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Based on the concept of the individualized nature of sepsis, we investigated the significance of the −251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n = 146), community-acquired pneumonia (CAP, n = 109), intra-abdominal infections (IAI, n = 119), and primary bacteremia (BSI, n = 105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8. [ABSTRACT FROM AUTHOR]

Abstract Background Current knowledge on the exact ligand causing expression of TREM-1 on neutrophils and monocytes is limited. The present study aimed at the role of underlying infection and of the causative pathogen in the expression of TREM-1 in sepsis. Methods Peripheral venous blood was sampled from 125 patients with sepsis and 88 with severe sepsis/septic shock. The causative pathogen was isolated in 91 patients. Patients were suffering from acute pyelonephritis, community-acquired pneumonia (CAP), intra-abdominal infections (IAIs), primary bacteremia and ventilator-associated pneumonia or hospital-acquired pneumonia (VAP/HAP). Blood monocytes and neutrophils were isolated. Flow cytometry was used to estimate the TREM-1 expression from septic patients. Results Within patients bearing intrabdominal infections, expression of TREM-1 was significantly lower on neutrophils and on monocytes at severe sepsis/shock than at sepsis. That was also the case for severe sepsis/shock developed in the field of VAP/HAP. Among patients who suffered infections by Gram-negative community-acquired pathogens or among patients who suffered polymicrobial infections, expression of TREM-1 on monocytes was significantly lower at the stage of severe sepsis/shock than at the stage of sepsis. Conclusions Decrease of the expression of TREM-1 on the membrane of monocytes and neutrophils upon transition from sepsis to severe sepsis/septic shock depends on the underlying type of infection and the causative pathogen.

Background: Addition of macrolide antibiotics to β-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a β-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome., Methods: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of β-lactam plus β-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044)., Findings: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment., Interpretation: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to β-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden., Funding: Hellenic Institute for the Study of Sepsis and Abbott Products Operations., Competing Interests: Declaration of interests EJG-B has received honoraria from Abbott Products Operations, bioMérieux, Brahms, GSK, InflaRx, Swedish Orphan Biovitrum, and Xbiotech; independent educational grants from Abbott Products Operations, bioMérieux, InflaRx, Johnson & Johnson, MSD, UCB, and Swedish Orphan Biovitrum; and funding from the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). GP has received honoraria or consulting fees from AstraZeneca, Gilead, GSK, Menarini, MSD, Norma, Pfizer, and Sobi, and research grants from the University of Minnesota/University College London, the Hellenic Institute for the Study of Sepsis, Bausch, Roche, Xenothera, FabNTech, and Pfizer. ICP has received honoraria or served as principal investigator for studies from Boehringer Ingelheim, GlaxoSmithKline, and AstraZeneca. HM reports receiving honoraria, consulting fees, and non-financial support from health-care companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. GND is an advisor or lecturer for Pfizer, Roche, Sanofi, and Sobi; has received research grants from Gilead; and has served as principal investigator in studies for Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics, Sobi, and Intercept Pharmaceuticals. KAk reports receiving honoraria and consulting fees from health-care companies, including Angelini, MSD, Pfizer, Swedish Orphan Biovitrum, 3M hellas, GSK/ViiV, and Gilead. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Serology routinely serves as a diagnostic tool to confirm Chlamydia infections in humans. Particularly in delayed settings, such as post-outbreak scenarios where the acute phase of infection has subsided, serology is invaluable. Multiple studies, nonetheless, indicate deficiencies in specificity and sensitivity of current chlamydial antibody detection assays. Incorporation of multiple antigens per target is known to improve the accuracy of chlamydial serological assays. We, therefore, used the recomLine test (Mikrogen diagnostics) on serological samples of two cohorts, as it is the only commercially available test allowing detection of antibodies against three human pathogenic Chlamydia species ( C. trachomatis , C. pneumoniae and C. psittaci ) using multiple antigens per target. The first cohort (n = 156; samples collected between 2008 and 2022 during a C. trachomatis screening initiative) comprised women from the Netherlands (NL) with past exposure to C. trachomatis , while the second cohort (n = 44; samples collected in 2018 in a health examination survey) consisted of Belgian citizens (BE) with occupational or recreational exposure to chickens, representing a risk population for C. psittaci . The test indicated a statistically equivalent C. pneumoniae seroprevalence in both cohorts (39.10% in NL and 34.09% in BE; p = 0.337). As expected C. trachomatis seroprevalence was significantly higher (p < 0.001) in the Dutch cohort (48.72%), as compared to the Belgian cohort (4.55%). Lastly, C. psittaci seroprevalence did not significantly differ between the two groups (2.27% in BE and 1.92% in NL; p = 0.633), even though a higher prevalence was expected for the Belgian cohort. This prompts us to question whether the Belgian cohort truly constituted a C. psittaci risk population or whether the recomLine test is susceptible to cross-reaction of species-specific antibodies, thereby increasing C. psittaci prevalence in the Dutch cohort. We advocate for the development of affordable, highly sensitive antibody detection assays that can effectively distinguish between chlamydial species, addressing the increasing demand for enhanced serological testing methodologies.

