The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic is a new wave of emerging infections that the world is struggling with. There are many unanswered questions in this regard, including sex‐specific outcome in coronavirus disease 2019 (COVID‐19).

The clinical consequences of SARS‐CoV‐2 infection vary from asymptomatic to severe or critical. Nearly 80% of cases are asymptomatic or with mild symptoms, 15% have severe disease and 5% become critical.1 Gender and age are major risk factors for SARS‐CoV‐2 infection.2 In addition to the effect of these factors on the prevalence of SARS‐CoV‐2, the clinical outcome varies according to both of them. One study found that in similar age groups, outcomes of COVID‐19 were more severe in men compared to women, as observed in SARS and Middle East respiratory syndrome infections.3 Other investigators reported that the highest mortality rate was found in older men with underlying diseases.4 Another study also reported that men with COVID‐19 had worse outcomes.5 In several country affected by SARSC‐OV‐2 pandemic, most people who die from COVID‐19 are men.6 These studies suggest that men are more susceptible to SARS‐CoV‐2 infection and its clinical outcomes are more severe in men than in women. The potential factors influencing these gender‐dependent differences, should be clarified. Numerous factors, such as the immune system, sex hormones, physiological factors, lifestyle, and sociocultural behaviors are likely to be responsible for these differences. Here we refer to some influential factors:

One of the possible factors causing different outcome of patients with COVID‐19 between two sexes is the immune system. In dealing with viral infections, women's immune systems act differently from men, which create a stronger immune response leading to viral clearance. In general, antibody production level is higher in women compare with men and last longer.7

Differences in women's immune responses can be related to sex hormones and factors related to chromosome X. Estrogen modulates pro‐inflammatory responses as well as immune regulatory genes are located on chromosome X8 so it can be assumed that, the cytokine storm linked to immune dysregulation, occurs less in women compared with men.

So far, researchers believe that the cytokine storm is responsible for lung tissue damage and immunopathogenesis of COVID‐19 infection. Interleukin‐6 is an important component of the cytokine storm and the driving force of the storm, as its level in men is higher than in women.8 High levels of interleukin 6 in men may be related to worse outcomes against women, can indicating a higher risk of cytokine storm formation in male patients.

One study showed that levels of neutralizing antibodies are higher in women with severe COVID‐19 than its level in men. Also, immunoglobulin G (IgG) antibody has been identified more frequently in the early stages of COVID‐19 infection in women, indicating that production of antibodies, specially IgG, in the early days of infection may prevent the disease from progressing and getting worse.9

In short, more antibody production and a lower chance of immune dysregulation in women, may explain the gender differences of outcome during COVID‐19 infection according to the immune system.

The second factor related to outcome, is the gender‐specific difference in the respiratory tract properties. It may be worth noting that men's lungs are larger than women's 10 and is a larger fertile ground to support more SARS‐COV‐2 replication in men. elevated virus replication leads to higher viral load and exacerbation of the COVID‐19 disease.

Another factor is angiotensin‐converting enzyme 2 (ACE2) as a viral receptor. There is conflict in evidence about ACE2 expression levels and its exact role (protective or not) in COVID‐19 infection. ACE2, on the one hand, is a receptor for virus entry to cells, and its higher expression as a viral receptor should exacerbate the infection. On the other hand, it is a key enzyme that prevents lung damage. ACE2 role in the pathogenesis of SARSC‐OV‐2 remains a mystery. one study indicates men have more ACE2 on the endothelium of the pulmonary vessels than women,8 and has a widespread distribution in men's lungs that at least five different cell type express this receptor, while fewer types of cells in women's lunges expose ACE2.11 Since the lung is the main tissue involved in the COVID‐19 pathogenesis,12, 13 a further expression of the ACE2 in this site can lead to an increase in the disease severity.

A recent study reported that ACE2 had a higher expression in different tissues of women, and also believe that high levels of ACE2 in women play a protective role against the COVID‐19 infection.14

ACE2 has two biological forms, membrane‐bound and a soluble form.15 The membrane‐bound form acts as a virus receptor, and its presence exacerbates infection outcome, while its soluble form prevents the virus from attaching to cells and plays a protective role, like neutralizing antibodies. Circulating ACE2 level (soluble form) appears to be higher in women and children than in men, so may play a protective role in these subjects 15 by Competitive inhibition of virus attachment and entry to the target cells. Circulating ACE2 level can act as a contributing factor in determining the disease severity.

it is recommended that more studies should be designed and implemented in the area of ACE2 role, protective or damaging, in pathogenesis and outcome of COVID‐19 infection.

Among other factors that cause sex differences in the outcome of COVID‐19, sex hormones should not be overlooked. As mentioned previously, sex hormones affect immune responses.9, 15 Some studies suggested, estrogen therapy has remarkable role in developing a protective immune responses against COVID‐19.16

Due to the age‐dependent decrease of sex hormones in older people, these hormones can be suggested as therapeutic options,17 and may help to reduce inflammation in elderly patients with COVID‐19.18

The higher mortality rate in men seems to be partly related to the frequency of underlying diseases. One of the most common comorbidities in the development of severe COVID‐19 is cardiovascular disease and also testosterone activates the main pathway of myocardial inflammation while estrogen has a protective effect on cardiovascular disease.19

Another cause of gender‐based disparities is lifestyle, such as smoking. According to one study, COVID‐19 was more severe in smokers than in non‐smokers,20 since men are more likely to smoke than women, smoking can be a potential factor in this disparity.

Although we pointed out some possible factors contributing to sex and gender‐based discrepancy, but since age is also a risk factor for COVID‐19 severity and mortality,7 comparison of the COVID‐19 outcome in both sexes should be performed after age matching.

