Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Dear Editor

We read the article of Tao Chen and researchers [1] with great interest. Their results show that recently coronavirus disease-19 (COVID-19) outbreak, 113 COVID-19 patients with sepsis and acute respiratory distress syndrome (ARDS) did not be survived. Of them, 95.8% (23/24) patients with hypoxic encephalopathy died in hospitalized. We agree with their work, but the diagnosed criteria of hypoxic encephalopathy was not described.

As we know, new sepsis-3 is defined sepsis as a life-threatening organ dysfunction due to a dysregulated host response to infection. [2] Moreover, in COVID-19 outbreak, older patients are especially at an high risk for life‐threatening respiratory, cardiovascular, and cerebral complications. [3] These cerebral complications or central nervous system (CNS) manifestations caused by COVID-19 can range from dizziness or headache, seizure and impaired consciousness, and acute cerebrovascular disease. [4] Actually, according to the new definition of sepsis-3, all abovemetioned term can generally be called sepsis-associated acute brain dysfunction, including COVID-19-associated encephalo -pathy without virus crossing the blood-brain barrier (BBB), meningitis/encephalitis due to COVID-19 direct into CNS, and vasculopathy/stroke caused by COVID-19.

To our knowledge, COVID-19-associated encephalopathy has been reported between Mar to May. [5,6] The authors reported two patients with COVID-19 pneumonia and one was intubated for acute hypoxemic respiratory failure. Their characteristics included systemic inflammatory response, impaired consciousness (from delirium to lethargy). The brain image of case 1 has not showed any acute lesion and another case showed a small hyperintense signal lesson on Diffusion weighted images(DWI) in the left parietocoritcal region. Electroencephalographies (EEG) of two cases were confirmed having diffuse slowing. The cerebrospinal fluid (CSF) analysis of two patients did not show any evidence of CNS infection ( i.e., normal cell count, negative PCR COVID-19, and negative other microbes). These authors indicated that the cause of the encephalopathy in COVID-19 is multifactorial. Also, some authors [7] reported a first case of COVID-19-associated acute necrotizing encephalopathy (ANE) with altered mental status; her DWI image showed hemorrhagic rim enhancing lesions in the bilateral thalami, medial temporal lobes, and subinsular regions. Moreover, CSF bacterial culture showed no growth, and tests for herpes simplex virus 1 and 2, varicella zoster virus, and West Nile virus were negative. But, the COVID-19 in the CSF was not to be performed and her CSF analysis was limited due to a traumatic lumbar puncture. These authors considered that ANE is a rare encephalopathy caused by COVID-19 and other virus due to an intracranial cytokine storm.

Interestingly, Scullen,et al in May [8] reported on twenty patients with COVID-19-associated encephalopathy, 2 cases with COVID-19- associated ANE，and 5 with COVID-19-associated vasculopathy in a series of 27 COVID-19. Due to respiratory failure and hypoxiemia, all cases was intubated and transferred to the RICU. Most of COVID-19-associated encephalopathy and vasculopathy with diffuse or multifocal subcortical lesions was confirmed by EEG or CT/MRI-DWI, only 1 case with features of hypoxic injury. More recently, Benameur et al [9] reported three COVID-19 cases (including 2 encephalopathy and 1 encephalitis) with increased cytokine in CSF, supporting that cytokine is most likely to lead to BBB leakage and brain edema. [10] Futhermore, the brain edema had been demonstrated by autopsy from died COVID-19 cases. [11]

Despite the data from Chen et al showing that 100% of sepsis patients had acute respiratory failure/ARDS and hypoxiemia, their data also showed that those patients had severe systemic inflammatory response and cytokine storms (increased tumour necrosis factor in blood)；suggesting that the mechanisms of encephalopathy are not likely to be explained by a single cause. Moreover, the potential mechanisms of COVID-19-associated encephalopathy or SAE is also related to the sereve inflammation, cytokine storm, sepsis-induced coagulopathy, hypoxiemia, and neurovirulence. [9-13] Thus, we consider that the COVID-19- associated encephalopathy may not only be masquerading as hypoxic encephalopathy, but also imitating as acute stroke.

Unlike meningitis/encephalitis caused by COVID-19, the CSF analysis can be showed an increased white cell count and with positive PCR. Whereas, the encephalopathy caused by COVID-19 pneumonia, its CSF analysis would only indicate an elevated pressure, mildly elevated protein level, and normal white cell count and glucose level as well as negative PCR. Yet, the diagnosis of COVID-19-associated encephalopathy has to be on the clinical manifestations with acute brain dysfunction (from altered mental status to focal or diffuse neurological deficits), images of COVID-19 pneumonia, without a significant evidence of direct CNS infection, and ruled out other encephalopathy/effects of sedatives.

According to the report from WHO, current about 8 million cases with COVID-19 were diagnosed in global, and near half million of them died of acute organ failure. Thus, recognizing the COVID-19- associated encephalopathy as a common acute organ failure and with high risk of death is very important for surviving COVID-19. Yet, it is necessary to further exploring its pathogenesis, clinical manifestations, and treatment.

Competing interests
No competing interests.

References
1. Chen T, Wu D, Chen H, et al, Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020 Mar 26;368:m1091.
2. SingerM,DuetschmenCS,SeymourCW,etal.TheThird International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:801-810.
3. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID‐19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323 (13):1239– 1242
4. Mao,L, Jin,H, Wang,M, et al.Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China. JAMA Neurol,2020; e201127
5.Filaov A, Sharma P, Hindi F, et al. neuroloical complications of coronavirus disease (COVID-19): encephalopathy. Cureus.2020 12: e7352.
6. Espinosa PS, Rizvi Z, Sharma P, et al. Neurological Complications of Coronavirus Disease (COVID-19): Encephalo –pathy, MRI Brain and Cerebrospinal Fluid Findings: Case2. Cureus. 2020 2;12(5):e7930. doi: 10.7759/ cureus. 7930.
7. Poyiadji N, Shahib G, Noujaim D, et al. COVID-19- associated acute hemorrhagic necrotizing encephalopathy: CT and MRI feayures. Radiology.2020 Mar 31:201187..
8. Scullen T, Keen J, Mathkour M,et al. COVID-19 associated encephalopathies and cerebrovascular disease: the New Orleans experience. .World Neurosurg. 2020 May 28:S1878- 8750(20) 31163-3. 12.
9.Benameur K, Agarwal A, Auld SC,et al. Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Altanta,Georgia, USA,2020. Emerging infectious disease.2020, 26(9)
10. Shulyatnikova T, Verkhratsky A. Astroglia in sepsis associated encephalopathy. Neurochem Res.2019 Feb 18.
11. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020; Feb 18..
12. Zhou Z,Kang H,Li S, et al. understanding the enuroyropic characteristics of SARS-CoV-2: from neurologival mannifestations of COVID-19 to potential neurotropic menchanisms. Journal of neurology.2020,26 May
13. Hess DC, Eldahshan W, Rutkowski E. COVID-19-Related Stroke. Transl Stroke Res. 2020 Jun;11(3):322-32