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Article ; Online: Ex vivo and in vitro Monocyte Responses Do Not Reflect in vivo Immune Responses and Tolerance.

Jansen, Aron / Bruse, Niklas / Waalders, Nicole / Gerretsen, Jelle / Rijbroek, Daniëlle / Pickkers, Peter / Kox, Matthijs

Journal of innate immunity

2022 Volume 15, Issue 1, Page(s) 174–187

Abstract: Cytokine production by ex vivo (EV)-stimulated leukocytes is commonly used to gauge immune function and frequently proposed to guide immunomodulatory therapy. However, whether EV cytokine production capacity accurately reflects the in vivo (IV) immune ... ...

Abstract	Cytokine production by ex vivo (EV)-stimulated leukocytes is commonly used to gauge immune function and frequently proposed to guide immunomodulatory therapy. However, whether EV cytokine production capacity accurately reflects the in vivo (IV) immune status is largely unknown. We investigated relationships between EV monocyte cytokine responses and IV cytokine responses in a large cohort of healthy volunteers using a highly standardized IV model of short-lived LPS-induced systemic inflammation, which captures hallmarks of both hyperinflammation and immunological tolerance. Therefore, 110 healthy volunteers were intravenously challenged with 1 ng/kg LPS twice: on day 0 to determine the extent of the IV (hyper)inflammatory response and on day 7 to determine the degree of IV endotoxin tolerance. Baseline EV monocyte cytokine production capacity was assessed prior to LPS administration. Short-term and long-term EV tolerance was assessed in monocytes isolated 4 h and 7 days after LPS administration, respectively. No robust correlations were observed between baseline EV cytokine production capacity and IV cytokine responses following LPS administration. However, highly robust inverse correlations were observed between IV cytokine responses and EV cytokine responses of monocytes isolated 4 h after IV LPS administration. No correlations between IV and EV tolerance were found. In conclusion, attenuated EV cytokine production capacity reflects ongoing IV inflammation rather than immune suppression. Results of EV assays should be interpreted with caution at the risk of improper use of immuno-stimulatory drugs.
MeSH term(s)	Humans ; Monocytes ; Lipopolysaccharides ; Cytokines ; Inflammation ; Immune Tolerance ; Immunity
Chemical Substances	Lipopolysaccharides ; Cytokines
Language	English
Publishing date	2022-08-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2454158-8
ISSN	1662-8128 ; 1662-811X
ISSN (online)	1662-8128
ISSN	1662-811X
DOI	10.1159/000525572
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Article ; Online: Relationships Between Systemic Inflammation, Intestinal Damage and Postoperative Organ Dysfunction in Adults Undergoing Low-Risk Cardiac Surgery.

Habes, Quirine L M / Kant, Niels / Beunders, Remi / van Groenendael, Roger / Gerretsen, Jelle / Kox, Matthijs / Pickkers, Peter

Heart, lung & circulation

2023 Volume 32, Issue 3, Page(s) 395–404

Abstract: Background: Approximately half of patients who undergo cardiac surgery develop systemic inflammatory response syndrome. Extracorporeal circulation and intestinal injury may play a role in this inflammatory response, although their relative contributions ...

