Biological Subphenotypes of Acute Respiratory Distress Syndrome Show Prognostic Enrichment in Mechanically Ventilated Patients without Acute Respiratory Distress Syndrome

Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment.Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS.Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latentclass analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS.Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive" subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed" subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles.Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial.

Clarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome. We conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics. Fifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed. Clarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55

Systems-based approach for the identification of novel genes influencing cardiac electrical traits

Plotse hartdood hangt samen met zowel genen als omgeving. Een abnormaal hartfilmpje is een risicofactor voor plotse hartdood. Bij muizen zijn nieuwe genen gevonden die het ECG beïnvloeden. De uitkomt van het ECG kan ook worden beïnvloed door reactiepaden in de mitochondriën (de energiecentrales van de cel), het afweermechanisme en het hartweefsel dat samentrekt. Uit het onderzoek van Brendon Scicluna blijkt dat chemokines (kleine eiwitten) een rol spelen bij de hartactiviteit en het risico op plotse hartdood

Are histones real pathogenic agents in sepsis?

Contains fulltext : 190785.pdf (publisher's version ) (Closed access

The immunopathology of sepsis and potential therapeutic targets

Contains fulltext : 174682.pdf (publisher's version ) (Closed access)Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target

The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia

OBJECTIVE: Pneumonia accounts for more deaths than any other infectious disease worldwide. The intestinal microbiota supports local mucosal immunity and is increasingly recognised as an important modulator of the systemic immune system. The precise role of the gut microbiota in bacterial pneumonia, however, is unknown. Here, we investigate the function of the gut microbiota in the host defence against Streptococcus pneumoniae infections. DESIGN: We depleted the gut microbiota in C57BL/6 mice and subsequently infected them intranasally with S. pneumoniae. We then performed survival and faecal microbiota transplantation (FMT) experiments and measured parameters of inflammation and alveolar macrophage whole-genome responses. RESULTS: We found that the gut microbiota protects the host during pneumococcal pneumonia, as reflected by increased bacterial dissemination, inflammation, organ damage and mortality in microbiota-depleted mice compared with controls. FMT in gut microbiota-depleted mice led to a normalisation of pulmonary bacterial counts and tumour necrosis factor-a and interleukin-10 levels 6 h after pneumococcal infection. Whole-genome mapping of alveolar macrophages showed upregulation of metabolic pathways in the absence of a healthy gut microbiota. This upregulation correlated with an altered cellular responsiveness, reflected by a reduced responsiveness to lipopolysaccharide and lipoteichoic acid. Compared with controls, alveolar macrophages derived from gut microbiota-depleted mice showed a diminished capacity to phagocytose S. pneumoniae. CONCLUSIONS: This study identifies the intestinal microbiota as a protective mediator during pneumococcal pneumonia. The gut microbiota enhances primary alveolar macrophage function. Novel therapeutic strategies could exploit the gut-lung axis in bacterial infection

Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis

The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-gamma, which suggested that metabolic processes might represent a therapeutic target in sepsis

Dysregulation of the MMP/TIMP Proteolytic System in Subependymal Giant Cell Astrocytomas in Patients With Tuberous Sclerosis Complex: Modulation of MMP by MicroRNA-320d In Vitro

Tuberous sclerosis complex (TSC), a rare genetic disorder caused by a mutation in the TSC1 or TSC2 gene, is characterized by the growth of hamartomas in several organs. This includes the growth of low-grade brain tumors, known as subependymal giant cell astrocytomas (SEGA). Previous studies have shown differential expression of genes related to the extracellular matrix in SEGA. Matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) are responsible for remodeling the extracellular matrix and are associated with tumorigenesis. This study aimed to investigate the MMP/TIMP proteolytic system in SEGA and the regulation of MMPs by microRNAs, which are important post-transcriptional regulators of gene expression. We investigated the expression of MMPs and TIMPs using previously produced RNA-Sequencing data, real-time quantitative PCR and immunohistochemistry in TSC-SEGA samples and controls. We found altered expression of several MMPs and TIMPs in SEGA compared to controls. We identified the lowly expressed miR-320d in SEGA as a potential regulator of MMPs, which can decrease MMP2 expression in human fetal astrocyte cultures. This study provides evidence of a dysregulated MMP/TIMP proteolytic system in SEGA of which MMP2 could be rescued by microRNA-320d. Therefore, further elucidating microRNA-mediated MMP regulation may provide insights into SEGA pathogenesis and identify novel therapeutic targets