ABSTRACT
IntroductionThe management of pneumonia caused by SARS-CoV-2 should rely on early recognition of the risk for progression to severe respiratory failure (SRF) and its prevention. We investigated if early suPAR (soluble urokinase plasminogen activator receptor)-guided anakinra treatment could prevent COVID-19-assocated SRF. MethodsIn this open-label prospective trial, 130 patients admitted with SARS-CoV-2 pneumonia SARS-CoV-2 and suPAR levels [≥]6 g/l were assigned to subcutaneous anakinra 100mg once daily for 10 days. The primary outcome was the incidence of SRF at day 14. Secondary outcomes were 30-day mortality, changes in sequential organ failure assessment (SOFA) score, of cytokine-stimulation pattern and of circulating inflammatory mediators. Equal number of propensity score-matched comparators for comorbidities, severity on admission and standard-of care (SOC) were studied. ResultsThe incidence of SRF was 22.3% (95% CI, 16.0-30.2%) among anakinra-treated patients and 59.2% (95% CI, 50.6-67.3%; P: 4.6 x 10-8) among SOC comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46). 30-day mortality was 11.5% (95% CI, 7.1-18.2%) and 22.3% (95% CI, 16.0-30.2%) respectively (hazard ratio 0.49; 95% CI 0.25-0.97%; P: 0.041). Anakinra treatment was associated with decrease in SOFA score and in circulating interleukin (IL)-6, sCD163 and sIL2-R; the serum IL-10/IL-6 ratio on day 7 was inversely associated with the change in SOFA score. Duration of stay at the intensive care unit and at hospital was shortened compared to the SOC group; the cost of hospitalization was decreased. ConclusionsEarly suPAR-guided anakinra treatment is associated with decrease of the risk for SRF and restoration of the pro- /anti-inflammatory balance. Trial RegistrationClinicalTrials.gov, NCT04357366
ABSTRACT
RationaleActivins are inflammatory and tissue-repair-related members of the TGF{beta}-superfamily that have been implicated in the pathogenesis of several immuno-inflammatory disorders including sepsis/acute respiratory distress syndrome (ARDS). We hypothesized that they might be of particular relevance to COVID-19 pathophysiology. ObjectivesTo assess the involvement of the Activin-Follistatin-axis in COVID-19 pathophysiology. MethodsLevels of Activins -A, -B and their physiological inhibitor Follistatin, were retrospectively analyzed in 314 serum samples from 117 COVID-19 patients derived from two independent centers and compared with common demographic, clinical and laboratory parameters. Optimal-scaling with ridge-regression was used to screen variables and establish a prediction model. Main ResultsThe Activin/Follistatin-axis was significantly deregulated during the course of COVID-19 and was independently associated with severity and in-hospital mortality. FACT-CLINYCoD, a novel disease scoring system, adding one point for each of Follistatin >6235 pg/ml, Activin-A >591 pg/ml, Activin-B >249 pg/ml, CRP >10.3 mg/dL, LDH >427 U/L, Intensive Care Unit (ICU) admission, Neutrophil/Lymphocyte-Ratio >5.6, Years of Age >61, Comorbidities >1 and D-dimers >1097 ng/ml, efficiently predicted and monitored fatal outcome independently of multiplicity and timing of sampling (AUC: 0.951{+/-}0.032, p<10-6). Validation in 35 samples derived from a third hospital indicated comparable AUC (0.958{+/-}0.086, p=0.032). ConclusionThis study unravels the link between Activin/Folistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that copes with the dynamic and heterogeneous nature of COCVID-19, predicts disease outcome and supports clinical decision making. Prospective large-scale validation of this calculator, as well as investigation of the mechanisms linking Activin/Folistatin-axis to COVID-19 pathogenesis is warranted.
