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Background: In the ACCESS trial, the addition of clarithromycin to standard-of-care antibiotics (SoC) enhanced early clinical response and attenuated the inflammatory burden in adults with community-acquired pneumonia (CAP) requiring hospitalisation. A post-hoc analysis was performed to investigate the benefit in specific subgroups., Methods: The primary endpoint comprised two conditions to be met during the first 72 h: ≥50% decrease in respiratory symptom severity score; and any of ≥30% decrease in sequential organ failure assessment score and favourable change in the kinetics of procalcitonin (PCT, defined as ≥80% PCT decrease or PCT <0.25 ng/mL). In this exploratory post-hoc analysis, achievement of the study composite primary endpoint was compared between the two treatment groups within subsets differentiated by demographic characteristics, comorbidities, CAP severity, baseline laboratory findings and corticosteroid co-administration. The impact of clarithromycin treatment on the need for mechanical ventilation (MV) in all subgroups was also analysed., Results: The addition of clarithromycin significantly increased the proportion of patients achieving the primary endpoint across all subgroups and decreased the need for MV in 19 out of the 37 subgroups studied. For instance, the primary endpoint was attained in 32.7% of placebo-treated patients and in 67% of clarithromycin-treated patients with CURB-65 score ≥2 (P<0.0001), whereas MV was required in 18.8% and 7.4% of patients, respectively (P=0.022). The addition of corticosteroids alone was not as clinically advantageous as the use of clarithromycin alone, when added to SoC., Conclusion: Adding clarithromycin to SoC in the ACCESS trial achieved early clinical anti-inflammatory responses and decreased the need for MV in subgroups of hospitalised patients with CAP., Competing Interests: Declarations Funding: The ACCESS trial was sponsored by the Hellenic Institute for the Study of Sepsis (HISS) and financially supported by Abbot Products Operations (Abbott). HISS oversaw the study design, implementation, data analysis, interpretation, and determination regarding publication. The funding source, Abbott, did not take part in the design, execution, analysis, or interpretation of the study, nor did it influence the decision to publish. Publication administration was facilitated by Hughes associates, Oxford, UK. Competing Interests: K. Akinosoglou reports receiving honoraria and consulting fees from healthcare companies, including MSD, Pfizer, 3M Hellas, GSK/ViiV and Gilead. I. Papanikolaou has received honoraria or served as PI for studies from Boehringer-ingelheim, GlaxoSmithKline and AstraZeneca. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer and Servier. E. J. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations, bioMérieux, GSK, UCB, Sobi AB and ThermoFisher Brahms GmbH; independent educational grants from Abbott Products Operations, AbbVie, bioMérieux Inc, Johnson & Johnson, InCyte, MSD, Novartis, UCB, Sanofi and Sobi; and the Horizon 2020 European Grants ImmunoSep and RISCinCOVID and the Horizon Health grants EPIC-CROWN-2, POINT and Homi-Lung (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not declare any conflict of interest. Ethical Approval: The study was approved by the National Ethics Committee of Greece. Approvals are provided in the Methods section. Sequence Information: Not applicable Randomised Controlled Trial: ClinicalTrials.gov NCT04724044, (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: It is suggested that sepsis may be classified into four clinical phenotypes, using an algorithm employing 29 admission parameters. We applied a simplified phenotyping algorithm among patients with bacterial sepsis and severe COVID-19 and assessed characteristics and outcomes of the derived phenotypes., Design: Retrospective analysis of data from prospective clinical studies., Setting: Greek ICUs and Internal Medicine departments., Patients and Interventions: We analyzed 1498 patients, 620 with bacterial sepsis and 878 with severe COVID-19. We implemented a six-parameter algorithm (creatinine, lactate, aspartate transaminase, bilirubin, C-reactive protein, and international normalized ratio) to classify patients with bacterial sepsis intro previously defined phenotypes. Patients with severe COVID-19, included in two open-label immunotherapy trials were subsequently classified. Heterogeneity of treatment effect of anakinra was assessed. The primary outcome was 28-day mortality., Measurements and Main Results: The algorithm validated the presence of the four phenotypes across the cohort of bacterial sepsis and the individual studies included in this cohort. Phenotype α represented younger patients with low risk of death, β was associated with high comorbidity burden, and δ with the highest mortality. Phenotype assignment was independently associated with outcome, even after adjustment for Charlson Comorbidity Index. Phenotype distribution and outcomes in severe COVID-19 followed a similar pattern., Conclusions: A simplified algorithm successfully identified previously derived phenotypes of bacterial sepsis, which were predictive of outcome. This classification may apply to patients with severe COVID-19 with prognostic implications., Competing Interests: Dr. Karakike has received funding by the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (grant number 676129- granted to the National and Kapodistrian University of Athens). Dr. Poulakou reports receiving grant funding and/or speaker’s honoraria from Gilead, Menarini, Merck Sharp & Dohme (MSD), Pfizer, Roche, and Sobi. Dr. Panagopoulos has received honoraria from GILEAD Sciences, Janssen, and MSD. Dr. Milionis reports receiving honoraria, consulting fees, and nonfinancial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. Dr. Dalekos has acted as advisor/lecturer for Abbvie, Bristol-Myers Squibb, Gilead, Novartis, Roche, Amgen, MSD, Janssen, Ipsen, Genkyotex, Sobi, and Pfizer; he has received grant support from Bristol-Myers Squib, Gilead, Roche, Janssen, Abbvie, and Bayer; and he was or is currently principal investigator in national and international protocols sponsored by Abbvie, Bristol-Myers Squibb, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Tiziana Life Sciences, Bayer, Astellas, Ipsen, Pfizer, Amyndas Pharamaceuticals, CymaBay Therapeutics, and Roche. Dr. Giamarellos-Bourboulis has received honoraria from Abbott Products Operations, bioMérieux, Brahms GmbH, GlaxoSmithKline, InflaRx GmbH, Pfizer, and Swedish Orphan BioVitrum; he received independent educational grants from Abbott Products Operations, bioMérieux, Johnson & Johnson, MSD, Union Chimique Belge, and Swedish Orphan BioVitrum; and he received funding from the Horizon 2020 European grants ImmunoSep and Optimal use of hospital resources and intervention using suPAR for improving prognosis and care for patients with COVID-19 and the Horizon Health grant Equine Polyclonal antibodies Immunotherapy against COVID-19/SARS-CoV2–VOC (granted to the Hellenic Institute for the Study of Sepsis). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

