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A novel virotherapy encoding human interleukin-7 improves ex vivo T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19.

ABSTRACT: A majority of patients with sepsis surviving the first days in intensive care units (ICU) enter a state of immunosuppression contributing to their worsening. A novel virotherapy based on the non-propagative Modified Virus Ankara (MVA) expressing the human interleukin-7 (hIL-7) cytokine fused to an Fc fragment, MVA-hIL-7-Fc, was developed and shown to enhance innate and adaptive immunity and confer survival advantages in murine sepsis models. Here, we assessed the capacity of hIL-7-Fc produced by the MVA-hIL-7-Fc to improve ex vivo T lymphocyte functions from ICU patients with sepsis. Primary hepatocytes were transduced with the MVA-hIL-7-Fc or an empty MVA, and cell supernatants containing the secreted hIL-7-Fc were harvested for in vitro and ex vivo studies. Whole blood from ICU patients [septic shock = 15, coronavirus disease 2019 (COVID-19) = 30] and healthy donors (n = 36) was collected. STAT5 phosphorylation, cytokine production, and cell proliferation were assessed upon T cell receptor (TCR) stimulation in presence of MVA-hIL-7-Fc-infected cell supernatants. Cells infected by MVA-hIL-7-Fc produced a dimeric, glycosylated, and biologically active hIL-7-Fc. Cell supernatants containing the expressed hIL-7-Fc triggered the IL-7 pathway in T lymphocytes as evidenced by the increased STAT5 phosphorylation in CD3+ cells from patients and healthy donors. The secreted hIL-7-Fc improved Interferon-γ (IFN-γ) and/or Tumor necrosis factor-α (TNF-α) productions and CD4+ and CD8+ T lymphocyte proliferation after TCR stimulation in patients with bacterial and viral sepsis. This study demonstrates the capacity of the novel MVA-hIL-7-Fc-based virotherapy to restore ex vivo T cells immune functions in ICU patients with sepsis and COVID-19, further supporting its clinical development.

SUBMITTER: Crausaz M

PROVIDER: S-EPMC9422896 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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A novel virotherapy encoding human interleukin-7 improves <i>ex vivo</i> T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19.

Crausaz Morgane M Monneret Guillaume G Conti Filippo F Lukaszewicz Anne-Claire AC Marchand Jean-Baptiste JB Martin Perrine P Inchauspé Geneviève G Venet Fabienne F

Frontiers in immunology 20220815

A majority of patients with sepsis surviving the first days in intensive care units (ICU) enter a state of immunosuppression contributing to their worsening. A novel virotherapy based on the non-propagative Modified Virus Ankara (MVA) expressing the human interleukin-7 (hIL-7) cytokine fused to an Fc fragment, MVA-hIL-7-Fc, was developed and shown to enhance innate and adaptive immunity and confer survival advantages in murine sepsis models. Here, we assessed the capacity of hIL-7-Fc produced by ...[more]

PMID: 36045686

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Project description:BackgroundThe proposed definition of septic shock in the Sepsis-3 consensus statement has been previously validated in critically ill patients. However, the subset of critically ill patients with sepsis and positive blood cultures needs further evaluation. To compare the combined (old and new septic shock) versus old definition of septic shock in sepsis patients that have positive blood cultures and are critically ill.MethodsA retrospective cohort study of adult patients (age ≥18 years), who had evidence of positive blood cultures, requiring intensive care unit (ICU) admission at a large tertiary care academic center from January 2009 through October 2015. Eligible subjects who opted out of research participation, those requiring intensive care admission after elective surgery, and those who were deemed to have a low probability of infection were excluded. Basic demographics data, clinical and laboratory parameters, and outcomes of interest were pulled from the validated institutional database/repository and contrasted between the patients who qualified the new and old definitions criteria (combined) of septic shock versus the group meeting the old septic shock criteria only.ResultsWe included a total of 477 patients in the final analysis who qualified for old and new septic shock definitions. For the entire cohort, median age was 65.6 (IQR, 55-75) years, with male predominance (N=258, 54%). When compared to patients in the group who only met the old definition (N=206), the patients who met the combined (new or both new and old, N=271) definition had a higher APACHE III scores, 92 (IQR, 76-112) vs. 76 (IQR, 61-95), P<0.001; a higher SOFA day-1 score of 10 (IQR, 8-13) vs. 7 (IQR, 4-10), P<0.001, but did not differ significantly in age 65.5 years (IQR, 55-74) vs. 66 years (IQR, 55-76) years, P=0.47. The patients who met the combined (new or both new and old) definition had higher chances of having conservative resuscitation preferences (DNI/DNR); 77 (28.4) vs. 22 (10.7), P<0.001. The same group also had worse outcomes in terms of hospital mortality (34.3% vs. 18%, P<0.001) and standardized mortality ratio (0.76 vs. 0.52, P<0.04).ConclusionsIn patients with sepsis with positive blood cultures, the group of patients meeting the combined definition (new or both new and old) have higher severity of illness, higher mortality, and a worse standardized mortality ratio as compared to patients meeting the old definition of septic shock.

