Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial.

BACKGROUND: Endotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial. METHODS: Adult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment. RESULTS: At baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013). CONCLUSION: We identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype. Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial.

Background: The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. Methods: This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Findings: Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Interpretation: Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90. Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia.

OBJECTIVES: Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19. METHODS: Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death. RESULTS: IP-10 had the best prognostic performance: baseline concentrations 2000 pg/ml or higher predicted equally well to suPAR (sensitivity 85.0 %; negative predictive value 96.6 %). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000 pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations. CONCLUSIONS: IP-10 concentrations of 2,000 pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14 days from hospital admission for COVID-19 and they may guide anakinra treatment. CLINICALTRIALS: gov, NCT04680949 and NCT04357366.

Development and validation of SCOPE score: A clinical score to predict COVID-19 pneumonia progression to severe respiratory failure.

Most patients infected with SARS-CoV-2 (COVID-19) experience mild, non-specific symptoms, but many develop severe symptoms associated with an excessive inflammatory response. Elevated plasma concentrations of soluble urokinase plasminogen activator receptor (suPAR) provide early warning of progression to severe respiratory failure (SRF) or death, but access to suPAR testing may be limited. The Severe COvid Prediction Estimate (SCOPE) score, derived from circulating concentrations of C-reactive protein, D- dimers, interleukin-6, and ferritin among patients not receiving non-invasive or invasive mechanical ventilation during the SAVE-MORE study, offers predictive accuracy for progression to SRF or death within 14 days comparable to that of a suPAR concentration of ≥6 ng/mL (area under receiver operator characteristic curve 0.81 for both). The SCOPE score is validated in two similar independent cohorts. A SCOPE score of 6 or more is an alternative to suPAR for predicting progression to SRF or death within 14 days of hospital admission for pneumonia, and it can be used to guide treatment decisions.

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.

Dapagliflozin decreases ambulatory central blood pressure and pulse wave velocity in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors reduce the incidence of heart failure and death in patients with type-2 diabetes mellitus. Arterial stiffness is a prominent risk factor for heart failure and overall mortality. The aim of this study was to evaluate the effects of dapagliflozin on ambulatory brachial and central blood pressure (BP) levels and arterial stiffness parameters in patients with type-2 diabetes mellitus. METHODS: This is a double-blind, randomized, placebo-controlled clinical trial including 85 adult patients with type-2 diabetes mellitus on monotherapy or combination therapy with two of: metformin, sulphonylurea, DPP-4 inhibitor, or insulin. Patients were randomized in a 1 : 1 ratio to oral dapagliflozin 10 mg per day or placebo for 12 weeks. Study participants underwent 24-h ambulatory BP monitoring with the Mobil-O-Graph NG monitor at baseline and study-end. RESULTS: Baseline demographic, clinical and laboratory parameters were similar in the two groups. During follow-up, 24-h brachial SBP/DBP (129.0 ±â€Š12.6/77.3 ±â€Š7.3 vs. 123.2 ±â€Š12.4/75.1 ±â€Š6.4 mmHg; P < 0.001/P = 0.008) and central SBP/DBP (117.4 ±â€Š10.5/78.9 ±â€Š7.3 vs. 113.3 ±â€Š8.8/77.3 ±â€Š6.5 mmHg; P = 0.002/P = 0.047) significantly decreased in dapagliflozin but not in the placebo group. Corresponding reductions of 24-h brachial SBP (-5.8 ±â€Š9.5 vs. -0.1 ±â€Š8.7, P = 0.005) and central SBP (-4.1 ±â€Š8.0 vs. -0.7 ±â€Š7.8; P = 0.046) were greater with dapagliflozin than placebo. Twenty-four-hour heart-rate adjusted augmentation index significantly decreased with dapagliflozin and insignificantly with placebo. Importantly, there was a significant difference in change of estimated 24-h PWV (-0.16 ±â€Š0.32 vs. 0.02 ±â€Š0.27; P = 0.007) favoring dapagliflozin. In generalized linear mixed models including 24-h brachial SBP as a random covariate, the adjusted marginal means of delta 24-h central SBP and delta 24-h PWV were not significantly different between-groups. CONCLUSION: Treatment with dapagliflozin significantly reduces ambulatory brachial and central BP levels and PWV in patients with type-2 diabetes mellitus. Improvement in these parameters may substantially contribute to the cardiovascular benefits of SGLT-2 inhibitors.

Dapagliflozin Does Not Affect Short-Term Blood Pressure Variability in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Increased blood pressure variability (BPV) is associated with increased cardiovascular and all-cause mortality in patients with type-2 diabetes mellitus (T2DM). Sodium-glucose co-transporter 2 (SGLT-2) inhibitors decrease the incidence of cardiovascular events, renal events, and death in this population. This study aimed to evaluate the effect of dapagliflozin on short-term BPV in patients with T2DM. METHODS: This is a secondary analysis of a double-blind, randomized, placebo-controlled trial in 85 patients with T2DM. Subjects were randomized to dapagliflozin 10 mg/day or placebo for 12 weeks. All participants underwent 24-hour ambulatory blood pressure (BP) monitoring with Mobil-O-Graph-NG device at baseline and study-end. SD, weighted SD (wSD), coefficient of variation, average real variability (ARV), and variation independent of mean were calculated for the 24-hour, daytime and nighttime periods. RESULTS: Dapagliflozin reduced 24-hour brachial BP compared with placebo. From baseline to study-end 24-hour brachial BPV indexes did not change with dapagliflozin (SBP-ARV: 11.51 ± 3.45 vs. 11.05 ± 3.35; P = 0.326, SBP-wSD: 13.59 ± 3.60 vs. 13.48 ± 3.33; P = 0.811) or placebo (SBP-ARV: 11.47 ± 3.63 vs. 11.05 ± 3.00; P = 0.388, SBP-wSD: 13.85 ± 4.38 vs. 13.97 ± 3.87; P = 0.308). Similarly, no significant changes in BPV indexes for daytime and nighttime were observed in any group. At study-end, no between-group differences were observed for any BPV index. Deltas (Δ) of all indexes during follow-up were minimal and not different between groups (SBP-wSD: dapagliflozin: -0.11 ± 3.05 vs. placebo: 0.12 ± 4.20; P = 0.227). CONCLUSIONS: This study is the first to evaluate the effects of an SGLT-2 inhibitor on short-term BPV in T2DM, showing no effect of dapagliflozin on all BPV indexes studied. CLINICAL TRIALS REGISTRATION: Trial Number NCT02887677.