To the Editor :

We read with interest the article of Guillen et al.1 Here, the authors described the management of a kidney transplanted patient infected by SARS‐CoV‐2 that causes novel Coronavirus disease 2019 (COVID‐19). The authors stated that immunosuppressed patients might present with atypical clinical manifestation (fever, diarrhea, fatigue) without respiratory symptoms. Also Li and colleagues2 reported SARS‐CoV‐2 infection in two solid organ transplanted patients. The two heart transplanted patients presented with variable severity of COVID‐19 (one mild and another with more severe manifestations requiring a prolonged hospitalization), however, both survived the event.

It could be possible that the activation of the immune system is responsible for the damage caused by SARS‐CoV‐2. The activation of the immune system, especially T cells, represents a landmark of histological picture of lung injury related to COVID‐19. Xu et al3 investigated the pathological characteristics of COVID‐19 by human postmortem biopsies. They found that histological picture of lung injury related to COVID‐19 is similar to Acute Respiratory Distress Syndrome (diffuse alveolar damage, cellular fibromyxoid exudates, desquamation of pneumocytes and hyaline membranes). Also, they analyzed the characteristics of peripheral CD4 and CD8 T cells. They found a hyperactivated status, with an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells. The authors concluded that overactivation of T cells accounts for, in part, the severe immune injury.

Although immunosuppressed solid organ transplanted patients could be more susceptible to SARS‐CoV‐2 infection with severe clinical manifestations, the anti‐inflammatory effects of immunosuppression could diminish the clinical expression of disease.4 Tacrolimus (FK506) and cyclosporine (Cyclosporin A, CsA), the most commonly used drugs for maintenance immunosuppression following solid organ transplantation, reduce the production of interleukin‐2 (IL‐2), a regulator of proliferation, survival, and maturation for all T cell. Furthermore, FK506 and mycophenolic acid inhibit interleukin‐17 (IL‐17) production with a stronger inhibitory effect on Th17.5

If clinical manifestation and lung injury of COVID‐19 are in part mediated by overactivation of T cells immune response, data reported in the literature suggests that clinical conditions associated with impairment in T cell response, like immunosuppression in solid organ transplanted patients, could alter the clinical course and reduced the rate and severity of lung injury. Although transplanted patients could be more susceptible to SARS‐CoV‐2 infection with atypical manifestations, the chronic use of immunosuppressive drugs could represent a “protective factor” for the serious clinical complication of the disease. This hypothesis could also explain why patients with lymphopenia are those with the worst outcomes. Lymphopenia could be caused by lung sequestration of hyperactivated T cell and immunodepression drug‐related could limit this effect.

Actually, except for the case reports mentioned above, we found no data about the incidence and outcome of COVID‐19 in this cluster of patients. Furthermore, immunosuppressive drugs could be a valid “therapeutic” choice, reducing the activity of the T cell immune system and preventing organ injury.

致编辑：

我们饶有兴趣地阅读了 Guillen 等人的文章。1在这里，作者描述了感染 SARS-CoV-2 并导致 2019 年新型冠状病毒病 (COVID-19) 的肾移植患者的处理。作者指出，免疫抑制患者可能会出现不典型的临床表现（发烧、腹泻、疲劳）而没有呼吸道症状。Li 及其同事2还报告了两名实体器官移植患者感染了 SARS-CoV-2。两名心脏移植患者的 COVID-19 严重程度各不相同（一名轻度，另一名表现较严重，需要长期住院），但是，他们都在事件中幸存下来。

免疫系统的激活可能是造成 SARS-CoV-2 造成损害的原因。免疫系统，尤其是 T 细胞的激活，代表了与 COVID-19 相关的肺损伤组织学图像的一个里程碑。徐等3通过人体死后活检研究了 COVID-19 的病理特征。他们发现与 COVID-19 相关的肺损伤的组织学图像类似于急性呼吸窘迫综合征（弥漫性肺泡损伤、细胞纤维粘液样渗出物、肺细胞和透明膜的脱屑）。此外，他们还分析了外周 CD4 和 CD8 T 细胞的特征。他们发现了一种过度激活状态，CD4 T 细胞中高度促炎性 CCR6+ Th17 的浓度增加。作者得出结论，T 细胞的过度激活在一定程度上解释了严重的免疫损伤。

尽管免疫抑制的实体器官移植患者可能更容易感染具有严重临床表现的 SARS-CoV-2，但免疫抑制的抗炎作用可以减少疾病的临床表现。4他克莫司 (FK506) 和环孢素 (Cyclosporin A, CsA) 是实体器官移植后维持免疫抑制最常用的药物，可减少白细胞介素 2 (IL-2) 的产生，白细胞介素 2 (IL-2) 是细胞增殖、存活和成熟的调节因子所有 T 细胞。此外，FK506 和霉酚酸抑制白介素-17 (IL-17) 的产生，对 Th17 具有更强的抑制作用。5个

如果 COVID-19 的临床表现和肺损伤部分是由 T 细胞免疫反应的过度激活介导的，文献中报道的数据表明，与 T 细胞反应受损相关的临床状况，如实体器官移植患者的免疫抑制，可能会改变临床过程并降低肺损伤的发生率和严重程度。尽管移植患者可能更容易感染表现不典型的 SARS-CoV-2，但长期使用免疫抑制药物可能是该病严重临床并发症的“保护因素”。这个假设也可以解释为什么淋巴细胞减少症患者的结局最差。淋巴细胞减少可能是由于过度活化的 T 细胞在肺部的隔离引起的，与免疫抑制药物相关的药物可能会限制这种影响。

实际上，除了上述病例报告外，我们没有发现关于这组患者中 COVID-19 的发病率和结果的数据。此外，免疫抑制药物可能是一种有效的“治疗”选择，可降低 T 细胞免疫系统的活性并防止器官损伤。