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., (© 2024. The Author(s).)

Abstract: We aimed to evaluate heparin-binding protein (HBP) as a marker of prognosis of unfavorable outcome in COVID-19 pneumonia. This was a post hoc analysis of the SAVE clinical trial investigating anakinra treatment, guided by suPAR (soluble urokinase plasminogen activator receptor) levels ≥6 ng/mL, for the prevention of severe respiratory failure in hospitalized patients with COVID-19 pneumonia. Baseline HBP plasma levels were measured in 534 patients by fluorescence dry quantitative immunoassay using the Jet-iStar 800 analyzer. Concentrations higher than 35 ng/mL predicted 30-day mortality with a moderate specificity of 53.3% and negative predictive value 78.1%; sensitivity was low (29.0%). After multivariate Cox analysis, HBP higher than 35 ng/mL was an independent predictor of 30-day unfavorable outcome (adjusted hazard ratio, 1.77; 95% CI, 1.06-2.94; P = 0.028) and these patients were also at greater risk of death after 90 days (hazard ratio, 1.85; 95% CI, 1.25-2.74; P = 0.002). The cutoff was not predictive of development of severe respiratory failure, septic shock or acute kidney injury. Among patients with baseline HBP levels higher than 35 ng/mL, anakinra treatment was associated with decreased mortality (7.2%) versus comparators (18.1%; P < 0.001). Results confirm that HBP may be an early biomarker of poor outcome among preselected patients at risk from COVID-19 pneumonia.ClinicalTrials.gov registration NCT04357366., (Copyright © 2024 by the Shock Society.)

The link between type 2 diabetes (T2D) and the severe outcomes of COVID-19 has raised concerns about the optimal management of patients with T2D. This study aimed to investigate the clinical characteristics and outcomes of T2D patients hospitalized with COVID-19 and explore the potential associations between chronic T2D treatments and adverse outcomes. This was a multicenter prospective cohort study of T2D patients hospitalized with COVID-19 in Greece during the third wave of the pandemic (February-June 2021). Among the 354 T2D patients included in this study, 63 (18.6%) died during hospitalization, and 16.4% required ICU admission. The use of DPP4 inhibitors for the chronic management of T2D was associated with an increased risk of in-hospital death (adjusted odds ratio (adj. OR) 2.639, 95% confidence interval (CI) 1.148-6.068, p = 0.022), ICU admission (adj. OR = 2.524, 95% CI: 1.217-5.232, p = 0.013), and progression to ARDS (adj. OR = 2.507, 95% CI: 1.278-4.916, p = 0.007). Furthermore, the use of DPP4 inhibitors was significantly associated with an increased risk of thromboembolic events (adjusted OR of 2.249, 95% CI: 1.073-4.713, p = 0.032) during hospitalization. These findings highlight the importance of considering the potential impact of chronic T2D treatment regiments on COVID-19 and the need for further studies to elucidate the underlying mechanisms.