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 大流行是世界正在努力应对的新一波新兴感染。在这方面有许多悬而未决的问题，包括 2019 年冠状病毒病 (COVID‐19) 的性别特异性结果。

SARS-CoV-2 感染的临床后果从无症状到严重或危重不等。近80%的病例无症状或症状轻微，15%病情严重，5%病情危重。1性别和年龄是感染 SARS-CoV-2 的主要危险因素。2除了这些因素对 SARS-CoV-2 流行的影响之外，临床结果也因两者而异。一项研究发现，在相似的年龄组中，与女性相比，男性 COVID-19 的结果更严重，正如在 SARS 和中东呼吸综合征感染中观察到的那样。3其他研究人员报告说，患有基础疾病的老年男性死亡率最高。4另一项研究还报告说，患有 COVID-19 的男性预后更差。5在几个受 SARSC-OV-2 大流行影响的国家，死于 COVID-19 的大多数人是男性。6这些研究表明，男性更容易感染 SARS-CoV-2，其临床结果在男性中比女性更严重。应该澄清影响这些性别相关差异的潜在因素。许多因素，如免疫系统、性激素、生理因素、生活方式和社会文化行为可能是造成这些差异的原因。这里我们提到一些影响因素：

导致两性 COVID-19 患者结局不同的可能因素之一是免疫系统。在处理病毒感染时，女性的免疫系统与男性不同，这会产生更强的免疫反应，从而清除病毒。一般来说，与男性相比，女性的抗体产生水平更高，持续时间更长。7

女性免疫反应的差异可能与性激素和与 X 染色体相关的因素有关。雌激素调节促炎反应以及免疫调节基因位于 X 8号染色体上，因此可以假设，细胞因子风暴与免疫失调有关，与男性相比，女性较少发生。

到目前为止，研究人员认为，细胞因子风暴是导致 COVID-19 感染的肺组织损伤和免疫发病机制的原因。白细胞介素 6 是细胞因子风暴的重要组成部分和风暴的驱动力，因为其在男性中的水平高于女性。8男性中高水平的白细胞介素 6 可能与对女性的较差结果有关，这可能表明男性患者形成细胞因子风暴的风险较高。

一项研究表明，患有严重 COVID-19 的女性的中和抗体水平高于男性。此外，在女性感染 COVID-19 的早期阶段更频繁地发现了免疫球蛋白 G (IgG) 抗体，这表明在感染早期产生抗体，特别是 IgG，可以防止疾病进展和恶化。9

简而言之，女性产生更多的抗体和较低的免疫失调机会，可以解释根据免疫系统在 COVID-19 感染期间结果的性别差异。

与结果相关的第二个因素是呼吸道特性的性别差异。值得注意的是，男性的肺比女性的 10大，是支持更多 SARS-COV-2 在男性中复制的肥沃土壤。病毒复制升高会导致病毒载量增加和 COVID-19 疾病恶化。

另一个因素是血管紧张素转换酶 2 (ACE2) 作为病毒受体。关于 ACE2 表达水平及其在 COVID-19 感染中的确切作用（保护与否）的证据存在冲突。一方面，ACE2 是病毒进入细胞的受体，它作为病毒受体的更高表达会加剧感染。另一方面，它是防止肺损伤的关键酶。ACE2 在 SARSC-OV-2 发病机制中的作用仍然是一个谜。一项研究表明，男性肺血管内皮上的 ACE2 比女性多，8并且在男性肺中广泛分布，至少有五种不同的细胞类型表达这种受体，而女性弓步中暴露 ACE2 的细胞类型较少。11由于肺是参与 COVID-19 发病机制的主要组织，12、13在该部位进一步表达 ACE2 可导致疾病严重程度增加。

最近的一项研究报告称，ACE2 在女性的不同组织中都有较高的表达，也认为女性体内高水平的 ACE2 对 COVID-19 感染具有保护作用。14

ACE2 有两种生物形式，膜结合形式和可溶形式。15膜结合形式充当病毒受体，其存在会加剧感染结果，而其可溶形式可防止病毒附着在细胞上并发挥保护作用，如中和抗体。女性和儿童的循环 ACE2 水平（可溶形式）似乎高于男性，因此可能 通过竞争性抑制病毒附着和进入靶细胞而在这些受试者中发挥保护作用15 。循环 ACE2 水平可以作为确定疾病严重程度的一个因素。

建议在 ACE2 的作用、保护性或破坏性、COVID-19 感染的发病机制和结果方面设计和实施更多的研究。

在导致 COVID-19 结果出现性别差异的其他因素中，不应忽视性激素。如前所述，性激素会影响免疫反应。9, 15一些研究表明，雌激素治疗在产生针对 COVID-19 的保护性免疫反应方面具有显着的作用。16

由于老年人中性激素的年龄依赖性降低，这些激素可被建议作为治疗选择，17并可能有助于减少老年 COVID-19 患者的炎症。18

男性较高的死亡率似乎部分与基础疾病的频率有关。严重 COVID-19 发展中最常见的合并症之一是心血管疾病，睾酮激活心肌炎症的主要途径，而雌激素对心血管疾病具有保护作用。19

性别差异的另一个原因是生活方式，例如吸烟。根据一项研究，吸烟者的 COVID-19 比不吸烟者更严重，20由于男性比女性更容易吸烟，吸烟可能是造成这种差异的一个潜在因素。

虽然我们指出了一些可能导致性别和性别差异的因素，但由于年龄也是 COVID-19 严重程度和死亡率的风险因素，7应在年龄匹配后对两性 COVID-19 结果进行比较。