Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Time to Treatment Initiation and HIV Viral Suppression in People Diagnosed With HIV-1 During COVID-19 Pandemic in Ex-Aquitaine, France (ANRS CO3 AQUIVIH-NA Cohort-QuAliCOV Study).

OBJECTIVES: The COVID-19 pandemic's impact on initiation and effectiveness of antiretroviral therapy (ART) in people diagnosed with HIV remains unclear. We evaluated critical delays in HIV care in people diagnosed before and during the pandemic in ex-Aquitaine, France. METHODS: We considered adults diagnosed with HIV-1 in 2018-2021 and enrolled in the ANRS CO3 AQUIVIH-NA and followed them until October 10, 2022 for those diagnosed during the pandemic (April 01, 2020-December 31, 2021) and until March 31, 2020 for historical controls. We compared their characteristics at inclusion and the median time between diagnosis and ART initiation, ART initiation and viral suppression, and diagnosis and virologic, suppression (effective management). RESULTS: Eighty-three individuals were diagnosed during the pandemic versus 188 during the prepandemic period. Median follow-up was 549 (interquartile range: 329-713) days. Populations were similar in sex, age, HIV acquisition mode, hospital type, and clinical characteristics at diagnosis; however, fewer were foreign-born during the pandemic (15.7% versus 33.5%, P = 0.003). The probability of ART initiation, therapeutic success, and effective management was higher in people living with HIV (PLWH) diagnosed during the pandemic in adjusted analyses (hazard ratio [HR]: 2.0; 95% CI: 1.5 to 2.7; HR: 1.7; 95% CI: 1.2 to 2.3; HR: 1.8; 95% CI: 1.3 to 2.6, respectively). Those diagnosed during the pandemic were 2.3 (95% CI: 1.2 to 4.1) times more likely to be virologically suppressed within six months of diagnosis compared with historical controls. CONCLUSIONS: Pandemic-related reorganizations may have resulted in newly diagnosed PLWH being prioritized; however, the lower proportion of foreign-born PLWH diagnosed during the pandemic period, likely because of reduced migration and potential delays in diagnosis, may contribute to these preliminary findings.

Efficacy of carbapenem vs non carbapenem ß-lactam therapy as empiric antimicrobial therapy in patients with extended-spectrum ß-lactamase-producing Enterobacterales urinary septic shock: a propensity-weighted multicenter cohort study.

BACKGROUND: The rise in antimicrobial resistance is a global threat responsible for about 33,000 deaths in 2015 with a particular concern for extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) and has led to a major increase in the use of carbapenems, last-resort antibiotics. METHODS: In this retrospective propensity-weighted multicenter observational study conducted in 11 ICUs, the purpose was to assess the efficacy of non carbapenem regimen (piperacillin-tazobactam (PTZ) + aminoglycosides or 3rd-generation cephalosporin (3GC) + aminoglycosides) as empiric therapy in comparison with carbapenem in extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) urinary septic shock. The primary outcome was Day-30 mortality. RESULTS: Among 156 patients included in this study, 69 received a carbapenem and 87 received non carbapenem antibiotics as empiric treatment. Baseline clinical characteristics were similar between the two groups. Patients who received carbapenem had similar Day-30 mortality (10/69 (15%) vs 6/87 (7%), OR = 1.99 [0.55; 5.34] p = 0.16), illness severity, resolution of septic shock, and ESBL-E infection recurrence rates than patients who received an empiric non carbapenem therapy. The rates of secondary infection with C. difficile were comparable. CONCLUSIONS: In ESBL-E urinary septic shock, empiric treatment with a non carbapenem regimen, including systematically aminoglycosides, was not associated with higher mortality, compared to a carbapenem regimen.

Ultrasonography performed by an infectiologist in hip and knee prosthetic joint and native joint infections.

INTRODUCTION: Clinical ultrasonography (US) by infectiologists has only recently been developing, and as now there is little literature on the subject. Our study focuses on the conditions and diagnostic performance of clinical ultrasound imaging by infectiologists in cases of hip and knee prosthetic and native joint infection. METHODS: A retrospective study carried out between June 1st 2019 and March 31st 2021 in the University Hospital of Bordeaux, South-Western France. We measured US sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV), combined or not with the analysis of articular fluid, compared to the MusculoSketetal Infection Society (MSIS) score in prosthetic joints, or to expert diagnosis in native joints. RESULTS: Fifty-four patients underwent US by an infectiologist in an infectious disease ward, including 11 (20.4%) for native joint and 43 (79.6%) for prosthetic joint. Joint effusion and/or periarticular collection were highlighted in 47 (87%) patients, and US led to 44 punctures. In all patients (n = 54), Se, Sp, PPV and NPV of US alone were 91%, 19%, 64% and 57%, respectively. When US was combined with fluid analysis, Se, Sp, PPV, NPV were 68%, 100%, 100%, 64% in all patients (n = 54), 86%, 100%, 100%, 60% in acute arthritis (n = 17) and 50%, 100%, 100% and 65% respectively in non-acute arthritis (n = 37). CONCLUSION: These results suggest that US by infectiologists effectively diagnoses osteoarticular infections (OAIs). This approach has many applications in infectiology routines. Consequently, it would be interesting to define the contents of a first level of infectiologist competence in US clinical practice.