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.)

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 long-term impact of the coronavirus disease 2019 (COVID-19) pandemic is a critical public health concern. The presence of residual symptoms in COVID-19 survivors has been investigated with various results; however, there is limited data documenting outcomes longer than 6 months post-hospitalization. We aimed to investigate the 12-month lasting effects of COVID-19 in hospitalized patients. From October 2020 through March 2021, 92 patients were enrolled. At admission and 1, 3, 6, and 12 months post-hospitalization, demographic, clinical, laboratory and imaging data, and echocardiography and spirometry test results were recorded. Possible cognitive and functional impairment, as well as the quality of life (QoL), were also assessed. In our cohort (median age: 61 years), 31.5% had severe disease at admission, which correlated with worse laboratory findings and a longer hospital stay (p < 0.001). Inflammatory markers were associated with severity initially, but reverted to normal after 3 months. In total, 55%, 37%, 19%, and 15.5% of patients reported at least one persistent symptom in months 1, 3, 6, and 12, respectively, while "brain fog" persisted up to 12 months in 10% of patients. Spirometry and echocardiography tests returned to normal in most patients during the evaluation, and no one had substantial residual disease. Our study provides insight into the long-term effects of COVID-19 on patients' physical and mental health. Despite the lack of significant residual disease or major complications after a year of thorough follow-up, COVID-19 survivors experienced lasting symptoms and a negative impact on their QoL., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The aim was to assess the performance of a blood assay combining measurements of MxA (myxovirus resistance protein A) and CRP (C-reactive protein) to differentiate viral from bacterial respiratory infections., Methods: In a prospective study, MxA and CRP were measured in the blood by the AFIAS panel in adults admitted with respiratory infection. Patients were split into discovery and validation cohorts. Final diagnosis was adjudicated by a panel of experts. Microbiology-confirmed cases comprised the discovery cohort, and infections adjudicated as highly probable viral or bacterial comprised the validation cohort., Results: A total of 537 patients were analyzed: 136 patients were adjudicated with definitive viral infections and 131 patients with definitive bacterial infections. Using logistic regression analysis, an equation was developed to calculate the probability for bacterial infection using the absolute value of MxA and CRP. Calculated probability ≥ 0.5 and/or MxA to CRP ratio less than 2 applied as the diagnostic rule for bacterial infections. This rule provided 91.6% sensitivity and 90.4% negative predictive value for the diagnosis of bacterial infections. This diagnostic sensitivity was confirmed in the validation cohort. A MxA/CRP ratio less than 0.15 was associated with unfavorable outcome., Conclusion: The calculation of the probability for bacterial infection using MxA and CRP may efficiently discriminate between viral and bacterial respiratory infections., (© 2023. The Author(s).)

