This retrospective cohort study identified several risk factors for death in adults in Wuhan who were hospitalised with COVID-19. In particular, older age, d-dimer levels greater than 1 μg/mL, and higher SOFA score on admission were associated with higher odds of in-hospital death. Additionally, elevated levels of blood IL-6, high-sensitivity cardiac troponin I, and lactate dehydrogenase and lymphopenia were more commonly seen in severe COVID-19 illness. Sustained viral detection in throat samples was observed in both survivors and non-survivors.
Previously, older age has been reported as an important independent predictor of mortality in SARS and MERS.14, 15 The current study confirmed that increased age was associated with death in patients with COVID-19. Previous studies in macaques inoculated with SARS-CoV found that older macaques had stronger host innate responses to virus infection than younger adults, with an increase in differential expression of genes associated with inflammation, whereas expression of type I interferon beta was reduced.16 The age-dependent defects in T-cell and B-cell function and the excess production of type 2 cytokines could lead to a deficiency in control of viral replication and more prolonged proinflammatory responses, potentially leading to poor outcome.17
SOFA score is a good diagnostic marker for sepsis and septic shock, and reflects the state and degree of multi-organ dysfunction.18, 19 Although bacterial infections are usually regarded as a leading cause of sepsis, viral infection can also cause sepsis syndrome. Previously, we determined that sepsis occurred in nearly 40% of adults with community-acquired pneumonia due to viral infection.20 In the current study, we found that more than half of patients developed sepsis. Additionally, we found that more than 70% of patients had white blood cell count below 10·0 × 109 per L or procalcitonin below 0·25 ng/mL, and no bacterial pathogens were detected in these patients on admission. Sepsis was a common complication, which might be directly caused by SARS-CoV-2 infection, but further research is needed to investigate the pathogenesis of sepsis in COVID-19 illness.
Cardiac complications, including new or worsening heart failure, new or worsening arrhythmia, or myocardial infarction are common in patients with pneumonia. Cardiac arrest occurs in about 3% of inpatients with pneumonia.21 Risk factors of cardiac events after pneumonia include older age, pre-existing cardiovascular diseases, and greater severity of pneumonia at presentation.22 Coronary heart disease has also been found to be associated with acute cardiac events and poor outcomes in influenza and other respiratory viral infections.22, 23, 24 In this study, increased high-sensitivity cardiac troponin I during hospitalisation was found in more than half of those who died. The first autopsy of a 53-year-old woman with chronic renal failure in Jinyintan Hospital showed acute myocardial infarction (data not published; personal communication with a pathologist from the Chinese Academy of Science). About 90% of inpatients with pneumonia had increased coagulation activity, marked by increased d-dimer concentrations.25 In this study, we found d-dimer greater than 1 μg/mL is associated with fatal outcome of COVID-19. High levels of d-dimer have a reported association with 28-day mortality in patients with infection or sepsis identified in the emergency department.26Contributory mechanisms include systemic pro-inflammatory cytokine responses that are mediators of atherosclerosis directly contributing to plaque rupture through local inflammation, induction of procoagulant factors, and haemodynamic changes, which predispose to ischaemia and thrombosis.27, 28, 29 In addition, angiotensin converting enzyme 2, the receptor for SARS-CoV-2, is expressed on myocytes and vascular endothelial cells,30, 31 so there is at least theoretical potential possibility of direct cardiac involvement by the virus. Of note, interstitial mononuclear inflammatory infiltrates in heart tissue has been documented in fatal cases of COVID-19, although viral detection studies were not reported.32
The level and duration of infectious virus replication are important factors in assessing the risk of transmission and guiding decisions regarding isolation of patients. Because coronavirus RNA detection is more sensitive than virus isolation, most studies have used qualitative or quantitative viral RNA tests as a potential marker for infectious coronavirus. For SARS-CoV, viral RNA was detected in respiratory specimens from about a third of patients as long as 4 weeks after disease onset.33 Similarly, the duration of MERS-CoV RNA detection in lower respiratory specimans persisted for at least 3 weeks,34, 35 whereas the duration of SARS-CoV-2 RNA detection has not been well characterised. In the current study, we found that the detectable SARS-CoV-2 RNA persisted for a median of 20 days in survivors and that it was sustained until death in non-survivors. This has important implications for both patient isolation decision making and guidance around the length of antiviral treatment. In severe influenza virus infection, prolonged viral shedding was associated with fatal outcome and delayed antiviral treatment was an independent risk factor for prolonged virus detection.36 Similarly, effective antiviral treatment might improve outcomes in COVID-19, although we did not observe shortening of viral shedding duration after lopinavir/ritonavir treatment in the current study. Randomised clinical trials for lopinavir/ritonavir (ChiCTR2000029308) and intravenous remdesivir (NCT04257656, NCT04252664) in treatment of COVID-19 are currently in progress.
Our study has some limitations. First, due to the retrospective study design, not all laboratory tests were done in all patients, including lactate dehydrogenase, IL-6, and serum ferritin. Therefore, their role might be underestimated in predicting in-hospital death. Second, patients were sometimes transferred late in their illness to the two included hospitals. Lack of effective antivirals, inadequate adherence to standard supportive therapy, and high-dose corticosteroid use might have also contributed to the poor clinical outcomes in some patients. Third, the estimated duration of viral shedding is limited by the frequency of respiratory specimen collection, lack of quantitative viral RNA detection, and relatively low positive rate of SARS-CoV-2 RNA detection in throat-swabs.37 Fourth, by excluding patients still in hospital as of Jan 31, 2020, and thus relatively more severe disease at an earlier stage, the case fatality ratio in our study cannot reflect the true mortality of COVID-19. Last but not least, interpretation of our findings might be limited by the sample size. However, by including all adult patients in the two designated hospitals for COVID-19, we believe our study population is representative of cases diagnosed and treated in Wuhan.
To the best of our knowledge, this is the largest retrospective cohort study among patients with COVID-19 who have experienced a definite outcome. We found that older age, higher SOFA score, and elevated d-dimer at admission were risk factors for death of adult patients with COVID-19. The prolonged viral shedding provides the rationale for testing novel coronavirus antiviral interventions in efforts to improve outcomes.