High-resolution Free-breathing late gadolinium enhancement Cardiovascular magnetic resonance to diagnose myocardial injuries following COVID-19 infection.

PURPOSE: High-resolution free-breathing late gadolinium enhancement (HR-LGE) was shown valuable for the diagnosis of acute coronary syndromes with non-obstructed coronary arteries. The method may be useful to detect COVID-related myocardial injuries but is hampered by prolonged acquisition times. We aimed to introduce an accelerated HR-LGE technique for the diagnosis of COVID-related myocardial injuries. METHOD: An undersampled navigator-gated HR-LGE (acquired resolution of 1.25 mm3) sequence combined with advanced patch-based low-rank reconstruction was developed and validated in a phantom and in 23 patients with structural heart disease (test cohort; 15 men; 55 ± 16 years). Twenty patients with laboratory-confirmed COVID-19 infection associated with troponin rise (COVID cohort; 15 men; 46 ± 24 years) prospectively underwent cardiovascular magnetic resonance (CMR) with the proposed sequence in our center. Image sharpness, quality, signal intensity differences and diagnostic value of free-breathing HR-LGE were compared against conventional breath-held low-resolution LGE (LR-LGE, voxel size 1.8x1.4x6mm). RESULTS: Structures sharpness in the phantom showed no differences with the fully sampled image up to an undersampling factor of x3.8 (P > 0.5). In patients (N = 43), this acceleration allowed for acquisition times of 7min21s ± 1min12s at 1.25 mm3 resolution. Compared with LR-LGE, HR-LGE showed higher image quality (P = 0.03) and comparable signal intensity differences (P > 0.5). In patients with structural heart disease, all LGE-positive segments on LR-LGE were also detected on HR-LGE (80/391) with 21 additional enhanced segments visible only on HR-LGE (101/391, P < 0.001). In 4 patients with COVID-19 history, HR-LGE was definitely positive while LR-LGE was either definitely negative (1 microinfarction and 1 myocarditis) or inconclusive (2 myocarditis). CONCLUSIONS: Undersampled free-breathing isotropic HR-LGE can detect additional areas of late enhancement as compared to conventional breath-held LR-LGE. In patients with history of COVID-19 infection associated with troponin rise, the method allows for detailed characterization of myocardial injuries in acceptable scan times and without the need for repeated breath holds.

Covichem: A biochemical severity risk score of COVID-19 upon hospital admission.

Clinical and laboratory predictors of COVID-19 severity are now well described and combined to propose mortality or severity scores. However, they all necessitate saturable equipment such as scanners, or procedures difficult to implement such as blood gas measures. To provide an easy and fast COVID-19 severity risk score upon hospital admission, and keeping in mind the above limits, we sought for a scoring system needing limited invasive data such as a simple blood test and co-morbidity assessment by anamnesis. A retrospective study of 303 patients (203 from Bordeaux University hospital and an external independent cohort of 100 patients from Paris Pitié-Salpêtrière hospital) collected clinical and biochemical parameters at admission. Using stepwise model selection by Akaike Information Criterion (AIC), we built the severity score Covichem. Among 26 tested variables, 7: obesity, cardiovascular conditions, plasma sodium, albumin, ferritin, LDH and CK were the independent predictors of severity used in Covichem (accuracy 0.87, AUROC 0.91). Accuracy was 0.92 in the external validation cohort (89% sensitivity and 95% specificity). Covichem score could be useful as a rapid, costless and easy to implement severity assessment tool during acute COVID-19 pandemic waves.

Retrospective Study Comparing WBC scan and 18F-FDG PET/CT in Patients with Suspected Prosthetic Vascular Graft Infection.

