Kinetics of Biomarkers Associated with Organ Dysfunction and Inflammatory Status and Their Association with Disease Outcomes in Severe COVID-19: A Longitudinal Cohort Study (preprint)

BACKGROUND: COVID-19 can induce pulmonary and systemic inflammation and subsequent multi-organ dysfunction. In patients with severe COVID-19, no data are available on the longitudinal evolution of biochemical abnormalities and their ability to predict disease outcomes. METHODS: Using a retrospective, longitudinal cohort study design on consecutive patients with severe COVID-19, we monitored biomarker kinetics to estimate the occurrence of organ dysfunction and the severity of the inflammatory reaction and their association with acute respiratory failure (ARF) and death through multilevel modeling adapted for repeated measures. FINDINGS: A total of 162 patients were assessed and did not receive antiviral therapy against SARS-CoV-2. During the study period, 1151 biochemical explorations were carried out for up to 59 biochemical markers in blood and urine, totaling 15,260 biochemical values. The spectrum of biochemical abnormalities and their kinetics were consistent with a multi-organ involvement, including lung, kidney, heart, liver (major cytolysis, cholestasis, conjugated hyperbilirubinemia), muscle (major cytolysis), and pancreas (hyperlipasemia) along with a severe inflammatory syndrome. On the 20 more representative biochemical markers (>250 iterations), only CRP >90 mg/L (odds ratio [OR] 6·87, 95% CI, 2·36–20·01) and urea nitrogen >0·36 g/L (OR 3·91, 95% CI, 1·15–13·29) were independently associated with the risk of ARF. Urea nitrogen >0·42 g/L was the only marker associated with the risk of COVID-19 related death. The proportion of patients who developed an acute kidney injury (AKI) stage 3, increased significantly during follow-up (0·9%, day 0; 21·4%, day 14; P <0·001). INTERPRETATION: Our results point out the lack of the association between the inflammatory markers and the risk of death but rather highlight a significant association between renal dysfunction and the risk of COVID-19 related acute respiratory failure and death. Further studies should address the significance of acute kidney injury in the prediction of COVID-19 related death. FUNDING: No funding.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).

A longitudinal study of immune cells in severe COVID-19 patients. (preprint)

Little is known about the time-dependent immune responses in severe COVID-19. Data of 15 consecutive patients were sequentially recorded from intensive care unit admission. Lymphocyte subsets and total monocyte and subsets counts were monitored as well as the expression of HLA-DR. For 5 patients, SARS-CoV-2-specific T-cell polyfunctionality was assessed against Spike and Nucleoprotein SARS-CoV-2 peptides. Non-specific inflammation markers were increased in all patients. Median monocyte HLA-DR expression was below the 8,000 AB/C threshold defining acquired immunodepression. A "V" trend curve for lymphopenia, monocyte numbers, and HLA-DR expression was observed with a nadir between days 11-14 after symptoms onset. Intermediate CD14++CD16+ monocytes increased early with a reduction in classic CD14++CD16- monocytes. Polyfunctional SARS-Cov-2-specific CD4 T-cells were present and functional, whereas virus-specific CD8 T-cells were less frequent and not efficient. We report a temporal variation of both innate and adaptive immunity in severe COVID-19 patients, helpful in guiding therapeutic decisions (e.g. anti-inflammatory vs. immunostimulatory ones). We describe a defect in virus-specific CD8 T-cells, a potential biomarker of clinical severity. These combined data also provide helpful knowledge for vaccine design. Trial registration numberNCT04386395

Almitrine as a non ventilatory strategy to improve intrapulmonary shunt in COVID-19 patients (preprint)

In severe COVID-19 pulmonary failure, hypoxia is mainly related to pulmonary vasodilation with altered hypoxic pulmonary vasoconstriction (HPV). Besides prone positioning, other non-ventilatory strategies may reduce the intrapulmonary shunt. This study has investigated almitrine, a pharmacological option to improve oxygenation. Patients and Method. A case control series of 17 confirmed COVID-19 mechanically ventilated patients in prone or supine positioning was collected: 10 patients received two doses of almitrine (4 and 12 mcg/kg/min) at 30-45 min interval each, and were compared to 7 control COVID-matched patients conventionally treated. The end-point was the reduction of intra-pulmonary shunt increasing the PaO2 and ScvO2. Results Patients were male (59%) with median (25th, 75th percentiles) age of 70 (54-78) years and a BMI of 29 (23-34). At stable mechanical ventilatory settings, PaO2 (mmHg) at FiO2 1 (135 (85, 195) to 214 (121, 275); p = 0.06) tended to increase with almitrine. This difference was significant when the best PaO2 between the 2 doses was used : 215 (123,294) vs baseline (p = 0.01). A concomitant increase in ScvO2 occurred ((73 (72, 76) to 82 (80, 87); p = 0.02). Eight over 10 almitrine-treated patients increased their PaO2, with no clear dose-effect. During the same time, the controls did not change PaO2. In conclusion, in early COVID-19 with severe hypoxemia, almitrine infusion is associated with improved oxygenation in prone or supine positioning. This pharmacological intervention may offer an alternative and/or an additional effect to proning and might delay or avoid more demanding modalities such as ECMO.