key: cord-286477-0euaaspo
authors: Li, Xiaochen; Xu, Shuyun; Yu, Muqing; Wang, Ke; Tao, Yu; Zhou, Ying; Shi, Jing; Zhou, Min; Wu, Bo; Yang, Zhenyu; Zhang, Cong; Yue, Junqing; Zhang, Zhiguo; Renz, Harald; Liu, Xiansheng; Xie, Jungang; Xie, Min; Zhao, Jianping
title: Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan
date: 2020-04-12
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2020.04.006
sha: 
doc_id: 286477
cord_uid: 0euaaspo

Abstract Background In December 2019, COVID-19 outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited. Objective The severity on admission, complications, treatment, and outcomes of COVID-19 patients were evaluated. Methods Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020 to February 5, 2020 were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients. Results We identified 269 (49.1%) of 548 patients as severe cases on admission. Elder age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-a), and high LDH level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in COVID-19 patients was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male, elder age, leukocytosis, high LDH level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19. Conclusions Patients with elder age, hypertension, and high LDH level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have high risk of death.

The SARS-CoV-2 virus, as a betacoronavirus, shares 88% of two bat-derived SARS-like 133 coronaviruses and distances from SARS-CoV (around 79%) and Middle East respiratory 134 syndrome coronavirus (MERS-CoV, around 50%). 1 SARS and MERS epidemics posed threats to 135 global health due to high mortality rates of 9.6% for SARS-CoV and 34.4% for MERS-CoV 136 globally. 2, 3 Epidemiological data released by the Chinese Center for Disease Control and 137 Prevention showed that 50,005 confirmed cases have been identified in Wuhan and 31,513 in 138 mainland China except Wuhan as of March 22, 2020. The mortality rate of COVID-19 patients 139 was 5.0% in Wuhan, which was close to that in the world (4.2%) and much higher than that in 140 mainland China except Wuhan (2.4%). This study aims to describe and compare the 141 epidemiological, demographic, clinical, laboratory and radiological characteristics as well as the 142 complications, treatment and outcomes of hospitalized patients with nonsevere and severe 143 COVID-19. Potential risk factors for severe COVID-19 and factors associated with death in severe 144 cases were analyzed to provide scientific data for relieve severe cases and reduce mortality. 145

This study was an ambispective cohort study of consecutive hospitalized patients with COVID-19 159 enrolled at Sino-French New City Branch of Tongji Hospital, Huazhong University of Science and 160

Technology in Wuhan from January 26, 2020 to February 5, 2020. The final date of follow-up was 161

March 3, 2020. Sino-French New City Branch of Tongji hospital is one of the major nationally 162 designated hospitals only providing medical care for adult COVID-19 patients in Wuhan. All 163 cases with COVID-19 enrolled in this study were diagnosed based on the WHO interim guidance 4 164 and the diagnostic and treatment guideline for COVID-19 issued by Chinese National Health 165

Committee (version 5). Detection of SARS-CoV-2 nucleic acids was shown in text in the Online 166

Repository. 5 This study was approved by Institutional Review Board of Tongji Hospital, 167

Huazhong University of Science and Technology. Written informed consent was waived in light 168 of the urgent need to collect data. 169

The epidemiological and demographic data were obtained by face-to-face or telephone interview. 170

Clinical symptoms, laboratory, and radiological findings on admission as well as the 171 complications, treatment and outcomes during hospitalization were extracted from electronic 172 medical records. Serum cytokines (IL-1β, IL-2R, IL-6, IL-8, IL-10 and TNF-α) were measured on 173 admission. Patient data were cross-checked for consistency before final data entry and then 174 entered into a computerized database. 175

The presence of underlying comorbidities was identified based on the International Classification 176 of Diseases and Injuries-10 diagnostic codes. The complications of COVID-19 after admission 177

were assessed and the definitions were shown in text in the Online Repository. Cardiac injury was 178 one of the complications, which was defined as a serum hypersensitive cardiac troponin I level 179 higher than 15.6 pg/ml without acute coronary symptoms or abnormal electrocardiogram. The 180 clinical outcomes were classified into discharge from hospital, in-hospitalization, and death. 181

Severe COVID-19 was defined according to 2019 clinical practice guideline from Infectious 182 Diseases Society of America and American Thoracic Society for diagnosis and treatment of adults 183 with community-acquired pneumonia. 6 Based on whether or not requiring ventilatory support on admission, severe cases upon admission were divided into two cohorts, severely ill and critically ill cases. 186

The descriptive statistics are median and interquartile range (IQR) for continuous data. 

