Neurological Implications of Non-critically Ill Patients With Coronavirus Disease 2019 in a Fangcang Shelter Hospital in Wuhan, China

Background: Coronavirus disease 2019 (COVID-19) is a new viral respiratory disease and has become a pandemic. Fever, weakness, and dry cough are the main clinical manifestations. However, little is known about neurological symptoms of non-critically ill COVID-19 patients. Objective: To investigate the neurological symptoms and implications of patients with non-critically ill COVID-19 patients. Materials and Methods: This retrospective cohort study investigated all COVID-19 patients admitted to Wuhan East-West Lake Fangcang shelter hospital. Demographic data, clinical manifestations, comorbidities, radiological data, the result of nucleic acid test, and treatments were collected and analyzed. Results: Among 1,682 patients with confirmed non-critically ill COVID-19, 509 patients (30.3%) had neurological symptoms, including myalgia (311, 18.5%), headache (216, 12.8%), fatigue (83, 4.9%), and dizziness (15, 0.9%). One hundred and fourteen patients (6.8%) were the expansion of pulmonary infection according to their chest CT images and medical history. Compared with patients without neurological symptoms, patients with neurological symptoms had a significantly longer length of hospital stay, time of nucleic acid turning negative, and the mean time from onset of symptom to hospital admission (p < 0.05). Patients with neurological symptoms were more likely to occur the expansion of pulmonary infection compared with the patients without neurological symptoms (46/509 [9.0%] vs. 68/1,173 [5.8%]). Conclusions: Non-critically ill COVID-19 patients commonly have neurological symptoms. Neurological symptoms are significantly associated with the processes of COVID-19. Early identification and aggressive treatment are particularly important for COVID-19 patients with neurological symptoms.


INTRODUCTION
COVID-19 is a potentially severe acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has spread rapidly around the world (1)(2)(3)(4). On March 11, the World Health Organization (WHO) declared that the COVID-19 outbreak can be characterized as a pandemic (5). As of 27 June 2020, the data from WHO indicate that there have been 9,653,048 confirmed cases, including 491,128 deaths in just 4 months, which has affected more than 200 countries and regions. The human respiratory system is recognized as the SARS-CoV-2 primary target. Fever, cough, and dyspnea are the most common clinical symptoms at the onset of illness (6,7). Moreover, several studies have confirmed that SARS-CoV-2 is highly similar to SARS-CoV; the latter can invade human multiple systems including lung, trachea/bronchus, stomach, small intestine, brain, and liver, not just the respiratory system (8)(9)(10)(11). Recent researches have shown that digestive symptoms are common in patients with COVID-19, including nausea, vomiting, and diarrhea, and the fecal-oral route may be a potential route for SARS-CoV-2 infection (12)(13)(14)(15)(16). Some experts hold the view that SARS-CoV-2 may invade the brain and central nervous system by the ACE2 receptor (17,18), which is present in the nervous system and skeletal muscles.
A recent study showed that 81% of SARS-CoV-2 nucleic acid-positive patients were classified as mild (non-critically ill patients), which displays non-pneumonia or only mild pneumonia (19). In order to address the drawbacks of home isolation and ease pressures on the designated traditional hospitals, 15 Fangcang shelter hospitals special for noncritically ill COVID-19 patients were rapidly established by the urgent renovation of stadiums and exhibition centers. The diagnostic and classification criteria of COVID-19 are based on the diagnosis and treatment program for novel coronavirus pneumonia issued by the National Health Commission (NHC) of the People's Republic of China (Trial Version 6). All patients who are nucleic acid positive, have mild to moderate symptoms (respiratory rate <30 breaths/min and blood oxygen saturation >93% at resting state), and are quarantined at home are unified transferred to nearby Fangcang shelter hospitals by the government (20)(21)(22)(23).
At present, most of the studies focused on the clinical characteristics of severe or critically ill patients. However, specific information characterizing neurological symptoms of noncritically ill COVID-19 patients remains obscure. The present study aims to investigate the neurological implications of noncritically ill COVID-19 patients and provide references for the prevention and treatment of the disease.

