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Background: The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis., Methods: We analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals., Results: Older age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients < 50 years, showed decreased expression of genes involved in cytokine signaling, and innate and adaptive immunity, and increased expression of genes involved in hemostasis and endothelial cell activation. The diminished expression of gene pathways related to innate immunity and cytokine signaling in subjects ≥ 70 years was sepsis-induced, as healthy subjects ≥ 70 years showed enhanced expression of these pathways compared to healthy individuals < 50 years., Conclusions: This study provides novel evidence that older age is associated with relatively mitigated sepsis-induced endothelial cell activation and dysfunction, and a blood leukocyte transcriptome signature indicating impaired innate immune and cytokine signaling. These data suggest that age should be considered in patient selection in future sepsis trials targeting the immune system and/or the endothelial cell response., (© 2022. The Author(s).)

Objective: Patients admitted to the Intensive Care Unit (ICU) oftentimes show immunological signs of immune suppression. Consequently, immune stimulatory agents have been proposed as an adjunctive therapy approach in the ICU. The objective of this study was to determine the relationship between the degree of immune suppression and systemic inflammation in patients shortly after admission to the ICU. Design: An observational study in two ICUs in the Netherlands., Methods: The capacity of blood leukocytes to produce cytokines upon stimulation with lipopolysaccharide (LPS) was measured in 77 patients on the first morning after ICU admission. Patients were divided in four groups based on quartiles of LPS stimulated tumor necrosis factor (TNF)-α release, reflecting increasing extents of immune suppression. 15 host response biomarkers indicative of aberrations in inflammatory pathways implicated in sepsis pathogenesis were measured in plasma., Results: A diminished capacity of blood leukocytes to produce TNF-α upon stimulation with LPS was accompanied by a correspondingly reduced ability to release of IL-1β and IL-6. Concurrently measured plasma concentrations of host response biomarkers demonstrated that the degree of reduction in TNF-α release by blood leukocytes was associated with increasing systemic inflammation, stronger endothelial cell activation, loss of endothelial barrier integrity and enhanced procoagulant responses., Conclusions: In patients admitted to the ICU the strongest immune suppression occurs in those who simultaneously display signs of stronger systemic inflammation. These findings may have relevance for the selection of patients eligible for administration of immune enhancing agents., Trial Registration: ClinicalTrials.gov identifier NCT01905033., Competing Interests: The authors have declared that no competing interests exist.

Background: Immunomodulatory therapies that improve the outcome of sepsis are not available. We sought to determine whether treatment of critically ill patients with sepsis with low-dose erythromycin-a macrolide antibiotic with broad immunomodulatory effects-decreased mortality and ameliorated underlying disease pathophysiology., Methods: We conducted a target trial emulation, comparing patients with sepsis admitted to two intensive care units (ICU) in the Netherlands for at least 72 h, who were either exposed or not exposed during this period to treatment with low-dose erythromycin (up to 600 mg per day, administered as a prokinetic agent) but no other macrolides. We used two common propensity score methods (matching and inverse probability of treatment weighting) to deal with confounding by indication and subsequently used Cox regression models to estimate the treatment effect on the primary outcome of mortality rate up to day 90. Secondary clinical outcomes included change in SOFA, duration of mechanical ventilation and the incidence of ICU-acquired infections. We used linear mixed models to assess differences in 15 host response biomarkers reflective of key pathophysiological processes from admission to day 4., Results: In total, 235 patients started low-dose erythromycin treatment, 470 patients served as controls. Treatment started at a median of 38 [IQR 25-52] hours after ICU admission for a median of 5 [IQR 3-8] total doses in the first course. Matching and weighting resulted in populations well balanced for proposed confounders. We found no differences between patients treated with low-dose erythromycin and control subjects in mortality rate up to day 90: matching HR 0.89 (95% CI 0.64-1.24), weighting HR 0.95 (95% CI 0.66-1.36). There were no differences in secondary clinical outcomes. The change in host response biomarker levels from admission to day 4 was similar between erythromycin-treated and control subjects., Conclusion: In this target trial emulation in critically ill patients with sepsis, we could not demonstrate an effect of treatment with low-dose erythromycin on mortality, secondary clinical outcomes or host response biomarkers., (© 2022. The Author(s).)

