key: cord-1030012-ri2cyxim authors: Li, Lingzhi; Zhang, Shudi; He, Bing; Chen, Xiaobei; Wang, Shihong; Zhao, Qingyan title: Risk factors and electrocardiogram characteristics for mortality in critical inpatients with COVID‐19 date: 2020-10-22 journal: Clin Cardiol DOI: 10.1002/clc.23492 sha: 63707ab571d5ba0fcb5d81c60e906d34a86a9e5a doc_id: 1030012 cord_uid: ri2cyxim 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 × 10(9)/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. 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. 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. As shown in Table 1 , the following factors were associated with a high risk of death from COVID-19: white blood cell count greater than 9.5 × 10 9 /L (P = .001), initial neutrophil count greater than 6.5 × 10 9 /L (P < .001), initial lymphocyte count less than 0.6 × 10 9 /L (P = .011), C-reactive protein greater than 100 mg/L (P < .001), Ddimer greater than 20 mg/L (P = .003), hypersensitive troponin I greater than 0.04 pg/mL (P = .004), blood urea nitrogen greater than 8 mmol/L (P = .011), lactate dehydrogenase greater than 300 U/L (P < .001), and lactic acid greater than 3 mmol/L (P = .014). However, there were no differences in hemoglobin less than 120 g/L, platelet count less than 100 × 10 9 /L, procalcitonin greater than 0.5 ng/mL, creatine kinase-MB greater than 5 ng/mL, alanine aminotransferase greater than 50 U/L, aspartate aminotransferase greater than 40 U/L, albumin less than 30 g/L, creatinine greater than 100 μmol/L, creatine kinase greater than 200 U/L, and B-type natriuretic peptide (BNP) greater than 900 pg/mL between the death group and recovery group. 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. 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. 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 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. 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. This study was funded by the National Natural Science Foundation of China (No.81670303) and (No.81970277). Clinical features of patients infected with 2019 novel coronavirus in Wuhan 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 Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical management of severe acute respiratory infection when novel coronavirus infection is suspected, interim guidance National Health Commission of the People's Republic of China. Guideline on the management of COVID-19 Interim Laboratory Biosafety Guidelines for Handling and Processing Specimens Associated with Coronavirus Disease QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin A Geroscience perspective on COVID-19 mortality Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Naive T cell maintenance and function in human aging Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology Clinical diagnosis of pandemic a (H1N1) 2009 influenza in children with negative rapid influenza diagnostic test by lymphopenia and lower C-reactive protein levels. Influenza Other Respir Viruses Prognostic value of lactate dehydrogenase for mid-term mortality in acute decompensated heart failure: a comparison to established biomarkers and brain natriuretic peptide The NLRP3 inflammasome in acute myocardial infarction Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes Median nerve stimulation prevents atrial electrical remodelling and inflammation in a canine model with rapid atrial pacing Clinical characteristics of coronavirus disease 2019 in China Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial Effects of chloroquine on viral infections: an old drug against today's diseases Life threatening severe QTc prolongation in patient with systemic lupus Erythematosus due to Hydroxychloroquine Risk factors and electrocardiogram characteristics for mortality in critical inpatients with COVID-19 The authors declare no potential conflict of interest.