Objective Severely ill COVID-19 patients may end in acute respiratory distress syndrome (ARDS) and multi-organ failure. Some of them develop a systemic hyperinflammatory state produced by the massive release of inflammatory agents, known as cytokine storm syndrome (CSS). Inhibition of IL-1 by Anakinra (ANK) is a potential life-saving therapy for severe CSS cases. We propose a rationale for the use of subcutaneous ANK and review our initial experience in a small cohort of severe COVID-19 CSS patients. Methods Retrospective cohort study of COVID-19 patients developing ARDS (PaO2/FiO2 <300) and exhibiting signs of hyperinflammation (ferritin >1000 ng/mL and/or d-dimers > 1.5 μg/mL, plus IL-6 < 40 mg/mL) that received ANK. For comparison, a propensity score matched historical cohort of patients treated with IL-6 inhibitor Tocilizumab (TCZ) was used. Patients had previously received combinations of azithromycin, hydroxy-chloroquine, and methyl-prednisolone. Laboratory findings, respiratory function and adverse effects were monitored. Resolution of ARDS within the first 7 days of treatment was considered a favorable outcome. Results Subcutaneous ANK (100 mg every 6 h) was given to 9 COVID-19 ARDS CSS patients (77.8% males). Median age was 62 years (range, 42 to 87). A TCZ cohort of 18 patients was selected by propensity score matching and treated with intravenous single dose of 600 mg for patients weighing >75 Kg, or 400 mg if < 75 Kg. Prior to treatment, median PaO2/FiO2 ratio of the ANK and TCZ cohorts were 193 and 249, respectively (p = 0.131). After 7 days of treatment, PaO2/FiO2 ratio improved in both groups to 279 (104–335) and 331 (140–476, p = 0.099) respectively. On day 7, there was significant reduction of ferritin (p = 0.046), CRP (p = 0.043), and IL-6 (p = 0.043) levels in the ANK cohort but only of CRP (p = 0.001) in the TCZ group. Favorable outcome was achieved in 55.6% and 88.9% of the ANK and TCZ cohorts, respectively (p = 0.281). Two patients that failed to respond to TCZ improved after ANK treatment. Aminotransferase levels significantly increased between day 1 and day 7 (p = 0.004) in the TCZ group. Mortality was the same in both groups (11%). There were not any opportunistic infection in the groups nor other adverse effects attributable to treatment. Conclusion Overall, 55.6% of COVID-19 ARDS CSS patients treated with ANK exhibited favorable outcome, not inferior to a TCZ treated matched cohort. ANK may be a potential alternative to TCZ for patients with elevated aminotransferases, and may be useful in non-responders to TCZ.

Objectives. To assess the influence of corticosteroid pulses on 60-day mortality in hospitalized patients with severe COVID-19. Methods. We designed a multicenter retrospective cohort study in three teaching hospitals of Castilla y León, Spain (865,096 people). We selected patients with confirmed COVID-19 and lung involvement with a pO2/FiO2<300, excluding those exposed to immunosuppressors before or during hospitalization, patients terminally ill at admission, or those who died in the first 24 hours. We performed a propensity score matching (PSM) adjusting covariates that modify the probability of being treated. Then, we used a Cox regression model in the PSM group to consider factors affecting mortality. Results. From 2933 patients, 257 fulfilled the inclusion and exclusion criteria. 124 patients were on corticosteroid pulses (250 mg of methylprednisolone for three days), and 133 were not. 30.3% (37/122) of patients died in the corticosteroid pulse group and 42.9% (57/133) in the nonexposed cohort. These differences (12.6%, 95% CI [8·54-16.65]) were statically significant (log-rank 4.72, p = 0 , 03 ). We performed PSM using the exact method. Mortality differences remained in the PSM group (log-rank 5.31, p = 0.021 ) and were still significant after a Cox regression model (HR for corticosteroid pulses 0.561; p = 0.039 ). Conclusions. This study provides evidence about treatment with corticosteroid pulses in severe COVID-19 that might significantly reduce mortality. Strict inclusion and exclusion criteria with that selection process set a reliable frame to compare mortality in both the exposed and nonexposed groups.