MATERIALS AND METHODS
This single-center retrospective cohort study was performed at Wuhan East-West Lake Fangcang shelter hospital, which is the first largest shelter hospital designated by the government to admitting non-critically ill COVID-19 patients in the city, constructed and led by Zhongnan Hospital of Wuhan University from February 4, 2020, to March 10, 2020. We retrospectively analyzed all COVID-19 patients admitted to Wuhan East-West Lake Fangcang shelter hospital. Moreover, we only excluded a few patients with incomplete data. All patients were confirmed COVID-19 by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in designated hospitals before admission. Throat-swab specimens were obtained for the nucleic acid test.
The diagnostic and classification criteria issued by the National Health Commission (NHC) of the People's Republic of China (Trial Version 6) classified the disease severity of patients to 4 levels: mild, moderate, severe, and critical. The mild grade represents patients with mild clinical symptoms and no sign of pneumonia on imaging. The moderate grade represents patients who have a fever and respiratory symptoms with radiologic findings of pneumonia. The severe grade represents patients meet any of the following criteria: (1) respiratory distress (≥30 breaths/min); (2) oxygen saturation ≤93% at rest; and (3) PaO 2 FiO 2 ≤300 mm Hg or chest imaging showing obvious lesion progression >50% within 24-48 h. The critical grade represents patients meeting any of the following criteria: (1) respiratory failure and requiring mechanical ventilation; (2) shock; (3) having other organ failures that require ICU care (24).

Data Collection
A trained team of physicians reviewed electronic medical records, nursing records, laboratory findings, and radiologic examinations for all patients during the epidemic period. Patient data including demographic, medical history, chest CT imaging, treatments, the result of nucleic acid test, and comorbidities were collected and analyzed. Clinical symptoms from onset to hospital admission were provided by COVID-19 patients who were conscious, cognitively, and mentally normal.

Statistical Analysis
Continuous variables were described as mean ± standard deviation (SD) or median (interquartile range, IQR) and compared with independent group t-test or the Mann-Whitney U test if appropriate. Categorical variables were described as a percentage and compared by χ 2 test or Fisher's exact test if appropriate. All statistical analyses were performed using SPSS 22.0 software (SPSS Inc. Chicago, IL). A value of P < 0.05 at two-sided was considered statistically significant.

Clinical Characteristics of Patients With Non-critically Ill COVID-19
A total of 1,682 patients with COVID-19 were included in the analysis, and 17 patients were excluded due to incomplete data. The demographic and clinical characteristics are shown in Table 1

