OBJECTIVES:There are few data on the penetration of daptomycin into the cerebrospinal fluid (CSF) of patients with bacterial meningitis. This ancillary study of the AddaMap trial aimed to assess the CSF penetration of intravenous daptomycin in 13 patients with pneumococcal meningitis. PATIENTS AND METHODS:Daptomycin was administered at 10 mg/kg/day to 13 patients with pneumococcal meningitis admitted to the Dijon University Hospital. Blood and CSF samples were collected on days 3 and 8. The population pharmacokinetics of daptomycin in plasma and CSF were studied using a two-compartment model. RESULTS:A large inter-individual variability in plasma areas under the curve (median, 25-75-percentile), 7843 h.mg/L (6606-9264), plasma peak, 107.5 mg/L (81.4-126.3) and trough 14 mg/L (7.6-19.3) concentrations and elimination half-lives, 8.8 hours (7.9-10.8), was observed. In CSF, the maximum concentration was 0.88 mg/L (0.57-2.82), and the elimination half-life was 23.8 hours (18.7-39.3). The AUC CSF/plasma ratio was 2.20% (1.7-2.3). Daptomycin CSF penetration was significantly correlated with CSF levels of proteins and lactate. CSF concentrations, 0.67 mg/L (0.39-0.86), were above the MIC90 of pneumococci resistant to beta-lactam. Simulations showed that a loading dose could reduce the time required to reach a biologically active concentration in CSF. CONCLUSION:We conclude that daptomycin administered at a dose of 10 mg/kg/day achieves CSF concentrations that may exert non-lytic anti-pneumococcal effects and demonstrate significant activity against highly resistant pneumococcal strains. These findings suggest that daptomycin could be considered as a valuable adjunctive therapy in the treatment of pneumococcal meningitis.

Acute community-acquired pneumonia (CAP) is a leading cause of infection-related mortality worldwide. Endotoxemia, characterized by elevated plasma lipopolysaccharide (LPS), is a key driver of inflammation and thrombosis in Gram-negative sepsis and has been suggested to occur in severe pneumonia, irrespective of etiology. However, current immunoassays for LPS quantification lack sensitivity and specificity. We aimed to quantify plasma LPS in severe CAP patients, including COVID-19, using a validated mass spectrometry method, and to explore associations with immune activation, coagulation, gut translocation, and clinical outcomes. In this prospective ancillary study of the LYMPHONIE cohort, we included 34 non-COVID-19 severe CAP (sCAP), 34 severe COVID-19 (sCOVID-19) and 34 matched healthy volunteers. Plasma LPS was measured by LC–MS/MS detecting 3-hydroxy fatty acids of lipid A. Clinical data, immune biomarkers, coagulation biomarkers, and gut injury markers were measured. Unexpectedly, median plasma LPS concentrations were significantly lower in sCAP patients (724 pmol/ml in sCAP; 750 pmol/ml in sCOVID-19) compared to healthy volunteers (1009 pmol/ml, p < 0.001). LPS levels did not correlate with severity scores or mortality. Low positive correlations were observed between LPS and markers of endothelial activation (sVCAM-1) and coagulation (D-dimer). However, patients with high LPS showed no increased risk of thrombotic or cardiovascular events. Using a highly specific LC–MS/MS method, we found no evidence of increased circulating LPS in severe pneumonia patients, challenging the hypothesis of gut-derived endotoxemia as a major contributor to systemic inflammation in severe CAP, including COVID-19. Take-home message Using a highly specific mass-spectrometry assay, we found no evidence of elevated circulating lipopolysaccharide in severe community-acquired pneumonia, including COVID-19. These findings challenge the concept that gut-derived endotoxemia is a major driver of systemic inflammation in severe pneumonia. Tweet Mass spectrometry reveals no rise in plasma LPS in severe pneumonia or COVID-19, questioning gut endotoxemia’s role in inflammation.