Abstract	Background: Approximately half of patients who undergo cardiac surgery develop systemic inflammatory response syndrome. Extracorporeal circulation and intestinal injury may play a role in this inflammatory response, although their relative contributions remain elusive. Moreover, it is largely unknown to what extent these factors contribute to cardiac surgery-induced postoperative organ dysfunction. Method: In this secondary analysis, we measured circulating levels of the intestinal damage marker intestinal fatty acid binding protein (I-FABP) and of the inflammatory cytokines tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-10, IL-1RA, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and MIP-1β in 180 patients undergoing on-pump cardiac surgery. The average Z-score of levels of the different cytokines was used as an integral measure of the cytokine response. Relationships between duration of extracorporeal circulation, extent of intestinal injury, inflammation, and postoperative organ dysfunction were explored. Results: Plasma I-FABP levels increased during surgery, with peak levels observed at the end of cardiopulmonary bypass (CPB). Except for TNF-α, the levels of all cytokines increased during surgery, with peak levels observed either 2 (MCP-1, MIP-1α, and MIP-1β), 4 (IL-6, IL-8, and IL-1RA) or 6 (IL-10) hours after the end of CPB. While the duration of CPB significantly correlated with cytokine Z-score (r=0.544, p<0.05), no relationship with I-FABP levels was found. Furthermore, no significant correlations between I-FABP and cytokine levels were observed. The duration of CPB correlated with a deterioration in postoperative kidney function (estimated glomerular filtration rate [eGFR]) and troponin levels. Cytokine Z-score was associated with postoperative troponin levels, fluid administration, inotropic score, pulmonary alveolar-arterial gradient on the first postoperative morning, and deterioration of kidney function (eGFR). I-FABP levels did not correlate with any of the cardiovascular, pulmonary, or renal parameters. Conclusions: In patients undergoing low-risk cardiac surgery, the duration of CPB represents an important determinant of the systemic cytokine response, whereas both the CPB duration and the systemic inflammatory response contribute to subsequent organ dysfunction. Intestinal damage does not appear to play a relevant role in the postoperative inflammatory response and development of postoperative organ dysfunction in these patients.
MeSH term(s)	Humans ; Adult ; Interleukin-10/metabolism ; Chemokine CCL4 ; Interleukin-8 ; Interleukin 1 Receptor Antagonist Protein ; Multiple Organ Failure/etiology ; Cytokines ; Interleukin-6 ; Inflammation/etiology ; Cardiac Surgical Procedures/adverse effects ; Cardiopulmonary Bypass/adverse effects ; Tumor Necrosis Factor-alpha ; Intestinal Diseases/etiology
Chemical Substances	Interleukin-10 (130068-27-8) ; Chemokine CCL4 ; Interleukin-8 ; Interleukin 1 Receptor Antagonist Protein ; Cytokines ; Interleukin-6 ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2023-01-06
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2020980-0
ISSN	1444-2892 ; 1443-9506
ISSN (online)	1444-2892
ISSN	1443-9506
DOI	10.1016/j.hlc.2022.12.006
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Zs.A 4988: Show issues

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Article ; Online: Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions.

Kox, Matthijs / Waalders, Nicole J B / Kooistra, Emma J / Gerretsen, Jelle / Pickkers, Peter

JAMA

2020

Keywords	covid19
Language	English
Publishing date	2020-09-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2958-0
ISSN	1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
ISSN (online)	1538-3598
ISSN	0254-9077 ; 0002-9955 ; 0098-7484
DOI	10.1001/jama.2020.17052
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Article ; Online: The impact of ADRB2 polymorphisms on immune responses and norepinephrine-induced immunosuppression.

Stolk, Roeland F / Bruse, Niklas / Ter Horst, Rob / Jansen, Aron / Ricaño Ponce, Isis / Gerretsen, Jelle / van der Hoeven, Johannes / Kumar, Vinod / Netea, Mihai G / Pickkers, Peter / Kox, Matthijs

Journal of leukocyte biology

2023 Volume 113, Issue 1, Page(s) 84–92

Abstract: Rationale: To evaluate whether common nonsynonymous variants [single-nucleotide polymorphisms (SNPs) or SNP haplotypes] in the β2-adrenergic receptor render subjects more susceptible to norepinephrine-induced immunosuppression and whether they are ... ...

Abstract	Rationale: To evaluate whether common nonsynonymous variants [single-nucleotide polymorphisms (SNPs) or SNP haplotypes] in the β2-adrenergic receptor render subjects more susceptible to norepinephrine-induced immunosuppression and whether they are associated with dysregulated ex vivo and in vivo inflammatory responses. Methods: Peripheral blood mononuclear cells from healthy volunteers (main cohort: n = 106, secondary cohort: n = 408) were ex vivo stimulated with various stimuli and production of cytokines was assessed. Additionally, ex vivo modulation of cytokine production by norepinephrine was evaluated in the main cohort. Volunteers from the main cohort also underwent experimental endotoxemia (administration of 1 ng/kg lipopolysaccharide), during which in vivo plasma cytokine concentrations and clinical inflammatory parameters were measured. Subjects were genotyped, common SNPs in the ADRB2 gene were extracted (rs1042711, rs1042713, and rs1042714), and the presence of haplotypes was identified (CysGlyGln, CysArgGln, and ArgGlyGlu). Results: In both cohorts, presence of ADRB2 SNPs or haplotypes was not associated with altered ex vivo cytokine responses. Norepinephrine attenuated production of the proinflammatory cytokines TNF and IL-6 [-26% (-22% to -30%) and -14% (-9% to -18%), respectively, both P < 0.0001] and enhanced release of the anti-inflammatory IL-10 [+9% (+3% to +15%), P = 0.003]. These effects were not modulated by the presence of ADRB2 SNPs or haplotypes (all P values >0.37). In addition, no influence of SNPs or haplotypes on in vivo cytokine concentrations or clinical inflammatory parameters was observed (P values >0.14). Conclusions: Common nonsynonymous variants in the ADRB2 gene influence neither ex vivo cytokine production or norepinephrine-mediated immunosuppression nor the systemic in vivo inflammatory response induced by lipopolysaccharide administration in healthy volunteers.
MeSH term(s)	Humans ; Norepinephrine ; Leukocytes, Mononuclear ; Lipopolysaccharides ; Polymorphism, Single Nucleotide ; Cytokines/genetics ; Immunosuppression Therapy ; Immunity ; Receptors, Adrenergic, beta-2
Chemical Substances	Norepinephrine (X4W3ENH1CV) ; Lipopolysaccharides ; Cytokines ; ADRB2 protein, human ; Receptors, Adrenergic, beta-2
Language	English
Publishing date	2023-02-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1093/jleuko/qiac005
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Zs.A 603: Show issues

