Pneumococcal pneumonia and endotoxemia: An experimental and clinical reappraisal.

BACKGROUND: Circulating endotoxins could result from bacterial digestive translocation during sepsis, thus contributing to uncontrolled systemic inflammation, leading in turn to organ dysfunction. We addressed this issue in the setting of severe pneumococcal pneumonia. METHODS: Endotoxemia was measured in a clinically relevant rabbit model of ventilated pneumococcal pneumonia and in 110 patients with bacteraemic pneumonia, using a patented mass spectrometry (LC-MS/MS) method for detection of 3-OH fatty acids (C10, C12, C14, C16 and C18), which are molecules bound to the lipid A motif of LPS. RESULTS: Whereas higher levels of systemic inflammation and organ dysfunctions were found, there was no significant difference in lipopolysaccharide concentrations when infected rabbits were compared to non-infected ones, or when patients were compared to healthy volunteers. CONCLUSIONS: Seemingly, endotoxins do not drive the overwhelming inflammation associated with severe forms of pneumococcal pneumonia.

CMV Infection and Lymphopenia: Warning Markers of Pneumocystis Pneumonia in Kidney Transplant Recipients.

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.

The evolution of lung computed tomography findings in COVID-19 from 2020 to 2023: more signs of co-infection.

Significant changes were observed in the lung imaging of hospitalised COVID-19 patients from 2020 to 2023, with the emergence of more signs of co-infection https://bit.ly/3TaQlJ2.

Children Hospitalized With Respiratory Syncytial Virus Infection: A Pre Versus Late COVID-19 Pandemic Comparison.

Our study aimed to compare children under 5 years hospitalized with respiratory syncytial virus in prepandemic and late-pandemic periods. We included 209 children at the Dijon University Hospital (France). We observed a nearly 3-fold increase in the number of cases in the late period, with older children, but less frequently requiring intensive care. These observations could help prepare a new pandemic.

Acyclovir treatment of varicella-zoster virus meningeal infections and acute kidney injury: a multicentre case series study.

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.

Amoxicillin and Ceftriaxone: A Synergistic Association Against Listeria monocytogenes.

Among 15 strains of Listeria monocytogenes tested, a synergy between amoxicillin and ceftriaxone was observed in 14 (93%) according to minimal inhibitory concentration strips and 12 (80%) per the checkerboard methods, as well as for 2 of the 3 strains tested by the time-killing curve. This association may be an alternative treatment for listeriosis in the future.

Adequacy to immunosuppression management guidelines in kidney transplant recipients with severe COVID-19 pneumonia: a practice survey.

Introduction: Coronavirus disease 2019 (COVID-19) poses an important risk of morbidity and of mortality, in patients after solid organ transplantation. Recommendations have been issued by various transplantation societies at the national and European level to manage the immunosuppressive (IS) regimen upon admission to intensive care unit (ICU). Method: The aim of this study was to evaluate the adequacy of IS regimen minimization strategy in kidney transplant recipients hospitalized in an ICU for severe COVID-19, in relation to the issued recommendations. Results: The immunosuppressive therapy was minimized in all patients, with respectively 63% and 59% of the patients meeting the local and european recommendations upon admission. During ICU stay, IS was further tapered leading to 85% (local) and 78% (european) adequacy, relative to the guidelines. The most frequent deviation was the lack of complete withdrawal of mycophenolic acid (22%). Nevertheless, the adequacy/inadequacy status was not associated to the ICU- or one-year-mortality. Discussion: In this single-center cohort, the only variable associated with a reduction in mortality was vaccination, emphasizing that the key issue is immunization prior to infection, not restoration of immunity during ICU stay.

Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals.

BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).

Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study.

OBJECTIVES: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. METHODS: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. RESULTS: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19). DISCUSSIONS: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS.