Risk factors and electrocardiogram characteristics for mortality in critical inpatients with COVID‐19

Abstract Background The novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has spread worldwide. Hypothesis The possible risk factors that lead to death in critical inpatients with coronavirus disease 2019 (COVID‐19) are not yet fully understood. Methods In this single‐center, retrospective study, we enrolled 113 critical patients with COVID‐19 from Renmin Hospital of Wuhan University between February 1, 2020 and March 15, 2020. Patients who survived or died were compared. Results A total of 113 critical patients with COVID‐19 were recruited; 50 (44.3%) died, and 63 (55.7%) recovered. The proportion of patients with ventricular arrhythmia was higher in the death group than in the recovery group (P = .021) and was higher among patients with myocardial damage than patients without myocardial damage (P = .013). Multivariate analysis confirmed independent predictors of mortality from COVID‐19: age > 70 years (HR 1.84, 95% CI 1.03‐3.28), initial neutrophil count over 6.5 × 109/L (HR 3.43, 95% CI 1.84‐6.40), C‐reactive protein greater than 100 mg/L (HR 1.93, 95% CI 1.04‐3.59), and lactate dehydrogenase over 300 U/L (HR 2.90, 95% CI 1.26‐6.67). Immunoglobulin treatment (HR 0.39, 95% CI 0.21‐0.73) can reduce the risk of death. Sinus tachycardia (HR 2.94, 95% CI 1.16‐7.46) and ventricular arrhythmia (HR 2.79, 95% CI 1.11‐7.04) were independent ECG risk factors for mortality from COVID‐19. Conclusions Old age (>70 years), neutrophilia, C‐reactive protein greater than 100 mg/L and lactate dehydrogenase over 300 U/L are high‐risk factors for mortality in critical patients with COVID‐19. Sinus tachycardia and ventricular arrhythmia are independent ECG risk factors for mortality from COVID‐19.

March 15, 2020 were enrolled. All patients were confirmed to have COVID-19 by performing RT-PCR on samples from the respiratory tract. The diagnosis of COVID-19 was based on the WHO interim guidelines. 7 All patients met the clinical criteria for critical-type COVID-19. Critical-type COVID-19 was defined based on the New Coronavirus Pneumonia Prevention and Control Program in China (sixth edition). 8 Patients who met one of the following criteria were considered to have critical-type COVID-19: respiratory failure requiring mechanical ventilation; shock state; and patients with other types of organ failure that need to be monitored in the ICU. This study was approved by the Institutional Ethics Committee of Renmin Hospital of Wuhan University.

| Data collection
Demographic characteristics, clinical records, laboratory data, ECG characteristics, treatments, and outcome data were obtained with data collection forms from electronic medical records. Two experienced clinicians entered and reviewed the data. Recorded information included demographic data, medical history, symptoms and signs, chronic diseases, laboratory findings, ECG data, and treatment measures. The date of disease onset was defined as the day when the symptom was noticed. The criteria for a confirmed diagnosis of SARS-CoV-2 were that at least one gene site was amplified and considered positive for the nucleocapsid protein (NP) gene and open reading frame (ORF) gene. 9 Myocardial injury was defined as blood levels of cardiac biomarkers (hs-TnI) above the 99th-percentile upper reference limit, regardless of new abnormalities in electrocardiography and echocardiography. 4 QT prolongation was defined as an absolute QTc interval > 500 ms (or a JTc interval > 410 ms to adjust for patients with QRS duration >120 ms). 10 Table S1). There was a significant difference among age groups (>70 years and < 70 years) and clinical outcomes (death and recovery) (P = .008). Hypertension (P = .042) and temperature greater than 39 C (P = .039) were more common in patients who died.

| Outcomes
There were no significant differences in sex, chronic diseases, (such as, diabetes, cerebrovascular disease, COPD, chronic kidney disease and chronic liver disease), or initial symptoms, (such as, fever, cough, fatigue, anorexia, myalgia, dyspnea, pharyngalgia, diarrhea, vomiting, and dizziness) between the death group and recovery group.

T A B L E 1 Characteristics of laboratory results in patients with COVID-19
Laboratory results No.(%) P-value All cases (n = 113) Death cases (n = 50) Recovery cases (n = 63) White blood cell count>9.5 × 10 9 /L 22 ( Table 3 shows that the proportion of patients with Arbidol (82.5% vs 58.0%; P = .004) and hydroxychloroquine treatment (23.8% vs 4.0%; P = .003) was higher in the recovery group than in the death group.

| Treatment characteristics
Other antiviral drugs, such as lopinavir/ritonavir, ribavirin, interferon α-2b injection, ganciclovir, and oseltamivir, showed no difference between the death group and recovery group. In addition, glucocorticoid therapy, immunoglobulin, albumin therapy, oxygen therapy, noninvasive ventilation (NIV), and invasive mechanical ventilation (IMV) were not significantly different between critical patients in the death group and recovery group.

