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Purpose The heterogeneity in sepsis is held responsible, in part, for the lack of precision treatment. Many attempts to identify subtypes of sepsis patients identify those with shared underlying biology or outcomes. To date, though, there has been limited effort to determine overlap across these previously identified subtypes. We aimed to determine the concordance of critically ill patients with sepsis classified by four previously described subtype strategies. Methods This secondary analysis of a multicenter prospective observational study included 522 critically ill patients with sepsis assigned to four previously established subtype strategies, primarily based on: (i) clinical data in the electronic health record ([alpha], [beta], [gamma], and [delta]), (ii) biomarker data (hyper- and hypoinflammatory), and (iii-iv) transcriptomic data (Mars1-Mars4 and SRS1-SRS2). Concordance was studied between different subtype labels, clinical characteristics, biological host response aberrations, as well as combinations of subtypes by sepsis ensembles. Results All four subtype labels could be adjudicated in this cohort, with the distribution of the clinical subtype varying most from the original cohort. The most common subtypes in each of the four strategies were [gamma] (61%), which is higher compared to the original classification, hypoinflammatory (60%), Mars2 (35%), and SRS2 (54%). There was no clear relationship between any of the subtyping approaches (Cramer's V = 0.086-0.456). Mars2 and SRS1 were most alike in terms of host response biomarkers (p = 0.079-0.424), while other subtype strategies showed no clear relationship. Patients enriched for multiple subtypes revealed that characteristics and outcomes differ dependent on the combination of subtypes made. Conclusion Among critically ill patients with sepsis, subtype strategies using clinical, biomarker, and transcriptomic data do not identify comparable patient populations and are likely to reflect disparate clinical characteristics and underlying biology., Author(s): Rombout B. E. van Amstel [sup.1] [sup.2], Jason N. Kennedy [sup.3], Brendon P. Scicluna [sup.4] [sup.5], Lieuwe D. J. Bos [sup.1] [sup.2], Hessel Peters-Sengers [sup.6] [sup.7], Joe M. Butler [...]

Rationale: Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. Objectives: To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. Methods: We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release. We explored if decreased concentrations of lymphocyte-derived proteins in patients with lymphopenia were associated with an increase in mortality. We sought to identify host response phenotypes in patients with lymphopenia by cluster analysis of plasma biomarkers. Measurements and Main Results: A total of 439 general ward patients with COVID-19 were stratified by baseline lymphocyte counts: normal (>1.0 × 109/L; n = 167), mild lymphopenia (>0.5 to ⩽1.0 × 109/L; n = 194), and severe lymphopenia (⩽0.5 × 109/L; n = 78). Lymphopenia was associated with alterations in each host response domain. Lymphopenia was associated with increased mortality. Moreover, in patients with lymphopenia (n = 272), decreased concentrations of several lymphocyte-derived proteins (e.g., CCL5, IL-4, IL-13, IL-17A) were associated with an increase in mortality (at P < 0.01 or stronger significance levels). A cluster analysis revealed three host response phenotypes in patients with lymphopenia: "hyporesponsive" (23.2%), "hypercytokinemic" (36.4%), and "inflammatory-injurious" (40.4%), with substantially differing mortality rates of 9.5%, 5.1%, and 26.4%, respectively. A 10-biomarker model accurately predicted these host response phenotypes in an external cohort with similar mortality distribution. The inflammatory-injurious phenotype showed a remarkable combination of relatively high inflammation and organ damage markers with high antiinflammatory cytokine levels yet low proinflammatory cytokine levels. Conclusions: Lymphopenia in COVID-19 signifies a heterogenous group of patients with distinct host response features. Specific host responses contribute to lymphopenia-associated mortality in COVID-19, including reduced CCL5 levels. [ABSTRACT FROM AUTHOR]

Background: In traumatic bleeding, transfusion practice has shifted toward higher doses of platelets and plasma transfusion. The aim of this systematic review was to investigate whether a higher platelet-to-red blood cell (RBC) transfusion ratio improves mortality without worsening organ failure when compared with a lower ratio of platelet-to-RBC.Methods: Pubmed, Medline, and Embase were screened for randomized controlled trials (RCTs) in bleeding trauma patients (age ≥16 years) receiving platelet transfusion between 1946 until October 2020. High platelet:RBC ratio was defined as being the highest ratio within an included study. Primary outcome was 24 hour mortality. Secondary outcomes were 30-day mortality, thromboembolic events, organ failure, and correction of coagulopathy.Results: In total five RCTs (n = 1757 patients) were included. A high platelet:RBC compared with a low platelet:RBC ratio significantly improved 24 hour mortality (odds ratio [OR] 0.69 [0.53-0.89]) and 30- day mortality (OR 0.78 [0.63-0.98]). There was no difference between platelet:RBC ratio groups in thromboembolic events and organ failure. Correction of coagulopathy was reported in five studies, in which platelet dose had no impact on trauma-induced coagulopathy.Conclusions: In traumatic bleeding, a high platelet:RBC improves mortality as compared to low platelet:RBC ratio. The high platelet:RBC ratio does not influence thromboembolic or organ failure event rates. [ABSTRACT FROM AUTHOR]

