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Background COVID-19-related ARDS has unique features when compared with ARDS from other origins, suggesting a distinctive inflammatory pathogenesis. Data regarding the host response within the lung are sparse. The objective is to compare alveolar and systemic inflammation response patterns, mitochondrial alarmin release, and outcomes according to ARDS etiology (i.e., COVID-19 vs. non-COVID-19). Methods Bronchoalveolar lavage fluid and plasma were obtained from 7 control, 7 non-COVID-19 ARDS, and 14 COVID-19 ARDS patients. Clinical data, plasma, and epithelial lining fluid (ELF) concentrations of 45 inflammatory mediators and cell-free mitochondrial DNA were measured and compared. Results COVID-19 ARDS patients required mechanical ventilation (MV) for significantly longer, even after adjustment for potential confounders. There was a trend toward higher concentrations of plasma CCL5, CXCL2, CXCL10, CD40 ligand, IL-10, and GM-CSF, and ELF concentrations of CXCL1, CXCL10, granzyme B, TRAIL, and EGF in the COVID-19 ARDS group compared with the non-COVID-19 ARDS group. Plasma and ELF CXCL10 concentrations were independently associated with the number of ventilator-free days, without correlation between ELF CXCL-10 and viral load. Mitochondrial DNA plasma and ELF concentrations were elevated in all ARDS patients, with no differences between the two groups. ELF concentrations of mitochondrial DNA were correlated with alveolar cell counts, as well as IL-8 and IL-1β concentrations. Conclusion CXCL10 could be one key mediator involved in the dysregulated immune response. It should be evaluated as a candidate biomarker that may predict the duration of MV in COVID-19 ARDS patients. Targeting the CXCL10-CXCR3 axis could also be considered as a new therapeutic approach. Trial registration ClinicalTrials.gov, NCT03955887

(1) Background: Several smaller studies have shown that COVID-19 patients with cancer are at a significantly higher risk of death. Our objective was to compare patients hospitalized for COVID-19 with cancer to those without cancer using national data and to study the effect of cancer on the risk of hospital death and intensive care unit (ICU) admission. (2) Methods: All patients hospitalized in France for COVID-19 in March–April 2020 were included from the French national administrative database, which contains discharge summaries for all hospital admissions in France. Cancer patients were identified within this population. The effect of cancer was estimated with logistic regression, adjusting for age, sex and comorbidities. (3) Results: Among the 89,530 COVID-19 patients, we identified 6201 cancer patients (6.9%). These patients were older and were more likely to be men and to have complications (acute respiratory and kidney failure, venous thrombosis, atrial fibrillation) than those without cancer. In patients with hematological cancer, admission to ICU was significantly more frequent (24.8%) than patients without cancer (16.4%) (p < 0.01). Solid cancer patients without metastasis had a significantly higher mortality risk than patients without cancer (aOR = 1.4 [1.3–1.5]), and the difference was even more marked for metastatic solid cancer patients (aOR = 3.6 [3.2–4.0]). Compared to patients with colorectal cancer, patients with lung cancer, digestive cancer (excluding colorectal cancer) and hematological cancer had a higher mortality risk (aOR = 2.0 [1.6–2.6], 1.6 [1.3–2.1] and 1.4 [1.1–1.8], respectively). (4) Conclusions: This study shows that, in France, patients with COVID-19 and cancer have a two-fold risk of death when compared to COVID-19 patients without cancer. We suggest the need to reorganize facilities to prevent the contamination of patients being treated for cancer, similar to what is already being done in some countries.

Lipopolysaccharide (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. A 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. Meningitis 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). Our results suggest that LPS is not a key determinant of the excessive inflammation associated with severe forms of pneumococcal meningitis.

Background Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. Methods Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. Results At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7–22] vs. 4 (0–15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1β, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-β), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. Conclusion We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.