A total of 549 patients with COVID-19 were enrolled, of whom 548 cases were included in the 219 study. One case not meeting inclusion criteria was excluded due to inclusion criteria. Almost half 220 of the patients (49.1%, 269 of 548) were identified as severe cases and 50.9% (279 of 548) were 221 nonsevere cases on admission. 68.7% (347 of 505) of cases were positive for SARS-CoV-2 222 nucleic acid test pre-admission. Comparison of findings between nonsevere and severe cases in 223 the patients with positive viral nucleic acid test pre-admission showed essentially the similar 224 differences to that in the total patients (see Table E1 in the Online Repository). 225

The epidemiological and demographic characteristics are shown in Table 1 . 52 (9.5%) of 546 226 patients got the infection in hospital. 45 (8.2%) of 547 patients were health-care workers and 67 227 (12.2%) patients were family members of health-care workers. Nonsevere cases had a higher 228

proportion of health-care workers and family members than severe cases (P<0.001). The date of 229 onset of the first reported case with COVID-19 was December 1, 2019. 7 The median time from 230

December 1, 2019 to the onset of COVID-19 was 54 days, ranging from 19 days to 63 days. 231

The median age of study population was 60 years (IQR 48-69), ranging from 18 years to 95 years, 232 of whom 210 (38.3%) were aged 65 years or older. The patients aged 65 years or older in severe 233 cases were almost twice as nonsevere cases of the same age (50.2% vs. 26.9%, P<0.001). Slightly 234 more than half (50.9%) of all patients were male and the proportion of males in severe cases is 235 higher than in nonsevere cases (56.9% vs. 45.2%, P=0.006). 236

19.2% of patients with severe COVID-19 were smokers (Table 1) asthma (0.9%) were identified in total population. 42 (7.7%) of 545 patients regularly took 242 angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers; no significant 243 difference was found between nonsevere and severe cases. sore throat (5.1%), cough (75.5%), chest pain (7.5%), dyspnea (56.6%), chest tightness (38.1%), 246 dizziness (10.2%), confusion (3.1%), headache (11.3%), myalgia (20.3%), vomiting (8.2%), 247 diarrhea (32.7%), abdominal pain (2.9%). 6 patients were asymptomatic and diagnosed by CT 248 screening. Duration of fever pre-admission was significantly longer among severe cases compared 249 with that in nonsevere cases (P=0.031). Severe cases experienced longer duration from onset to 250 outpatient visit and longer duration from onset to hospitalization compared with nonsevere cases 251 (p=0.018 and p=0.035, respectively). 64 (11.9%) of 540 patients were treated with corticosteroids 252 delivered by oral or intravenous pre-admission. 304 (56.5%) of 538 patients had received at least 253 one of the following antiviral medications: umifenovir (32.9%), oseltamivir (35.1%), 254 lopinavir/ritonavir (2.4%), and ribavirin (1.5%). 255

CT scans for 461 patients were evaluated pre-admission, and showed multilobar pulmonary 257 infiltrates in 436 patients ( Table 2 ). The median time from onset to pneumonia diagnosed by CT 258 scan was 4 days. On admission, oxygen saturation (SpO2) less than 93.1% on room air presented 259 in 33.3% of all patients, of whom 163 (89%) were severe cases. 90.2% of all patients experienced 260 lymphopenia (<1500 cells per mm 3 ) and 29.1% of all patients had thrombocytopenia (<150,000 261 cells per mm 3 ). Compared with nonsevere cases, inflammation-related marker levels (hsCRP, ESR, 262 and ferritin) were significantly higher in severe cases The levels of procalcitonin, globulin, lactate 263 dehydrogenase (LDH), NT-proB-type natriuretic peptide (NT-proBNP), d-dimer, alanine 264 aminotransferase, aspartate aminotransferase, total bilirubin, conjugated bilirubin, blood urea 265 nitrogen, and creatinine were elevated in 9.5%, 40.4%, 73.6%, 27.5%, 67.4%, 23.1%, 33.1%, 266 4.4%, 9.2%, 15.8%, and 27.1% of all patients, respectively. Serum cytokine levels of IL-2R, IL-6, 267 IL-10, and TNF-α were significantly higher in severe patients than those in nonsevere patients (all

Of the 269 severe cases, 46 were classified as critically ill for requiring respiratory support. 271

Compared with severely ill cases, the time from December 1, 2019 to onset was shorter and the 272 time from onset to outpatient visit was longer in critically ill cases (see Table E2 in the Online high procalcitonin, high NT-proBNP, high LDH, high d-dimer, low albumin, and high creatinine) 276

were observed in critically ill cases compared with severely ill cases (all P<0.05). 34.1% of 277 critically ill patients received systemic corticosteroids pre-admission, the proportion of whom was 278 significantly higher than that in severely ill cases (12.2%, P<0.001). 279