Rationale: Systemic molecular phenotypes of critical illness are prognostically informative, yet their temporal kinetics and implications of changing phenotypes remain incompletely understood., Objectives: To determine the temporal nature of the Hyperinflammatory and Hypoinflammatory phenotypes and assess the impact of transition between the phenotypes on mortality., Methods: We used data from one prospective observational cohort (MARS) and two randomized controlled trials in ARDS (ALVEOLI) and sepsis (CLOVERS). Critically ill patients having biomarkers available at multiple timepoints (Day 0-4) were included. We employed a validated classifier model incorporating plasma interleukin-8, protein C and serum bicarbonate to assign phenotypes on each day. We determined the association of longitudinal phenotype transition and 90-day all-cause mortality., Measurements and Main Results: Data from 2407, 527 and 868 patients were included in MARS, ALVEOLI and CLOVERS, respectively. In MARS, 36.0% were classified by the parsimonious model as Hyperinflammatory at day 0, decreasing to 15.6% by day 2 and 6.3% by day 4. In ALVEOLI and CLOVERS, 26.4% and 24.8% of patients were Hyperinflammatory at day 0, decreasing to 13.4% and 5.7% at day 3, respectively. In all three cohorts, switching classification from Hyperinflammatory (Day 0) to Hypoinflammatory over time was associated with significantly improved mortality compared to persistently Hyperinflammatory patients. Mediation analysis indicated that only a minor proportion of this improvement could be attributed to ameliorating organ failure., Conclusion: The prevalence of the Hyperinflammatory phenotype, as assigned by a parsimonious biomarker classifier model, decreases over the first several days of critical illness, irrespective of ARDS diagnosis. The transition from Hyperinflammatory to Hypoinflammatory mediates a trajectory towards recovery beyond the resolution of organ failure.

Objectives: Sepsis is an evolving process and proposed subtypes may change over time. We hypothesized that previously established sepsis subtypes are dynamic, prognostic of outcome, and trajectories are associated with host response alterations., Design: A secondary analysis of two observational critically ill sepsis cohorts: the Molecular diAgnosis and Risk stratification of Sepsis (MARS) and the Medical Information Mart for Intensive Care-IV (MIMIC-IV)., Setting: ICUs in the Netherlands and United States between 2011-2014 and 2008-2019, respectively., Participants: Patient admission fulfilling the Sepsis-3 criteria upon ICU admission adjudicated to one of four previously identified subtypes, comprising 2,416 admissions in MARS and 10,745 in MIMIC-IV., Main Outcomes and Measures: Subtype stability and the changes per subtype on days 2, 4 and 7 of ICU admission were assessed. Next, the associated between change in clinical subtype and outcome and host response alterations., Results: In MARS, upon ICU admission, 6% ( n = 150) of the patient admissions were α-type, 3% ( n = 70) β-type, 55% ( n = 1317) γ-type, and 36% ( n = 879) δ-type; in MIMIC-IV, this was α = 22% ( n = 2398), β = 22% ( n = 2365), γ = 31% ( n = 3296), and δ = 25% (2686). Overall, prevalence of subtypes was stable over days 2, 4, and 7. However, 28-56% (MARS/MIMIC-IV) changed from α on ICU admission to any of the other subtypes on day 2, 33-71% from β, 57-32% from γ, and 50-48% from δ. On day 4, overall subtype persistence was 33-36%. γ or δ admissions remaining in, or transitioning to, subtype γ on days 2, 4, and 7 exhibited lower mortality rates compared with those remaining in, or transitioning to, subtype δ. Longitudinal host response biomarkers reflecting inflammation, coagulation, and endothelial dysfunction were most altered in the δ-δ group, followed by the γ-δ group, independent of the day or biomarker domain., Conclusions and Relevance: In two large cohorts, subtype change to δ was associated with worse clinical outcome and more aberrant biomarkers reflecting inflammation, coagulation, and endothelial dysfunction. These findings underscore the importance of monitoring sepsis subtypes and their linked host responses for improved prognostication and personalized treatment strategies., Competing Interests: The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Thrombocytopenia is associated with increased mortality in COVID-19 patients., Objective: To determine the association between thrombocytopenia and alterations in host response pathways implicated in disease pathogenesis in patients with severe COVID-19., Patients/methods: We studied COVID-19 patients admitted to a general hospital ward included in a national (CovidPredict) cohort derived from 13 hospitals in the Netherlands. In a subgroup, 43 host response biomarkers providing insight in aberrations in distinct pathophysiological domains (coagulation and endothelial cell function; inflammation and damage; cytokines and chemokines) were determined in plasma obtained at a single time point within 48 h after admission. Patients were stratified in those with normal platelet counts (150-400 × 10 9 /L) and those with thrombocytopenia (<150 × 10 9 /L)., Results: 6.864 patients were enrolled in the national cohort, of whom 1.348 had thrombocytopenia and 5.516 had normal platelets counts; the biomarker cohort consisted of 429 patients, of whom 85 with thrombocytopenia and 344 with normal platelet counts. Plasma D-dimer levels were not different in thrombocytopenia, although patients with moderate-severe thrombocytopenia (<100 × 10 9 /L) showed higher D-dimer levels, indicating enhanced coagulation activation. Patients with thrombocytopenia had lower plasma levels of many proinflammatory cytokines and chemokines, and antiviral mediators, suggesting involvement of platelets in inflammation and antiviral immunity. Thrombocytopenia was associated with alterations in endothelial cell biomarkers indicative of enhanced activation and a relatively preserved glycocalyx integrity., Conclusion: Thrombocytopenia in hospitalized patients with severe COVID-19 is associated with broad host response changes across several pathophysiological domains. These results suggest a role of platelets in the immune response during severe COVID-19., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19., Methods: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort., Results: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively)., Conclusions: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19., Competing Interests: Conflicts of interest: The authors declare no potential conflicts of interest., (Copyright ©The authors 2023.)

