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Background: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1., Methods: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h., Results: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively., Conclusions: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018., (© 2024. The Author(s).)

Introduction: The anti-inflammatory effect of macrolides prompted the study of oral clarithromycin in moderate COVID-19., Methods: An open-label non-randomized trial in 90 patients with COVID-19 of moderate severity was conducted between May and October 2020. The primary endpoint was defined at the end of treatment (EOT) as no need for hospital re-admission and no progression into lower respiratory tract infection (LRTI) for patients with upper respiratory tract infection and as at least 50% decrease of the respiratory symptoms score without progression into severe respiratory failure (SRF) for patients with LRTI. Viral load, biomarkers, the function of mononuclear cells and safety were assessed., Results: The primary endpoint was attained in 86.7% of patients treated with clarithromycin (95% CIs 78.1-92.2%); this was 91.7% and 81.4% among patients starting clarithromycin the first 5 days from symptoms onset or later (odds ratio after multivariate analysis 6.62; p 0.030). The responses were better for patients infected by non-B1.1 variants. Clarithromycin use was associated with decreases in circulating C-reactive protein, tumour necrosis factor-alpha and interleukin (IL)-6; by increase of production of interferon-gamma and decrease of production of interleukin-6 by mononuclear cells; and by suppression of SARS-CoV-2 viral load. No safety concerns were reported., Conclusions: Early clarithromycin treatment provides most of the clinical improvement in moderate COVID-19., Trial Registration: ClinicalTrials.gov, NCT04398004., (© 2021. The Author(s).)

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/β 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., (© 2021. The Author(s).)

Objective: Youth experiencing homelessness represent a major social problem in Canada and, as demonstrated in the first national survey of this population conducted in 2015, are experiencing significant mental health challenges. The present study examines the findings of a second national survey completed in 2019. These findings afford the opportunity to examine the reliability of the findings of the first study with another large, representative sample and to attempt to articulate the unique characteristics of youth experiencing the greatest distress among this at-risk population., Methods: This study analyzed the mental-health-related data from the 2019 Without a Home-National Youth Homelessness Survey that was administered through convenience sampling at 98 agencies serving homeless youth in 49 communities across Canada. The survey was cross-sectional and self-administered, assessing a range of demographic information, pre- and post-homelessness variables, and mental health indicators. Multinomial logistic regression and linear regression were implemented to evaluate associations with distress level., Results: Survey data were obtained from 1,375 youth accessing Canadian homeless services in 9 provinces. Thirty-five percent reported at least 1 suicide attempt, and 33.1% reported a drug overdose requiring hospitalization. The findings of this survey replicated most of the key findings from the 2015 survey. The current findings emphasized, for this high-risk population, the heightened adversity faced by young women, Lesbian, Gay, Bisexual, Transgender, Queer, Two-Spirit (LGBTQ2S), and Indigenous subpopulations, as well as the centrality of violence exposure in determining risk and distress. Sexual violence, in particular, emerged as a key factor in the identification of youth experiencing the greatest distress with risk buffered by contact with family., Conclusions: These findings can inform prevention and intervention policies and services and reinforce the importance of attending to violence exposure and trauma as central to the mental health trajectories of youth who have experienced homelessness.

Hydrogen sulfide (H2S) has recently been recognized as a novel gaseous transmitter with several anti-inflammatory properties. The role of host- derived H2S in infections by Pseudomonas aeruginosa was investigated in clinical and mouse models. H2S concentrations and survival was assessed in septic patients with lung infection. Animal experiments using a model of severe systemic multidrug-resistant P. aeruginosa infection were performed using mice with a constitutive knock-out of cystathionine-γ lyase (Cse) gene (Cse-/-) and wild-type mice with a physiological expression (Cse+/+). Experiments were repeated in mice after a) treatment with cyclophosphamide; b) bone marrow transplantation (BMT) from a Cse+/+ donor; c) treatment with H2S synthesis inhibitor aminooxyacetic acid (ΑΟΑΑ) or propargylglycine (PAG) and d) H2S donor sodium thiosulfate (STS) or GYY3147. Bacterial loads and myeloperoxidase activity were measured in tissue samples. The expression of quorum sensing genes (QS) was determined in vivo and in vitro. Cytokine concentration was measured in serum and incubated splenocytes. Patients survivors at day 28 had significantly higher serum H2S compared to non-survivors. A cut- off point of 5.3 μΜ discriminated survivors with sensitivity 92.3%. Mortality after 28 days was 30.9% and 93.7% in patients with H2S higher and less than 5.3 μΜ (p = 7 x 10-6). In mice expression of Cse and application of STS afforded protection against infection with multidrug-resistant P. aeruginosa. Cyclophosphamide pretreatment eliminated the survival benefit of Cse+/+ mice, whereas BMT increased the survival of Cse-/- mice. Cse-/- mice had increased pathogen loads compared to Cse+/+ mice. Phagocytic activity of leukocytes from Cse-/- mice was reduced but was restored after H2S supplementation. An H2S dependent down- regulation of quorum sensing genes of P.aeruginosa could be demonstrated in vivo and in vitro. Endogenous H2S is a potential independent parameter correlating with the outcome of P. aeruginosa. H2S provides resistance to infection by MDR bacterial pathogens., Competing Interests: The authors have declared that no competing interests exist.