Compared with nonsevere cases, systemic corticosteroid use pre-admission was more common in 280 severe cases with larger cumulative dose and longer duration (P=0.007; P<0.001; P<0.001; 281 respectively). Stratification of patients by corticosteroid exposure is presented in Table E3 in the 282

Online Repository. Severe patients treated with corticosteroids had higher LDH level compared 283 with severe patients without corticosteroid use pre-admission (P<0.05). 284

Nonsevere cases were more likely to receive antiviral drugs pre-admission, including umifenovir 285 and oseltamivir (P<0.001 and P=0.005; respectively). In severe case subgroup, the patients 286 receiving umifenovir were younger than those without umifenovir use (P<0.05). A comparison of 287 baseline demographic and clinical characteristics between patients with and without antiviral drug 288 use revealed no marked difference in SpO2 or laboratory findings in both nonsevere and severe 289 case subgroups (see Table E4 and E5 in the Online Repository). 290

In the final logistic regression model, variables such as age 65 or older (OR 2.2; 95% CI 1.5-3.5), 292 hypertension (OR 2.0; 95% CI 1.3-3.2), LDH >445 U/L (OR 4.4; 95% CI 2.6-7.6), and 293 d-dimer >1 mg/L (OR 2.2; 95% CI 1.4-3.3) were significantly associated with severe cases with 294 COVID-19 ( Figure 1) . 295

In the follow-up period, the complications of COVID-19 were assessed , including acute 297 respiratory distress syndrome (ARDS) (38.3%), cardiac injury (21.7%), liver dysfunction (19.3%), 298 acute kidney injury (17.3%), bacteremia (7.7%), diffuse intravascular coagulation (7.7%), and 299 hyperglycemia (33.2%) ( This study provided a comprehensive data on the epidemiological, demographic, clinical, 338 laboratory, and radiological characteristics as well as the complications, treatment, and outcomes 339 of hospitalized patients with nonsevere and severe COVID-19 in Wuhan. Almost half of the 340 patients in this study were identified as severe cases, which may differ from the results of the 341 previous studies. 8 The proportion of patients aged 65 years or older were higher in our study than 342

in Nanshan Zhong's study (38.8% vs. 15.1%, respectively). 9 The time from December 1, 2019 to 343 the onset of most patients was longer than 50 days. During mid-January to early February, Wuhan 344 experienced the highest peak of COVID-19 outbreak, with a family cluster and high prevalence of 345 COVID-19 in older adults. Longer wait for access to medical care was observed in severe cases 346 compared with that in nonsevere cases. More than half of the patients experienced at least two 347 hospital visits, which may increase the risk of nosocomial transmission events. Diagnosis and 348 treatment may be delayed due to the long wait for access to medical care. Severe COVID-19 349 patients would likely develop ARDS and died of respiratory failure. Although there are currently 350 no effective antiviral drugs for SARS-CoV-2, prompt identification and early respiratory support 351 would relieve severe cases and reduce mortality. The severity of disease in patients with initial 352 positive nucleic acid test was similar to that of all COVID-19 patients. We thus propose that 353 urgent timely diagnosis is crucial, and that early intervention should not be delayed based on 354 nucleic acid test. proinflammatory cytokine levels (INF-γ, IL-1β, IL-6, IL-8, IL-12, and TNF-α) and were 362 associated with the development of ARDS. 11-13 In our study, severe COVID-19 patients had (0.9%) in our study was markedly lower than that reported in the adult population of Wuhan 366 (6.4%). 14- 16 We thus speculate that Th2 immune response in asthmatic patients may counter the 367 inflammation process induced by SARS-CoV-2 infection. Further studies are required to 368 characterize the immune response and inflammation features of The majority of severe patients showed rapid progression and multiple organ dysfunction. The to onset in critically ill cases than that in severely ill cases may reflect a higher virulence of 378 SARS-Cov-2, or earlier onset of The risk factors for severity identified in this study included age, high LDH level, and high 380 d-dimer level, consistent with those in previous reports. 15, 20 However, different from the findings 381 of previous studies 21 , hypertension was the only comorbidity associated with the severity of 382 COVID-19 after adjustment for age, sex and smoking status. The distinct features of pneumonia 383 and high severity in patients with COVID-19 in this study may lead to this difference from 384 previous reports. ACE2, a gateway to SARS, was reported to be a protective factor against 385 SARS-CoV-induced lung injury. 22, 23 The association between ACE2 expression and hypertension 386 was confirmed in a previous study. 24 This fact may partly explain the high prevalence of severe 387 COVID-19 in patients with hypertension. LDH has been recognized as a marker for severe 388 prognosis in various diseases, including cancer and infection. 25 The high LDH level in COVID-19 389 in severe cases suggested that LDH may be associated with lung injury and tissue damage, 390