Pneumocystis pneumonia (PcP) remains life-threatening in kidney transplant recipients (KTR). Our study investigated risk factors one-year before PcP. We conducted a monocentric, case-control study including all KTR at the Dijon University Hospital (France) with a diagnosis of PcP between 2005 and 2022 (cases), and matched control KTR with no history of PcP (3 controls/case). Among all 1,135 KTR, 57 cases (5%) and 169 matched-controls were included. PcP was associated with 18% mortality. Compared to controls, cases were older, with a higher immunological risk, and CMV infection was more frequent in the year preceding the occurrence of PcP (23% vs. 4%; p < 0.001). As early as 1 year before PcP, lymphocyte counts were lower and serum creatinine levels were higher in cases, but immunosuppressive regimens were not significantly different. Multivariable analysis identified lymphocyte count, serum creatinine level, being treated by immunosuppressive therapy other than anti-rejection drugs, and CMV infection in the year preceding the time PcP as independently associated with the occurrence of PcP. PcP was associated with an increased risk of subsequent chronic rejection (27% vs. 3%; p = 0.001) and return to dialysis (20% vs. 3%; p = 0.002). The occurrence of CMV infection and a low lymphocyte count could redefine the indications for continuation or reinitiation of anti- Pneumocystis prophylaxis.

IntroductionObesity is commonly reported in COVID-19 patients and is associated with poorer outcomes. It is suggested that leptin could be the missing link between obesity and severe COVID-19. Our study aimed to unravel the link between adipokines, COVID-19 status, immune response, and outcomes in severe pneumonia.MethodsIn this prospective observational single-center study, 63 immunocompetent patients with severe pneumonia (36 non-COVID-19 and 27 COVID-19) were enrolled, most required intensive care. Clinical and biological characteristics (glucose metabolism, plasma adipokines, and cytokine concentrations) and outcomes were compared.ResultsAt similar baseline severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (p = 0.0049). Plasma concentrations of leptin and adiponectin were respectively positively and negatively correlated with BMI and glucose metabolism (glycemia and insulinemia), but not significantly different between the two groups. Leptin levels were negatively correlated with IL-1β and IL-6, but the adipokines were not correlated with most other inflammatory mediators, baseline severity (SOFA score), or the duration of mechanical ventilation.ConclusionAdipokine levels were correlated with BMI but not with most inflammatory mediators, severity, or outcomes in severe pneumonia, regardless of the origin. The link between obesity, dysregulated immune response, and life-threatening COVID-19 requires further investigation.Clinical trialClinicalTrials.gov: NCT03505281.

BackgroundThe leading cause of acute bacterial meningitis in adults is Streptococcus pneumoniae. This infection is associated with high rates of mortality and morbidity related, among other factors, to the excessive host response to the pneumococcal lysis. Experimental in vitro and in vivo data show that the combination of corticosteroids/third-generation cephalosporins and the non-lytic antibiotic, daptomycin, has synergistic effects with (1) a rapid cerebrospinal fluid sterilisation, (2) less brain damages and (3) less loss of cognitive performances. Despite these encouraging results, daptomycin has never been evaluated in adult patients with pneumococcal meningitis.Methods and analysisThe AddaMAP trial is a phase II, open-label, Simon’s two-stage, multicentre trial that has been designed to assess the efficacy and safety of adding daptomycin (10 mg/kg/d for 8 days) to the recommended treatment (corticosteroids+third generation cephalosporin) in adults with confirmed pneumococcal meningitis. The main endpoint is the disability-free survival (defined as modified Rankin Scale mRS≤2) at day 30. Secondary outcomes are overall mortality, disability at D30 and D90 (mRS, Glasgow Coma Scale and Glasgow Outcome Scales, mini-mental score), hearing loss (Hearing Handicap Inventory Test at D30 and D90, routine audiometric test and Hearing-it test at D30), and quality of life (12-item Short Form Survey and WHO QOL BREF). Seventy-two analysable patients are required.Ethics and disseminationThe study protocol was approved by the Institutional Review Board of the IDF 1 of the ethics committee on 16 January 2018, and authorisation was obtained from the Agence Nationale de Securité des Médicaments et des Produits de Santé on 22 September 2017. The results will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03480191.

