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Follow-Up of Multi-Organ Dysfunction and Inflammation Using Biomarker Kinetics in Patients with Severe COVID-19 Disease and Association with Disease Outcomes: Results from a Referral Center Cohort in the North East of France
54 Pages Posted: 8 Jun 2020
More...Abstract
BACKGROUND: COVID-19 disease can induce pulmonary and systemic inflammation and subsequent multi-organ dysfunction. In patients with severe COVID-19 disease, no data are available on the follow-up of multi-organ dysfunction and inflammation by assessing the kinetics of biochemical biomarkers and its association with disease-related complications.
METHODS: We carried out a retrospective, longitudinal cohort study on all newly diagnosed consecutive patients among the first cases of severe COVID-19 disease that required hospitalization at the University Hospital of Nancy from March 1, 2020, to March 25, 2020. The final date of follow-up was March 31, 2020. The primary aim was to assess the occurrence of multi-organ dysfunction (kidney, lung, heart, liver, muscle) and inflammation as evaluated by biomarker kinetics in patients with severe COVID-19 disease. The secondary aims were to assess the association between biomarkers variation and the occurrence of COVID-19 related acute respiratory failure (ARF) and death. We estimated the kinetics over time of the biochemical markers using the isotonic regression method. We used a multistep approach to assess the association between the occurrence of kidney, lung, heart, and liver dysfunctions and inflammation as evaluated by biomarker kinetics and the occurrence of the secondary endpoints (ARF, death). Bivariate analyses were performed using receiver operating characteristic (ROC) analysis and time-series analyses. To look for independent predictors, we performed multivariable multilevel analysis using two-level hierarchical logistic models.
FINDINGS: A total of 162 patients were assessed. During the study period, 1151 biochemical explorations were carried out for up to 59 biochemical markers, totaling 15,260 biochemical values. The most frequently observed biochemical abnormalities during the follow-up (≥25% of the observed time) were increased urea nitrogen, hyperosmolality, hypocalcemia, low hemoglobin, and hypoxemia; major cytolysis with severe cholestatic syndromes and conjugated hyperbilirubinemia; increased C-reactive protein (CRP); increased troponin, N-Terminal pro-Brain Natriuretic Peptide, and muscle markers; and hypoalbuminemia with hypertriglyceridemia. The evolution of phosphorus followed a biphasic curve with a decrease during the first four days, followed by a progressive increase in parallel with urea nitrogen and creatinine. The proportion of patients who developed an acute kidney injury (AKI) stage 3, increased significantly over time (0·9%, day 0; 21·4%, day 14; P <0·001). In the multivariable multilevel analysis, three variables were independently associated with the risk of ARF: CRP >90 mg/L (odds ratio [OR] 6·87, 95% CI, 2·36–20·01), urea nitrogen >0·36 g/L (OR 3·91, 95% CI, 1·15–13·29), and type 2 diabetes (OR 4·49, 95% CI, 1·07–18·89). In bivariate analyses, urea nitrogen >0·42 g/L, but not CRP, was associated with the risk of COVID-19 related death.
INTERPRETATION: In this retrospective, longitudinal cohort study using an extensive biochemical dataset on consecutive patients with newly diagnosed severe COVID-19 disease, the follow-up of biochemical biomarkers kinetics was consistent with a severe multi-organ involvement along with a severe acute inflammatory response. Our study pointed out new biochemical abnormalities targeting other organs than lungs and kidneys, including the liver and biliary tract with marked cholestatic syndromes. High levels of CRP and urea nitrogen were potential predictors of ARF among patients with severe COVID-19 disease. Further studies should address the significance of acute kidney injury in the prediction of COVID-19 related death.
FUNDING STATEMENT: None.
DECLARATION OF INTERESTS: The authors who have taken part in this study declare that they do not have anything to disclose regarding conflicts of interest concerning this manuscript.
ETHICS APPROVAL STATEMENT: The “Nancy Biochemical Database” is registered at the French National Commission on Informatics and Liberty, CNIL, under the record N°1763197v0. The Ethics committee of the University Hospital of Nancy approved the study (ID: 2020/264).
Keywords: COVID-19 Disease; SARS-CoV-2; Biomarker Kinetics; Multi-organ involvement; Disease outcomes; Big data approach
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