Introduction A growing evidence suggests that immune dysregulation and thrombotic phenomena are key features in the pathophysiology of COVID-19. Apart from antivirals and respiratory support, anticoagulants, corticoids and immunomodulators are increasingly being prescribed, especially for more severe cases. We describe the clinical outcome of a large cohort of patients preferentially treated with glucocorticoids and interleukin inhibitors. Methods Single center and retrospective case series. Adult patients admitted with COVID-19 related respiratory insufficiency were included.Patients who died within 2 days after admission and those testing positive but asymptomatic were excluded. We defined two study periods: from March 3rd to March 31 st, 2020 (beginning of epidemic until peak of incidence) and April 1 st to May 7 th,2020 (second half of epidemic). The majority of patients received respiratory support,combinations of antimicrobials, anticoagulants, corticoids and interleukin inhibitors.Antivirals were preferentially given in the first period. The clinical outcome (death and ventilator dependency) of both periods was compared. Results From March 3 rd to May 7 th, 685 patients were included for analysis (58.4% males, mean age 68.9 years). Patients in the first period (n=408) were younger (66.6 vs 71.1 years, p=0.003),presented lower mean P a O 2/F i O2 ratio at admission (256.5 vs 270.4 mm Hg,p=0.0563), higher ferritin (1520 vs 1221 ng/ml, p=0.01), higher IL-6 (679 vs 194 pg/ml,p<0.0001) and similar D-dimer levels (3.59 vs 3.39 μg/mL, p=0.65) compared to the second period (n=277). Lopinavir/ritonavir and interferon were preferentially given in the first period (23.8% and 32% vs 1.8% and 11.9%, p<0.0001). Use of corticoids (88.2% vs 87.4%, p=0,74) and tocilizumab (26.29 vs 20.22% p=0.06) were similarly administered in both periods. Patients in the second period needed less mechanical ventilation (4.9% vs 16.9%, p<0.0001), fewer ICU admission (6.1% vs 20.1%,p<0.0001) and showed similar mortality (17.7% vs 15.4%, p=0.43). Infectious and thrombotic complications were comparable in both periods (both around 8%, with no statistical difference). Patients treated with tocilizumab (n=163) had lower mortality rate compared to those untreated under the same indication (7.9% vs 24.2%, p<0.0001).Conclusions In this large retrospective COVID-19 in-hospital cohort, lopinavir/ritonavir and interferon showed no significant impact on survival. Extensive use of corticosteroids and tocilizumab resulted in good overall outcome and showed acceptable complication rates.

Quantifying the importance of the key sites on haemagglutinin in determining the selection advantage of influenza virus: Using A/H3N2 as an example Dear Editor , Authors' contributionsSZ and MHW conceived the study. SZ carried out the analysis, and drafted the first manuscript. SZ and MHW discussed the results. All authors read, revised the manuscript, and gave final approval for publication. Declaration of Competing InterestMHW is a shareholder of Beth Bioinformatics Co., Ltd, and BCYZ is a shareholder of Beth Bioinformatics Co., Ltd and Health View Bioanalytics Ltd. Declarations Ethics approval and consent to participateThe ethical approval or individual consent was not applicable. Availability of data and materialsAll influenza viruses sequence data were collected via the influenza virus database (IVD) of the National center for Biotechnology Information (NCBI). Please see the online supporting information for details. Consent for publicationNot applicable.

Objectives: To assess the influence of corticosteroid pulses on 60-days mortality in hospitalized patients with severe COVID-19, intensive care admission, and hospital stay. Methods: We designed a multicenter retrospective cohort study in three teaching hospitals of Castilla y Leon, Spain (865.096 people). We selected patients with confirmed COVID-19 and lung involvement with a pO2/FiO2 < 300, excluding those exposed to immunosuppressors before or during hospitalization, patients terminally ill at admission, or died the first 24 hours. We performed a propensity score matching (PSM) adjusting covariates that modify the probability of being treated. Then we used a Cox regression model in the PSM group to consider factors affecting mortality. Results: From 2933 patients, 257 fulfilled the inclusion and exclusion criteria. 124 patients were on corticosteroid pulses, and 133 were not. 30,3% (37/122) of patients died in the corticosteroid pulses group and 42,9% (57/133) in the non-exposed cohort. These differences (12,6%) were statically significant (log-rank 4.72, p=0,03). We performed PSM using the exact method. Mortality differences remained in the PSM group (log-rank 5.31, p=0,021) and were still significant after a Cox regression model (HR for corticosteroid pulses 0,561, p= 0,039). There were no significant differences in intensive care admission rate (p=0,173). The hospital stay was longer in the corticosteroid group (p<0,001). Conclusions: This study provides evidence about treatment with corticosteroid pulses in severe COVID-19 that might significantly reduce mortality. Strict inclusion and exclusion criteria with that selection process set a reliable frame to compare mortality in both exposed and non-exposed groups.