BACKGROUND:The European Society of Cardiology (ESC) diagnostic criteria for infective endocarditis (IE) were updated in 2023. Using a prospective multicentre cohort of patients treated for IE, we compared the performance of the 2023 ESC classification to that of 2015 ESC, 2019 European Heart Rhythm Association (EHRA) and 2023 Duke-International Society for Cardiovascular Infectious Diseases (ISCVID) classifications in patients with or without cardiac implantable electronic devices (CIEDs). METHODS:A total of 1180 patients treated for IE between January 2017 and October 2022 were categorised as having either definite or possible/rejected IE within each classification. The gold standard diagnosis of IE was independently adjudicated by experts as 'certain' or not. Definite and 'certain' cases of IE were cross-tabulated to calculate sensitivity, specificity and accuracy.Suspicion of lead IE was defined by specific anatomical or metabolic features of cardiac lead infection on imaging; or by pulmonary embolism without valvular vegetation; or by positive culture of a lead extracted during open-heart surgery. RESULTS:In the 269 patients with CIEDs, 208 (77.3%) were adjudicated as 'certain IE'; 2023 Duke-ISCVID and 2023 ESC classifications achieved higher sensitivity (97.1% and 93.8%, respectively) but markedly lower specificity (31.1% and 41.0%, respectively) than 2015 ESC and 2019 EHRA classifications.In the 159 patients with CIEDs and lead IE (78.6% 'certain IE'), while sensitivity remained high for all classifications, specificity dropped for 2023 Duke-ISCVID and 2023 ESC classifications (11.8% and 32.4%, respectively), but not for 2019 EHRA classification (67.6%).In the 911 patients without CIEDs (81.0% 'certain IE'), sensitivity was higher than 96% for all classifications and specificity was 55.5%, 52.6% and 48.0% for 2015 ESC, 2023 Duke-ISCVID and 2023 ESC classifications, respectively. CONCLUSIONS:The 2023 ESC and 2023 Duke-ISCVID classifications had a higher sensitivity but a lower specificity than the 2015 ESC classification in patients with CIEDs, especially among those with lead IE. In patients with CIEDs, the 2019 EHRA classification was the most accurate.

Background: Pneumococcal meningitis is a severe infection associated with high mortality and neurofunctional sequelae in up to 50% of survivors, despite appropriate antibiotic therapy and dexamethasone. Cerebrospinal fluid inflammation is exacerbated by pneumococcal components released during antibiotic-induced bacterial lysis. Among bactericidal, non-lytic antibiotics, daptomycin has shown the most promising preclinical efficacy. We conducted a proof-of-concept trial to assess the safety and potential clinical impact of adjunctive daptomycin added to standard treatment for pneumococcal meningitis. Methods: The AddaMAP study (NCT03480191) was a single-arm trial. Daptomycin (10 mg/kg/d 8 days) was added to the standard treatment with third-generation cephalosporin and dexamethasone in adult patient with pneumococcal meningitis. The primary outcome was the 30-day disability-free survival (DFS), defined as a modified Rankin Scale (mRS) score ≤ 2. Findings: Between 2018 and 2024, 86 patients were included (mean age 60 ± 14 years). Daptomycin was discontinued in four patients. At day 30, 10 patients had died (12%). Fifty-six patients achieved an mRS ≤2, corresponding to a DFS of 65·1% [95% CI, 54·1-75·1]. Interpretation: Adjunctive daptomycin added to standard treatment for pneumococcal meningitis was clinically active and well tolerated. The observed results suggest a potential clinical benefit compared to historical data, warranting further evaluation in a controlled trial to confirm its impact on patient outcomes. Optimization strategies, such as initial administration of dexamethasone followed by daptomycin and then beta-lactam therapy, as well as the use of a loading dose, could further improve outcomes.

OBJECTIVE:Invasive listeriosis carries high mortality, and acute kidney injury (AKI) may complicate hospitalization and worsen outcomes. However, its incidence, risk factors, and prognostic impact in this setting remain poorly described. We aimed to evaluate AKI in patients hospitalized for invasive listeriosis. METHODS:We conducted a retrospective multicenter cohort study including adults with microbiologically confirmed invasive listeriosis across six French university hospitals (2010-2023). AKI within 14 days was defined according to modified KDIGO criteria as a ≥ 1.5-fold increase in serum creatinine from admission value to peak during the first 14 days. Data included comorbidities, exposures, treatment, renal recovery, and mortality. AKI predictors were assessed using multivariable Cox regression. RESULTS:Among 150 patients (median age 76 years), 31% developed AKI within 14 days. In multivariable analysis, hypertension (HR: 6.60; 95% CI: 2.00-21.77; P = 0.002) and qSOFA ≥1 (HR: 2.90; 95% CI: 1.41-5.94; P = 0.003) were independently associated with AKI. Gentamicin-based therapy was not associated with AKI. AKI was associated with higher 30-day and 90-day mortality (37% vs 18% and 56% vs 24%, respectively; P < 0.001). CONCLUSIONS:AKI is frequent in listeriosis and associated with increased mortality. These findings highlight the importance of early risk stratification and renal monitoring in this population.

