Clinical features in mild type and severe type of COVID-19 patients

Background Coronavirus Disease 2019 (COVID-19) outbroke in Wuhan and spread to the world quickly. We aim to describe the clinical features and compare them between mild type and severe type of COVID-19 patients. Methods Laboratory conrmed COVID-19 patients were included in this study. Patients’ demographic data and clinical data were recorded and compared between mild type and severe type. Fifteen patients were conrmed COVID-19 and enrolled in this study. Six patients were of mild type, while 9 patients were of severe type. Statistical differences were found between mild type and severe type patients in retirement, epidemiological history, baseline blood level of lactate dehydrogenase and Oxygenation Index (All p < 0.05). All patients had ground-glass opacities without consolidation in initial chest computed tomography images, 2 (16.7%) patients had pulmonary nodules. There were no statistical differences between mild type and severe type patients in initial chest CT ndings (All p > 0.05). Differences can be found in baseline clinical features between mild type and severe type of COVID-19 patients to help health care providers making early judgement to the severity and proper treatment. Respiratory dysfunction is indicated if the Oxygenation Index is less than 300 mm Hg. Other biochemical parameters for inammation, liver function, coagulation function, cardiac function, renal function and pulmonary function were similar in two groups. Interestingly, lymphopenia is seen in both groups without statistical difference, as it could be used as a reference index in the diagnosis of COVID-19. Dynamic observation of lymphocyte count may be used as a reference index in degree of severity. Initial chest CT images in our study demonstrated that ground-glass opacities without consolidation were found in all patients without specicity. Bilateral involvement was found in 12 (80%) patients and multi-lobes involvement was found in 13 (86.7%) patients. Similar ndings were reported [13, 14] . It was dicult to distinguish COVID-19 from other pneumonia in early stage by initial chest CT images. As there were no statistical differences between mild and severe type patients in initial chest CT ndings in our study, it also seemed to be dicult to distinguish the two types from each other by initial chest CT images. However, subsequent consecutive chest CT examinations are necessary to assure the change of pneumonia and make proper treatment. lung for patients with acute respiratory deciency syndrome for a short duration. effect on mortality, delayed viral clearance antibiotics therapy, oxygen support therapy and symptomatic therapy all in management of COVID-19. ICU care and vital support are urgent if vital signs are unstable. In our study, days from symptom onset to undetectable SARS-CoV-2 RNA were 20.5 ± 12.1, days from admission to undetectable SARS-CoV-2 RNA were 16.7 ± 11.6. A retrospective cohort study shown median duration of viral shedding was 20.0 days in survivors [27] . It indicated that SARS-CoV-2 invaded into human body and sustained for a long time, although antiviral therapy what we thought to be effective for SARS-CoV-2 was given to the patients. No statistical differences were found between mild and severe type patients in days from symptom onset to undetectable SARS-CoV-2 RNA or days from admission to undetectable SARS-CoV-2 RNA. The duration for positive SARS-CoV-2 RNA in the two types of patients was similar. First, fteen COVID-19 patients included pediatrics or adolescent patients; suspected but exclusive diagnosed cases were ruled out in the analyses. Second, nal clinical outcome of all patients unavailable at time of analysis. Third, changes of viral load and antibody titers not available since the patients were conrmed diagnosed. early of clinical of mild and severe type


