key: cord-0847333-ej040gme
authors: Zheng, Xinchun; Chen, Jiehua; Deng, Lisi; Fang, Zhaoxiong; Chen, Gongqi; Ye, Di; Xia, Jinyu; Hong, Zhongsi
title: Risk factors for the COVID‐19 severity and its correlation with viral shedding: A retrospective cohort study
date: 2020-09-16
journal: J Med Virol
DOI: 10.1002/jmv.26367
sha: 6151937fad703c2cbe34243f62f08463cfb633ef
doc_id: 847333
cord_uid: ej040gme

Coronavirus disease 2019 (COVID‐19) have become a pandemic in the world. This study is aim to explore risk factors for COVID‐19 severity in the early stage and the correlation between the viral shedding and COVID‐19 severity. We included inpatient with laboratory confirmed COVID‐19 who had been discharged by 9 March 2020. The medical record data and dynamic change of biochemical indicators in‐hospital were compared between common and severe patients. Eighty patients were included in this study. Multivariable regression demonstrated increasing odds of severity associated with the duration of fever (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.10‐1.82, per day increase; P = .007), C‐reactive protein (CRP) (OR, 1.26; 95% CI, 1.04‐1.52; P = .02), and PO(2) < 80 mm Hg (28.07, 95% CI, 1.50‐524.12; P = .026) on admission. We found severe acute respiratory syndrome coronavirus 2 viral RNA could be long‐term presence in respiratory tract and fecal sample, up to 43 and 46 days, respectively. However, the duration of viral shedding have no correlation with the COVID‐19 severity. The duration of fever, elevated CRP and PO(2) < 80 mm Hg on admission were associated with the COVID‐19 severity in the early stage and there is no correlation between the viral shedding and COVID‐19 severity.

However, the estimation of risk factors for the severity of this disease in the early stage and the association between viral shedding and the severity of this disease is unclear. In this study, we investigate risk factors for the severity of patients with COVID-19 in the early stage and the relationship of viral shedding and the severity of COVID-19, and describe the dynamical changes of laboratory findings of inpatients from a single hospital in Zhuhai, China.

This study included two cohorts of inpatients from the Fifth Affiliated Hospital of Sun Yat-Sen University (Zhuhai, China), which was the only designated hospitals for transfer of patients with COVID-19 from other hospitals in Zhuhai city, Guangdong province. All patients diagnosed with COVID-19 according to WHO interim guidance were enrolled in our study, who were discharged between 17 January 2020 (ie, when the first patients were admitted) and 9 March 2020. Clinical classification for patients with COVID-19 according to the Chinese management guideline for COVID-19 (version 6.0) 9 : (a) mild type: clinical symptoms were mild, no pneumonia was found on imaging; (b) common type, with fever, respiratory tract and other symptoms, imaging evidence of pneumonia;

(c) severe type: any of the following: shortness of breath, breathing frequency ≥30 times /min; At rest, oxygen saturation ≤93%; Arterial partial pressure (PaO 2 )/oxygen absorption concentration (FiO 2 ) ≤300 mm Hg; (d) critical type: meet any of the following: respiratory failure, and the need for mechanical ventilation; Shock; or with other organ failure requiring intensive care unit (ICU) care. The early stage of patient with COVID-19 in our study was defined clinically as from the onset of viral infection to progression to common type COVID-19 (with fever, respiratory and other symptoms, and imaging changes of pneumonia) according to the clinical classification. To simplify the analysis process, the severe type and critical type cases diagnosed after discharge were combined as "severe type" in this study. Mild patients with no change in their condition during hospitalization were not included in this study. All patients included were divided into common and severe type group. Oral consent was obtained from patients. The clinical outcomes (ie, discharges, length of stay) were monitored up to 9 March 2020, the final date of follow-up. The study was approved by the Research Ethics Commission of the Fifth Affiliated Hospital of Sun Yat-Sen University (No·ZDWY [2020] Lunzi No·(K22-1)).

