key: cord-0970296-2dje7ts9 authors: Zhang, Jixiang; Wang, Xiaoli; Jia, Xuemei; Li, Jiao; Hu, Ke; Chen, Guozhong; Wei, Jie; Gong, Zuojiong; Zhou, Chenliang; Yu, Hongang; Yu, Mosheng; Lei, Hongbo; Cheng, Fan; Zhang, Binghong; Xu, Yu; Wang, Gaohua; Dong, Weiguo title: Risk factors for disease severity, unimprovement, and mortality of COVID-19 patients in Wuhan, China date: 2020-04-15 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2020.04.012 sha: 53566950a322e0dccfb3fa6fd0dfd9b5d639db03 doc_id: 970296 cord_uid: 2dje7ts9 Abstract Objective Since December 2019, coronavirus disease (COVID-19) emerged in Wuhan. However, the characteristics and risk factors associated with disease severity, unimprovement and mortality are unclear. Methods All consecutive patients diagnosed with COVID-19 admitted to the Renmin Hospital of Wuhan University from January 11 to February 6, 2020 were enrolled in this retrospective cohort study. Results A total of 663 COVID-19 patients were included in this study. Among those, 247 (37.3%) had at least one kind of chronic disease. A total of 0.5% (n=3) of patients were diagnosed with mild COVID-19, while 37.8% (251/663), 47.5% (315/663), and 14.2% (94/663) were in moderate, severe, and critical condition, respectively. In our hospital during follow-up, 251 of 663 (37.9%) patients were improved and 25 patients died, leading to a mortality rate of 3.77%. Older patients (>60 years old) and those with chronic diseases were prone to have severe and critical COVID-19 conditions, show unimprovement, and die (P < 0.001, < 0.001). Multivariate logistic regression analysis identified being male (OR = 0.486, 95% CI 0.311-0.758; P = 0.001), having severe COVID-19 conditions (OR = 0.129, 95% CI 0.082-0.201; P < 0.001), expectoration (OR = 1.796, 95% CI 1.062-3.036; P = 0.029), muscle ache (OR = 0.309, 95% CI 0.153-0.626; P = 0.001), and decreased albumin (OR = 1.929, 95% CI 1.199-3.104; P = 0.007) were associated with unimprovement in COVID-19 patients. Conclusion Being male, in severe COVID-19 conditions, expectoration, muscle ache, and decreased albumin were independent risk factors which influence the improvement of COVID-19 patients. In modern human history, infectious diseases have posed a threat to public health several times. Coronavirus, which usually causes respiratory-tract infections in humans, has been linked to several infectious diseases and subsequent global challenges (1, 2) . In December 2019, clusters of patients with viral pneumonia were confirmed to be infected with a novel coronavirus. The infection caused by the novel coronavirus was named as Coronavirus Moreover, human-to-human hospital-associated transmission of SARS-CoV-2 was shown to be possible (5) (6) . This study aimed to provide additional data regarding the clinical features of patients diagnosed with COVID-19 and specifically to analyze the factors associated with disease severity, unimprovement, and mortality. All consecutive patients diagnosed with COVID-19 admitted to the Renmin Hospital of Wuhan University from January 11 th to February 6 th , 2020 were enrolled in this retrospective cohort study. We obtained oral informed consent from all patients enrolled in the study. A confirmed COVID-19 case was defined as a positive result on real-time reverse transcription polymerase chain reaction (RT-PCR) for the presence of SARS-CoV-2 in both the nasal and pharyngeal swab specimens. Open reading frame 1ab (ORF1ab) and nucleocapsid protein (N) were simultaneously amplified and tested during the real-time RT-PCR assay. The real-time RT-PCR assay was performed using a SARS-CoV-2 nucleic acid detection kit, according to the manufacturer's protocol (Shanghai bio-germ Medical Technology Co Ltd). This study was approved by the Ethics Committee of the Renmin Hospital of Wuhan University. Our primary outcomes included disease severity at admission, unimprovement and mortality during follow-up. The disease severity and improvement were defined according to the interim guidelines from the World Health Organization and the National Health Commission of China (7, 8) . According to the patients' symptoms, laboratory results and imaging findings at admission, the disease severity of COVID-19 patients (also known as patients' conditions) can be divided into four types, including mild, moderate, severe, and critical conditions. Patients with slight clinical symptoms and without imaging findings of pneumonia are treated as mild condition. When patients have fever or respiratory symptoms, they are identified as moderate condition. If patients have one of the three situations, they are considered as severe condition: respiratory distress and the respiratory rate is higher than 30 times per minute; fingertip blood oxygen saturation is less than 93% at rest; Partial arterial oxygen pressure (PaO 2 ) / fraction of inspiration oxygen (FiO 2 ) ≤300mmHg. When patients contain one of the following three situation, they are identified as critical condition: respiratory failure, requiring mechanical ventilation; shock condition; with other organ failure requires ICU treatment. Acute kidney injury was diagnosed according to the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines (9) . Acute respiratory distress syndrome (ARDS) was diagnosed according to the Berlin definition (10) . Meanwhile, patients exhibiting one of the following situations