BACKGROUND:Switching to oral therapy has become an option for treating infective endocarditis (IE) in well-selected patients. This study aimed to assess its effectiveness in real-life settings, including patients who would not have been eligible under current guidelines based on the POET trial results. METHODS:All adults treated for IE in two French tertiary centers from January 2016 to December 2023 were included in a retrospective cohort. For each participant, clinical, microbiological, and therapeutic data were collected retrospectively. Patients who received at least 10 days of effective antibiotic therapy were included and categorized based on the route of administration (exclusively intravenous or with a switch to oral therapy). POET-ineligible patients were those who were not eligible in the POET trial. Treatment failure (death, recurrence, or need for suppressive therapy, within 3 months following completion of the initial antibiotic course) was assessed using propensity score (PS) analysis, with oral switch as a time-dependent variable. RESULTS:Three hundred and thirty-three participants were included (233 in the intravenous group and 100 patients in the oral group). No significant difference in treatment failure was observed between groups after adjustment using a PS (HR = 0.55 in favor of oral switch, 95% CI = .27-1.17). The results were similar in the POET-ineligible subgroup, which accounted for 44.7% of participants. Days alive outside the hospital were significantly higher in the oral group (59 vs 47 days, P = .001). CONCLUSIONS:Oral switch is a suitable option beyond "classical" frontiers in the management of IE, with potential direct and indirect benefits.

Background:Doxycycline is occasionally used as step-down therapy in periprosthetic joint infections (PJI), but evidence supporting its efficacy is limited. This study aimed to estimate the effect of doxycycline on 12-month treatment failure in patients with gram-positive PJI. Methods:Adult patients with hip, knee, or shoulder PJI caused by Staphylococcus, Corynebacterium, or Cutibacterium who underwent surgery between April 2013 and April 2023 at Dijon University Hospital (France) were included. Demographic, clinical, biological, and therapeutic data were collected retrospectively. Treatment failure at 12 months was defined as clinical recurrence, new intraoperative microorganisms, surgical revision for infection, or death. The average treatment effect (ATE) of doxycycline was estimated using causal inference methods. Results:Three hundred and eighty-six patients with PJI (median age 72 years, interquartile range [IQR] = 65-80) were analyzed. Most infections involved the hip (62%) were caused by Staphylococcus aureus (64%) and/or polymicrobial (42%). Doxycycline was prescribed in 19% of patients (n = 72), for a median of 64 days (IQR = 42-84). At 12 months, treatment failure occurred in 35%, without significant difference between exposed and unexposed patients (33% vs 36%, P = .68). Overall, doxycycline was not significantly associated with treatment failure (ATE(IPTW) = -0.09; 95% CI = -0.24 to 0.05; P = .19). Subgroup analyses suggested that doxycycline reduced treatment failure by 23%-26% in S. aureus infections (P < .001), 25%-28% in patients without fever (P < .001), and 34%-35% when both conditions were present (P < .001). Conclusions:Doxycycline in combination with other antibiotics was not associated with 12-month treatment failure in PJI caused by Staphylococcus, Corynebacterium, or Cutibacterium, with potential benefits in S. aureus infection warranting confirmation in prospective studies.