Background
In December 2019, a series of pneumonia cases with unknown etiology were reported in Wuhan city, Hubei province, China [1] . Soon after that, World Health Organization (WHO) reported this situation [2,3] . Gene sequencing analysis of the lower respiratory tract samples from the patients indicated a novel coronavirus [4] . The novel coronavirus was similar to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) [5] and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [6] . It was o cially named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection was called Coronavirus Disease 2019  and spread to the world quickly. A total of global 4593 con rmed COVID-19 cases, of which 4537 were from China, had been reported by January 28, 2020 [7] . COVID-19 was declared as a global health emergency by WHO on January 30, 2020. The death rate was about 4.08% (3331 deaths out of 81740 cases) in People's Republic of China [8] , 12.63% (17127 deaths out of 135586 cases) in Italy [9] , and 2.69% (8910 deaths out of 330891 cases) in United States of America [10] . There have been 1279722 con rmed cases of COVID-19 in 211 countries, including 72616 (5.67%) deaths, reported to WHO on April 7, 2020 [11] .
As death rate reached 5.67% globally, it is very important to make early diagnosis, early judgement to the severity and proper treatment to COVID- 19 patients. An early prospective study analyzed clinical features of 41 con rmed COVID- 19 [12] . Some symptoms, signs and laboratory tests were found to be predictors for ICU care patients. Otherwise, all 41 patients had abnormal ndings on chest computed tomography (CT), with bilateral abnormal lung opacities. Chung et al [13] and Song et al [14] also demonstrated that ground-glass opacities (GGO) were found in initial chest CT images from most of the patients. As GGO are usually seen in other viral pneumonia and immune lung injury, it is di cult to distinguish COVID-19 from them in early stage. It is unknown whether the initial chest CT ndings can make early judgement to the severity of COVID-19. According to COVID-19 guideline from People's Republic of China [15] , patients can be divided into mild type and severe type (even critical type). Early judgement and proper treatment to these two types are urgent in clinical practice. More data from COVID-19 patients is needed as little is known about it.
In this study, we aim to describe epidemiological, clinical, laboratory, and radiological characteristics of COVID-19 patients. We also aim to compare the clinical features between mild type and severe type patients, helping health care providers to make early judgement to the severity and proper treatment. We hope our study ndings will be supplementary data to COVID-19 and its clinical features ever known.

Patients
According to COVID-19 guideline [15] , suspected COVID-19 patients were admitted to isolation unit, Department of Infectious Diseases of Severe type and mild type de nition Severe type was de ned as the patient met one of the following criteria [15] : respiratory rate ≥ 30 breaths per minute, pulse oxygen saturation (SpO 2 ) ≤ 93% without oxygen support therapy, or Oxygenation Index (arterial partial pressure of oxygen to fraction of inspiration oxygen [PaO 2 /FiO 2 ]) ≤ 300mmHg.
Mild type was de ned as the patient did not meet any of the criteria for severe type mentioned above.

Criteria for discharge
Patients would be discharged if they met all of the following criteria [15] : normal body temperature maintaining for 3 days, obvious improvement of respiratory symptoms, absorption of in ammation in chest radiographic manifestation and two negative results of detecting SARS-CoV-2 RNA from respiratory samples with an interval of more than 24 hours.

Statistical Analysis
Continuous data were indicated with the mean ± standard deviation (SD) while categorical data were reported with number and percentage (%). Student's independent t-test was used to compare the means between the two groups.

Results
Baseline characteristics A total of 106 suspected patients were admitted to isolation unit from January 22 nd 2020 to April 6 th 2020. Fifteen patients (9 males and 6 females) were con rmed COVID-19 and enrolled in this study. The average age of the 15 COVID-19 patients was 43.6 ± 13.4 years, and days from symptom onset to admission were 3.8 ± 2.3. Fourteen (93.3%) patients had a fever. Other symptoms included fatigue, myalgia, cough, sputum production, sore throat, dry throat, chest tightness and diarrhea. Six patients were of mild type, while 9 patients were of severe type.
No patients retired in mild type, while 5 (55.5%) patients retired in severe type (p < 0.05). Epidemiological history showed no patients were Hubei residents in mild type, while 6 (66.7%) patients were Hubei residents in severe type (p < 0.05). Respiratory rate was 18.0 ± 1.3 breaths per minute in mild type patients and 22.2 ± 5.8 breaths per minute in severe type patients (p < 0.05). No statistical differences were found between mild and severe type patients in age, sex, smoking history, days from onset to admission, fever, highest body temperature, fatigue, myalgia, cough, sputum production, sore throat, dry throat, chest tightness, heart rate, systolic pressure, diastolic pressure or comorbidity.
Baseline characteristics of COVID-19 patients were shown in Table 1.

Baseline laboratory test results
From the baseline laboratory test results, there were 6 (100%) patients with normal blood level of lactate dehydrogenase in mild type and 4 (44.4%) patients in severe type (p < 0.05). The Oxygenation Index was 511.2 ± 95.2 mm Hg in mild type patients and 358.5 ± 121.5 mm Hg in severe type patients (p < 0.05). No statistical differences were found between mild and severe type patients in normal blood cell count, or normal blood level of aspartate aminotransferase, alanine aminotransferase, albumin, total bilirubin, blood urea nitrogen, creatinine, creatine kinase, myoglobin, pro-brain natriuretic peptide, cardiac troponin I, prothrombin time, prothrombin time -international normalized ratio, procalcitonin, C-reactive protein, erythrocyte sedimentation rate, or PaO 2 . Baseline laboratory results of COVID-19 patients were shown in Table 2.

