key: cord-296746-j47306hx
authors: Chen, Fang-fang; Zhong, Ming; Liu, Ya; Zhang, Yi; Zhang, Kai; Su, De-zhen; Meng, Xiao; Zhang, Yun
title: The characteristics and outcomes of 681 severe cases with COVID-19 in China
date: 2020-07-08
journal: J Crit Care
DOI: 10.1016/j.jcrc.2020.07.003
sha: 
doc_id: 296746
cord_uid: j47306hx

PURPOSE: To clarify the epidemiological, clinical, and therapeutic features of patients with severe COVID-19. METHODS: In this study, we enrolled 681 patients with confirmed cases of severe COVID-19. The epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected. RESULTS: The median age of the study participants was 65 years, 53.2% were male, and 104 (15.3%) died. Age, Neutrophil-To-Lymphocyte Ratio (NLR), acute myocardial injury, and levels of C-reactive protein (CRP), lactate dehydrogenase (LDH), and CD3 T cells counts were independently and negatively associated with death, while arbidol and ribavirin were protective from death. The combination of NLR and acute myocardial injury on admission (AUC = 0.914) predicted mortality better than NLR, CRP, LDH, and acute myocardial injury. There were 312 (45.8%) patients with cardiovascular disease, of whom 23.4% died. β-blockers, ACEI/ARB, arbidol, and ribavirin might have a beneficial effect for severe COVID-19 patients with cardiovascular disease. CONCLUSION: The combination of NLR and acute myocardial injury on admission was highly predictive of mortality and survival. Clinicians should adopt more aggressive strategies for patients with a high NLR (>6.66) combined with myocardial injury. β-blockers and ACEI/ARB, as well as arbidol and ribavirin, were effective in COVID-19 patients with cardiovascular disease.

, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), first emerged in Wuhan, China in December of 2019. It has since spread rapidly throughout most of the world and become a global public health crisis. As of April 24, 2020, there have been more than 2.5 million confirmed cases and 160,000 deaths, and these numbers are continuing to rise.

COVID-19 is a highly infectious disease spread via human-to-human transmission, including through droplets, direct contact, and ocular tissues. Each patient can spread the virus to two to three new people. [1] SARS-CoV-2-infected patients are infectious even during the asymptomatic stage, which differs from SARS-CoV. [1] Although the majority of patients infected by SARS-CoV-2 have mild symptoms, the viruses can cause severe lung pneumonia, acute respiratory distress syndrome (ARDS), multiple organ failure, and death. [2] People with mild cases may only require early isolation and close follow-up. [3] For more severe cases, aggressive treatment and intensive care may be urgently needed. To date, the largest case series study enrolled 1591 COVID-19 patients who required ICU admission in Italy. [4] However, the majority (58%) of patients remained in the hospital, and there was no extra description of their medical therapy. [4] In severe cases, the disease progressed quickly while data guiding management remains limited and scarce. In China, Renmin Hospital of Wuhan University was a designated treatment hospital for patients with COVID-19. In this study, we recruited 681 people with confirmed, severe cases of COVID-19 with a clear endpoint (death or discharge) to clarify their epidemiological, clinical, and therapeutic features.

This retrospective, cohort study included 681 adult patients (≥18 years old) with COVID-19 who mmHg (1 mmHg = 0.133 kPa); or (4) lung imaging showing more than 50% of lesions progressing within 24-48 hours. The Research Ethics Commission of Qilu Hospital of Shandong University and Renmin Hospital of Wuhan University approved this protocol and written informed consent was obtained from all participants.

The primary outcomes were all-cause mortality during hospitalization and discharge. The outcomes were used to divide participants into two groups: survivors and non-survivors. Two physicians reviewed the electronic medical records and extracted the epidemiological, demographic, clinical, laboratory, treatment, and outcome data of all patients. All data were confirmed by a third researcher. Neutrophil-To-Lymphocyte Ratio (NLR) was calculated as absolute neutrophil counts divided by absolute lymphocyte counts. Acute myocardial injury was diagnosed if serum levels of cardiac troponin I (cTnI) were above the upper limit of the reference range (> 0.04ng/ml).