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., Competing Interests: A.An. is partly funded by the Italian Ministry of Health under “Fondi Ricerca Corrente” – L1P1. L.D. has received consultation honoraria from Sobi. M.B. has received funds for research grants and/or advisor/consultant and/or speaker/chairman from Angelini, Astellas, Bayer, Biomerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi and Nabriva. M.G.N. was supported by an ERC Advanced Grant (833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. P.P. has received honoraria from GILEAD Sciences, Janssen, and MSD. H.M. reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. G.N.D. is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, Sobi, received research grants from Abbvie, Gilead and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. E.J.G.-B. has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and Xbiotech Inc; independent educational grants from Abbott CH, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and Xbiotech Inc. and funding from the Horizon 2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (granted to the National and Kapodistrian University of AthensNational and Kapodistrian University of Athens), the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not disclose any conflict of interest., (© 2022 The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [ER, AA are employees at MeMed Diagnostics. GB’s work was partly funded by the Italian Ministry of Health ‘Fondi Ricerca Corrente’ to IRCCS Sacro Cuore Don Calabria Hospital. GND has acted as advisor/lecturer for Ipsen, Pfizer, Genkyotex, Novartis and Sobi; received research grants from Abbvie and Gilead; PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc., Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. MGN was supported by an ERC Advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. EJGB has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AbbVie, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Novartis, Sobi, UCB and XBiotech Inc.; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis) and from the Horizon Europe project EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not have any competing interest to declare.]., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The need for oral, cost-effective treatment for complicated skin and skin structure infections (cSSSIs) due to methicillin-resistant Staphylococcus aureus (MRSA) was addressed by the non-inferiority comparisons of oral minocycline plus rifampicin with linezolid., Methods: In the AIDA multicenter, open label, randomized, controlled clinical trial, hospitalized adults with cSSSI and documented MRSA were randomly assigned at a 2:1 ratio to either oral 600 mg rifampicin qd plus 100 mg minocycline bid or oral 600 mg linezolid bid for 10 days. The primary endpoint was the clinical cure rate in the clinically evaluable (CE) population at the test-of-cure visit (14 days). Non-inferiority was confirmed if the lower confidence limit (CI) did not fall below the accepted error margin of 15%. The study is registered with EudraCT number 2014-001276-56., Findings: 123 patients recruited between November 2014 and January 2017 were randomly assigned to treatment (81 patients to minocycline plus rifampicin and 42 patients to linezolid). Cure rates were 78.% (46/59, 90% CI 67.3-86.5) and 68.6% (24/35, 90% CI 53.4-81.3), respectively ( P  = 0.337). The percent difference in cure rates was 9.4% (90% CI -7.2 to 26.8%). Minocycline plus rifampicin combination was deemed non-inferior to linezolid as the lower CI was -7.2% i.e. smaller than the accepted error margin of -15%. Although statistically not significant, the overall rate of adverse events was higher in the linezolid group (47.6%, 20/42 versus 38.3%, 31/81)., Interpretation: Oral minocycline plus rifampicin was non-inferior to oral linezolid treatment providing alternative oral treatment for cSSSI., Funding: The EU Seventh Research Framework Programme., Competing Interests: Helen Sambatakou has received honoraria from MSD Greece, Elpen Hellas, Mylan Hellas and Pfizer Greece. E.J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and XBiotech Inc.; and funding from the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISCinCOVID (granted to the Hellenic Institute for the Study of Sepsis). Alasdair MacGowan has research grants/activities with the following: Merck, Shionogi, Venatorx, InfectoPharm, GSK, Bioversys, MRC (UK), NIHR (UK). All other authors declare no competing interests., (© 2022 The Authors.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cytotoxicity may involve inhibition of peroxisome proliferator-activated receptor alpha. Fenofibrate activates peroxisome proliferator-activated receptor alpha and inhibits SARS-CoV-2 replication in vitro. Whether fenofibrate can be used to treat coronavirus disease 2019 (COVID-19) infection in humans remains unknown. Here, we randomly assigned inpatients and outpatients with COVID-19 within 14 d of symptom onset to 145 mg of oral fenofibrate nanocrystal formulation versus placebo for 10 d, in a double-blinded fashion. The primary endpoint was a severity score whereby participants were ranked across hierarchical tiers incorporating time to death, mechanical ventilation duration, oxygenation, hospitalization and symptom severity and duration. In total, 701 participants were randomized to fenofibrate (n = 351) or placebo (n = 350). The mean age of participants was 49 ± 16 years, 330 (47%) were female, mean body mass index was 28 ± 6 kg/m 2 and 102 (15%) had diabetes. Death occurred in 41 participants. Compared with placebo, fenofibrate had no effect on the primary endpoint. The median (interquartile range) rank in the placebo arm was 347 (172, 453) versus 345 (175, 453) in the fenofibrate arm (P = 0.819). There was no difference in secondary and exploratory endpoints, including all-cause death, across arms. There were 61 (17%) adverse events in the placebo arm compared with 46 (13%) in the fenofibrate arm, with slightly higher incidence of gastrointestinal side effects in the fenofibrate group. Overall, among patients with COVID-19, fenofibrate has no significant effect on various clinically relevant outcomes ( NCT04517396 )., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The trajectory from moderate and severe COVID-19 into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) is a field of active research. We determined serum levels within 24 h of presentation of 20 different sets of mediators (calprotectin, pro- and anti-inflammatory cytokines, interferons) of patients with COVID-19 at different stages of severity (asymptomatic, moderate, severe and ARDS/MV). The primary endpoint was to define associations with critical illness, and the secondary endpoint was to identify the pathways associated with mortality. Results were validated in serial measurements of mediators among participants of the SAVE-MORE trial. Levels of the proinflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were significantly higher in patients with ARDS and MV. Levels of the anti-inflammatory IL-1ra and IL-33r were also increased; IL-38 was increased only in asymptomatic patients but significantly decreased in the more severe cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin were associated with significant probability for worse outcome. Calprotectin was serially increased from baseline among patients who progressed to ARDS and MV. Further research is needed to decipher the significance of these findings compared to other acute-phase reactants, such as C-reactive protein (CRP) or ferritin, for the prognosis and development of effective treatments.