Initial chest CT image ndings
In initial chest CT images, unilateral involvement was found in 3 (20%) patients, bilateral involvement was found in the rest 12 (80%) patients. Only one lobe was involved in 2 (13.3%) patents, multi-lobes were involved in the rest 13 (86.7%) patients. The right upper lobe and right middle lobe were involved in 8 (53.3%) patients, the right lower lobe and left upper lobe were involved in 10 (66.7%) patients, the left lower lobe was involved in 11 (73.3%) patients. All patients had GGO without consolidation, 2 (13.3%) patients had pulmonary nodules. Pulmonary Fibrosis, pulmonary emphysema, cavitation, pleural effusion and lymphadenopathy were absence. Initial chest CT ndings of COVID-19 patients were shown in Table 3. No statistical differences were found between mild and severe type patients in initial chest CT ndings. Initial chest CT images of the 9 severe type patients were shown in Figure 1.

Treatment and current clinical outcome
All COVID-19 patients received antiviral therapy. Twelve (80%) patients received oral arbidol. Fifteen (100%) patients received oral lopinavir and ritonavir. Four (26.7%) patients received interferon alfa-2b inhalation. Thirteen (86.7%) patients received antibiotics therapy. Four (26.7%) patients received corticosteroid and human immunoglobulin intravenous injection. Two (13.3%) patients received thymosin α1 subcutaneous injection. Twelve (80%) patients received oxygen support therapy. One (6.7%) patient needed care in ICU. Days from symptom onset to undetectable SARS-CoV-2 RNA were 20.5 ± 12.1. Days from admission to undetectable SARS-CoV-2 RNA were 16.7 ± 11.6. No statistical differences were found between mild and severe type patients in days from symptom onset to undetectable SARS-CoV-2 RNA or days from admission to undetectable SARS-CoV-2 RNA. Fourteen (93.3%) patients recovered and discharged. One (6.7%) patient was receiving treatment in hospital currently. Treatment and current clinical outcome of COVID-19 patients were shown in Table 4.