Indolent systemic mastocytosis (ISM) represents the most common form of SM, typically following a slow clinical course. While anaphylactic reactions may come up in the life course of an ISM patient, these are often moderate and do not pose a threat to patient's health. Here, we present an undiagnosed case of ISM with recurrent severe anaphylactic episodes following consumption of food and emotional stress. One of these episodes led to anaphylactic shock, necessitating temporary mechanical ventilation and intensive care unit (ICU) support. Besides hypotension, a diffuse, itchy, red rash was the only notable clinical finding. Upon recovery, we found abnormally high baseline serum tryptase level as well as 10% bone marrow (BM) infiltration by multifocal, dense clusters of CD117 + /mast cell tryptase + /CD25 + mast cells (MCs), consolidating the diagnosis of ISM. Prophylactic treatment with a histamine receptor antagonist was initiated, resulting in milder episodes thereafter. Diagnosis of ISM requires a high level of suspicion; its prompt recognition and treatment are important in preventing potentially life-threatening anaphylactic episodes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Boukouris, Michelakis, Metaxas, Karapati, Kanellis, Lioni and Tzavara.)

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.)

Since the outbreak of COVID-19, research has been focused on establishing effective treatments, especially for patients with severe pneumonia and hyperinflammation. The role and dose of corticosteroids remain obscure. We evaluated 58 patients with severe COVID-19 during two periods. 24 patients who received methylprednisolone pulses (250 mg/day intravenously for 3 days) were compared with 34 patients treated according to the standard dexamethasone protocol of 6 mg/day. Among non-intubated patients, the duration of hospitalization was shorter for those who received methylprednisolone pulses (9.5 vs 13.5, p<0.001). In a subgroup analysis of patients who required intubation, those treated with the dexamethasone protocol demonstrated a relative risk=1.89 (p=0.09) for dying, in contrast to the other group which showed a tendency towards extubation and discharge from the hospital. A 'delayed' need for intubation was also observed (6 vs 2 days, p=0.06). Treatment with methylprednisolone pulses significantly reduced hospitalization time. Although there was no statistically significant influence on the necessity for intubation, methylprednisolone pulses revealed a tendency to delay intubation and hospital discharges. This treatment could benefit patients in the hyperinflammatory phase of the disease., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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).)