Purpose: There is limited knowledge on how the source of infection impacts the host response to sepsis. We aimed to compare the host response in sepsis patients with a single, known source at admission (< 24 h) to the intensive care unit., Methods: From the molecular diagnosis and risk stratification of sepsis (MARS) prospective cohort, we measured 16 plasma host response biomarkers reflective of key host response pathways in 621 sepsis patients. In a subgroup (n = 335), blood leukocyte transcriptomes were compared between the sources. Differences in clinical patient profiles and survival were compared in the whole sepsis cohort (n = 2019)., Results: The plasma biomarker cohort was categorized into sepsis originating from the respiratory tract (n = 334, 53.8%), abdomen (n = 159, 25.6%), urinary tract (n = 44, 7.1%), cardiovascular (n = 41, 6.6%), central nervous system (CNS) (n = 18, 2.9%), or skin (n = 25, 4%). This analysis revealed stronger inflammatory and cytokine responses, loss of vascular integrity and coagulation activation in abdominal sepsis relative to respiratory. Endothelial cell activation was prominent in urinary, cardiovascular and skin infections, while CNS infection was associated with the least host response aberrations. The leukocyte transcriptional response showed the largest overlap between abdominal and pulmonary infections (76% in common); notable differences between the sources were detected regarding hemostasis, cytokine signaling, innate and adaptive immune, and metabolic transcriptional pathways. After adjustment for confounders, the source of infection remained an independent contributor to 30-day mortality (unadjusted p = 0.001, adjusted p = 0.028)., Conclusion: Sepsis heterogeneity is partly explained by source-specific host response dysregulations and should be considered when selecting patients for trials testing immune modulatory drugs., (© 2021. The Author(s).)

Objectives: Plasma ferritin levels above 4,420 ng/mL have been proposed as a diagnostic marker for macrophage activation-like syndrome in sepsis and used for selection of sepsis patients for anti-inflammatory therapy. We here sought to determine the frequency, presentation, outcome, and host response aberrations of macrophage activation-like syndrome, as defined by admission ferritin levels above 4,420 ng/mL, in critically ill patients with community-acquired pneumonia., Design: A prospective observational cohort study., Setting: ICUs in two tertiary hospitals in the Netherlands., Patients: One hundred fifty-three patients admitted with community-acquired pneumonia., Measurements and Main Results: Patients were stratified in community-acquired pneumonia-macrophage activation-like syndrome (n = 15; 9.8%) and community-acquired pneumonia-control groups (n = 138; 90.2%) based on an admission plasma ferritin level above or below 4,420 ng/mL, respectively. Community-acquired pneumonia-macrophage activation-like syndrome patients presented with a higher disease severity and had a higher ICU mortality (46.7% vs 12.3% in community-acquired pneumonia-controls; p = 0.002). Twenty-three plasma biomarkers indicative of dysregulation of key host response pathways implicated in sepsis pathogenesis (systemic inflammation, cytokine responses, endothelial cell activation, and barrier function, coagulation activation) were more disturbed in community-acquired pneumonia-macrophage activation-like syndrome patients. Hematologic malignancies were overrepresented in community-acquired pneumonia-macrophage activation-like syndrome patients (33.3% vs 5.1% in community-acquired pneumonia-controls; p = 0.001). In a subgroup analysis excluding patients with hematologic malignancies (n = 141), differences in mortality were not present anymore, but the exaggerated host response abnormalities in community-acquired pneumonia-macrophage activation-like syndrome patients remained., Conclusions: Macrophage activation-like syndrome in critically ill patients with community-acquired pneumonia occurs more often in patients with hematologic malignancies and is associated with deregulation of multiple host response pathways., Competing Interests: Dr. Brands received funding from the Netherlands Organization for Health Research and Development (ZonMW number 50-53000-98-139). Dr. Peters-Sengers received funding from the Dutch Kidney Foundation (Kolff Grant Nr. 19OK009). Dr. van Engelen received funding from the Amsterdam Medical Center PhD Scholarship. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

