Dose-Response Association between Risk Factors and Incidence of COVID-19 in 325 Hospitalized Patients: A Multicenter Retrospective Cohort Study

Background: Epidemiological and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) have been reported but dose-response relationship and risk factors for mortality and severe cases and a detailed clinical course of illness have not been well described. Methods: In this retrospective, multicentre cohort study, we included patients with confirmed COVID-19 infection from Zhongnan Hospital of Wuhan University and The Central Hospital of Wuhan who had been discharged or had died by 6 February 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression and Cox proportional hazard methods to determine the risk factors and the dose-response relationship between risk factors and incidence of COVID-19. Findings: 325 patients (165 from Zhongnan Hospital and 160 from Central Hospital of Wuhan) were included in this study, of whom 308 were discharged and 17 died in hospital. 69 (21.2%) patients had comorbidity. Multivariable regression showed increasing odds of in-hospital death were associated with older age (HR:1.04, 95%CI:1.01-1.09), higher lactate dehydrogenase (HR:1.04, 95% CI:1.01-1.10), higher C-reactive protein (HR:1.10, 95%CI:1.01-1.23), and elevated procalcitonin (Natural log transformed HR:1.88, 95%CI:1.22-2.88), and d-dimer greater than 1μg/mL at admission (Natural log transformed HR: 1.63, 95%CI: 1.03-2.58). We evaluated the association of age, lactate dehydrogenase (LDH), d-dimer (DD), and procalcitonin (PCT) model with incident COVID-19 and the potential modifying effect of major COVID-19 risk factors related to LDH, DD, PCT by using Cox proportional hazard model. DD and PCT were log-linearly associated with COVID-19 mortality risk, while there were linear dose-response associations between age, LDH, DD and PCT were log-linearly associated with COVID-19 mortality risk, which were independent of established risk factors. Further, the adjusted HR for incident COVID-19 of severe cases increased gradually with the higher LDH, the elevated blood glucose, the increasing PCT levels, white cell count and total cholesterol, and the OR was 1.06 (95% CI: 1.02-1.10), 1.15 (95% CI: 1.01-1.32), Natural log transformed OR:1.75 (95%CI: 1.16-2.65), 1.20(95%CI:1.01-1.45), and 1.65 (95%CI:1.09-2.50), respectively. In particular, the dose-response association of LDH and PCT were more evident in individuals with severe cases (all P for overall association <0. 05). ROC analysis indicated that the AUC of the combination of age, sex, high-sensitivity C-reactive protein, d-dimer, lactate dehydrogenase, and procalcitonin model (0.947) was higher than that of any one of these variables-based model alone. The AUC of the Stage 5 score was highest among all stages. Interpretation: The potential risk factors of older age, higher lactate dehydrogenase and C-reactive protein, elevated procalcitonin and d-dimer greater than 1μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Higher lactate dehydrogenase, the elevated d-dimer, the increasing procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality. The combination of prognostic factors and six stages could provide the rationale for testing novel coronavirus managements in efforts to improve outcomes in the future. Funding Statement: No funding is provided in this study. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the Ethics of Committees of Zhongnan Hospital of Wuhan University, and in accordance with the Helsinki Declaration. Written informed consent was provided by all patients before examination. The anonymous data was collected and analyzed to facilitate better clinical decisions and treatment.