Objectives: Interstitial pneumonia with autoimmune features (IPAF) refers to patients with interstitial lung disease and autoimmune features not fulfilling the classification criteria for a specific connective tissue disease. We sought to study the characteristics, disease progression, response to treatment and complications of patients with IPAF in 1-year follow-up period., Methods: Clinical and laboratory findings, comorbidities, medications, pulmonary function tests (PFTs), chest HRCT and complications during the one-year follow-up period were documented for each of the 39 enrolled patients with IPAF., Results: The mean age at the time of IPAF diagnosis was 63.2 (±11) years, and 62% of patients were female. The most common clinical features were arthritis (82%) and rash (54%-not included in the IPAF criteria). Antinuclear antibodies (ANA) (59%) and non-specific interstitial pneumonia (NSIP-61.5%) were the most prevalent autoantibodies and radiological pattern respectively. PFTs at 12 months from baseline stabilized or improved in 79.5% of patients (p> 0.05). Infections were observed in 23.1% of patients during the first and in 12.8% during the second semester of follow-up. Two patients (5.1%) required hospitalization. All infections occurred in patients with non-usual interstitial pneumonia (UIP) pattern (p=0.02)., Conclusions: Arthritis and rash are among the most common features in IPAF suggesting rash could be included into IPAF criteria. Almost 80% of patients had stable/improved PFTs at the end of follow-up. Infections occurred mainly in the first semester of treatment and in patients with non-UIP radiological pattern probably due to higher doses of corticosteroids used in these patients., (© 2020 The Mediterranean Journal of Rheumatology (MJR).)

We describe a case of a 40-year-old woman who was admitted to the intensive care unit with a rapid onset of dyspnea and orthopnea. She presented progressive weakness, weight loss and secondary amenorrhea during last year, while intermittent fever was present for the last two months. Initial biochemical evaluation showed anemia, hyponatremia and increased C-reactive protein levels. Clinical and echocardiographic evaluation revealed cardiac tamponade, which was treated with pericardiocentesis. Pleural fluid samples were negative for malignancy, tuberculosis or bacterial infection. Hormonal and serologic evaluation led to the diagnosis of autoimmune polyglandular syndrome (APS) type 2 (including primary adrenal insufficiency and autoimmune thyroiditis), possibly coexisting with systemic lupus erythematosus. After symptomatic rheumatologic treatment followed by replacement therapy with hydrocortisone and fludrocortisone, the patient fully recovered. In patients with the combination of polyserositis, cardiac tamponade and persistent hyponatremia, possible coexistence of rheumatologic and autoimmune endocrine disease, mainly adrenal insufficiency, should be considered. Early diagnosis and non-invasive treatment can be life-saving., Learning Points: In patients with the combination of polyserositis, cardiac tamponade and persistent hyponatremia, possible coexistence of rheumatologic and autoimmune endocrine disease, mainly adrenal insufficiency, should be considered.Early diagnosis and non-invasive treatment can be life-saving for these patients.Primary adrenal insufficiency requires lifelong replacement therapy with oral administration of 15-25 mg hydrocortisone in split doses and 50-200 µg fludrocortisone once daily.

Bacteroides fragilis is a rare cause of pyomyositis or septic arthritis. We present the case of a 74-year-old otherwise healthy male who presented with fever and right hip pain ten days after a course of intramuscular injections. Magnetic resonance imaging (MRI) showed septic arthritis of the right hip joint and pyomyositis of the right gluteus minimus muscle. Blood cultures and pus aspirated from the muscle grew Bacteroides fragilis. The patient was treated successfully with surgical debridement and metronidazole, administered for six weeks intravenously and five weeks orally. Simultaneous pyomyositis and hip septic arthritis due to Bacteroides fragilis is rare, but should be considered possible after intramuscular injections.

Introduction: Elevated serum leptin levels are associated with cardiovascular events. We investigated the role of serum leptin in patients undergoing carotid endarterectomy (CEA)., Methods: A total of 74 patients (55 men; 38 symptomatic and 36 asymptomatic; mean age 66.9 +/- 8.2 years) undergoing CEA for >70% carotid artery stenosis were enrolled., Results: Serum leptin levels were lower in symptomatic compared with asymptomatic patients (7.1 +/- 1.3 vs 14.4 +/- 4.7 ng/dL; P < .001). Interleukin-6 (IL-6) levels were higher in symptomatic compared with asymptomatic patients (4.3 +/- 1.7 vs 3.3 +/- 1.1 pg/dL; P = .017). Symptomatic patients had more intense macrophage accumulation (0.7% +/- 0.1% vs 0.3% +/- 0.1%; P < .001). Serum leptin and serum IL-6 levels were independently associated with the presence of symptoms in multivariate analysis., Conclusion: Serum leptin levels were decreased in symptomatic carotid artery disease. This finding requires further investigation in larger studies.