The extent of non-coding RNA alterations in patients with sepsis and their relationship to clinical characteristics, soluble mediators of the host response to infection, as well as an advocated in vivo model of acute systemic inflammation is unknown. Here we obtained whole blood from 156 patients with sepsis and 82 healthy subjects among whom eight were challenged with lipopolysaccharide in a clinically controlled setting (human endotoxemia). Via next-generation microarray analysis of leukocyte RNA we found that long non-coding RNA and, to a lesser extent, small non-coding RNA were significantly altered in sepsis relative to health. Long non-coding RNA expression, but not small non-coding RNA, was largely recapitulated in human endotoxemia. Integrating RNA profiles and plasma protein levels revealed known as well as previously unobserved pathways, including non-sensory olfactory receptor activity. We provide a benchmark dissection of the blood leukocyte 'regulome' that can facilitate prioritization of future functional studies., Competing Interests: BS, FU, Lv, MW, AH, IB, MF, PN, JH, OC, MB, MS, Tv No competing interests declared, (© 2020, Scicluna et al.)

Tenascin C (TNC) is an extracellular matrix protein able to modulate the immune response. Knowledge regarding its role during sepsis and general critical illness is still limited. We here assessed the temporal dynamics of plasma TNC during sepsis and nonseptic critical illness, its capacity to predict patient outcome, and its specificity toward infection. TNC plasma concentrations were measured in 895 consecutive sepsis patients on ICU admission, day 2 and 4 thereafter, and, in a subset, before ICU discharge. To assess TNC diagnostic value, we compared patients with abdominal sepsis (N = 143) to noninfectious abdominal surgery controls (N = 98), and patients with severe community-acquired pneumonia (CAP, N = 227) to patients whose CAP diagnosis was retrospectively refuted (no-CAP controls, N = 70). Plasma TNC levels were persistently elevated in sepsis patients compared with healthy volunteers throughout the ICU stay. TNC levels varied by the site of infection and increased with the number of organs failing. Association of TNC levels with 30-day mortality could be wholly attributed to differences in disease severity. Noninfectious ICU patients also showed elevated TNC levels, albeit with different temporal dynamics. Although admission TNC was higher in CAP than in no-CAP patients, it performed poorly in distinguishing the 2 groups.TNC plasma levels are persistently elevated during sepsis and nonseptic critical illness. In sepsis patients, they are reflective of disease severity more than independent predictors of mortality. Despite higher levels in patients with infection compared with noninfectious controls, TNC does not perform sufficiently to be used as a standalone biomarker discriminating sepsis from noninfectious critical illness.

Objectives: The impact of at-risk drinking on the outcomes of nontrauma patients is not well characterized. The aim of this study was to determine whether at-risk drinking is independently associated with the survival of nontrauma patients in an ICU and within 1 year following ICU discharge., Design: Observational cohort study., Setting: A 21-bed mixed ICU in a university hospital., Patients: A total of 662 patients who experienced an ICU stay of 3 days or more and for whom alcohol consumption could be assessed., Interventions: None., Measurements and Main Results: ICU-related variables were collected prospectively, and a 1-year follow-up was determined retrospectively. Analyses were adjusted based on prognostic determinants of short- and long-term outcomes, as previously described in ICU patients and alcohol abusers. Two hundred and eight patients (33%) were identified as at-risk drinkers according to the National Institute on Alcohol Abuse and Alcoholism criteria. Additionally, 111 patients (17%) died in the ICU, and 97 (15%) died after ICU discharge. From the ICU admission until the end of the 1-year follow-up period, the at-risk drinkers exhibited poorer survival than the non-at-risk drinkers (p = 0.0004, as determined by the log-rank test). More specifically, 50 at-risk drinkers (24%) versus 61 non-at-risk drinkers (13%) died in the ICU (p = 0.0009 for the comparison). After adjustment, at-risk drinking remained independently associated with mortality in the ICU (adjusted odds ratio of 1.83; 95% CI of 1.16-2.89; p = 0.01) and with mortality within the year following ICU discharge (adjusted hazard ratio of 1.70; 95% CI of 1.15-2.52; p = 0.008). The causes of death in the at-risk and non-at-risk drinkers were similar., Conclusions: In this population of critically ill nontrauma patients, at-risk drinking was independently associated with death in the ICU and within the year following ICU discharge.