All statistical analysis was performed using SPSS Statistics 26.0 (IBM Corp.) and MedCalc (MedCalc Software bvba, Ostend, Belgium). Data are presented as median (IQR) for continuous variables and n (%) for categorical variables. A Mann-Whitney U test, chi-square test, or Fisher's exact test were used to compare the differences between survivors and non-survivors. A P value of < 0.05 was considered statistically significant. We used univariable and multivariable logistic regression models to explore the risk factors associated with outcomes. Receiver operating characteristic (ROC) curves were constructed to evaluate the sensitivity and specificity of the parameters. A crossover analysis was performed according to the research of D.W. Hosmer. To

The demographic data, clinical characteristics, and laboratory findings of patients were shown in Table 1 . The median age of all subjects was 65.0 years (IQR 54.0-72.0), ranging from 27 to 98 years old. Males accounted for 53.2% of the subjects. Hypertension (43.0%) was the most common comorbidity, followed by diabetes (16.7%) and coronary artery disease (CAD, 11.7%).

The main clinical symptoms were fever (85.9%), dry cough (67.8%), and fatigue (51.9%).

Compared with the survivors, non-survivors were older, more male, and had a higher heart rate and systolic blood pressure (SBP) (P<0.05). Non-survivors had higher hypertension, CAD, and cerebral infarction comorbidity rates (P<0.001), as well as significantly higher white blood cell and neutrophil counts and CRP, interleukin-6 (IL-6), NLR, aspartate aminotransferase (AST), creatinine, blood glucose, triglycerides (TG), LDH, creatine kinase-myocardial isoenzyme (CK-MB), and cTnI levels. Lymphocyte, platelet, CD3, CD4, CD8 counts and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were lower (P<0.05) in non-survivors. There were also more cases of acute myocardial injury (72.1% vs. 11.1%) and BNP elevation (42.1% vs. 8.0%) among non-survivors as compared to the survivors. There was no significant difference in diastolic blood pressure (DBP), aspartate aminotransferase (ALT), potassium, sodium, and hemoglobin between the two groups (Table1, Supplementary Table1).

Oxygen support was administered to patients according to hypoxemia severity. Non-survivors received more noninvasive and invasive ventilation (P<0.01). Among the total 681 patients, 666 (97.8%) received antiviral treatment, including arbidol, ribavirin, ganciclovir, or oseltamivir, etc.

The proportion of patients who received antibiotic therapy or immunoglobulin and glucocorticoid treatment was 83.8%, 54.6%, and 48.8%, respectively. Compared with the survivors, non-survivors used more antibiotics, glucocorticoids, immunoglobulin, and antifungal drugs, while less arbidol was administered (P<0.05) ( Table 2) .

We performed a multivariable logistic regression to determine the parameters associated with J o u r n a l P r e -p r o o f Journal Pre-proof death in patients with severe cases of COVID-19. We found that NLR (odds ratio (95% CI), 1.057 (1.010-1.107); P=0.018) and acute myocardial injury (7.716 (3.812-15.619); P=0.000) were independently and negatively associated with death in patients with severe COVID-19. The risk of death increases by 5.7% for every one-unit increase in NLR. In addition, age, CRP, LDH, CD3 counts, arbidol, and ribavirin were independently and negatively associated with adverse outcomes (Table 3) .

ROC analysis identified an NLR of 6.66 as the optimal cutoff to discriminate between We further analyzed the relationship between survival probability, NLR, and acute myocardial injury. Increased NLR levels and acute myocardial injury reduced the survival probability. There were significant differences between the survival probability when NLR ≤ 6.66 and NLR > 6.66, with or without acute myocardial injury (P<0.001, Supplementary Figure 1) . A decision tree was built to predict death using the NLR cutoff threshold and acute myocardial injury as the predictor variable. Patients were split into two groups according to acute myocardial injury and then stratified into two subgroups according to NLR (≤ 6.66 or > 6.66). A total of 91 patients who had COVID-19 cases with a definite endpoint in China. First, we found that age, CRP and LDH levels, CD3 counts, NLR, and acute myocardial injury were independently and negatively associated with death in severe COVID-19 patients. The combination of NLR and acute myocardial injury was highly predictive of mortality and survival exclusion diagnosis, more so than NLR or acute myocardial injury alone. Second, arbidol and ribavirin may be a beneficial therapy for COVID-19

and may be associated with improved survival rates. Third, β-receptor blocking agents, ACEI/ARB, arbidol, and ribavirin were independently and positively associated with death in patients who had COVID-19 and cardiovascular disease. These treatments might be effective in this patient population.

comorbidities. [5] Compared to survivors, non-survivors were typically older -73.1% of were over the age of 65 years, while 2.9% were younger than 40 years old -and had more comorbid conditions. Multivariable logistic regression revealed that older age was independently and negatively associated with death in COVID-19 patients. Meanwhile, 375 patients had underlying comorbidities, with hypertension being the most common, followed by diabetes, and CAD.

