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Background: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. Methods: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. Results: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. Conclusion: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

Contains fulltext : 237989.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anakinra might improve the prognosis of patients with moderate to severe COVID-19 (ie, patients requiring oxygen supplementation but not yet receiving organ support). We aimed to assess the effect of anakinra treatment on mortality in patients admitted to hospital with COVID-19. METHODS: For this systematic review and individual patient-level meta-analysis, a systematic literature search was done on Dec 28, 2020, in Medline (PubMed), Cochrane, medRxiv, bioRxiv, and the ClinicalTrials.gov databases for randomised trials, comparative studies, and observational studies of patients admitted to hospital with COVID-19, comparing administration of anakinra with standard of care, or placebo, or both. The search was repeated on Jan 22, 2021. Individual patient-level data were requested from investigators and corresponding authors of eligible studies; if individual patient-level data were not available, published data were extracted from the original reports. The primary endpoint was mortality after 28 days and the secondary endpoint was safety (eg, the risk of secondary infections). This study is registered on PROSPERO (CRD42020221491). FINDINGS: 209 articles were identified, of which 178 full-text articles fulfilled screening criteria and were assessed. Aggregate data on 1185 patients from nine studies were analysed, and individual patient-level data on 895 patients were provided from six of these studies. Eight studies were observational and one was a randomised controlled trial. Most studies used historical controls. In the individual patient-level meta-analysis, after adjusting for age, comorbidities, baseline ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen (PaO(2)/FiO(2)), C-reactive protein (CRP) concentrations, and lymphopenia, mortality was significantly lower in patients treated with anakinra (38 [11%] of 342) than in those receiving standard of care with or without placebo (137 [25%] of 553; adjusted odds ratio [OR] 0·32 [95% CI 0·20-0·51]). The mortality benefit was similar across subgroups regardless of comorbidities (ie, diabetes), ferritin concentrations, or the baseline PaO(2)/FiO(2). In a subgroup analysis, anakinra was more effective in lowering mortality in patients with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17-0·47]). Anakinra showed a significant survival benefit when given without dexamethasone (OR 0·23 [95% CI 0·12-0·43]), but not with dexamethasone co-administration (0·72 [95% CI 0·37-1·41]). Anakinra was not associated with a significantly increased risk of secondary infections when compared with standard of care (OR 1·35 [95% CI 0·59-3·10]). INTERPRETATION: Anakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. FUNDING: Sobi.

RationaleMacrophage activation syndrome (MAS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19.ObjectiveTo investigate the outcome of personalized immunotherapy in critical COVID-19.MethodsIn this open-label prospective trial, 102 patients with SOFA (sequential organ failure assessment) score ≥2 or ARDS by SARS-CoV-2 were screened for MAS (ferritin more than 4420 ng/ml) and CID (ferritin ≤4420 ng/ml and low expression of HLA-DR on CD14-monocytes). Patients with MAS and CID with increased aminotransferases were assigned to intravenous anakinra; those with CID and normal aminotransferases to tocilizumab. The primary outcome was at least 25% decrease of SOFA score and/or 50% increase of respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28; serum biomarkers and cytokine production by mononuclear cells were secondary endpoints.Measurements and Main ResultsThe primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (odds ratio 3.11; 95% CIs 1.29-7.73; P: 0.011). No differences were found in mortality and in SOFA score changes. By day 4, ferritin was decreased among anakinra-treated patients; interleukin (IL)-6, soluble urokinase plasminogen activator receptor (suPAR) and the expression of HLA-DR were increased among tocilizumab-treated patients. Anakinra increased capacity of mononuclear cells to produce IL-6. Survivors by day 28 who received anakinra were distributed to scales of the WHO clinical progression of lower severity. Greater incidence of secondary infections was found with tocilizumab treatment.ConclusionsBiomarkers may guide favourable anakinra responses in critically ill patients with COVID-19.Trial RegistrationClinicalTrials.gov, NCT04339712

Background: It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19. Methods: A total of 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100 mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied. Results: 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95% CI, 0.20–0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25–0.97). Anakinra was associated with decrease in circulating interleukin (IL)−6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata. Conclusions: Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance. Funding: This study was funded by the Hellenic Institute for the Study of Sepsis, Technomar Shipping Inc, Swedish Orphan Biovitrum, and the Horizon 2020 Framework Programme. Clinical trial number: NCT04357366., eLife digest People infected with the SARS-CoV-2 virus, which causes COVID-19, can develop severe respiratory failure and require a ventilator to keep breathing, but this does not happen to every infected individual. Measuring a blood protein called suPAR (soluble urokinase plasminogen activator receptor) may help identify patients at the greatest risk of developing severe respiratory failure and requiring a ventilator. Previous investigations have suggested that measuring suPAR can identify pneumonia patients at highest risk for developing respiratory failure. The protein can be measured by taking a blood sample, and its levels provide a snapshot of how the body’s immune system is reacting to infection, and of how it may respond to treatment. Anakinra is a drug that forms part of a class of medications called interleukin antagonists. It is commonly prescribed alone or in combination with other medications to reduce pain and swelling associated with rheumatoid arthritis. Kyriazopoulou et al. investigated whether treating COVID-19 patients who had developed pneumonia with anakinra could prevent the use of a ventilator and lower the risk of death. The findings show that treating COVID-19 patients with an injection of 100 milligrams of anakinra for ten days may be an effective approach because the drug combats inflammation. Kyriazopoulou et al. examined various markers of the immune response and discovered that anakinra was able to improve immune function, protecting a significant number of patients from going on a ventilator. The drug was also found to be safe and cause no significant adverse side effects. Administering anakinra decreased of the risk of progression into severe respiratory failure by 70%, and reduced death rates significantly. These results suggest that it may be beneficial to use suPAR as an early biomarker for identifying those individuals at highest risk for severe respiratory failure, and then treat them with anakinra. While the findings are promising, they must be validated in larger studies.

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 μg/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