Background: While difficult-to-treat multidrug-resistant Gram-negative bacteria infections increase over time, the real-world effectiveness, use, and safety of ceftazidime-avibactam (CAZ-AVI) for treating hospitalized patients was assessed in 41 French centers. Procedures: OZAVIE was a prospective, multicenter, observational study conducted between March 2019 and November 2021. Hospitalized adult patients having initiated CAZ-AVI for infections within 14 days before enrolment were eligible. Demographic, clinical, microbiological, and therapeutic data were collected. Outcome was categorized as "failure" if the patient died from the initial infection, or if the infections persisted and required another antibiotic or surgery, or if CAZ-AVI was discontinued due to intolerance, and as "global success" otherwise. Patients whose outcome was not "failure", did not die and required no other antibiotics during the index hospitalization were categorized as "therapeutic success". Results: 257 patients were enrolled: 76 females/181 males, mean age 58.4 years, with diabetes (30.0 %), chronic renal failure (25.7 %), end-stage liver disease (9.3 %) and/or immunocompromised (31.1 %). CAZ-AVI was prescribed for nosocomial pneumonia (34.2 %), complicated urinary tract infections (17.5 %), complicated intraabdominal infections (14.8 %) and other specified sites (27.6 %). The main pathogens were Pseudomonas aeruginosa (52.4 %), Klebsiella spp. (34.9 %), Enterobacter spp. (18.4 %). Global and therapeutic successes were observed in 79.0 % and 63.4 % of patients, respectively, and 28-day mortality was 20.2 %. Overall, adverse events possibly related to CAZ-AVI were reported in 17.4 % of patients, including serious AEs in 6.2 %. Conclusions: CAZ-AVI is effective and well tolerated for treating various infections - including difficult-to-treat infection sites - and for treating various infections strains, including Pseudomonas aeruginosa and Enterobacter spp.

By the end of the nineties, new immunomodulatory options impacting on the determinants of many immune-mediated diseases became available. These drugs were also called biologicals. Their use was associated with a significant improvement in the management of the patients and on their clinical evolution over time. On the other hand, their use was found to be also associated with an over-risk of infectious complications, in particular of viral origin, even though the savings of other at-risk treatments (e.g. corticosteroids or cyclophosphamide) allowed by these new therapies could have contributed to reduce it. These viral infections may be linked to an increased susceptibility to new infections because of impaired immunity and/or lower responsiveness to vaccination, to a higher risk of reactivation of latent infections, and to a higher severity than observed in the general population. Viruses mostly involved are respiratory (influenza, RSV, and SARS-CoV2), Varicella-Zoster, hepatitis B, or JC viruses, in particular. The viral risk depends not only on the type of biologicals, but also on the underlying disease, the associated comorbidities, the associated treatments, the epidemiological environment, and the individual and collective immunity. At an individual level, prevention and management of the infectious risk are of utmost importance in the global management of patients on biologicals.

Actinotignum schaalii is an emerging urogenital pathogen rarely reported as a cause of endocarditis. A 54-year-old man developed recurrent embolic strokes seven and eight years post-Bentall procedure with mechanical aortic valve. Blood cultures grew Gram-positive bacilli, initially misidentified as Corynebacterium spp., later confirmed as Actinotignum schaalii. Cardiac CT revealed a 12 mm × 15 mm × 20 mm perivalvular abscess fistulizing into the sinus of Valsalva and prosthetic graft. 18 F-FDG PET/CT confirmed intense hypermetabolism around the prosthesis. Despite targeted amoxicillin therapy, intraoperative exploration revealed complete Bentall conduit dehiscence from extensive aorto-mitral trigone destruction. Reconstruction was deemed unfeasible, and the patient died following multidisciplinary decision to limit interventions. No urological source was identified. Actinotignum schaalii can cause indolent prosthetic valve endocarditis with devastating perivalvular complications. Prolonged blood culture incubation is crucial for early diagnosis in patients with prosthetic material and unexplained embolic events. Not applicable.

OBJECTIVES:To report long-term clinical efficacy, safety, pharmacokinetics, immunogenicity and seroneutralization results of AZD7442 (monoclonal antibodies tixagevimab-cilgavimab) in patients hospitalized with COVID-19. METHODS:In this phase 3, double-blind, randomized, multicentre trial, hospitalized adults with PCR-confirmed SARS-CoV-2 infection were randomly assigned 1:1 to receive AZD7442 or placebo, and followed-up until day 456, with repeated blood sample collections until day 365. Clinical endpoints included clinical status, mortality, rehospitalization, SARS-CoV-2 reinfection, and adverse events. Antidrug antibodies and serum drug concentrations were measured. Analyses were performed on the modified intention-to-treat (mITT) populations, defined as participants who actually received the intervention. RESULTS:Between April 28, 2021, and June 23, 2022, 237 participants were randomly assigned to AZD7442 (n = 127) or placebo (n = 110), and 123 participants actually received AZD7442. Participants were infected with pre-Omicron variants in 58.8% (133/226) of cases, versus 33.2% (75/226) of Omicron BA1, BA2, or BA5, and 8% (18/226) missing data. There was no significant difference in the distribution of the 7-point ordinal scale between the AZD7442 and placebo groups, either on day 15 (primary endpoint) (OR = 0.93 [0.54-1.61], p 0.81), or any other time point. Significantly more rehospitalizations occurred between discharge and day 456 among participants who received AZD7442 in the global mITT population (OR = 2.04 [1.03-4.05], p 0.04), but not in the antigen-positive mITT population (OR = 1.78 [0.80-3.94], p 0.15). No significant differences were observed in mortality, SARS-CoV-2 reinfection, or adverse events. In the AZD7442 group, 12 of 87 participants (13.8%) had treatment-emergent antidrug antibodies versus 5 of 69 (7.2%) in the placebo group (OR = 2.02 [0.66-6.14], p 0.21). Serum drug concentrations were detectable up to day 365 for all sampled participants (35/35). Neutralizing antibody titres were significantly higher in the AZD7442 group up to day 180. CONCLUSIONS:AZD7442 did not demonstrate any clinical benefit and was safe up to 15 months. This study also provides valuable data on the pharmacokinetics, immunogenicity, and neutralizing activity of AZD7442 in patients hospitalized with COVID-19.