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Article ; Online: The gut microbiota composition has no predictive value for the endotoxin-induced immune response or development of endotoxin tolerance in humans invivo.

Bruse, Niklas / Jansen, Aron / Gerretsen, Jelle / Rijbroek, Danielle / Wienholts, Kiedo / Arron, Melissa / van Goor, Harry / Ederveen, Thomas H A / Pickkers, Peter / Kox, Matthijs

Microbes and infection

2023 Volume 25, Issue 7, Page(s) 105174

Abstract: Background: It is largely unknown whether the gut microbiome regulates immune responses in humans. We determined relationships between the microbiota composition and immunological phenotypes in 108 healthy volunteers, using 16S sequencing, an ex vivo ... ...

Abstract	Background: It is largely unknown whether the gut microbiome regulates immune responses in humans. We determined relationships between the microbiota composition and immunological phenotypes in 108 healthy volunteers, using 16S sequencing, an ex vivo monocyte challenge model, and an in vivo challenge model of systemic inflammation induced by lipopolysaccharide (LPS). Results: Significant associations were observed between the microbiota composition and ex vivo monocytic cytokine responses induced by several stimuli, most notably IL-10 production induced by Pam3Cys, Pseudomonas aeruginosa and Candida albicans, although the explained variance was rather low (0.3-4.8%). Furthermore, a number of pairwise correlations between Blautia, Bacteroides and Prevotella genera and cytokine production induced by these stimuli were identified. LPS administration induced a profound transient in vivo inflammatory response. A second LPS challenge one week after the first resulted in a severely blunted response, reflecting endotoxin tolerance. However, no significant relationships between microbiota composition and in vivo parameters of inflammation or tolerance were found (explained variance ranging from 0.4 to 1.5%, ns). Conclusions: The gut microbiota composition explains a limited degree of variance in ex vivo monocytic cytokine responses to several pathogenic stimuli, but no relationships with the LPS-induced in vivo immune response or tolerance was observed.
MeSH term(s)	Humans ; Endotoxins/toxicity ; Lipopolysaccharides ; Gastrointestinal Microbiome ; Endotoxin Tolerance ; Cytokines ; Inflammation ; Immunity
Chemical Substances	Endotoxins ; Lipopolysaccharides ; Cytokines
Language	English
Publishing date	2023-06-20
Publishing country	France
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1465093-9
ISSN	1769-714X ; 1286-4579
ISSN (online)	1769-714X
ISSN	1286-4579
DOI	10.1016/j.micinf.2023.105174
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Zs.A 5014: Show issues

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Article ; Online: Comparison of different lots of endotoxin and evaluation of in vivo potency over time in the experimental human endotoxemia model.

Kiers, Dorien / Leijte, Guus P / Gerretsen, Jelle / Zwaag, Jelle / Kox, Matthijs / Pickkers, Peter

Innate immunity

2019 Volume 25, Issue 1, Page(s) 34–45

Abstract: The experimental human endotoxemia model is used to study the systemic inflammatory response in vivo. The previously used lot of endotoxin, which was used for over a decade, is no longer approved for human use and a new Good Manufacturing Practices-grade ...

