Immune suppression is associated with enhanced systemic inflammatory, endothelial and procoagulant responses in critically ill patients

Xanthe Brands, Fabrice Uhel, Lonneke A van Vught, Maryse A Wiewel, Arie J Hoogendijk, René Lutter, Marcus J Schultz, Brendon P Scicluna, Tom van der Poll, Xanthe Brands, Fabrice Uhel, Lonneke A van Vught, Maryse A Wiewel, Arie J Hoogendijk, René Lutter, Marcus J Schultz, Brendon P Scicluna, Tom van der Poll

Abstract

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Whole-blood leukocyte responsiveness to LPS…
Fig 1. Whole-blood leukocyte responsiveness to LPS in critically ill patients.
(A) LPS-induced whole blood leukocyte cytokine production in critically ill patients on the first day after admission (n = 77) stratified according to quartiles of TNF-α production capacity (normal, slightly reduced, moderately reduced, and strongly reduced), and in age and sex-matched healthy controls (n = 19). Dotted lines indicate median cytokine concentrations in unstimulated control samples. Data are expressed as box and whisker diagrams as specified by Tukey. HV, healthy volunteers; ICU, critically ill patients. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Dot plots depicting the relationship between LPS-induced TNF-α and (B) IL-1β, and (C) IL-6 whole blood production capacity in critically ill patients. Rho, Spearman’s correlation coefficient.
Fig 2. Biomarkers of systemic inflammatory responses…
Fig 2. Biomarkers of systemic inflammatory responses in critically ill patients stratified according to whole blood TNF-α production capacity.
Data are presented as box and whiskers, as specified by Tukey. Dotted lines represent median values obtained in age-matched healthy subjects. Comparisons between groups were performed using the Kruskall-Wallis test followed by Dunn’s post-tests adjusted for multiple comparisons (Bonferroni). * P

Fig 3. Endothelial cell activation biomarkers in…

Fig 3. Endothelial cell activation biomarkers in critically ill patients stratified according to whole blood…

Fig 3. Endothelial cell activation biomarkers in critically ill patients stratified according to whole blood TNF-α production capacity.
Data are presented as box and whiskers, as specified by Tukey. Dotted lines represent median values obtained in age-matched healthy subjects. Comparisons between groups were performed using the Kruskall-Wallis test followed by Dunn’s post-tests adjusted for multiple comparisons (Bonferroni). ** P

Fig 4. Coagulation activation biomarkers in critically…

Fig 4. Coagulation activation biomarkers in critically ill patients stratified according to whole blood TNF-α…

Fig 4. Coagulation activation biomarkers in critically ill patients stratified according to whole blood TNF-α production capacity.
Dotted lines represent median values obtained in age-matched healthy subjects. Comparisons between groups were performed using the Kruskall-Wallis test followed by Dunn’s post-tests adjusted for multiple comparisons (Bonferroni). * P
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References
    1. Deutschman CS, Tracey KJ. Sepsis: Current Dogma and New Perspectives. Immunity. 2014;40:463–75. doi: 10.1016/j.immuni.2014.04.001 - DOI - PubMed
    1. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17:407–20. doi: 10.1038/nri.2017.36 - DOI - PubMed
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This research was performed within the framework of the Center for Translational Molecular Medicine (CTMM) (www.ctmm.nl), project Molecular Diagnosis and Risk Stratification of Sepsis (grant 04I-201). The sponsor CTMM was not involved in the design and conduction of the study; nor was the sponsor involved in collection, management, analysis, and interpretation of the data or preparation, review or approval of the article. Decision to submit the article was not dependent on the sponsor. X.B. was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMW #50-53000-98-139).
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Fig 3. Endothelial cell activation biomarkers in…
Fig 3. Endothelial cell activation biomarkers in critically ill patients stratified according to whole blood TNF-α production capacity.
Data are presented as box and whiskers, as specified by Tukey. Dotted lines represent median values obtained in age-matched healthy subjects. Comparisons between groups were performed using the Kruskall-Wallis test followed by Dunn’s post-tests adjusted for multiple comparisons (Bonferroni). ** P

Fig 4. Coagulation activation biomarkers in critically…

Fig 4. Coagulation activation biomarkers in critically ill patients stratified according to whole blood TNF-α…

Fig 4. Coagulation activation biomarkers in critically ill patients stratified according to whole blood TNF-α production capacity.
Dotted lines represent median values obtained in age-matched healthy subjects. Comparisons between groups were performed using the Kruskall-Wallis test followed by Dunn’s post-tests adjusted for multiple comparisons (Bonferroni). * P
Similar articles
References
    1. Deutschman CS, Tracey KJ. Sepsis: Current Dogma and New Perspectives. Immunity. 2014;40:463–75. doi: 10.1016/j.immuni.2014.04.001 - DOI - PubMed
    1. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol. 2017;17:407–20. doi: 10.1038/nri.2017.36 - DOI - PubMed
    1. Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat Immunol. 2018;19:327–41. doi: 10.1038/s41590-018-0064-8 - DOI - PMC - PubMed
    1. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87. doi: 10.1016/j.it.2009.07.009 - DOI - PubMed
    1. Ward NS, Casserly B, Ayala A. The Compensatory Anti-inflammatory Response Syndrome (CARS) in Critically Ill Patients. Clin Chest Med. 2008;29:617–25. doi: 10.1016/j.ccm.2008.06.010 - DOI - PMC - PubMed
Show all 36 references
Publication types
Associated data
Grant support
This research was performed within the framework of the Center for Translational Molecular Medicine (CTMM) (www.ctmm.nl), project Molecular Diagnosis and Risk Stratification of Sepsis (grant 04I-201). The sponsor CTMM was not involved in the design and conduction of the study; nor was the sponsor involved in collection, management, analysis, and interpretation of the data or preparation, review or approval of the article. Decision to submit the article was not dependent on the sponsor. X.B. was supported by a grant from the Netherlands Organization for Health Research and Development (ZonMW #50-53000-98-139).
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig 4. Coagulation activation biomarkers in critically…
Fig 4. Coagulation activation biomarkers in critically ill patients stratified according to whole blood TNF-α production capacity.
Dotted lines represent median values obtained in age-matched healthy subjects. Comparisons between groups were performed using the Kruskall-Wallis test followed by Dunn’s post-tests adjusted for multiple comparisons (Bonferroni). * P

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