Detrimental effect of apoptosis of lymphocytes at an early time point of experimental abdominal sepsis

<p>Abstract</p> <p>Background</p> <p>Apoptosis of lymphocytes is considered a late sequelum in the sepsis cascade. The role of apoptosis of lymphocytes as a driver of final outcome was investigated.</p> <p>Methods</p> <p>Abdominal sepsis was induced after cecal ligation and puncture (CLP) in 31 rabbits. Blood was sampled at serial time intervals and peripheral blood mononuclear cells (PBMCs) were isolated. Apoptosis of lymphocytes and monocytes was measured through flow cytometric analysis. PBMCs were stimulated with LPS and Pam3Cys for the release of tumor necrosis factor-alpha (TNFα). Tissue bacterial growth was quantitatively measured. In a second set of experiments, CLP was performed in another 40 rabbits; 20 received single intravenous infusions of ciprofloxacin and of metronidazole 4 hours after surgery.</p> <p>Results</p> <p>Animals were divided into two groups based on the percentage of lymphocyte apoptosis at 4 hours after surgery; less than or equal to 32% and more than 32%. Survival of the former was shorter than the latter (p: 0.017). Tissue growth was similar between groups. Apoptosis of lymphocytes and of monocytes was lower in the former group over follow-up. Release of ΤNFα did not differ. The above findings on survival were repeated in the second set of experiments. Administration of antimicrobials prolonged survival of the former group (p: 0.039) but not of the latter group (pNS).</p> <p>Conclusions</p> <p>Lymphocyte apoptosis at an early time point of experimental peritonitis is a major driver for death. A lower percentage of apoptosis leads earlier to death. Antimicrobials were beneficial even at that disease state.</p

Injection injuries: seemingly minor injuries with major consequences

Background: High-pressure injection injuries are rare injuries, characterized by a small puncture wound that is often underestimated by physicians and patients. The injected substance leads to extensive tissue damage and sometimes to loss of the limb. Aim: To underline the severity of these injuries and to alert physicians to recognize them and treat them appropriately

Angiopoietin-2 associations with the underlying infection and sepsis severity

Angiopoietin-2 (Ang-2) is an important mediator in sepsis. We have previously shown that endotoxemia levels are related to the underlying infection and affect septic patients' outcome. Based on this background we now investigated if circulating Ang-2 (cAng-2) and monocyte Ang-2 expression in septic patients are associated with the underlying infection and organ failure. We measured cAng-2 in 288 septic patients (121 with sepsis, 167 with severe sepsis/septic shock) at less than 24 h post study inclusion (day 1) and on days 3 and 7. Peripheral blood mononuclear cells (PBMCs) were additionally isolated; Ang-2 gene expression was estimated by means of real-time PCR. Levels of cAng-2 were higher under severe sepsis and septic shock, as compared to uncomplicated sepsis; PBMC Ang-2 copies were higher in severe sepsis. On day 1, cAng-2 and Ang-2 gene copies were greater under severe sepsis/septic shock in sufferers from all types of infections with the exception of community-acquired pneumonia and ventilator-associated pneumonia. cAng-2 increased proportionally to the number of failing organs, and was higher under metabolic acidosis and acute coagulopathy as compared to no failing organ. On day 1, copies of Ang-2 were higher in survivors, whereas cAng-2 was higher in non-survivors. In a large cohort of septic patients, cAng-2 kinetics appears associated with the underlying infection and organ failure type. (c) 2015 Elsevier Ltd. All rights reserved

Angiopoietin-2 associations with the underlying infection and sepsis severity

Angiopoietin-2 (Ang-2) is an important mediator in sepsis. We have previously shown that endotoxemia levels are related to the underlying infection and affect septic patients&apos; outcome. Based on this background we now investigated if circulating Ang-2 (cAng-2) and monocyte Ang-2 expression in septic patients are associated with the underlying infection and organ failure. We measured cAng-2 in 288 septic patients (121 with sepsis, 167 with severe sepsis/septic shock) at less than 24. h post study inclusion (day 1) and on days 3 and 7. Peripheral blood mononuclear cells (PBMCs) were additionally isolated; Ang-2 gene expression was estimated by means of real-time PCR. Levels of cAng-2 were higher under severe sepsis and septic shock, as compared to uncomplicated sepsis; PBMC Ang-2 copies were higher in severe sepsis. On day 1, cAng-2 and Ang-2 gene copies were greater under severe sepsis/septic shock in sufferers from all types of infections with the exception of community-acquired pneumonia and ventilator-associated pneumonia. cAng-2 increased proportionally to the number of failing organs, and was higher under metabolic acidosis and acute coagulopathy as compared to no failing organ. On day 1, copies of Ang-2 were higher in survivors, whereas cAng-2 was higher in non-survivors. In a large cohort of septic patients, cAng-2 kinetics appears associated with the underlying infection and organ failure type. © 2015 Elsevier Ltd