| Risk factors associated with death
Kaplan-Meier survival analysis was used to analyze patient survival.
Supplemental Figure S1 shows the survival curves of patients of different ages (<70 years and >70 years). Elderly patients were more common in the death group than in the recovered group (P = .009).
The survival curve of those who had an initial neutrophil count >6.5 × 10 9 /L was lower than that of patients with an initial neutrophil count <6.5 × 10 9 /L (P < .001) (Supplemental Figure S2). The survival curve of patients with C-reactive protein >100 mg/L was lower than that of patients with C-reactive protein <100 mg/L (P < .001) (Supplemental Figure S3). The survival curve of patients with lactate dehydrogenase >300 U/L was lower than that of patients with lactate dehydrogenase <300 U/L (P < .001) (Supplemental Figure S4). Immunoglobulin therapy was more common in the recovered group than in the death group (P = .227) (Supplemental Figure S5).
All the factors in Tables S1, 1 and 3 were included in multivariate analysis to explore independent predictors of mortality from COVID- 19. As there were only 70 ECG data points, the factors in Table 2 were used in multivariate analysis alone to explore only the ECG risk factors for mortality from COVID-19. As show in

| DISCUSSION
This present retrospective study identified several risk factors for mortality from COVID-19. In particular, old age (>70 years), neutrophilia, C-reactive protein greater than 100 mg/L and lactate dehydrogenase greater than 300 U/L were associated with a higher likelihood of critical in-hospital death. Our study also showed that the In slightly over 3 months, SARS-CoV-2 spread worldwide and caused far greater morbidity and mortality than either SARS or MERS. 11 Previous studies have shown that older age, D-dimer greater than 1 μg/mL and greater cardiac troponin are potential risk factors for inpatients with COVID-19. 12,13 The number of cases has rapidly increased throughout the world, and there are more severe cases.
However, the risk factors for death are not fully understood in critical cases. In the present study, we analyzed possible risk factors for death from COVID-19. All patient characteristics and laboratory findings were included to examine the relationship between risk factors and death from critical COVID-19 at an early stage. The risk factors related to death included older age, neutrophilia, C-reactive protein greater than 100 mg/L, and lactate dehydrogenase greater than 300 U/L.
Chen suggested that SARS-CoV-2 is more likely to infect older adult males with chronic comorbidities as a result of the weaker immune functions of these patients. 2 We also found that the proportion of elderly patients and hypertension patients was higher in patients who died. Therefore, as an independent risk factor, age-related chronic diseases still play an important role in the outcome of critical cases. In addition, the results of the present study showed that patients with COVID-19 who died had significantly higher neutrophil counts than survivors. Considering that older age is associated with decreased immune function, 14 older age may be related to death due to less robust immune responses.
Cytokine storm and the viral evasion of cellular immune responses are thought to play important roles in disease severity. 15 The present findings showed that CRP greater than 100 mg/L was significantly associated with fatality. A significant increase in CRP levels, as documented for bacterial infections, can also occur with viral infections. 16 CRP is a classic acute phase protein. Hydroxychloroquine is known to have anti-inflammatory and antiviral effects and is used for rheumatoid arthritis and SARS. 23,24 The side effects of hydroxychloroquine may include gastrointestinal symptoms and QT prolongation syndrome, especially in patients with renal or hepatic dysfunction. 25 However, our results showed that hydroxychloroquine treatment was not associated with a higher likelihood of survival in critical in-hospital patients. Furthermore, hydroxychloroquine treatment during hospitalization was not associated with QT prolongation.
There were several limitations to this study. First, most of the patients did not have a 24-hour Holter monitor. Short bursts of arrhythmias may have been missed. Second, few patients were given antiarrhythmic drugs, such as, amiodarone and propafenone. Whether antiarrhythmic drugs affect the occurrence of arrhythmia needs further study. Third, due to the retrospective study design and the limited number of patients, data from larger populations and multiple centers are needed to further confirm the risk of mortality during hospitalization. Finally, this was a retrospective and observational study, and most of the patients were seriously ill at the time of admission.
Very few patients had echocardiographic data, and patient height and weight data were also missing, so we could not obtain results of echocardiography and BMI.

| CONCLUSIONS
Old age (>70 years), neutrophilia, C-reactive protein greater than 100 mg/L, and lactate dehydrogenase greater than 300 U/L are highrisk factors related to the fatality of critical patients with COVID-19.
Immunoglobulin treatment can reduce the risk of death. The proportion of patients with ventricular arrhythmia was higher in deceased patients than in survivors. Sinus tachycardia and ventricular arrhythmia were independent ECG risk factors for mortality in critical inpatients with COVID-19.

ACKNOWLEDGMENT
This study was funded by the National Natural Science Foundation of China (No.81670303) and (No.81970277).