Facing the COVID‐19 pandemic, we were intrigued by the difference of incidence and disease severity between men and women (60%‐70% of deaths occurring in men). This disparity remains significant even after age stratification in all age groups (postmenopausal women vs age‐matched men), suggesting a partially hormone‐independent mechanism.

Coincidentally, during the last month we were reviewing the infectious complications of Bacillus Calmette‐Guerin (BCG) bladder instillation. BCG is used for non–muscle‐invasive bladder cancer (NMIBC) after standard surgical treatment: surprisingly, among 243 BCGitis cases reported in the literature, only three were female.

The higher number of BCGitis in men has been justified so far considering the worldwide M/F ratio for bladder cancer (3.5:1).¹ In addition, for anatomical reasons, traumatic catheterization is more common in men, potentially providing a wider port of entry for systemic BCG dissemination.² However, these two issues are not strong enough to justify the overwhelming unbalanced gender ratio found in BCGitis (M/F 49:1).

Bacillus Calmette‐Guerin acts against NMIBC mainly by stimulating non‐specific immune response and a torrent of Th‐1 cytokines, including IFN‐γ.³ IFN‐γ plays a role against intracellular infection by pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis.⁴ A reduced level of IFN‐γ has been observed in men, both prior than after surgery.⁵

Bacillus Calmette‐Guerin used as a tubercular vaccine is generally administered to young patients and induced IgG and IFNγ generally diminish with age if a booster dose is not given.⁴ On the contrary, BCG used as immune therapy for non–muscle‐invasive bladder cancer is administered to adult elderly patients, and according to the schedule of the treatment, the instillations are repeated periodically resulting in a more sustained immune response.

Constitutional differences in male and female immune systems have long been described. The underlying biological mechanisms are not fully understood. They are supposed to result from steroid hormones secreted by gonads and/or different cytokines response.

With regard to steroid hormones, in vivo studies^6-8 reported a protective role of oestrogens against respiratory infections. For instance, high levels of 17β‐estradiol are related to better clinical outcomes in mice infected with influenza A.⁶

Inflammatory immune responses, as well as the number and activity of innate immune cells, are higher in women. Human studies demonstrated that plasmacytoid dendritic cells of woman exhibit increased expression of interferon (IFN)‐α, following toll‐like receptor (TLR)‐7 stimulation.⁹ Furthermore, TLR‐associated genes that activate IFN pathway are significantly upregulated in woman after vaccinations.¹⁰

To be kept in mind, both in vitro and in vivo studies demonstrated the efficient role of IFNs against SARS‐CoV.^{11, 12}

In light of the above, we hypothesize that major susceptibility of male gender to COVID‐19 and to BCG infection might share a common interferon‐centred physiopathological basis that needs to be deeply investigated (Figure 1).

面对 COVID-19 大流行，我们对男性和女性之间发病率和疾病严重程度的差异（60%-70% 的死亡发生在男性）很感兴趣。即使在所有年龄组（绝经后女性与年龄匹配的男性）中进行年龄分层后，这种差异仍然显着，这表明部分激素独立机制。

巧合的是，在上个月，我们正在审查卡介苗 (BCG) 膀胱灌注的感染并发症。BCG 用于标准手术治疗后的非肌肉浸润性膀胱癌 (NMIBC)：令人惊讶的是，在文献报道的 243 例 BCG 炎病例中，只有 3 例为女性。

The higher number of BCGitis in men has been justified so far considering the worldwide M/F ratio for bladder cancer (3.5:1).¹ In addition, for anatomical reasons, traumatic catheterization is more common in men, potentially providing a wider port of entry for systemic BCG dissemination.² However, these two issues are not strong enough to justify the overwhelming unbalanced gender ratio found in BCGitis (M/F 49:1).

Bacillus Calmette‐Guerin acts against NMIBC mainly by stimulating non‐specific immune response and a torrent of Th‐1 cytokines, including IFN‐γ.³ IFN‐γ plays a role against intracellular infection by pathogens such as Mycobacterium tuberculosis and Mycobacterium bovis.⁴ A reduced level of IFN‐γ has been observed in men, both prior than after surgery.⁵

Bacillus Calmette‐Guerin used as a tubercular vaccine is generally administered to young patients and induced IgG and IFNγ generally diminish with age if a booster dose is not given.⁴ On the contrary, BCG used as immune therapy for non–muscle‐invasive bladder cancer is administered to adult elderly patients, and according to the schedule of the treatment, the instillations are repeated periodically resulting in a more sustained immune response.

Constitutional differences in male and female immune systems have long been described. The underlying biological mechanisms are not fully understood. They are supposed to result from steroid hormones secreted by gonads and/or different cytokines response.

关于类固醇激素，体内研究^6-8报道了雌激素对呼吸道感染的保护作用。例如，高水平的 17β-雌二醇与感染甲型流感的小鼠的更好临床结果有关。⁶

女性的炎症免疫反应以及先天免疫细胞的数量和活性更高。人体研究表明，在 toll 样受体 (TLR)-7 刺激后，女性浆细胞样树突状细胞的干扰素 (IFN)-α 表达增加。⁹此外，在女性接种疫苗后，激活 IFN 通路的 TLR 相关基因显着上调。¹⁰

请记住，体外和体内研究都证明了 IFN 对 SARS-CoV 的有效作用。^11、12

鉴于上述情况，我们假设男性对 COVID-19 和 BCG 感染的主要易感性可能具有共同的以干扰素为中心的生理病理学基础，需要深入研究（图 1）。