Dear Editor,

This study concerns the clinicopathologic correlation of 50 decedents of 2019 coronavirus disease (COVID‐19) due to severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) from among 250 reported patients succumbing to COVID‐19 illness (1-7) who underwent detailed postmortem neuropathological studies. This disease, which starts in the lungs, is a multisystem disorder affecting all major organs including the brain. These cases provide a more complete picture of COVID‐19 illness, and are important in the development of effective treatment strategies.

As shown in Table 1, older age, male gender, increased serum cytokine and pro‐coagulation markers, and critical care hospitalization for ≤10 days prior to death characterized the cohort. Immediate causes of death were ascribed to cardiopulmonary and multiple organ failure, intracranial hemorrhage and pulmonary embolus. SARS‐CoV‐2 detection in brain tissue by polymerase chain reaction was negative in all cases. Seventeen (36%) cases showed focal or diffuse cortical, brainstem, or leptomeningeal inflammation, characterized (in five) as T‐cell‐mediated based upon flow cytometry. A variety of comorbid pathology in 11 cases (22%) included chronic stroke, Alzheimer, or Lewy body disease and primary brain tumor.

Eight patients had unsuspected encephalitis affecting predominant subcortical white matter (2), brainstem nuclei and white matter tracts (3) and the cerebellum (5). Inflammatory T‐cell infiltrates with clusters of macrophages and axonal injury tracking along vessels resembled acute disseminated encephalomyelitis (ADEM) in two cases (2, 5), including one (5) with neuronophagia and microglial nodules, and another with expression of angiotensin converting enzyme (ACE)2 receptor along capillary endothelia cells (2). Six patients of different ages and with differing comorbidity showed histopathological features of encephalitis including localized perivascular and interstitial infiltrates with neuronal cell loss and axonal degeneration involving brainstem nuclei and tracts without territorial infarctions, or evidence of virus infiltration.

This small cohort of critically ill cases of COVID‐19 reveals several important findings. First, hypoxia‐ischemia evident in the majority of cases does not account for all relevant neuropathological features of severe COVID‐19. Second, patients presenting with elevated levels of circulating interleukin (IL)‐6, IL‐8, and tumor necrosis factor (TNF)‐α, suggests activation of innate and adaptive immunity indicative of a cytokine storm. Together with increased serum d‐dimer and markers of hypercoagulability in 42% of cases (1, 2), affected patients risk thrombotic, and hemorrhagic parenchymal tissue infarction so noted in nine (18%) cases. Third, eight (16%) cases with ADEM‐like features (2, 5) or frank histologic evidence of brainstem encephalitis suggest the need for an index of suspicion in clinically compatible cases.

There were several limitation to this study. First, there was missing data about age, gender, and the cause of death in some cases. Second, case series were often small and unselected. Third, among the various studies included, there were often contradictory conclusions about the significance of inflammatory vascular changes in regards to active central nervous system involvement. In this regard, all patients were in a very critical condition necessitating intensive care due to cardiopulmonary and systemic organ failure. In the absence of comparison to controls, it is not possible to know with certainty whether the histopathological findings suggesting inflammatory vasculopathy, in up to a third of cases, were merely nonspecific.

Awaiting randomized, placebo‐controlled trials of antiviral therapy to treat severe COVID‐19, or a safe and effective vaccine, this small sample adds to the urgent call to identity neuroprotective therapy. Present research focuses on inhibitors of the cytokine storm using the IL‐6 receptor antagonist tocilizumab (ClinicalTrials.gov Identifier: NCT04377659) and the anti‐IL‐6 monoclonal antibody clazakizumab (ClinicalTrials.gov Identifier: NCT04363502).

亲爱的编辑，

本研究涉及 250 名报告的死于 COVID-19 疾病的患者中 50 名死于严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）的 2019 冠状病毒病（COVID-19）死者的临床病理学相关性（1-7 ) 谁接受了详细的死后神经病理学研究。这种从肺部开始的疾病是一种影响包括大脑在内的所有主要器官的多系统疾病。这些病例提供了对 COVID-19 疾病的更完整的描述，并且对于制定有效的治疗策略很重要。

如表 1 所示，年龄较大、男性、血清细胞因子和促凝标志物增加以及死亡前 ≤ 10 天的重症监护住院是该队列的特征。直接死亡原因归咎于心肺和多器官衰竭、颅内出血和肺栓塞。在所有病例中，通过聚合酶链反应在脑组织中检测到的 SARS-CoV-2 均为阴性。17 例 (36%) 病例显示局灶性或弥漫性皮质、脑干或软脑膜炎症，根据流式细胞术表征（5 例）为 T 细胞介导。11 例 (22%) 的多种合并症病理包括慢性中风、阿尔茨海默病或路易体病和原发性脑肿瘤。

8 名患者出现意外脑炎，主要影响皮质下白质 ( 2 )、脑干核和白质束 ( 3 ) 以及小脑 ( 5 )。炎性 T 细胞浸润与巨噬细胞簇和沿血管追踪的轴突损伤类似于急性播散性脑脊髓炎 (ADEM)，在两例 ( 2, 5 ) 中，其中一例 ( 5 ) 伴有神经吞噬症和小胶质结节，另一例伴有血管紧张素转换酶的表达(ACE)2 受体沿毛细血管内皮细胞 ( 2）。六名不同年龄和不同合并症的患者表现出脑炎的组织病理学特征，包括局部血管周围和间质浸润，伴有神经元细胞丢失和轴索变性，涉及脑干核和脑干束，无局部梗死或病毒浸润的证据。

这一小组 COVID-19 重症病例揭示了几个重要的发现。首先，在大多数病例中明显的缺氧缺血并不能解释严重 COVID-19 的所有相关神经病理学特征。其次，循环白细胞介素 (IL)-6、IL-8 和肿瘤坏死因子 (TNF)-α 水平升高的患者表明先天性和适应性免疫的激活表明细胞因子风暴。连同42% 的病例 ( 1, 2 ) 中血清d-二聚体和高凝状态标志物的增加，受影响的患者有血栓形成和出血性实质组织梗塞的风险，因此在 9 例 (18%) 病例中注意到。第三，八个 (16%) 具有类似 ADEM 特征的案例 ( 2, 5) 或脑干脑炎的明确组织学证据表明需要对临床相容的病例进行怀疑。

这项研究有几个局限性。首先，在某些情况下，缺少有关年龄、性别和死因的数据。其次，病例系列通常很小且未经选择。第三，在纳入的各种研究中，关于炎症性血管变化对活动性中枢神经系统受累的重要性的结论往往相互矛盾。在这方面，所有患者都处于非常危急的状态，由于心肺和全身器官衰竭而需要重症监护。在没有与对照组进行比较的情况下，不可能确切地知道在多达三分之一的病例中提示炎性血管病变的组织病理学发现是否仅仅是非特异性的。

在等待治疗严重 COVID-19 的抗病毒疗法的随机、安慰剂对照试验或安全有效的疫苗，这个小样本增加了对识别神经保护疗法的紧迫呼吁。目前的研究重点是使用 IL-6 受体拮抗剂托珠单抗（ClinicalTrials.gov 标识符：NCT04377659）和抗 IL-6 单克隆抗体 clazakizumab（ClinicalTrials.gov 标识符：NCT04363502）来抑制细胞因子风暴。