Background It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19.Methods 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100mg 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.Trial Registration: ClinicalTrials.gov, NCT04357366

Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruses, including SARS-CoV-2, Ebola, chikungunya, and influenza, across 34 cohorts from 18 countries, and single-cell RNA sequencing profiles of 702,970 immune cells from 289 samples across three cohorts. Severe viral infection was associated with increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells. We identified protective and detrimental gene modules that defined distinct trajectories associated with mild versus severe outcomes. The interferon response was decoupled from the protective host response in patients with severe outcomes. These findings were consistent, irrespective of age and virus, and provide insights to accelerate the development of diagnostics and host-directed therapies to improve global pandemic preparedness.

Introduction The 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. Methods In 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. Results The 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. Conclusions Early suPAR-guided anakinra treatment is associated with decrease of the risk for SRF and restoration of the pro- /anti-inflammatory balance.

SARS-CoV-2 pandemic, the fourth pandemic of the decade, has underscored gaps in global pandemic preparedness and the need for generalizable tests to avert overwhelming healthcare systems worldwide, irrespective of a virus. We integrated 4,780 blood transcriptome profiles from patients infected with one of 16 viruses across 34 independent cohorts from 18 countries, and 71 scRNA-seq profiles of 264,224 immune cells across three independent cohorts. We found a myeloid cell-dominated conserved host response associated with severity. It showed increased hematopoiesis, myelopoiesis, and myeloid-derived suppressor cells with increased severity. We identified four gene modules that delineate distinct trajectories associated with mild and severe outcomes, and show the interferon response was decoupled from protective host response during severe viral infection. These modules distinguished non-severe from severe viral infection with clinically useful accuracy. Together, our findings provide insights into immune response dynamics during viral infection, and identify factors that may influence patient outcomes.

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