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., Competing Interests: EK, SM, NG, EK, MS, GL, AS, DP, SG, OT, VP, KT, MK, VL, MD, IP, KA, DM, AG, AS, TG, KK, TM, IT, KS, LC, SC, NV, CA, SC, MK No competing interests declared, PP honoraria from GILEAD Sciences, Janssen, and MSD, GD Advisor/Lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen and Pfizer, has received Grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie and Bayer and was or is currently PI in National & International Protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer and Roche, GP independent educational grants from Pfizer, MSD, Angelini, and Biorad, HM honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier, Jv Senior editor, eLife, JE cofounder, shareholder and CSO of ViroGates A7S, Denmark and is named inventor on patents on suPAR owned by Copenhagen University Hospital Hvidovre, Denmark, MN supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. He has also received independent educational grants from TTxD, GSK and ViiV HealthCare, EG Reviewing editor, eLife, (© 2021, Kyriazopoulou et al.)

Background: The accuracy of a new optical biosensor (OB) point-of-care device for the detection of severe infections is studied., Methods: The OB emits different wavelengths and outputs information associated with heart rate, pulse oximetry, levels of nitric oxide and kidney function. At the first phase, recordings were done every two hours for three consecutive days after hospital admission in 142 patients at high-risk for sepsis by placing the OB on the forefinger. At the second phase, single recordings were done in 54 patients with symptoms of viral infection; 38 were diagnosed with COVID-19., Results: At the first phase, the cutoff value of positive likelihood of 18 provided 100% specificity and 100% positive predictive value for the diagnosis of sepsis. These were 87.5 and 91.7% respectively at the second phase. OB diagnosed severe COVID-19 with 83.3% sensitivity and 87.5% negative predictive value., Conclusions: The studied OB seems valuable for the discrimination of infection severity.

Background: The pneumonia of COVID-19 illness has often a subtle initial presentation making mandatory the use of biomarkers for evaluation of severity and prediction of final patient disposition. We evaluated the use of hydrogen sulfide (H2S) for the outcome of COVID-19 pneumonia., Patients and Methods: We studied 74 patients with COVID-19. Clinical data were collected, and survival predictors were calculated. Blood was collected within 24 h after admission (day 1) and on day 7. H2S was measured in sera by monobromobimane derivation followed by high-performance liquid chromatography and correlated to other markers like procalcitonin and C-reactive protein (CRP). Tumor necrosis factor alpha and interleukin (IL)-6 were also measured in serum., Results: Survivors had significantly higher H2S levels on days 1 and 7 after admission. A cut-off point of 150.44 μM could discriminate survivors from non-survivors with 80% sensitivity, 73.4% specificity, and negative predictive value 95.9%. Mortality after 28 days was 32% with admission levels lower than or equal to 150.44 μM and 4.1% with levels above 150.44 μM (P: 0.0008). Mortality was significantly greater among patients with a decrease of H2S levels from day 1 to day 7 greater than or equal to 36% (p: 0.0005). Serum H2S on day 1 was negatively correlated with IL-6 and CRP and positively correlated with the absolute lymphocyte count in peripheral blood., Conclusion: It is concluded that H2S is a potential marker for severity and final outcome of pneumonia by the SARS-CoV-2 coronavirus. Its correlation with IL-6 suggests anti-inflammatory properties.

Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7-8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation., Competing Interests: Declaration of Interests E.J.G.-B. has received honoraria from AbbVie USA, Abbott CH, InflaRx GmbH, MSD Greece, XBiotech Inc. and Angelini Italy; independent educational grants from AbbVie, Abbott, Astellas Pharma Europe, AxisShield, bioMérieux Inc, InflaRx GmbH, and XBiotech Inc; and funding from the FrameWork 7 program HemoSpec (granted to the National and Kapodistrian University of Athens), the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grant ImmunoSep (granted to the Hellenic Institute for the Study of Sepsis). A.A. has received honoraria and independent educational grants from Gilead, Pfizer, MSD, ViiV, Astellas, and Biotest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background/aims: High-density lipoprotein (HDL) has important anti-atherogenic functions, including antioxidant effects. However, it is unclear whether the antioxidative activity of HDL is associated with the severity and outcome of acute ischemic stroke. We aimed to evaluate this association., Methods: We prospectively studied 199 consecutive patients admitted with acute ischemic stroke and followed them up until discharge. We measured HDL antioxidant capacity, HDL-associated paraoxonase-1 (PON1) activity and HDL-associated myeloperoxidase (MPO) levels. Severe stroke was defined as National Institutes of Health Stroke Scale (NIHSS) at admission ≥5. Dependency was defined as modified Rankin scale at discharge between 2 and 5., Results: Patients with severe stroke had lower HDL antioxidant capacity, higher MPO levels and higher MPO/PON1 ratio. Independent risk factors for severe stroke were female gender (RR 2.80, 95% CI 1.37-5.70, p = 0.005), glucose levels (RR 1.01, 95% CI 1.0-1.02, p < 0.01) and HDL antioxidant capacity (RR 1.03, 95% CI 1.01-1.06, p < 0.05). Patients who were dependent at discharge had lower HDL antioxidant capacity, higher MPO levels and higher MPO/PON1 ratio. Independent predictors of dependency at discharge were lack of lipid-lowering treatment (RR 6.86, 95% CI 1.83-25.67, p < 0.005) and NIHSS (RR 1.56, 95% CI 1.29-1.88, p < 0.0001). The HDL antioxidant capacity did not differ between patients who died during hospitalization and those who were discharged. The only independent predictor of in-hospital mortality was NIHSS (RR 1.16, 95% CI 1.06-1.27, p < 0.005)., Conclusions: Impaired antioxidative activity of HDL is associated with more severe acute ischemic stroke and might also predict a worse functional outcome in these patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)