IntroductionLipopolysaccharide (LPS) is a major virulence factor during both meningococcal and Haemophilus influenzae meningitis. Pneumococcus does not produce LPS but could be responsible for bacterial digestive translocation as a consequence of sepsis. We addressed this question in the context of pneumococcal meningitis.MethodsA cross-sectional study on 24 patients with pneumococcal meningitis (20 (83%) admitted in intensive care unit, 4 (17%) with septic shock) and 34 prospectively-enrolled healthy volunteers. Interleukin 6 and C-reactive proteins plasma concentrations were measured as markers of systemic inflammation. Endotoxemia was measured using mass spectrometry (LC-MS/MS) for detection of molecules bound to the lipid A, namely 3-OH fatty acids.ResultsMeningitis patients had significantly higher levels of plasma C-reactive protein (237 (74-373) vs. 2 (2-2) mg/l, p < 0.001 and interleukin 6 (43 (13-128) vs. 4.6 (4.6-16.6) pg/ml; p < 0.001) than healthy volunteers. However, we observed no significant difference in plasma lipopolysaccharide concentrations between patients and healthy volunteers (674 (554-896) vs. 668 (623-777) pmol/ml; p = 0.546).ConclusionsOur results suggest that LPS is not a key determinant of the excessive inflammation associated with severe forms of pneumococcal meningitis.

BACKGROUND:Single-sampling strategy (SSS) for blood cultures (BCs) has not been evaluated in infective endocarditis (IE). We assessed the diagnostic performance of SSS versus conventional multisampling strategy (MSS) in IE diagnosis. METHODS:Patients suspected of IE were prospectively enrolled in 8 tertiary-care centers. Five BC bottle pairs were sampled from each patient. Pairs 1, 2, and 3 were sampled simultaneously, followed by 2 additional separate pairs (4 and 5) sampled more than 1 hour later. Pairs 1, 2, and 3 emulated SSS and pairs 1, 4, and 5 emulated MSS. The sensitivity and specificity of the major microbiologic criterion of the 2015 European Society of Cardiology IE diagnostic criteria, based on the SSS and MSS BC results, were calculated using the endocarditis team's diagnosis as the gold standard. RESULTS:An IE was diagnosed in 101 (39.4%) of the 256 patients enrolled. Sensitivity rates of SSS and MSS were 50.5% (95% CI: 40.7-60.2) and 45.5% (95% CI: 35.8-55.3), respectively (P = .063), whereas specificity rates were 94.8% (95% CI: 91.4-98.3) and 95.5% (95% CI: 92.2-98.8), respectively (P = 1). In IE patients, SSS compared to MSS accurately upgraded the diagnosis from possible to definite IE in 1 patient and downgraded it in none. CONCLUSIONS:Using SSS to define the major microbiologic criterion was as sensitive and specific as using MSS for diagnosing IE. Using SSS instead of MSS BC results did not lead to erroneous changes in diagnostic class according to the 2015 European Society of Cardiology criteria. Consequently, SSS may be regarded as standard practice for IE diagnosis.