Background: Statin treatment is considered as first line therapy in patients with atherosclerotic disease. We evaluated the effect of pre-treatment with statins on carotid plaque infiltration by macrophages and on the circulating levels of proinflammatory cytokines in patients who underwent carotid endarterectomy., Patients and Methods: One hundred fourteen patients were enrolled; 89 men and 25 women (mean age 67+/-8 years; range 42-83 years). Fifty three patients (46%) were on statin treatment at least 3 months before endarterectomy and 61 (54%) had never received statin treatment. The serum levels of high sensitivity C reactive protein (hsCRP), serum amyloid A (SAA), tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1beta and IL-6 were evaluated preoperatively. The intensity of macrophage infiltration was evaluated by immunochemistry, using the monoclonal antibody CD 68. The area of the plaque covered by macrophages was measured as a proportion of the whole plaque area, using a custom designed image tool analysis., Results: Patients on statins had lower serum total cholesterol levels (172+/-50 vs 194+/-35 mg/dl, p= 0.014), lower low density cholesterol levels (103+/-44 vs 123+/-31 mg/dl, p= 0.010) and lower serum hsCRP levels (1.8 [1.1-3.4] vs 3.4 [1.3-4.9] mg/l, p= 0.03), while SAA, TNFalpha, IL-6 and IL-1beta levels did not differ between the 2 groups. The infiltration of atherosclerotic plaque by macrophages was similar in statin treated patients and in controls (0.55+/-0.15% vs 0.49+/-0.19%, p= 0.21)., Conclusion: Patients on statins have similar macrophage accumulation in their carotid atherosclerotic plaques compared with patients not on statins. Inflammatory markers were also similar in both groups except for hsCRP which was significantly lower in those taking statins.

Background: Treatment with statins is considered a first line therapy in atherosclerotic disease. Intraplaque angiogenesis is involved in plaque progression and instability. It remains unclear whether the beneficial effect of statin treatment in humans is achieved through reduced intraplaque angiogenesis. The aim of this study was to evaluate the capillaries density in carotid plaques removed from patients treated with statin versus untreated patients., Methods and Results: We studied 102 patients who underwent carotid endarterectomy: 98 of them met the inclusion criteria and entered the study; 75 men and 23 women; mean age 66+/-8 years (range 42-83 years). Forty-three patients (44%) were on statin treatment at least 3 months before endarterectomy and 55 (56%) had never received statin treatment. The intensity of intraplaque angiogenesis was evaluated with immunohistochemistry using the antibody CD34. The number of capillaries per mm(2) was measured with a custom designed image tool analysis. With the exception of serum total cholesterol levels and serum low-density cholesterol levels, the two groups of patients did not vary significantly in cardiovascular risk factors and in parameters pertaining to the procedure profile. Patients on statin treatment had less capillaries per mm(2) than patients not receiving this kind of drugs (0.97+/-0.61 per mm(2) versus 1.39+/-0.98 per mm(2), p=0.031). Univariate associations between possible explanatory variables and number of capillaries per mm(2) were tested using Spearman rank R. Variables associated with a p-value <0.20 (age, serum creatinine, serum total cholesterol, serum low-density lipoprotein, serum homocysteine, presence of diabetes mellitus and statin treatment) were entered in a multivariable model. Multivariate analysis showed that statin treatment was the only independent predictor (t=-5.39, p<0.001) of intraplaque angiogenesis., Conclusions: Statin therapy is associated with reduced intraplaque angiogenesis in the carotid arteries. This could provide an explanation for the beneficial effects of this kind of drug on patients with atherosclerotic disease.