Purpose of Review: Critical care medicine revolves around syndromes, such as acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury. Few interventions have shown to be effective in large clinical trials, likely because of between-patient heterogeneity. Translational evidence suggests that more homogeneous biological subgroups can be identified and that differential treatment effects exist. Integrating biological considerations into clinical trial design is therefore an important frontier of critical care research., Recent Findings: The pathophysiology of critical care syndromes involves a multiplicity of processes, which emphasizes the difficulty of integrating biology into clinical trial design. Biological assessment can be integrated into clinical trials using predictive enrichment at trial inclusion, time-dependent variation to better understand treatment effects and biological markers as surrogate outcomes., Summary: Integrating our knowledge on biological heterogeneity into clinical trial design, which has revolutionized other medical fields, could serve as a solution to implement personalized treatment in critical care syndromes. Changing the trial design by using predictive enrichment, incorporation of the evaluation of time-dependent changes and biological markers as surrogate outcomes may improve the likelihood of detecting a beneficial effect from targeted therapeutic interventions and the opportunity to test multiple lines of treatment per patient., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Different reference methods are used for the accuracy assessment of continuous glucose monitoring (CGM) systems. The effect of using venous, arterialized-venous, or capillary reference measurements on CGM accuracy is unclear., Methods: We evaluated 21 individuals with type 1 diabetes using a capillary calibrated CGM system. Venous or arterialized-venous reference glucose samples were taken every 15 min at two separate visits and assessed per YSI 2300 STAT Plus. Arterialization was achieved by heated-hand technique. Capillary samples were collected hourly during the venous reference visit. The investigation sequence (venous or arterialized-venous) was randomized. Effectiveness of arterialization was measured by comparing free venous oxygen pressure (PO2) of both visit days. Primary endpoint was the median absolute relative difference (ARD)., Results: Median ARD using arterialized-venous reference samples was not different from venous samples (point estimated difference 0.52%, P = 0.181). When comparing the three reference methods, median ARD was also not different over the full glycemic range (venous 9.0% [n = 681], arterialized-venous 8.3% [n = 684], and capillary 8.1% [n = 205], P = 0.216), nor over the separate glucose ranges. Arterialization was successful (PO2 venous 5.4 kPa vs. arterialized-venous 8.9 kPa, P < 0.001). Arterialized-venous glucose was significantly higher than venous glucose and numerically higher than capillary glucose (arterialized-venous 142 mg/dL vs. venous 129 mg/dL [P < 0.001] and vs. capillary 134 mg/dL [P = 0.231]). Inconvenience related to arterialization included transient mild edema and redness of the hand in 4 out of 21 (19%) patients., Conclusions: The use of venous, arterialized-venous, or capillary reference measurements did not significantly impact CGM accuracy. Venous reference seems preferable due to its ease of operation.