during follow-up were considered to have improvement: continuously decreased temperature or normal temperature (below 37.3 ℃ ), improved respiratory symptoms (disappeared or obviously relieved), gradual reduction of pulmonary inflammation upon imaging analysis (obviously reduced shadow area), negative results of SARS-CoV-2 real-time RT-PCR detection. Otherwise, they were considered to show unimprovement. Three physicians collected and reviewed the data. The epidemiological data, medical history, underlying comorbidities, symptoms and signs both at admission and during follow-up, laboratory findings, chest computed tomographic (CT) scans, real-time RT-PCR detection results, and survival data were obtained from patients' electronic medical records. The date of disease onset was defined as the day when the symptoms were noticed. Laboratory values and chest CT scans were collected at admission. Symptoms and signs at admission and during the hospital stay were also both collected. The clinical outcomes were followed up until February 9 th , 2020. Categorical variables were reported as percentages and compared using the χ² test. Fisher's exact test was also used to estimate continuous variables if one set contained less than 5 expected subjects. When continuous measurements were normally distributed, they were presented as mean ± standard deviation (SD) and an independent group t-test was used. Otherwise, the interquartile range (IQR) values and the Mann-Whitney U test was used. A P value of less than 0.05 was considered statistically significant. A logistic regression was used to explore the risk factors associated with the primary outcomes. All variables associated with the primary outcomes were included in the univariate regression model. Variables with P < 0.05 level in previous analyses were entered into logistic multivariate regression models. Continuous variable was dichotomized. The variables included in the final model were selected by an automatic procedure. We tested in the model interactions that were significant on a stratified analysis Odds ratio (OR) was presented with 95% confidence intervals (CI). Statistical analyses were conducted using the SPSS software (version 19.0). A total of 663 COVID-19 patients confirmed via PCR detection of SARS-CoV-2 were included in this study. condition than others (≦ 60 years old, P < 0.001). Among the mild, moderate, severe, and critical patients, 100% (3/3), 76.5% (192/251), 60.0% (189/315), and 34.0% (32/94), respectively, had no chronic disease, which indicated that patients with chronic disease are more prone to severe forms of COVID-19 (P < 0.001). Moreover, the presence of previously diagnosed respiratory (P = 0.003), cardiovascular (P=0.000), endocrine system (P = 0.007), and inflammatory diseases (P = 0.020) was associated with disease severity (Table 1) . Regarding the symptoms, dyspnea (P < 0.001), chest tightness (P < 0.001), diarrhea (P = 0.003), fatigue (P = 0.015), dizziness (P = 0.009), muscle ache (P = 0.028), and unconsciousness (P = 0.020) were significantly linked to severe COVID-19 cases (Table 2) . Moreover, increased white blood cell (P < 0.001) and neutrophil counts (P < 0.001), decreased lymphocyte counts (P < 0.001), decreased hemoglobin (P < 0.001), increased ALT (P = 0.015) and/or AST (P < 0.001), increased serum creatinine and/or decreased glomerular filtration rate (P < 0.001), increased CRP (P < 0.001), decreased albumin(P < 0.001), and increased LDH (P < 0.001) at admission were significantly associated with severe and critical disease conditions (Table 3) . A total of 251 (37.9%) patients were improved in hospital during follow-up ( With respect to the systemic symptoms at admission, fever (P = 0.007), dizziness (P = 0.023), and muscle ache (P < 0.001) were found to influence patients' improvement in hospital ( Table 2 ). The patients who exhibited expectoration, dyspnea, and chest tightness at admission were more likely to respond to therapy and had better overall outcomes (P < 0.001, < 0.001, < 0.001, respectively). However, digestive symptoms had no effect on patients' improvement. At admission, increased white blood cell counts were significantly associated with patients who responded to treatment (P = 0.011). Moreover, when patients had neutrophil counts above the normal range, they were more likely to exhibit improved symptom during follow-up (P < 0.001). Patients with improvement were also found to have lymphocyte counts below the normal range (P < 0.001). Additionally, decreased hemoglobin (P = 0.006), increased ALT (P = 0.001) and/or AST (P < 0.001), increased serum creatinine and/or decreased glomerular filtration rate (P < 0.001), increased CRP (P < 0.001), decreased albumin (P < 0.001), and increased LDH (P < 0.001) were also shown to be associated with COVID-19 improvement. Furthermore, patients with both unilateral pneumonia as diagnosed by CT scans were more likely to be improved (P < 0.001, factors associated with unimprovement during follow-up. (Table 4 ). Additionally, a total of 25 patients included in the study died, leading to a mortality rate of 3.77% ( (Table 2) . When comparing the dead and surviving patient populations, the only two symptoms which exhibited significant differences was dyspnea (P = 0.019) and unconsciousness (P < 0.001). Compared to other patients, the proportion of patients with