warranting an investigation for the potential mechanism. 391

This study evaluated pre-admission medications for patients with severe COVID-19. Although the 392 proportion of nonsevere cases in patients receiving oseltamivir was higher than that in patients 393 without oseltamivir use, stratification analysis showed that there was no significant difference in case subgroup. Therefore, oseltamivir use may just be an indicator of disease severity. The 396 patients receiving umifenovir were younger than those without umifenovir use, indicating that 397 younger patients may have easier access to drugs or prefer umifenovir. 398

Older age, leukocytosis and high LDH level were reported to be risk factors associated with 399 in-hospital death in previous studies. 20, 26, 27 The present study also revealed that hyperglycemia 400 was related with increased mortality in COVID-19 patients. The prevalence of hyperglycemia may 401 be associated with underlying diabetes and corticosteroid therapy. However, the localization of 402 ACE2 expression in the pancreas in SARS was reported to damage islets, resulting in 403 hyperglycemia 19 ; this finding suggested that hyperglycemia may also be an indicator of severe 404

This study indicated that corticosteroid use was more common in severe cases than in nonsevere 406 cases and that high-dose corticosteroid use was related to high risk of death in severe COVID-19 407 patients. High-dose steroid use may be an indicator of disease severity rather than a predisposing 408 factor. In a previous study, treatment with methylprednisolone was shown to be beneficial for 409 COVID-19 patients who developed ARDS. 20 However, critically ill cases had more signs of 410 infection and abnormal laboratory findings, including high leukocyte, high procalcitonin, high 411 d-dimer, low albumin, and high creatinine levels. High-dose corticosteroid use should be used 412 with cautious in critically ill patients to avoid aggravating complications. 413 A recent study by Bin Cao et al showed that lopinavir/ritonavir treatment offered no significant 414 benefit over the standard care for hospitalized adult COVID-19 patients. 28 Cao's study also 415 reported that lopinavir/ritonavir led to a shorter median time to clinical improvement than the 416 standard care (HR 1.39; 95% CI 1.00 to 1.91) in a modified intention-to-treat analysis. Compared 417 with Cao's study, the severity of patients was more serious and lopinavir/ritonavir treatment was 418 associated with a lower risk of death in severe COVID-19 patients in this study. However, our 419 study was an observational study; thus, the benefit of lopinavir/ritonavir for severe COVID-19 420 patients needs to be further confirmed. 421

There were limitations to the current study. Firstly, epidemiological data were collected 422 respectively and recall bias might have occurred. Secondly, missing data on some variables, such 423 as detailed information of CT scan, may cause bias in the estimation and reduce the representativeness of the samples. Thirdly, laboratory findings were measured upon admission and may indicate the severity of COVID-19. The causal relationship between abnormal laboratory 426 findings and severity could not be determined. Fourthly, this study was an observational study 427 with limitations in terms of evaluating the efficacy of corticosteroids and antiviral drugs. Finally, 428 the absence of comparative data from COVID-19 patients not admitted or from other critically ill 429 patients were limitations of this study. 430

In conclusion, COVID-19 outbreak caused widespread concern and has threatened the global 

Clinical characteristics 523 of 140 patients infected with SARS-CoV-2 in Wuhan

An increased 525 prevalence of self-reported allergic rhinitis in major Chinese cities from

ACE2 528 links amino acid malnutrition to microbial ecology and intestinal inflammation

Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

Binding of SARS coronavirus to its receptor damages 534 islets and causes acute diabetes

Risk Factors Associated With Acute 536 Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Comorbidity and its 539 impact on 1590 patients with Covid-19 in China: A Nationwide Analysis

where N is the total number of patients with 638 available data. P values comparing nonsevere cases and severe cases are from χ² test, Fisher's exact test, 639 or Mann-Whitney U test

CoV-2 nucleic acid test was performed pre-admission

Table 3. Complications and treatment during hospitalization and clinical outcomes of COVID-19

Data are expressed as median (IQR), n (%), or n/N (%), where N is the total number of patients with 676 available data. P values comparing nonsevere cases and severe cases are from χ² test, Fisher's exact test

ARDS=acute respiratory distress syndrome