Introduction:Using three categories of stages of HIV disease at access to care (advanced, intermediate, early HIV disease), we explored the impact of delayed access on the risk of death at up to 5 years and whether progress in antiretroviral regimens has mitigated this impact. Methods:Adults from the French Hospital Database on HIV (ANRS CO4-FHDH) cohort with HIV-1 infection and first access to care during 2002-2021 were included. To study the impact of the stage of HIV disease at first access to care on the risk of death, only participants included from 2002 to 2016 were analysed to allow for at least 5 years of follow-up until 31 December 2021. Fine and Gray competing risk models considering lost to follow-up as a competing event were used adjusting for age, gender, mode of acquisition, region of origin, time between diagnosis and access to care, period of access to care (2002-2013 vs 2014-2016). Results:Among the 64 400 people living with HIV included, 18 305 (28.4%) had advanced and 13 042 (20.3%) intermediate HIV disease. The 5-year cumulative incidence of death was estimated as 1.8% (95% CI 1.7% to 1.9%) overall, from 0.9% (0.8% to 1.0%) for those with early HIV disease to 6.0% (5.4% to 6.7%) for those with AIDS. People with AIDS had a much higher risk of death than those with early HIV disease, with a sub-distribution HR (sHR) of 18.4 (95% CI 12.0 to 28.4) in the first 6 months of follow-up, which remained significant at 48-60 months: sHR=2.1 (1.3 to 3.3). The risk of death was higher for the other categories of advanced HIV disease but to a smaller extent. The risk of death was not statistically different depending on the calendar period. Conclusions:Delayed access to care remains associated with an elevated risk of death, even after 48 months. There was no significant improvement in the risk of death after 2014 when immediate initiation of combined antiretroviral therapy was recommended and integrase strand transfer inhibitor-based regimens became the preferred first-line.

Introduction Acute pneumonia (AP) remains a leading cause of death in the older population. Excess risk of death after AP is partly due to cardiovascular (CV) events. We aim to evaluate whether aspirin at a preventive dose (100 mg daily) introduced at the acute phase of AP reduces 90-day mortality.Methods and analysis The ASPirin for Acute Pneumonia in the elderlY study is a phase III multicentre randomised double-blind, placebo-controlled, superiority clinical trial, which will investigate the efficacy and safety of aspirin in older patients with AP hospitalised in a French university and non-university hospitals. Patients will be randomised in a 1:1 ratio between two groups receiving daily either 100 mg of aspirin or a placebo, within 84 hours following radiologically proven AP diagnosis for 90 days. This study aimed at assessing the efficacy of aspirin on all-cause mortality after AP at 90 days (D90) (primary objective), D30 and D120 after randomisation, CV mortality, major adverse CV events (MACE) (ie, myocardial infarction, stroke, heart failure, new atrial fibrillation and pulmonary embolism, CV death and sudden death) incidence, length of intensive care unit and hospital stay, unscheduled rehospitalisation, dependence, overall and MACE-free survival, as well as safety outcomes (bleeding incidence). The sample size, calculated considering a 90-day mortality of 25% and a reduction of 10% in the aspirin group, a two-sided alpha risk at 5% and power of 80%, is 500 patients to prove the superiority of aspirin over placebo. To account for screening failures and consent withdrawals, 600 patients (300 per arm) will be included.Ethics and dissemination This study has full approval from an independent Ethics Committee. Participants will sign a written informed consent ahead of participation. Findings will be published in peer-reviewed journals and conference presentations.Trial registration number EU CTIS: 2024-510811-32-00.

We investigated whether baseline levels of biomarkers related to endotheliopathy, thromboinflammation, and fibrosis were associated with clinical outcomes in hospitalized COVID-19 patients. We analyzed the associations between baseline levels of 21 biomarkers and time to hospital discharge and change in NEWS-2 score in patients from DisCoVeRy trial. We fitted multivariate models adjusted for baseline ISARIC 4C score, disease severity, D-dimer values, and treatment regimen. Between March 22 and June 29, 2020, 603 participants were randomized; 454 had a sample collected at baseline and analyzed. The backward selection of multivariate models showed that higher baseline levels of soluble suppressor of tumorigenicity 2 (sST2) and nucleosomes were statistically associated with a lower chance of hospital discharge before day 29 (sST2: aHR 0.24, 95% CI [0.15-0.38], p < 10-9; nucleosomes: aHR 0.62, 95% CI [0.48-0.81], p < 10-3). Likewise, higher levels of baseline sST2 were statistically associated with lower changes in the NEWS-2 score between baseline and day 15 (adjusted beta 4.47, 95% CI [2.65-6.28], p < 10-5). Moreover, we evaluated sST2 involvement in a confirmation cohort (SARCODO study, 103 patients) and found that elevated baseline sST2 levels were significantly associated with lower rates of hospital discharge before day 29 and a higher model performance (AUC at day 29 of 92%) compared to models without sST2. sST2 emerged as an independent predictor of clinical outcomes in two large cohort of hospitalized COVID-19 patients, warranting further investigation to elucidate its role in disease progression and potential as a therapeutic target.