Abstract	The experimental human endotoxemia model is used to study the systemic inflammatory response in vivo. The previously used lot of endotoxin, which was used for over a decade, is no longer approved for human use and a new Good Manufacturing Practices-grade batch has become available. We compared the inflammatory response induced by either bolus or continuous administration of either the previously used lot #1188844 or new lots of endotoxin (#94332B1 and #94332B4). Compared with lot #1188844, bolus administration of lot #94332B1 induced a more pronounced systemic inflammatory response including higher plasma levels of pro-inflammatory cytokines and more pronounced clinical signs of inflammation. In contrast, continuous infusion of lot #94332B4 resulted in a slightly less pronounced inflammatory response compared with lot #1188844. Furthermore, we evaluated whether lot #1188844 displayed in vivo potency loss by reviewing inflammatory parameters obtained from 17 endotoxemia studies performed in our centre between 2007 and 2016. Despite inter-study variability in endotoxemia-induced effects on temperature, heart rate, symptoms, and leukocyte counts, the magnitude of these effects did not decrease over time. In conclusion, although all lots of endotoxin induce a pronounced inflammatory response, the magnitude differs between lots. We observed no potency loss of endotoxin over time.
MeSH term(s)	Adolescent ; Adult ; Cytokines/therapeutic use ; Endotoxemia/chemically induced ; Endotoxemia/immunology ; Endotoxins/immunology ; Heart Rate ; Humans ; Hydrocortisone/metabolism ; Infusions, Intravenous ; Leukocyte Count ; Lot Quality Assurance Sampling/methods ; Male ; Time Factors ; Young Adult
Chemical Substances	Cytokines ; Endotoxins ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2019-02-16
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2381250-3
ISSN	1753-4267 ; 1753-4259
ISSN (online)	1753-4267
ISSN	1753-4259
DOI	10.1177/1753425918819754
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Article: Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions

Kox, Matthijs / Waalders, Nicole J B / Kooistra, Emma J / Gerretsen, Jelle / Pickkers, Peter

JAMA

Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #915080
Database	COVID19

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Article ; Online: Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions

Kox, Matthijs / Waalders, Nicole J. B. / Kooistra, Emma J. / Gerretsen, Jelle / Pickkers, Peter

JAMA

2020 Volume 324, Issue 15, Page(s) 1565

Keywords	General Medicine ; covid19
Language	English
Publisher	American Medical Association (AMA)
Publishing country	us
Document type	Article ; Online
ZDB-ID	2958-0
ISSN	1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
ISSN (online)	1538-3598
ISSN	0254-9077 ; 0002-9955 ; 0098-7484
DOI	10.1001/jama.2020.17052
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Article ; Online: Molecular mechanisms and treatment responses of pulmonary fibrosis in severe COVID-19.

Kooistra, Emma J / Dahm, Kilian / van Herwaarden, Antonius E / Gerretsen, Jelle / Nuesch Germano, Melanie / Mauer, Karoline / Smeets, Ruben L / van der Velde, Sjef / van den Berg, Maarten J W / van der Hoeven, Johannes G / Aschenbrenner, Anna C / Schultze, Joachim L / Ulas, Thomas / Kox, Matthijs / Pickkers, Peter

Respiratory research

2023 Volume 24, Issue 1, Page(s) 196

Abstract: Background: Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone ( ... ...

Abstract	Background: Coronavirus disease 2019 (COVID-19) patients can develop pulmonary fibrosis (PF), which is associated with impaired outcome. We assessed specific leukocytic transcriptome profiles associated with PF and the influence of early dexamethasone (DEXA) treatment on the clinical course of PF in critically ill COVID-19 patients. Methods: We performed a pre-post design study in 191 COVID-19 patients admitted to the Intensive Care Unit (ICU) spanning two treatment cohorts: the pre-DEXA- (n = 67) and the DEXA-cohort (n = 124). PF was identified based on radiological findings, worsening of ventilatory parameters and elevated circulating PIIINP levels. Longitudinal transcriptome profiles of 52 pre-DEXA patients were determined using RNA sequencing. Effects of prednisone treatment on clinical fibrosis parameters and outcomes were analyzed between PF- and no-PF-patients within both cohorts. Results: Transcriptome analyses revealed upregulation of inflammatory, coagulation and neutrophil extracellular trap-related pathways in PF-patients compared to no-PF patients. Key genes involved included PADI4, PDE4D, MMP8, CRISP3, and BCL2L15. Enrichment of several identified pathways was associated with impaired survival in a external cohort of patients with idiopathic pulmonary fibrosis. Following prednisone treatment, PF-related profiles reverted towards those observed in the no-PF-group. Likewise, PIIINP levels decreased significantly following prednisone treatment. PF incidence was 28% and 25% in the pre-DEXA- and DEXA-cohort, respectively (p = 0.61). ICU length-of-stay (pre-DEXA: 42 [29-49] vs. 18 [13-27] days, p < 0.001; DEXA: 42 [28-57] vs. 13 [7-24] days, p < 0.001) and mortality (pre-DEXA: 47% vs. 15%, p = 0.009; DEXA: 61% vs. 19%, p < 0.001) were higher in the PF-groups compared to the no-PF-groups within both cohorts. Early dexamethasone therapy did not influence these outcomes. Conclusions: ICU patients with COVID-19 who develop PF exhibit upregulated coagulation, inflammation, and neutrophil extracellular trap-related pathways as well as prolonged ICU length-of-stay and mortality. This study indicates that early dexamethasone treatment neither influences the incidence or clinical course of PF, nor clinical outcomes.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Prednisone ; Respiration, Artificial ; Idiopathic Pulmonary Fibrosis ; Dexamethasone ; Disease Progression
Chemical Substances	Prednisone (VB0R961HZT) ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2023-08-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2041675-1
ISSN	1465-993X ; 1465-993X
ISSN (online)	1465-993X
ISSN	1465-993X
DOI	10.1186/s12931-023-02496-1
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Article ; Online: Norepinephrine Contributes to Enterocyte Damage in Septic Shock Patients: A Prospective Cohort Study.