The medical records of patients were analyzed by the research team of Infectious Disease Prevention and Treatment center, the Fifth Affiliated Hospital of Sun Yat-Sen University. Epidemiological, clinical, laboratory, and treatment and outcomes data were collected with data collection forms from electronic medical records. These data were checked by a trained team of physicians. Information recorded included demographic data, medical history, exposure history, underlying comorbidities, symptoms, signs, laboratory findings, chest computed tomographic (CT) scans, and treatment measures (ie, antiviral therapy, corticosteroid therapy, antibiotics, and intravenous immunoglobin). The time of illness onset was defined as the day when the symptom was noticed. Fever was defined as axillary temperature of at least 37·3°C. The duration of fever was defined as from the day of fever symptom onset to the day of body temperature return to normal for three consecutive days after admission. Laboratory values every day and treatment measures during the hospital stay were also collected.

SARS-CoV-2 RNA in respiratory specimens was detected in our hospital lab by real-time reverse transcription-polymerase chain reaction and then was confirmed by the Chinese Center for Disease Control and Prevention, and only qualitative data were available. Throat-swab specimens were obtained for SARS-CoV-2 polymerase chain reaction reexamination every other day after clinical remission of symptoms. The criteria for discharge were absence of fever for at least 3 days, substantial improvement in both lungs in chest CT, clinical remission of respiratory symptoms, and two throat-swab and excrement samples negative for SARS-CoV-2 RNA obtained at least 24 hours apart. Routine blood examinations for blood count, coagulation profiles, serum biochemical tests (including renal and liver function, creatine kinase, and lactate dehydrogenase), myocardial enzymes tests, cardiac function detection arterial blood gas analysis were performed for all inpatients in our hospital.

Frequency of examinations was determined by the treating physician.

Continuous variables were described using mean ± standard deviation and categorical variables were presented as frequency rates and percentages. We use independent group t tests to compare means for continuous variables when the data were normally distributed; otherwise, the Mann-Whitney U test was used. For categorical variables, we used the χ 2 test, or Fisher's exact test to compare differences between common and severe type group where appropriate. To investigate the risk factors associated with the severity of COVID-19, univariable and multivariable logistic regression models were used. The correlation between the viral shedding of throat-swab and excrement and the severity of COVID-19 was determined by Kaplan-Meier method and positive ratio curves between different groups were calculated by log-rank test. A twosided α of less than 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 22.0 software (SPSS Inc).

Yat-Sen University were enrolled to analyze in this retrospective ZHENG ET AL. | 953 study. Twenty-eight patients were defined as severe type (six for ICU therapy, one of whom death) and 52 for common type according to the Chinese management guideline for COVID-19 (version 6.0). The mean age of the 80 patients was 50.2 years, ranging from 15 years to 80 years. The age of severe patients with COVID-19 was markedly older than that in the common patients ( .0), and the mean time from illness onset to hospital admission was 4.8 days (4.8 ± 4.9). The duration of fever was significant difference between common and severe type patients (2.4 ± 3.8 vs 7.1 ± 5.2 days; P = .000). The temperature on admission in severe patient was markedly higher than that in common patients (37.4 ± 0.6 vs 36.9 ± 0.6). There was no difference in blood type between the two groups.

For laboratory findings, we found that lymphocyte count, lymphocyte percentage, platelet count, eosinophil count, albumin, oxygen partial pressure (PO 2 ) and partial pressure of carbon dioxide (PCO 2 ) in severe patients significantly decreased on admission when compared with common patients, otherwise, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), Alphahydroxybutyric dehydrogenase, C-reactive protein (CRP), D-dimer, and fibrinogen showed increase in severe patients ( Table 2 ). In regard to therapy, 76 (95%) patients received antivirals (lopinavir/ritonavir, arbidol and chloroquine phosphate). Antibacterial drugs and antifungal agents were used more frequent in severe patients compared with common patients (Table 3) . Systematic corticosteroid, intravenous immunoglobulin, fresh frozen plasma and human serum albumin use differed significantly between common and severe patients (Table 3 ). 100% patients in the severe patients were treated with oxygen inhalation and six (7.5%) patients were transferred to ICU treatment (Table 3) .