OBJECTIVES: Prosthetic vascular graft infections (PVGIs) are associated with high mortality rates. To improve treatment outcome, an early and definite diagnosis is critical, and current diagnostic criteria are often insufficient. The accuracy of 2-deoxy-2-[fluorine-18]-fluoro-d-glucose positron emission tomography integrated with computed tomography (18F-FDG PET/CT) and white blood cell (WBC) scan for the diagnosis of PVGI were compared. METHODS: A retrospective single centre study was conducted on patients undergoing WBC scan and 18F-FDG PET/CT for a suspected PVGI between April 2013 and June 2016 at the Bordeaux University Hospital, France. The diagnostic value of both imaging tests was assessed for all grafts, using receiver operating characteristic (ROC) curve analysis. Images were independently interpreted by two nuclear medicine physicians blinded to the patients' clinical and other imaging data. RESULTS: Thirty-nine patients were included, of whom 15 had PVGI. Antibiotic treatment was started before nuclear imaging for 16 patients, including nine patients with a PVGI. The 96 grafts of these patients were analysed, and 19 were infected. The diagnostic value of the WBC scan was significantly higher than 18F-FDG PET/CT (ROC AUC = 0.902, 95% CI 0.824-0.980, and 0.759, CI 95% (0.659-0.858), respectively, p = .0071). Interobserver agreement was good for 18F-FDG PET/CT and excellent for WBC scan (kappa value of 0.76, 95% CI 0.62-0.9, and 0.97, 95% CI 0.92-1, respectively). Only one patient had a false negative 18F-FDG PET/CT result under antibiotic therapy. CONCLUSION: The WBC scan has a better diagnostic value than 18F-FDG PET/CT for PVGI diagnosis.

Limbic encephalitis as a relapse of Whipple's disease with digestive involvement and spondylodiscitis.

INTRODUCTION: Many clinical manifestations can be related to Tropheryma whipplei infection. CASE REPORT: We report a Tropheryma whipplei limbic encephalitis developed as a relapse of classical Whipple's disease. DISCUSSION: This case is to the best of our knowledge the first proof of the effective brain-blood barrier crossing of both doxycycline and hydroxychloroquine as demonstrated by direct concentration monitoring on brain biopsy.

Comparison of Genus Specific PCR and Culture with or without Sonication for Microbiological Diagnosis of Vascular Graft Infection.

OBJECTIVES: Vascular graft infections (VGIs) are severe and require prolonged adequate antimicrobial therapy. However, up to 45% of conventional cultures are negative. Sonication and genus specific PCRs for microbiological diagnosis of VGI was evaluated. METHODS: Samples were prospectively obtained from explanted vascular grafts in Bordeaux University Hospital. Conventional bacterial cultures with and without prior sonication of samples were performed. A genus specific PCR assay panel, targeting the most frequent bacteria involved in VGI (Staphylococcus, Streptococcus, Enterococcus, and Enterobacteriaceae), was also applied to sonicate fluids. The performance of these three diagnostic strategies was compared. RESULTS: Forty-five patients (118 samples) were included between July 2014 and October 2015. Six patients had no infection and 39 had a VGI. Sensitivities of graft culture, sonicate fluid culture, and genus specific PCR were 85.7%, 89.7%, and 79.5%, respectively. Specificities were 100%, 100%, and 83.3%, respectively. Sonicate fluid culture was positive for five graft samples (from four patients) with negative culture without sonication. Four VGIs were detected by PCR only (3 patients had previously received antibiotics). For 15 patients with positive graft cultures, PCR identified at least one additional bacterium compared with culture, thus 30 additional bacteria for all included patients. By combining sonicate fluid culture and PCR, a microbiological diagnosis was obtained for all patients with VGI. CONCLUSIONS: There was no statistical difference between performances of culture with and without sonication and genus specific PCR. However, combining sonicate fluid cultures and PCR may be the best strategy for microbiological diagnostic of VGI.

Multimorbidity, age-related comorbidities and mortality: association of activation, senescence and inflammation markers in HIV adults.

BACKGROUND: The widespread introduction of combination antiretroviral therapy (cART) has increased survival of HIV-infected patients. However, the prevalence of age-related comorbidities remains higher than that of the general population, suggesting that individuals with HIV suffer from accelerated aging. Immune activation, senescence and inflammation could play an important role in this process. METHODS: The CIADIS (Chronic Immune Activation anD Senescence) sub-study analyzed biomarkers of activation, differentiation and senescence of T cells in a cellular-CIADIS-weighted score, whereas biomarkers of inflammation were analyzed in a soluble CIADIS-weighted score using principal component analysis. Adjusted logistic regression and Cox proportional hazard models were used to determine the association between CIADIS-weighted scores and the presence of multimorbidity, time to occurrence of the first new age-related comorbidity and time to death, over a 3-year follow-up period. RESULTS: Of 828 patients with an undetectable viral load, a higher cellular-CIADIS-weighted score and higher TNFRI levels were independently associated with the presence of multimorbidity (OR 1.3; 95% CI 1.0-1.6; P = 0.02), but the soluble CIADIS-weighted score was not (OR = 1.1; 95% CI 0.9-1.3; P = 0.33). A higher cellular CIADIS-weighted score (hazard ratio 2.2; P < 0.01), higher levels of CD8 activation and a lower CD4/CD8 ratio were associated with a higher risk of age-related comorbidities. Only TNFRI was associated with mortality in a 3-year period. CONCLUSION: The cellular CIADIS-weighted score was independently associated with both multimorbidity at inclusion and the risk of new age-related comorbidity during a 3- year follow-up. TNFRI was associated a higher risk for mortality.