increased white blood cell counts (P < 0.001), neutrophil counts above the normal range (P = 0.001), lymphocytes counts below the normal range (P = 0.006), increased ALT (P = 0.011) and/or AST (P = 0.001), increased serum creatinine and/or decreased glomerular filtration rate (P = 0.021), increased CRP (P = 0.014), decreased albumin (P = 0.005), and increased LDH (P = 0.046) at admission was higher among the deceased patient population (Table 3 ). In our study population, there were 247 patients who had at least one kind of chronic disease. Cardiovascular diseases, endocrine system disease, and respiratory system disease were the three most common coexisting chronic diseases. There were 91 patients who had no fever at admission. Additionally, 22 of the included COVID-19 patients did not exhibit any symptoms and were only found to be positive via the results of the SARS-CoV-2 PCR test. Most patients had systemic, respiratory, and digestive symptoms. Fever, dry cough, and fatigue were the three most common symptoms. On admission, most patients had white blood cell and neutrophil counts in the normal range and lymphocyte counts below the normal range. About a quarter of COVID-19 patients had differing degrees of hepatic function abnormality and one in ten patients had kidney function abnormality. Most patients had increased CRP, decreased albumin, and increased LDH. The vast majority of patients also had bilateral pneumonia in CT imaging. One-third of the patients were improved in hospital during follow-up. Twenty-five patients died and the mortality rate was 3.77%. The mortality rate in our study was lower than that indicated in a previous report but higher than that reported in another study (5, 11) . This heterogeneity is probably due to differences in the case inclusion criteria. However, our results were closer to the mortality rate indicated by official national statistics, which is 3.97%. Cumulative studies confirmed that older age was associated with poor outcomes in COVID-19 patients. In our study, older patients were prone to have severe COVID-19 symptoms, unimprovemrnt, and were more likely to die in hospitals. Based on previous findings in animal studies, older animals were shown to have stronger host innate immune responses to SARS-CoV infection (12) . The unsatisfactory control of viral replication and more prolonged proinflammatory responses in older individuals due to age-dependent defects was found to lead to a marked decline in cell-mediated immune function and reduced humoral immune function, which potentially leads to poor outcomes (13, 14) . Fever, dizziness, muscle ache, expectoration, dyspnea, and chest tightness at admission were also found to influence patients' improvement in hospital. Dyspnea and unconsciousness were the only two symptoms which were associated with mortality. A recent study reported the presence of SARS-CoV-2 nucleic acid fragments in the stool samples of patients with abdominal symptoms and suggested that SARS-CoV-2 might also be transmitted via the fecal-oral route (15) . In our study, approximately one in six COVID-19 patients had digestive symptoms, especially diarrhea, which is more than was reported in a previous study (11) . The digestive symptoms of most COVID-19 patients were mild, which seemed to be inconsistent with the pathogenicity of SARS-CoV-2. A possible explanation is that SARS-CoV-2 in the sputum of COVID-19 patients is transmitted to the digestive tract through swallowing. There, under the action of various digestive enzymes, the virulence of SARS-CoV-2 in the digestive tract is weakened and the virus is degraded into fragments that only cause mild digestive symptoms but not serious gastrointestinal damage. In conclusion, being male, as well as having severe COVID-19 symptoms, expectoration, muscle ache, and decreased albumin were shown to be independent risk factors which influence patients' improvement during follow-up. Older age was associated with poor conditions and outcomes in COVID-19 patients. Table 1 Baseline characteristics of the 663 COVID-19 patients. Table 2 Clinical characteristics of the 663 COVID-19 patients. Table 3 Laboratory results and imaging finding of the 663 COVID-19 patients. Epidemiology, genetic recombination, and pathogenesis of coronaviruses Molecular Evolution of Human Coronavirus Genomes Director-General's remarks at the media briefing on SARS-CoV-2 on 16 Update on the epidemic situation of new coronavirus pneumonia as of on March 31. National Health and Health Commission Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance. World Health Organization Interim guidance for novel coronavirus pneumonia (Trial Implementation of Revised Fifth Edition). National Health and Health Commission KDIGO clinical practice guidelines for acute kidney injury Acute respiratory distress syndrome: the Berlin Definition Clinical Characteristics of Coronavirus Disease 2019 in China Exacerbated innate host response to SARS-CoV in aged non-human primates Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study The immunopathogenesis of sepsis in elderly patients The digestive system is a potential route of 2019 nCoV infection: a bioinformatics analysis based on single-cell transcriptomes We thank all patients involved in the study and for the editorial help we have received from Elsevier. We thank Dr.Jihui Zhang for statistical guidance.