Bacterial translocation in an experimental model of multiple organ dysfunctions

Background: In order to investigate the hypothesis that bacterial translocation from the intestine contributes to death after multiple organ dysfunction syndrome (MODS), a sterile MODS model was studied. Methods: MODS was induced in 139 male C57BL/6 mice by lipopolysaccharide (LPS) (endotoxin) infusion followed by zymozan infusion in four groups: Α, sham-operation; Β, LPS; C, LPS + 0.8 g/kg zymozan; and D, LPS + 1.2 g/kg zymozan. Mice were sacrificed at 24 and 48 h for quantitative tissue cultures, isolation, and stimulation of splenocytes, measurement of apoptosis of lymphocytes and macrophages, and of serum LPS and survival. Some mice with MODS were treated with the antibiotic ertapenem. Results: Enterobacteriaceae and Enterococcus spp were isolated from tissues. Group D had the highest bacterial load and the shortest survival. Release of interleukin-10, of interleukin-17, and of intgerferon-γ by splenocytes and the rate of apoptosis did not concur with immune paralysis. Serum LPS concentrations were higher in mice with MODS versus controls. Ertapenem prolonged survival and decreased the bacterial load. Conclusions: Bacterial translocation seems to be an important contributor leading from MODS to death and suggests a change in therapy towards adaptation of antimicrobial treatment upon early signs of MODS. © 2013 Elsevier Inc. All rights reserved

Validation of Inflammopathic, Adaptive, and Coagulopathic Sepsis Endotypes in Coronavirus Disease 2019

Objectives: Complex critical syndromes like sepsis and coronavirus disease 2019 may be composed of underling &quot;endotypes,&quot;which may respond differently to treatment. The aim of this study was to test whether a previously defined bacterial sepsis endotypes classifier recapitulates the same clinical and immunological endotypes in coronavirus disease 2019. Design: Prospective single-center observational cohort study. Setting: Patients were enrolled in Athens, Greece, and blood was shipped to Inflammatix (Burlingame, CA) for analysis. Patients: Adult patients within 24 hours of hospital admission with coronavirus disease 2019 confirmed by polymerase chain reaction and chest radiography. Interventions: None. Measurements and Main results: We studied 97 patients with coronavirus disease 2019, of which 50 went on to severe respiratory failure (SRF) and 16 died. We applied a previously defined 33-messenger RNA classifier to assign endotype (Inflammopathic, Adaptive, or Coagulopathic) to each patient. We tested endotype status against other clinical parameters including laboratory values, severity scores, and outcomes. Patients were assigned as Inflammopathic (29%), Adaptive (44%), or Coagulopathic (27%), similar to our prior study in bacterial sepsis. Adaptive patients had lower rates of SRF and no deaths. Coagulopathic and Inflammopathic endotypes had 42% and 18% mortality rates, respectively. The Coagulopathic group showed highest d-dimers, and the Inflammopathic group showed highest C-reactive protein and interleukin-6 levels. Conclusions: Our predefined 33-messenger RNA endotypes classifier recapitulated immune phenotypes in viral sepsis (coronavirus disease 2019) despite its prior training and validation only in bacterial sepsis. Further work should focus on continued validation of the endotypes and their interaction with immunomodulatory therapy. © 2020 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved

Genetic polymorphisms within tumor necrosis factor gene promoter region: A role for susceptibility to ventilator-associated pneumonia

Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator-associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376, -308 and -238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin for the production of TNFα and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patients bearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNFα and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied SNPs at the promoter region of the TNF-gene is associated with shorter time to development of VAP but it is not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines. © 2012 Elsevier Ltd

Activate: Randomized Clinical Trial of BCG Vaccination against Infection in the Elderly

Interim analysis of the phase III ACTIVATE trial to evaluate protection against infection in elderly patients reveals that BCG vaccination is safe, increases the time to first infection, and shows protection against viral respiratory infections. © 2020 Elsevier Inc. BCG vaccination in children protects against heterologous infections and improves survival independently of tuberculosis prevention. The phase III ACTIVATE trial assessed whether BCG has similar effects in the elderly. In this double-blind, randomized trial, elderly patients (n = 198) received BCG or placebo vaccine at hospital discharge and were followed for 12 months for new infections. At interim analysis, BCG vaccination significantly increased the time to first infection (median 16 weeks compared to 11 weeks after placebo). The incidence of new infections was 42.3% (95% CIs 31.9%–53.4%) after placebo vaccination and 25.0% (95% CIs 16.4%–36.1%) after BCG vaccination; most of the protection was against respiratory tract infections of probable viral origin (hazard ratio 0.21, p = 0.013). No difference in the frequency of adverse effects was found. Data show that BCG vaccination is safe and can protect the elderly against infections. Larger studies are needed to assess protection against respiratory infections, including COVID-19 (ClinicalTrials.gov NCT03296423). © 2020 Elsevier Inc

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Proper management of COVID-19 mandates better understanding of disease pathogenesis. Giamarellos-Bourboulis et al. describe two main features preceding severe respiratory failure associated with COVID-19: the first is macrophage activation syndrome; the second is defective antigen-presentation driven by interleukin-6. An IL-6 blocker partially rescues immune dysregulation in vitro and in patients. © 2020 Elsevier Inc. Proper management of COVID-19 mandates better understanding of disease pathogenesis. The sudden clinical deterioration 7–8 days after initial symptom onset suggests that severe respiratory failure (SRF) in COVID-19 is driven by a unique pattern of immune dysfunction. We studied immune responses of 54 COVID-19 patients, 28 of whom had SRF. All patients with SRF displayed either macrophage activation syndrome (MAS) or very low human leukocyte antigen D related (HLA-DR) expression accompanied by profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production by circulating monocytes was sustained, a pattern distinct from bacterial sepsis or influenza. SARS-CoV-2 patient plasma inhibited HLA-DR expression, and this was partially restored by the IL-6 blocker Tocilizumab; off-label Tocilizumab treatment of patients was accompanied by increase in circulating lymphocytes. Thus, the unique pattern of immune dysregulation in severe COVID-19 is characterized by IL-6-mediated low HLA-DR expression and lymphopenia, associated with sustained cytokine production and hyper-inflammation. © 2020 Elsevier Inc