In univariable analysis, we found that age, temperature on admission, the duration of fever, lymphopenia, platelet count, reduced albumin, direct bilirubin, elevated AST, LDH, Alpha-hydroxybutyric dehydrogenase, CRP, d-dimer, fibrinogen, oxygen partial pressure, and partial pressure of carbon dioxide were associated with the severity of COVID-19 (Table 4 ). Then we analyzed 80 patients with complete data for all variables in the multivariable logistic regression model. We found that the duration of fever (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.10-1.82, per day increase; P = .007), CRP (OR, 1.26; 95% CI, 1.04-1.52; P = .02), oxygen pressure less than 80mm Hg (OR, 28.07; 95% CI, 1.50-524.12; P = .026) on admission were associated with increased odds of the severity of COVID-19 (Table 4 ).

To explore the dynamic change of biochemical indicators in inpatients with COVID-19, we recorded the result data of laboratory tests performed daily in the hospital from the onset of illness to discharge. We found that within 20 days of illness onset, lymphocyte count, lymphocyte percentage, and platelet count were lower in the severe patients than in the normal patients, and these indicators tended to overlap after treatment intervention ( Figure 1A -C). Interestingly, we found that patients with COVID-19 showed a gradual increase in body temperature and CRP within 1 week of illness onset, and a gradual decrease and normalcy after treatment intervention ( Figure 1D ,E). In the early stage of the disease (about 2 weeks), the body temperature and CRP of patients in the severe patients were higher than those in the common patients ( Figure 1D ,E). In addition, we also observed that patients with severe illness are more likely to have increased N-terminal pro-brain natriuretic peptide (NT-proBNP) in the course of disease ( Figure 1F ), suggesting that these patients are prone to cardiac dysfunction. Then we observed the dynamical change of the markers of other routine blood test, liver function, myocardial enzyme, blood coagulation function and renal function, we find that these indicators do not show obvious difference as a whole in both group patients ( Figure S1-4) . Interestingly, the red blood cell and hemoglobin decreased gradually but eosinophils in- 

In this study, we found the duration of fever, CRP and PO 2 < 80mm

Hg on admission were associated with higher risk of the severity of patients with COVID-19 in the early stage of disease and there is no correlation between the duration of viral shedding and the severity of COVID-19. We also found that lymphocyte, lymphocyte percentage, and platelet within 20 days of illness onset were lower in the severe patients compared with common patients, the red blood cell and hemoglobin decreased gradually but eosinophils increased gra- Note: Data are mean ± SD, or n/N (%). P values were calculated by the t test, χ 2 test, or Fisher's exact test, as appropriate. Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; CK-MB, creatine kinase muscle-brain isoform; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; LDH, lactate dehydrogenase; NT-proBNP, N-terminal pro-brain natriuretic peptide; PO 2 , oxygen partial pressure; PCO 2 , partial pressure of carbon dioxide.

analysis shows that elevated CRP, oxygen partial pressure less than 80mm Hg and the duration of fever were associated with the severity of disease; which may be helpful to clinicians to judge the disease severity and to actively make a treatment avoiding illness aggravation and provide a reference for evaluating therapeutic effect at the same time.

In this study, the lymphocyte count, lymphocyte percentage and platelet count of severe patients on admission were significantly 

In this study, we found that the duration of fever, C-reactive protein and PO 2 < 80 mm Hg on admission were associated with the severity of COVID-19 in the early stage, which may be beneficial for clinicians to evaluate the disease severity and provide a reference for evaluating therapeutic effect. SARS-CoV-2 viral RNA could be long-term presence in respiratory tract and fecal sample and there is no correlation between the viral shedding and the severity of COVID-19.

The authors acknowledge all health-care workers involved in the diagnosis and treatment of patients in Zhuhai and thank all patients and their families involved in the study. This study was supported by the National Science Foundation for Young Scientists of China (Grant No· 81900568/H0318) and the "Three Major" constructions emergency projects for the new coronavirus prevention and control in 2020 of Sun Yat-sen University.

The authors declare that there are no conflict of interests. 

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XZ, JC, LD, GC, ZF, and DY collected the epidemiological and clinical data. XZ, JC, and ZH analyzed and summarized all data. XZ drafted the manuscript. ZH and JX revised the final manuscript.

The data that supports the findings of this study are available in this published article and its the supplementary material.

http://orcid.org/0000-0002-7409-8528