Project description:AimsSepsis-induced cardiomyopathy is a major complication of septic shock and contributes to its high mortality. This pilot study investigated myocardial tissue differentiation in critically ill, sedated, and ventilated patients with septic shock using cardiovascular magnetic resonance (MR).Methods and resultsFifteen patients with septic shock were prospectively recruited from the intensive care unit. Individuals received a cardiac MR scan (1.5 T) within 48 h after initial catecholamine peak and a transthoracic echocardiography at 48 and 96 h after cardiac MR. Left ventricular ejection fraction was assessed using both imaging modalities. During cardiac MR imaging, balanced steady-state free precession imaging was performed for evaluation of cardiac anatomy and function in long-axis and short-axis views. Native T1 maps (modified Look-Locker inversion recovery 5 s(3 s)3 s), T2 maps, and extracellular volume maps were acquired in mid-ventricular short axis and assessed for average plane values. Patients were given 0.2 mmol/kg of gadoteridol for extracellular volume quantification and late gadolinium enhancement imaging. Critical care physicians monitored sedated and ventilated patients during the scan with continuous invasive monitoring and realized breathholds through manual ventilation breaks. Laboratory analysis included high-sensitive troponine T and N terminal pro brain natriuretic peptide levels. Twelve individuals with complete datasets were available for analysis (age 59.5 ± 16.9 years; 6 female). Nine patients had impaired systolic function with left ventricular ejection fraction (LVEF) < 50% (39.8 ± 5.7%), and three individuals had preserved LVEF (66.9 ± 6.7%). Global longitudinal strain was impaired in both subgroups (LVEF impaired: 11.0 ± 1.8%; LVEF preserved: 16.0 ± 5.8%; P = 0.1). All patients with initially preserved LVEF died during hospital stay; in-hospital mortality with initially impaired LVEF was 11%. Upon echocardiographic follow-up, LVEF improved in all previously impaired patients at 48 (52.3 ± 9.0%, P = 0.06) and 96 h (54.9 ± 7.0%, P = 0.02). Patients with impaired systolic function had increased T2 times as compared with patients with preserved LVEF (60.8 ± 5.6 ms vs. 52.2 ± 2.8 ms; P = 0.02). Left ventricular GLS was decreased in all study individuals with impaired LVEF (11.0 ± 1.8%) and less impaired with preserved LVEF (16.0 ± 5.8%; P = 0.01). T1 mapping showed increased T1 times in patients with LVEF impairment as compared with patients with preserved LVEF (1093.9 ± 86.6 ms vs. 987.7 ± 69.3 ms; P = 0.03). Extracellular volume values were elevated in patients with LVEF impairment (27.9 ± 2.1%) as compared with patients with preserved LVEF (22.7 ± 1.9%; P < 0.01).ConclusionsSeptic cardiomyopathy with impaired LVEF reflects inflammatory cardiomyopathy. Takotsubo-like contractility patterns occur in some cases. Cardiac MR is safely feasible in critically ill, sedated, and ventilated patients using extensive monitoring and experienced staff.Trial registrationretrospectively registered (ISRCTN85297773).

Project description:Sepsis is commonly associated with acute kidney injury (AKI), particularly in those requiring dialysis (AKI-D). To date, Sepsis-3 criteria have not been applied to AKI-D patients. We investigated sepsis prevalence defined by Sepsis-3 criteria and evaluated the outcomes of septic-associated AKI-D among critically ill patients. Using the data collected from a prospective multi-center observational study, we applied the Sepsis-3 criteria to critically ill AKI-D patients treated in intensive care units (ICUs) in 30 hospitals between September 2014 and December 2015. We described the prevalence, outcomes, and characteristics of sepsis as defined by the screening Sepsis-3 criteria among AKI-D patients, and compared the outcomes of AKI-D patients with or without sepsis using the Sepsis-3 criteria. A total of 1078 patients (median 70 years; 673 (62.4%) men) with AKI-D were analyzed. The main etiology of AKI was sepsis (71.43%) and the most frequent indication for acute dialysis was oliguria (64.4%). A total of 577 (53.3% of 1078 patients) met the Sepsis-3 criteria, and 206 among the 577 patients (19.1%) had septic shock. Having sepsis and septic shock were independently associated with 90-day mortality among these ICU AKI-D patients (hazard ratio (HR) 1.23 (p = 0.027) and 1.39 (p = 0.004), respectively). Taking mortality as a competing risk factor, AKI-D patients with septic shock had a significantly reduced chance of weaning from dialysis at 90 days than those without sepsis (HR 0.65, p = 0.026). The combination of the Sepsis-3 criteria with the AKI risk score led to better performance in forecasting 90-day mortality. Sepsis affects more than 50% of ICU AKI patients requiring dialysis, and one-fifth of these patients had septic shock. In AKI-D patients, coexistent with or induced by sepsis (as screened by the Sepsis-3 criteria), there is a significantly higher mortality and reduced chance of recovering sufficient renal function, when compared to those without sepsis.

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A novel virotherapy encoding human interleukin-7 improves ex vivo T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19.

Publications

A novel virotherapy encoding human interleukin-7 improves <i>ex vivo</i> T lymphocyte functions in immunosuppressed patients with septic shock and critically ill COVID-19.

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