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., Competing Interests: E.J.G.-B. has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi, and XBiotech, Inc.; independent educational grants from Abbott CH, AxisShield, bioMérieux, InflaRx GmbH, Johnson & Johnson, MSD, Sobi, and XBiotech, Inc.; and funding from the Horizon 2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens) and the Horizon 2020 European Grants ImmunoSep and RISCinCOVID (granted to the Hellenic Institute for the Study of Sepsis). G.P. has received independent educational grants from Pfizer, MSD, Angelini, and Bio-Rad. H.M. reports receiving honoraria, consulting fees, and non-financial support from health care companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. L.D. has received consultation honoraria from SOBI. M.B. has received funds for research grants from and/or has been an advisor/consultant and/or speaker/chairman for Angelini, Astellas, Bayer, bioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Roche, Shionogi, and Nabriva. P.P. has received honoraria from GILEAD Sciences, Janssen, and MSD. G.N.D. is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, and Sobi; received research grants from Abbvie and Gilead; and has served as PI in studies for Abbvie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Inc., Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics, Inc., Sobi, and Intercept Pharmaceuticals. M.G.N. is supported by an ERC advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research. M.G.N. is a scientific founder of TTxD and he has received independent educational grants from TTxD, GSK, Ono Pharma, and ViiV HealthCare. The other authors declare no competing interests., (© 2022 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).)

Rationale: Although early antimicrobial discontinuation guided by procalcitonin (PCT) has shown decreased antibiotic consumption in lower respiratory tract infections, the outcomes in long-term sepsis sequelae remain unclear. Objectives: To investigate if PCT guidance may reduce the incidence of long-term infection-associated adverse events in sepsis. Methods: In this multicenter trial, 266 patients with sepsis (by Sepsis-3 definitions) with lower respiratory tract infections, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard of care. The discontinuation criterion was ≥80% reduction in PCT levels or any PCT ≤0.5 μg/L at Day 5 or later. The primary outcome was the rate of infection-associated adverse events at Day 180, a composite of the incidence of any new infection by Clostridioides difficile or multidrug-resistant organisms, or any death attributed to baseline C. difficile or multidrug-resistant organism infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy, and cost of hospitalization. Measurements and Main Results: The rate of infection-associated adverse events was 7.2% (95% confidence interval [CI], 3.8-13.1%; 9/125) versus 15.3% (95% CI, 10.1-22.4%; 20/131) (hazard ratio, 0.45; 95% CI, 0.20-0.98; P  = 0.045); 28-day mortality 15.2% (95% CI, 10-22.5%; 19/125) versus 28.2% (95% CI, 21.2-36.5%; 37/131) (hazard ratio, 0.51; 95% CI, 0.29-0.89; P  = 0.02); and median length of antibiotic therapy 5 (range, 5-7) versus 10 (range, 7-15) days ( P  < 0.001) in the PCT and standard-of-care arms, respectively. The cost of hospitalization was also reduced in the PCT arm. Conclusions: In sepsis, PCT guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.Clinical trial registered with www.clinicaltrials.gov (NCT03333304).