Background The 2023 Duke-International Society for Cardiovascular Diseases (ISCVID) criteria for infective endocarditis (IE) were proposed as an updated diagnostic classification of IE. Using an open prospective multicenter cohort of patients treated for IE, we compared the performance of these new criteria to that of the 2000 Modified Duke and 2015 European Society of Cardiology (ESC) criteria. Methods Cases of patients treated for IE between January 2017 and October 2022 were adjudicated as certain IE or not. Each case was also categorized as either definite or possible/rejected within each classification. Sensitivity, specificity, and accuracy were estimated with 95% confidence intervals. Results Of the 1194 patients analyzed (mean age, 66.1 years; 71.2% males), 414 (34.7%) had a prosthetic valve and 284 (23.8%) had a cardiac implanted electronic device (CIED); 946 (79.2%) were adjudicated as certain IE; 978 (81.9%), 997 (83.5%), and 1057 (88.5%) were classified as definite IE in the 2000 modified Duke, 2015 ESC, and 2023 Duke-ISCVID criteria, respectively. The sensitivity of each set of criteria was 93.2% (95% confidence interval [CI], 91.6-94.8), 95.0% (95% CI, 93.7-96.4), and 97.6% (95% CI, 96.6-98.6), respectively (P < .001 for all 2-by-2 comparisons). Corresponding specificity rates were 61.3% (95% CI, 55.2-67.4), 60.5% (95% CI, 54.4-66.6), and 46.0% (95% CI, 39.8-52.2), respectively. In patients without CIED, sensitivity rates were 94.8% (95% CI, 93.2-96.4), 96.5% (95% CI, 95.1-97.8), and 97.7% (95% CI, 96.6-98.8); specificity rates were 59.0% (95% CI, 51.6-66.3), 56.6% (95% CI, 49.3-64.0), and 53.8% (95% CI, 46.3-61.2), respectively. Conclusions Overall, the 2023 Duke-ISCVID criteria had a significantly higher sensitivity but a significantly lower specificity compared with older criteria. This decreased specificity was mainly attributable to patients with CIED.

BACKGROUND:Systematic treatment with intravenous acyclovir is usually given when varicella zoster virus (VZV) DNA is isolated in cerebrospinal fluid (CSF), indicating central nervous system (CNS) involvement. Our study aimed to describe therapeutic management and acute kidney injury (AKI) occurrence during acyclovir treatment of VZV infection with CNS involvement. METHODS:Multicentre, retrospective study including all patients from 2010 to 2022 with VZV DNA in CSF. Patient management and outcomes were compared according to clinical presentation and indications for intravenous acyclovir: i) definite (encephalitis, myelitis or stroke, peripheral nervous system (PNS) with ≥ 2 roots, herpes zoster ≥ 3 dermatomes, immunosuppression), ii) questionable (1 or 2 dermatomes) or iii) no indication (other situations). RESULTS:154 patients were included (median age 66 (interquartile range 43-77), 87 (56%) males); 60 (39%) had encephalitis, myelitis or stroke, 35 (23%) had PNS involvement, 37 (24%) had isolated meningitis, 14 (9%) had isolated cutaneous presentation, and 8 (5%) had other presentations. Overall, 128 (83%) received intravenous acyclovir for more than 72 h. AKI occurred in 57 (37%) patients. Finally, 42 (27%) and 25 (16%) patients had respectively no or a questionable indication for intravenous acyclovir, while 29 (69%) and 23 (92%) of them received it for more than 72 h, with AKI in 13 (35%) and 13 (52%) patients, respectively. In-hospital mortality was 12% (n = 18), and no deaths were reported in isolated meningitis. CONCLUSIONS:Intravenous acyclovir is widely prescribed when VZV DNA is isolated in CSF, regardless of the clinical presentation, with a high rate of AKI. Further studies are needed to better define the value of intravenous acyclovir in isolated VZV meningitis.