Community Acute Bacterial Meningitis (CABM) is a rare infectious disease leading to important impairments. Our aim was to describe CABM survivors' quality of life (QOL) 12 months post-CABM and to assess its associations with CABM sequelae. Patients included in the CABM COMBAT cohort were evaluated one year after the CABM episode. Data were collected by questionnaire, via phone calls with the patients. The WHOQOL-BREF was used to measure CABM survivors' QOL. Hierarchical multivariate linear regressions were performed. Study population was composed of 284 patients. At 12 months, 53.9% (153/284) reported at least incident headache/worsening headache intensity at 12 months post-CABM, and/or incident hearing impairment, and/or unfavourable disability outcome (GOS). Unfavourable disability outcome was associated with lower physical health QOL (B = -30.35, p<0.001), lower mental health QOL (B = -15.31, p<0.001), lower environmental QOL (B = -11.08, p<0.001) and lower social relationships QOL (B = -9.62, p<0.001). Incident headache/worsening headache since meningitis onset was associated with lower psychological health (B = -5.62, p = 0.010). Incident hearing impairment was associated with lower physical QOL (B = -5.34, p = 0.030). Hierarchical regressions showed that CABM impairments significantly increase explanatory power of multivariate models (for physical health R2 change = 0.42, p<0.001, for psychological health R2 change = 0.23, p<0.001, for social relationships R2 change = 0.06, p<0.001 and for environment domain R2 change was 0.15, p<0.001). 12 month-CABM burden is heavy. Early detection and management of CABM impairments should be performed in clinical practice as early as possible to optimize patients' psychological and psychosocial functioning. NCT01730690.

Community Acute Bacterial Meningitis (CABM) is a rare infectious disease leading to important impairments. Our aim was to describe CABM survivors' quality of life (QOL) 12 months post-CABM and to assess its associations with CABM sequelae. Study population was composed of 284 patients. At 12 months, 53.9% (153/284) reported at least incident headache/worsening headache intensity at 12 months post-CABM, and/or incident hearing impairment, and/or unfavourable disability outcome (GOS). Unfavourable disability outcome was associated with lower physical health QOL (B = -30.35, p<0.001), lower mental health QOL (B = -15.31, p<0.001), lower environmental QOL (B = -11.08, p<0.001) and lower social relationships QOL (B = -9.62, p<0.001). Incident headache/worsening headache since meningitis onset was associated with lower psychological health (B = -5.62, p = 0.010). Incident hearing impairment was associated with lower physical QOL (B = -5.34, p = 0.030). Hierarchical regressions showed that CABM impairments significantly increase explanatory power of multivariate models (for physical health R.sup.2 change = 0.42, p<0.001, for psychological health R.sup.2 change = 0.23, p<0.001, for social relationships R.sup.2 change = 0.06, p<0.001 and for environment domain R.sup.2 change was 0.15, p<0.001). 12 month-CABM burden is heavy. Early detection and management of CABM impairments should be performed in clinical practice as early as possible to optimize patients' psychological and psychosocial functioning.

Background This study assessed the impact of the COVID-19 epidemic on overall hospitalizations for pulmonary embolism (PE) in France in comparison with previous years, and by COVID-19 and non-COVID-19 status. Methods Hospitalization data (2017–2020) were extracted from the French National Discharge database (all public and private hospitals). We included all patients older than 18 years hospitalized during the 3 years and extracted PE status and COVID-19 status (from March 2020). Age, sex and risk factors for PE (such as obesity, cancer) were identified. We also extracted transfer to an intensive care unit (ICU) and hospital death. The number of PE and the frequency of death in patients in 2019 and 2020 were described by month and by COVID-19 status. Logistic regressions were performed to identify the role of COVID-19 among other risk factors for PE in hospitalized patients. Results The overall number of patients hospitalized with PE increased by about 16% in 2020 compared with 2019, and mortality also increased to 10.3% (+ 1.2%). These increases were mostly linked to COVID-19 waves, which were associated with PE hospitalization in COVID-19 patients (PE frequency was 3.7%; 2.8% in non-ICU and 8.8% in ICU). The final PE odds ratio for COVID-19 hospitalized patients was 4 compared with other hospitalized patients in 2020. The analyses of PE in non-COVID-19 patients showed a 2.7% increase in 2020 compared with the previous three years. Conclusion In 2020, the overall number of patients hospitalized with PE in France increased compared to the previous three years despite a considerable decrease in scheduled hospitalizations. Nevertheless, proactive public policy focused on the prevention of PE in all patients should be encouraged.