DISCUSSION
Recent studies revealed that fever, cough, and dyspnea are the most common and typical clinical symptoms in COVID-19 patients (25,26). However, atypical clinical manifestations including the digestive and nervous system were significant differences in different study populations (27). In this study, we found that neurological symptoms are common in patients with non-critically ill COVID-19. Among 1,682 non-critically ill COVID-19 patients, 509 patients (30.3%) had at least one neurological symptom. Compared with patients without neurological symptoms, patients with neurological symptoms had a significantly longer length of hospital stay and time of nucleic acid turning negative. Patients with neurological symptoms were more likely to occur the expansion of pulmonary infection compared with the patients without neurological symptoms (46/509 [9.0%] vs. 68/1,173 [5.8%]). These results suggest that neurological symptoms are significantly associated with the disease processes of COVID-19. Moreover, compared with patients without neurological symptoms, although the median [IQR] time of the two groups is basic consistent, the mean time from onset of symptom to hospital admission is longer in patients with neurological symptoms, it suggests that nervous system-related symptoms have not garnered much attention. Based on this finding, early identification and aggressive treatment are particularly important for COVID-19 patients with neurological symptoms.
The current study demonstrates that patients with hypertension and diabetes comorbidities are more prone to experience neurological symptoms during COVID-19. The exact pathophysiological mechanism underlying nervous system injury caused by COVID-19 is not fully understood. Genomic analysis reveals that SARS-CoV-2 belongs to betacoronavirus (βCoV) family that includes severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Research has confirmed that the infection of other CoVs, such as in SARS-CoV and MERS-CoV can cause neurologic injury by invading the brain. SARS-CoV had been detected in brain tissue and cerebrospinal fluid, and some SARS patients experienced central nervous symptoms and neurological sequelae (28)(29)(30). SARS-CoV-2 shares a highly homological sequence with human SARS-CoV (with 82% identity) and infects host cells by the same angiotensinconverting enzyme 2 (ACE2) receptor (31)(32)(33)(34). The expression of ACE2 protein was observed in multiple human organs including lung, small intestine, colon, liver, kidney, and brain; thus, these organs have been confirmed to be infected (35,36). A recent study shows that SARS-CoV-2 leads to neuronal damage by the expression of ACE2 in central nervous system tissue (18). In addition, another study also explained that SARS-CoV-2 invades gastrointestinal tissues, and large quantities of harmful metabolites were absorbed, which causes neurological symptoms through the gut-brain axis (15). These findings indicate the expression and distribution of ACE2 in the nervous system may play a key role in the interaction between SARS-CoV-2 and nervous system injury. Hypertension or diabetes patients are always treated with ACE inhibitors and ARBs, which results in an upregulation of ACE2 expression (37,38). We speculate that diabetes and hypertension treatment with ACE2-stimulating drugs may increase the risk of developing more neurological symptoms during COVID-19 infection.
The present study detailed investigates the neurological symptoms and implications of non-critically ill COVID-19 patients, which reminds clinicians not to overlook these neurological symptoms during treatment for COVID-19. We found 21 patients (4.1%) presented with only neurological symptoms in the absence of respiratory symptoms and digestive symptoms. In addition, recent reports suggest that anosmia or hypogeusia and dysgeusia are also one of the clinical manifestations. The current study demonstrates that neurological symptoms are significantly associated with the processes of COVID-19. Therefore, early identification and aggressive treatment are particularly important for COVID-19 patients with neurological symptoms. This study has several limitations. First, we only collected and analyzed non-critically ill patients with COVID-19. It would be better to include more patients with severe infection. Second, we only analysis the neurological symptoms. Considering that Fangcang shelter hospitals are not regular hospitals but temporary hospitals in the special circumstances, magnetic resonance imaging, cerebrospinal fluid (CSF) test, electroencephalogram (EEG), and electromyogram (EMG) cannot be implemented. Third, this study only presents a preliminary assessment of neurological symptoms and the implications of non-critically ill COVID-19 patients. Nevertheless, the study findings should supply important information regarding the neurological implications of non-critically ill COVID-2019 patients.
In conclusion, non-critically ill COVID-19 patients commonly have neurological symptoms. Neurological symptoms reflecting nervous system injury are significantly associated with the processes of COVID-19. Early identification and aggressive treatment are particularly important for COVID-19 patients with neurological symptoms.

DATA AVAILABILITY STATEMENT
All datasets presented in this study are included in the article/supplementary material.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by this study complied with the principles of the Declaration of Helsinki and was approved and written informed consent was waived by the ethics committee of the Zhongnan Hospital of Wuhan University (2020090K). The ethics committee waived the requirement of written informed consent for participation.

AUTHOR CONTRIBUTIONS
JZ had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis, and concept and design. NY, BM, YG, and ZX: acquisition, analysis, or interpretation of data. NY and ZX: drafting of the manuscript and statistical analysis. ZX, DL, and JZ: critical revision of the manuscript for important intellectual content. NY, ZX, and BM: administrative, technical, or material support. ZX and JZ: supervision. All authors contributed to the article and approved the submitted version.