However, a retrospective study involving 191 patients did not find that comorbidities can independently predict an increased risk of death.

[6] Our multivariable regression had similar findings and did not establish an independent predictive value between underlying diseases and mortality.

Although most SARS-CoV-2-infected patients are asymptomatic and have mild cases, severe cases can lead to acute respiratory distress syndrome (ARDS), multiple organ failure, and even death. [2] As of April 20, 2020, the total worldwide case-fatality rate of COVID-19 was 5.2%. However, the mortality was higher in severe and critical patients. One study of 41 patients indicated that 15% of patients died, while the mortality rate increased by 38% in patients requiring ICU admission. [5] In one report in China of 44,672 confirmed cases, including 2,087 (5%) critical cases, the overall case-fatality rate was 2.3%, while 49% were critical cases. [7] In another study in Italy of 1,591 patients confirmed to have COVID-19, 405 (26%) patients died in ICU. [4] Our mortality rate was 15.3%, and we found that 80% of cases died within 14 days of admission. This heterogeneity may be associated with differences in illness severity. Viral invasion and rapid replication cause the change of white blood cells and the production J o u r n a l P r e -p r o o f Journal Pre-proof of proinflammatory cytokines, resulting in a cytokine storm and pulmonary tissue damage. [8] Elevated inflammatory indicators are predictive of a fatal outcome. [9] Consistent with previous research [10] , we found that traditional infection markers, including the number of white blood cells and serum levels of CRP and IL-6, were significantly higher in non-survivors than in survivors. As a specific marker of systemic inflammation and infection, NLR has prognostic value in predicting the 30-day mortality rate in community-acquired pneumonia. [11] In our study, NLR was significantly higher in non-survivors as compared with survivors. Moreover, higher NLR at admission was associated with an increased risk of death.

SARS-CoV-2 can cause acute myocardial injury, which was present in 7.2%-30% of hospitalized patients. [9, 12] Acute myocardial injury might be an important cause of severe clinical phenotypes or adverse endpoint events and is considered a predictor of mortality in patients with COVID-19. [13] In this study, levels of LDH and CK-MB were significantly increased in non-survivors, and 72.1% of non-survivors had elevated serum cTnI levels while 11.1% of survivors did. We found that NLR and acute myocardial injury on admission were the two best predictors of mortality in patients with severe cases of COVID-19. Moreover, the combined diagnostic value of these two indicators was significantly better than either alone. The AUC of NLR and acute myocardial injury combined was significantly higher than that of traditional infection markers, such as CRP, and myocardial injury markers, such as LDH and CK-MB. We built a decision tree that showed a combination of NLR and acute myocardial injury was highly predictive of mortality and survival exclusion diagnosis. Therefore, patients with a high NLR (＞ 6.66) and myocardial injury require more aggressive treatment strategies, including appropriate respiratory support or admission to the ICU.

There are several limitations to our study. First, as this is a retrospective study, a number of confounding factors may influence the clinical outcomes. Second, the sample size of our study population was not large enough. Further, multicenter studies are required.

The combination of NLR and acute myocardial injury on admission was highly predictive of mortality and survival exclusion diagnosis. Patients with a high NLR (＞6.66) and myocardial injury require a more aggressive treatment strategy. Arbidol and ribavirin may be beneficial in severe cases of COVID-19. To the patients combined with COVID-19 and cardiovascular disease, β-blockers and ACEI/ARB as well as arbidol and ribavirin were also effective. We are anxiously awaiting the results of randomized, controlled clinical trials currently underway, which may provide therapy recommendations for patients with COVID-19. J o u r n a l P r e -p r o o f Journal Pre-proof 

A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19)

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China

COVID-19): current status and future perspective

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Clinical Characteristics of Coronavirus Disease 2019 in China

An Emerging Marker Predicting Prognosis in Elderly Adults with Community-Acquired Pneumonia

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study

COVID-19 and the cardiovascular system

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

P values are comparing Survivor and Non-survivor. CAD, coronary artery disease

CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease

CK-MB, creatine kinase-myocardial isoenzyme.; cTnI, cardiac troponin I

Xiao Meng and Yun Zhang participated in study design and study conception. Fangfang Chen and Ming Zhong performed data analysis. Yi Zhang, Kai Zhang and Dezhen Su recruited patients and collected data. Ya Liu checked the data. Fangfang Chen and Xiao Meng drafted the manuscript.All authors provided critical review of the manuscript and approved the final draft for publication.