Although clinical definitions of acute bacterial skin and skin-structure infection (ABSSSI) are now well established, guidance of the prediction of likely pathogens based on evidence is missing. This was a large survey of the microbiology of ABSSSIs in Greece. During the period November 2014 to December 2016, all admissions for ABSSSI in 16 departments of internal medicine or surgery in Greece were screened to determine the likely bacterial aetiology. Samples were cultured on conventional media. Expression of the SA442, mecA/mecC and SCCmec-orfX junction genes was assessed. Following univariate and forward logistic regression analysis, clinical characteristics were used to develop scores to predict the likely pathogen with a target of 90% specificity. In total, 1027 patients were screened and 633 had positive microbiology. Monomicrobial infection by Gram-positive cocci occurred in 52.1% and by Gram-negative bacteria in 20.5%, and mixed infection by Gram-positive cocci and Gram-negative bacteria in 27.3%. The most common isolated pathogens were Staphylococcus aureus and coagulase-negative staphylococci. Resistance to methicillin was 57.3% (53.5-61.1%). Three predictive scores were developed: one for infection by methicillin-resistant S. aureus, incorporating recent hospitalisation, atrial fibrillation, residency in long-term care facility (LTCF) and stroke; one for mixed Gram-positive and Gram-negative infections, incorporating localisation of ABSSSI in lumbar area, fluoroquinolone intake in last 6 days, residency in LTCF and stroke; and another for Gram-negative infection, incorporating skin ulcer presentation, peptic ulcer and solid tumour malignancy. In conclusion, methicillin-resistant staphylococci are the main pathogens of ABSSSIs. The scores developed may help to predict the likely pathogen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Based on the concept of the individualized nature of sepsis, we investigated the significance of the -251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n = 146), community-acquired pneumonia (CAP, n = 109), intra-abdominal infections (IAI, n = 119), and primary bacteremia (BSI, n = 105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8.

Introduction: Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time., Methods: The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer., Results: Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis., Conclusions: Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

In an attempt to define the most important driver responsible for recurrence of cystitis in women, 181 records were retrospectively analysed among 1010 consecutive references in a tertiary centre for lower urinary tract infections (UTIs). All 181 women had more than three episodes of cystitis per year; 129 were under continuous prophylaxis and 52 were under postcoital prophylaxis. Analysis revealed that the most important factor affecting successful outcome of chemoprophylaxis was the compliance of patients (odds ratio 0.074; P<0.0001). Among women treated for >or=6 months, the most effective regimen was nitrofurantoin, with a success rate of 96.8% compared with 82.8% for trimethoprim/sulphamethoxazole and 72.3% for norfloxacin (P=0.046 between agents). Failure of chemoprophylaxis was observed in 51 women in total; in 26 of them resistance to the administered agent had developed. Results of this retrospective study revealed that the most important driver leading to failure of prophylaxis for recurrent lower UTIs was the lack of compliance of women with their medication. Nitrofurantoin was the most potent among the administered agents.

One hundred sixty-three women with uncomplicated acute lower urinary tract infections were included in a multicenter randomized study comparing cefpodoxime-proxetil (one 100-mg tablet twice daily) with trimethoprim-sulfamethoxazole (one double-strength tablet [160/800 mg] twice daily) for 3 days. A total of 30 women in both arms were excluded from the study for various reasons. At 4 to 7 days after the discontinuation of therapy, 62 of 63 (98.4%) cefpodoxime-proxetil recipients and 70 of 70 (100%) trimethoprim-sulfamethoxazole patients were clinically cured and demonstrated bacteriological eradication, respectively. At 28 days after treatment, 48 of 55 (87.3%) and 43 of 50 (86%) cefpodoxime-proxetil recipients as well as 51 of 60 (85%) and 42 of 50 (84%) trimethoprim-sulfamethoxazole recipients were clinically cured and demonstrated bacteriological eradication, respectively. Independently of the prescribed regimen, a significant difference (P < 0.001) in failure rates was observed only for patients with a previous history of three or more episodes of acute cystitis per year. With the exception of one patient in the trimethoprim-sulfamethoxazole arm who discontinued therapy because of gastrointestinal pain, both antimicrobials were well tolerated. In conclusion, cefpodoxime-proxetil treatment for 3 days was as safe and effective as trimethoprim-sulfamethoxazole for 3 days for the treatment of uncomplicated acute cystitis in women.

It is well known that therapeutic habits and diabetic patient's compliance differ substantially between different populations. It is also accepted that if patients are recruited in specialized diabetes centers some important bias is likely to occur, e.g. an excess of insulin-treated subjects. Therefore, population studies are very helpful in order to establish treatment patterns in different populations. A descriptive study was performed during an epidemiological survey conducted on 12,842 randomly selected inhabitants of a suburb of Athens (both sexes, all ages). 509 persons were recorded as known diabetics. Information concerning the type of treatment was collected. Reliable data were available on 490 diabetic individuals. 145 (29.6%) of them were following diet alone, while 270 (55.1%) were receiving antidiabetic tablets and only 75 (15.1%) injected insulin. In patients 40 years old or more (n = 471), the corresponding numbers were 30.1, 56.5 and 13.4% respectively. Thus, it is obvious that insulin-treated patients represent a small percentage of the total diabetic population. It seems that these differences are caused by genetic as well as other factors.