Extra-rectal lymphogranuloma venereum in France: a clinical and molecular study.

OBJECTIVES: To describe a series of extrarectal lymphogranuloma venereum (LGV) cases diagnosed in France. METHODS: Consecutive LGV cases confirmed at the French Reference Centre for chlamydiae with an extrarectal sample from January 2010 to December 2015 were included. The first part of the study consisted of a retrospective case note review and analysis. In a second part, the complete ompA gene sequence of our samples was determined. RESULTS: There were 56 cases overall: 50 cases of genital LGV and six cases of pharyngeal LGV. Subjects were all men, median age 39 years, 27/53 were HIV-positive, 47/51 reported having sex with other men, 43/49 reported multiple sexual partners (a mean 25 in the last 6 months). Median time from symptom onset to diagnosis was 21 days. Subjects most commonly presented with inguinal adenopathy alone (19 of 50 genital cases) and adenopathy with genital ulcer (17 of 50). Three pharyngeal cases were symptomatic. Fever was reported in 11 cases. Inguinal abscess was reported in 22 of 42 cases presenting with lymphadenopathy. Co-infections were frequent: eight cases of syphilis, four non-LGV Chlamydia trachomatis infections, one case of gonorrhoea. Cure was always achieved with doxycycline therapy but prolonged treatment was necessary in eight cases with inguinal abscess. Genotyping according to ompA sequencing showed the co-circulation of genovars L2 (16 of 42 strains successfully typed) and L2b (24 of 42). There was no association between HIV status and disease severity or genovar distribution. CONCLUSION: In the span of 6 years, 56 extrarectal LGV cases were confirmed through genotyping in France. Extrarectal LGV seemed to share a common epidemiological background with rectal disease in terms of affected population and genovar distribution. HIV prevalence was lower than expected.

Renal Intravascular Large B-cell Lymphoma: A Case Report and Review of the Literature.

We herein report the case of a 52-year-old woman who consulted us because of a 2-month history of a fever, anorexia and weight loss. A physical examination was unremarkable. The blood count showed mild anemia and lymphopenia, and lactate dehydrogenase was elevated. Creatinine clearance was normal and proteinuria was undetectable. CT showed enlarged kidneys. A bone marrow biopsy was normal. PET-CT showed an intense uptake of 18fluorodeoxyglucose in both kidneys. A kidney biopsy provided the diagnosis of intravascular large B-cell lymphoma (IVLBCL). Kidney-limited IVLBCL without an impairment in the renal function or proteinuria has not been described. We analyzed the 38 published cases of IVLBCL involving the kidney to describe the main features of this entity.

Efficacy of debridement, antibiotic therapy and implant retention within three months during postoperative instrumented spine infections.

BACKGROUND: Postoperative instrumented spine infection (PISI) is a severe complication of invasive spine procedures. METHODS: Retrospective study of patients treated for PISI between 1st January 2008 and 31st December 2012 in a French University Hospital. The objectives of this study were to describe the outcome of patients treated with debridement-irrigation, antibiotic therapy and implant retention (DAIR) within three months after the occurrence of PISI and to identify factors associated with relapse. RESULTS: Among 4290 patients who underwent spinal arthrodesis surgery during the 5-year study period, 129 had PISI treated by debridement-irrigation in the first three months (3.0%, 95% confidence interval [95%CI]: 2.5-3.5). Fifty-two (40%) were female and the median age was 57 years. Fourteen patients (10.8%) had diabetes and 73 (56.6%) had a BMI (Body Mass Index) ≥25 kg/m2. Staphylocccus aureus, enterobacteria or polymicrobial infections were identified in 44.0, 18.0 and 13.0% of cases, respectively. One hundred and six patients (82.2%) and one hundred and twenty-one patients (93.8%) were cured after one DAIR and after two DAIR, respectively. In multivariate logistic analysis, polymicrobial infection was associated with relapse (Odd Ratio [OR] = 3.81; 95%CI: 1.06-13.66; p = .03), while a BMI ≥25 kg/m2 was a protective factor (OR =0.25; 95%CI: 0.07-0.89; p = .03). CONCLUSION: DAIR may be effective for PISI when performed within the first 3 months after onset of infection. Relapses are significantly associated with polymicrobial infection and negatively associated with moderate overweight. These results need to be confirmed in future prospective studies.