We report the case of an immunocompetent, 39 year old male who presented with diplopia and diffuse headache. The CT scan demonstrated the presence of a sizeable mass that took over the nasal cavity, the right maxillary sinus, the sphenoid and ethmoid sinus, extending to the sellar and suprasellar region, and eroding the adjacent bones. The patient also underwent MRI and endoscopic sinus surgery. Biopsy of the suspected tissue for pathology and culture demonstrated Aspergillus fumigatus.

Objective: To identify individuals with antinuclear antibodies (ANA) not fulfilling criteria for systemic lupus erythematosus (SLE) or other connective tissue diseases (CTD); to describe their clinical and serological features, to identify factors indicating evolution to SLE., Methods: A case-control study, based on retrospective evaluation of clinical files. The cases were ANA positive individuals (n = 50) examined in a medical outpatient setting, for symptoms compatible with SLE, but not fulfilling SLE classification criteria. Two patients with SLE were matched to each case in terms of age at initial symptom onset and sex. Thyroid autoimmunity was assessed by detecting antithyroid antibodies. Fisher's exact test and conditional logistic regression were used to evaluate the predictive ability of initial findings for SLE development., Results: ANA positive individuals suspected of having a CTD present a wide variety of symptoms and findings, usually at the 4th to 5th decade of life. Antibodies to Sm and U1RNP were absent; anti-Ro(SSA) and anti-La(SSB) occurred in 6%, while anti-dsDNA occurred in less than 10% of the cases. Arthritis, butterfly and discoid rash, Raynaud's phenomenon, and anti-Ro/SSA antibodies are the initial findings indicating evolution to SLE. Hematological abnormalities such as leukopenia and thrombocytopenia as well as constitutional symptoms such as easy fatigue and arthralgias are not associated with evolution to SLE. Antithyroid antibodies were detected in 16% of the cases and 2.3% of controls., Conclusion: ANA may connote a form of systemic autoimmunity that is expressed as a wide variety of complaints, even in the absence of a definite diagnosis of CTD. Arthritis, rash, Raynaud's phenomenon, and anti-Ro/SSA antibodies indicate evolution to SLE. Autoimmune thyroid disease occurs in ANA positive individuals not fulfilling SLE classification criteria rather than in patients with SLE.

The association of leukocytoclastic vasculitis or dermatomyositis with malignancies has been reported. We describe a patient who developed a skin rash, histologically compatible with dermatomyositis, which during the course of the disease switched to leukocytoclastic vasculitis, which was accompanied with peripheral blood pancytopenia in the absence of any specific pathological manifestation from the bone marrow three years prior to the diagnosis of acute myelomonocytic leukemia (AMML).

The levels of soluble form of E-Selectin (sEs), or endothelial-leukocyte adhesion molecule-1, were measured in 96 sera derived from 72 HIV-infected patients at different stages of the disease, 60 healthy blood donors, and 50 HIV-negative patients with infections, using a quantitative ELISA. Levels of sEs in HIV-infected individuals without AIDS, according to the 1993 classification system of the Centers for Disease Control, were higher than normal (mean +/- SEM 48 +/- 4 versus 35 +/- 3 ng/ml, p = 0.003). Patients with established AIDS, who were afebrile and had no evidence of acute concurrent infection, had even higher sEs serum levels (70 +/- 9 ng/ml, p = 0.009, compared to those without AIDS). A significant increase in clinical category disease progression was present. Individual concentrations of sEs correlated directly with levels of soluble intercellular adhesion molecule-1 (p < 0.00001) and IL-2 receptor (p = 0.001), but not with CD4+ T-cell counts. Zidovudine treatment was not associated with changes in sEs serum levels. Elevated sEs levels were also found in HIV-seronegative patients with other bacterial and protozoal infections. Since sEs is a biologically active molecule, further studies should investigate the pathogenetic significance of circulating sEs in HIV-related disease progression, and assess the prognostic value of sEs determination for these patients.