⁸

In mild cases of COVID‐19 about 80% of patients begin improving after Day 10; 20% worsen the second week. Zinc treated patients began improvement after 1.6 days on average. Patients older than 40 began recovery slightly later than under 40; however, the clinical outcome at 7 days was the same, and this is not the typical COVID‐19 course.

A recent report¹² by the CDC showed that among symptomatic adult COVID‐19 outpatients, 35% were still symptomatic 2–3 weeks after testing positive. For those with SOB, one‐third experienced these symptoms weeks later. By contrast, all nine of our patients who were SOB began improving after 2 days, and none were SOB after 7 days. Except for fatigue, all 28 patients were symptom free after 3 weeks.

This study has limitations intrinsic to any retrospective review: absence of blinding and a control group. However, given the low toxicity and cost of oral zinc, it would seem prudent to begin testing of zinc in a controlled trial.

先前的研究表明，锌可能会干扰RNA病毒¹和SARS-CoV-1的RNA聚合酶中蛋白质的蛋白水解过程。²冠状病毒经常引起普通感冒。最近对7项随机对照试验的荟萃分析显示，锌锭剂将普通感冒的平均持续时间缩短了33％（95％置信区间：21％–45％）。据报道，除标准治疗外，^3例住院的补充补充锌的COVID-19住院患者的死亡率较低，⁴且入院时锌水平较低的患者死亡率较高。⁵我们最近报道说，四名服用高剂量口服锌的门诊COVID-19患者似乎在锌开始后不久就恢复了。⁶

我们回顾性研究了连续的实验室确诊的COVID‐19病例（26例）或CDC病例定义（2例），这些病例是从葡萄糖酸锌/柠檬酸锭剂（23毫克元素锌，21例）或醋酸锌锭剂（15例）开始的mg元素锌，7例），总剂量为2–2.5 mg / kg /天。要求患者在清醒后2-4小时内在其舌头上放一个锭剂，持续至少10天。根据体重，患者每天服用6至12片锭剂。治疗前已获得书面或口头同意。从症状发作到开始锌摄入之间的中位数天数是4天，范围从症状发作后的1到21天。平均年龄为40岁：女17例，男11例，西班牙裔3例，亚裔3例，非裔美国人1例，白种人21例。每天联系患者进行症状评估，

根据COVID-19症状清单对十个症状进行了评分，分为3点制：0 =无症状，1 =轻度，2 =中度，3 =严重。发烧和呼吸急促进一步定义如下：发烧0 = ≤98.6，1 = ≥98.6–100.0，2 = ≥100.0–102.0，3 =≥102.0。呼吸急促（SOB）1 =中等强度的运动，2 =在平坦表面上行走，3 =任何运动或休息时。

还评估了咳嗽，恶心/呕吐，腹泻，喉咙痛，头痛，肌肉/身体疼痛，疲劳和气味/味觉丧失。

补锌7天后所有28例患者均得到改善。锌治疗后平均1.6天开始出现症状改善。40岁或以上的患者平均需要2.1天才能改善，而40岁以下的患者则需要1.4天（p  <.05，t检验）。40多名老年患者在7天时的平均COVID评分与40例相比没有差异。改善时间与症状发作后的天数无关。9名患者在服用锌前有发烧，咳嗽和SOB症状。治疗前平均COVID-19症状评分为8.6，而治疗后为1.6，p ≤.001，Wilcoxon符号秩检验。锌治疗后无患者住院。表1比较了锌7天之前和之后COVID-19清单得分的比较。锌后三周，两名患者仍感到疲劳：否则，所有患者均无症状。

案例18的临床过程如图1所示。经过2天的锌症状开始改善。

四名患者服用锌后抱怨恶心（三名服用醋酸盐，一名服用葡萄糖酸盐）。两名空腹摄入乙酸锌的患者呕吐。之后，在食用后仅使用葡萄糖酸锌。

在这项回顾性审查中，开始使用含锌锭剂后，连续28例COVID-19患者的症状和客观症状得到改善。最初选择葡萄糖酸锌或乙酸锌是因为它们在普通感冒的治疗中具有最理论上和实验上的有效性，⁷并且在我们的患者中发现葡萄糖酸锌比乙酸锌具有更好的耐受性。选择频繁且高剂量的治疗方案有以下三个原因。首先，锌可能直接抑制SARS-Cov-2的复制。这可能需要经常加药。第二，每天200毫克锌的2周毒性可忽略不计。第三，对普通感冒失败的锌的试验剂量不足。⁷我们对锌的使用与以前的回顾性报告有显着差异⁴ 频率（q2–4小时vs.每天一次），剂量时长（> 10 vs. 5天）和锌盐的类型（葡萄糖酸锌/乙酸锌对硫酸盐）。

锌可帮助COVID-19患者的机制尚不清楚，但包括直接抑制病毒复制，改善SARS-Cov-2的黏膜纤毛清除率，减少继发性细菌感染，改善缺血后肺和肾脏组织的愈合，调节T和B淋巴细胞的分布，以及干扰素α产生的恢复。^8，9补锌减少了肺炎的发生，¹⁰并改善了腹泻的预后。¹¹此外，在那些因COVID-19风险最高的人群中经常存在轻度锌缺乏症。即老年人，糖尿病，肥胖和高血压。⁸

在COVID-19的轻度病例中，约80％的患者在第10天后开始好转。第二周恶化了20％。锌治疗的患者平均1.6天后开始好转。40岁以上的患者开始康复的时间略晚于40岁以下的患者。但是，第7天的临床结局是相同的，这不是典型的COVID-19疗程。

CDC的最新报告¹²显示，在有症状的成年COVID-19成人门诊患者中，有35％的患者在测试呈阳性后2-3周仍然有症状。对于那些患有SOB的人，几周后出现了这些症状。相比之下，我们所有的9名SOB患者在2天后开始好转，而7天后无一例是SOB。除疲劳外，所有28例患者在3周后均无症状。

这项研究有任何回顾性审查固有的局限性：无盲法和对照组。但是，鉴于口服锌的低毒性和低成本，在对照试验中开始测试锌似乎是审慎的做法。