Discussion
This is a descriptive study on the clinical features of COVID-19 patients in Third A liated Hospital of Sun Yat-sen University located in Guangzhou city. Nine (60%) patients were of severe type, and one of them needed treatment in ICU and still hospitalized in ICU for more than 70 days (from January 22nd, 2020). This reminds us not to underestimate the severity of COVID-19. Early recognition and judgement to severe type of COVID-19 patients are urgent and important in clinical practice, in order to make proper treatment and reduce death rate.
Our study showed retirement, Hubei residents and faster respiratory rate were more frequent in severe type patients. It is consistent with the results from Huang's study [12] , which compared COVID-19 patients with ICU care and no ICU care. Other data, including age, sex, smoking history, comorbidity, symptoms and signs, were similar. Although age was of no statistical differences between the two types, the elderly was thought to be related to retirement, comorbidity and progression to severe type in clinical practice. Hubei residents seemed to be " rst generation" [16] or the next generation, infected with SARS-CoV-2 of relative strong virulence, making infection much more severe than patients from other cities. The common symptoms in COVID-19 patients includes fever, fatigue, myalgia, sore throat, cough, sputum production, dyspnea. These symptoms were also reported by other studies [12,17] . Close attention should be paid to symptom diarrhea, which may be evidence for digestive system impairment. SARS-CoV-2 RNA could be detected in blood and anal swab specimens [18] , that the virus invades circulatory and digestive systems. ACE2 was reported as a receptor for coronavirus replication [19] , as it was highly expressed in lung and intestine tissues. Whether SARS-CoV-2 could invade urinary system is still unknown, as urinary irritation symptoms and signs were absent in our study. More studies are needed.
In terms of baseline laboratory tests, higher blood level of lactate dehydrogenase and lower Oxygenation Index were demonstrated in severe type patients. Lactate dehydrogenase is one of the important enzymes for anaerobic glycolysis and gluconeogenesis. Its elevation prompts liver, lung, heart and kidney diseases. Oxygenation Index, an item of blood gas analysis, re ects oxygenation capability of tissue and organ. Respiratory dysfunction is indicated if the Oxygenation Index is less than 300 mm Hg. Other biochemical parameters for in ammation, liver function, coagulation function, cardiac function, renal function and pulmonary function were similar in two groups. Interestingly, lymphopenia is seen in both groups without statistical difference, as it could be used as a reference index in the diagnosis of COVID-19.
Dynamic observation of lymphocyte count may be used as a reference index in degree of severity.
Initial chest CT images in our study demonstrated that ground-glass opacities without consolidation were found in all patients without speci city. Bilateral involvement was found in 12 (80%) patients and multi-lobes involvement was found in 13 (86.7%) patients. Similar ndings were reported [13,14] . It was di cult to distinguish COVID-19 from other pneumonia in early stage by initial chest CT images. As there were no statistical differences between mild and severe type patients in initial chest CT ndings in our study, it also seemed to be di cult to distinguish the two types from each other by initial chest CT images. However, subsequent consecutive chest CT examinations are necessary to assure the change of pneumonia and make proper treatment.
COVID-19 lacks of con rmed effective antiviral treatment. All the experience is from treatment for SARS-CoV and MERS-CoV infection.
Combination of lopinavir and ritonavir was clinical bene cial among SARS-CoV patients [20] . A placebo-controlled trial of interferon beta-1b, lopinavir and ritonavir among patients with MERS infection was initiated in Saudi Arabia [21] . As Remdesivir may have potent e cacy to treat MERS-CoV and SARS-CoV infections [22,23] , clinical trials of Remdesivir in COVID-19 were initiated in China. It is recommended to use intravenous immunoglobulin to enhance the ability of anti-infection for severe patients. Corticosteroids (methylprednisolone 1-2 mg/kg per day) are recommended to control in ammatory-induced lung injury for patients with acute respiratory de ciency syndrome for a short duration. Corticosteroids may be a double-edged sword as it did not have an effect on mortality, but rather delayed viral clearance [24][25][26] . Otherwise, antibiotics therapy, oxygen support therapy and symptomatic therapy are all needed in management of COVID-19. ICU care and vital support are urgent if vital signs are unstable. In our study, days from symptom onset to undetectable SARS-CoV-2 RNA were 20.5 ± 12.1, days from admission to undetectable SARS-CoV-2 RNA were 16.7 ± 11.6. A retrospective cohort study shown median duration of viral shedding was 20.0 days in survivors [27] . It indicated that SARS-CoV-2 invaded into human body and sustained for a long time, although antiviral therapy what we thought to be effective for SARS-CoV-2 was given to the patients. No statistical differences were found between mild and severe type patients in days from symptom onset to undetectable SARS-CoV-2 RNA or days from admission to undetectable SARS-CoV-2 RNA. The duration for positive SARS-CoV-2 RNA in the two types of patients was similar.
This study has several limitations. First, only fteen COVID-19 patients were included without pediatrics or adolescent patients; suspected but exclusive diagnosed cases were ruled out in the analyses. Second, nal clinical outcome of all patients was unavailable at the time of analysis. Third, changes of viral load and antibody titers were not available since the patients were con rmed diagnosed.
However, the patients enrolled in this study are treated in Guangzhou, giving new perspectives out of the origin city Wuhan in China. The data in this study permit an early assessment of clinical features of mild type and severe type patients with COVID-19.

Conclusions
Differences can be found in baseline clinical features in mild type and severe type patients with COVID-19. This helps health care providers to make early judgement to severe type patients and give proper treatment for them.

Consent for publication
The patients voluntarily signed an informed consent form regarding publishing their data without their names and identi cation card numbers.

Availability of data and material
The data generated or analyzed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests Funding This study was supported by grants from Natural Science Foundation of China (NSFC) (grant number 81570539 and 81873572), Tackling of key scienti c and emergency special program of Sun Yat-sen University (SYSU-TKSESP) (without grant number) and Emergency special program for 2019-nCoV of Guangdong province science and technology project (GDSTP-ESP) (grant number 2020B111105001). The NSFC, SYSU-TKSESP and GDSTP-ESP had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, writing, review, or approval of the manuscript; and decision to submit the manuscript for publication.