Habes, Quirine L M / van Ede, Lisa / Gerretsen, Jelle / Kox, Matthijs / Pickkers, Peter

Shock (Augusta, Ga.)

2017 Volume 49, Issue 2, Page(s) 137–143

Abstract: Objectives: In septic patients, both systemic inflammation and splanchnic hypoperfusion may cause enterocyte damage. Catecholamines may exert additional detrimental effects on mesenteric blood flow in these patients, and thereby contribute to this ... ...

Abstract	Objectives: In septic patients, both systemic inflammation and splanchnic hypoperfusion may cause enterocyte damage. Catecholamines may exert additional detrimental effects on mesenteric blood flow in these patients, and thereby contribute to this damage. Enterocyte damage itself results in impairment of gut barrier function and consequent translocation of bacteria/toxins. This may contribute to multiple organ failure and death by sustaining or amplifying the systemic inflammatory response. The aim of the study was 2-fold: to investigate which factors contribute to enterocyte damage in septic patients, and to assess whether enterocyte damage is associated with a sustained or amplified systemic inflammatory response. Methods: In this prospective observational cohort study in 129 patients with septic shock admitted to the ICU, we serially measured plasma levels of Intestinal Fatty Acid-Binding Protein (I-FABP, a marker for enterocyte damage) and of cytokines Tumor Necrosis Factor (TNF)-α, Interferon (IFN)-y, Interleukin (IL)-1β, IL-6, IL-8, IL-1 Receptor Antagonist (RA), and IL-10. Clinical data were collected from electronic patient files. Results: A total of 129 patients were included in the study. The median age of the patients was 67 years [56-74]. The median norepinephrine infusion rate was 0.2 μg/kg/min [0.1-0.5]. Overall, 28-day mortality was 31 (24%). Similar to previous work, I-FABP levels at admission were independently associated with mortality (odds ratio 3.101 [1.138-8.448]). Acute Physiology and Chronic Health Evaluation II score and an increase in norepinephrine infusion rate between days 1 and 3 were independently associated with area under curve I-FABP levels, whereas mean arterial pressure and creatinine levels were not. No correlations were found between any of the measured cytokines and plasma I-FABP levels. Furthermore, high I-FABP levels were not related with the subsequent course of cytokine levels. Conclusions: In patients with septic shock, norepinephrine use is associated with more enterocyte damage. Although enterocyte damage is associated with increased 28-day mortality, it is not associated with a sustained or amplified systemic inflammatory response.
MeSH term(s)	Aged ; Cohort Studies ; Enterocytes/metabolism ; Enterocytes/pathology ; Fatty Acid-Binding Proteins/blood ; Female ; Humans ; Interleukin-10/blood ; Interleukin-1beta/blood ; Interleukin-6/blood ; Interleukin-8/blood ; Male ; Middle Aged ; Norepinephrine/administration & dosage ; Norepinephrine/therapeutic use ; Prospective Studies ; Shock, Septic/blood ; Shock, Septic/metabolism ; Shock, Septic/pathology ; Tumor Necrosis Factor-alpha/blood
Chemical Substances	Fatty Acid-Binding Proteins ; IL10 protein, human ; Interleukin-1beta ; Interleukin-6 ; Interleukin-8 ; Tumor Necrosis Factor-alpha ; Interleukin-10 (130068-27-8) ; Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2017-08-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	1185432-7
ISSN	1540-0514 ; 1073-2322
ISSN (online)	1540-0514
ISSN	1073-2322
DOI	10.1097/SHK.0000000000000955
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