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Immune response in a human endotoxin model and critical COVID-19
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Akademiska sjukhuset.ORCID iD: 0000-0002-3287-6504
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Sepsis arises, by definition, from a dysregulated immune response to infection, leading to organ dysfunction and high mortality. Despite advances in antimicrobial treatments and organ support, pharmacological breakthroughs remain limited. The human endotoxin model serves as a bridge between animal models and human trials, simulating systemic inflammatory response syndrome (SIRS) and sepsis for evaluating potential therapies. 

The COVID-19 pandemic, driven by SARS-CoV-2, caused widespread morbidity and mortality. Patients with severe disease exhibited immune dysregulation, characterized by hyperinflammation and immune suppression. Given the similarity in immune dysregulation, insights from previous SARS outbreaks and sepsis research were applied to the SARS-CoV-2, emphasizing the need to balance immune suppression and infection-fighting capacity in both conditions.

Methods: Part one involved a human endotoxemia model, where endotoxin was administered to healthy volunteers, to simulate systemic inflammatory response syndrome (SIRS). Inhaled nitric oxide (iNO) and glucocorticoid (GC) co-administration was assessed for immune modulation based on previous results from a porcine model. 

Part two focused on COVID-19 patients in the PRONMED cohort with severe disease admitted to the ICU, investigating longitudinal immune cells and biomarker levels. In addition potential sex-based differences in inflammatory profiles were evaluated.

Results: In the human endotoxemia model, iNO/GC failed to modify the immune response, despite promising results in a porcine study. Differences in species-specific responses and endotoxin dosing likely contributed to these outcomes. 

Among COVID-19 patients, elevated pro-inflammatory cytokines (TNFα, IL-6, IL-8), neutrophil activation, marked lymphopenia with attenuated expressions of lymphokines receptors were observed. In addition a dynamic aberrant expression of CD-markers was observed on neutrophils. 

Men had an overall heightened immune response compared to women, except for cytokines for Th1 response, where no difference was found.

Conclusions: The failure of iNO/GC to replicate animal results highlights challenges in translating findings across species.

In COVID-19 patients, significant immune dysregulation was observed. Tailored interventions—with precise patient selection, optimized timing and dosing, and potential influences from sex hormones—are likely key to improving outcomes and minimizing harm in sepsis patients. Additionally, further research is crucial to better understand the role of neutrophils in the adaptive immune response.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. , p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2092
Keywords [en]
Human endotoxin model, SIRS, inhaled nitric oxide, glucocorticoids, Sepsis, inflammation, COVID-19, lymphocytes, neutrophils, sex differences
National Category
Medical and Health Sciences
Research subject
Anaesthesiology and Intensive Care
Identifiers
URN: urn:nbn:se:uu:diva-540368ISBN: 978-91-513-2269-8 (print)OAI: oai:DiVA.org:uu-540368DiVA, id: diva2:1905659
Public defence
2024-12-02, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 08:00 (Swedish)
Opponent
Supervisors
Available from: 2024-11-08 Created: 2024-10-15 Last updated: 2024-11-11
List of papers
1. Nitric oxide inhalation and glucocorticoids as combined treatment in human experimental endotoxemia
Open this publication in new window or tab >>Nitric oxide inhalation and glucocorticoids as combined treatment in human experimental endotoxemia
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2008 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 36, no 11, p. 3043-3047Article in journal (Refereed) Published
Abstract [en]

Objective: 

Inhaled nitric oxide and glucocorticoids as a combination therapy may attenuate endotoxin-induced inflammatory responses in humans as indicated by levels of cytokines and clinical signs. Since other authors have shown that combined inhaled nitric oxide and steroids improved the histologic damage both in pulmonary and systemic organs in a porcine endotoxin model, we examined if an anti-inflammatory interaction could be demonstrated in humans.

Design: 

Double-blind, crossover, placebo-controlled randomized study.

Setting: 

The intensive care unit in a university hospital.

Subjects: 

Fifteen healthy white volunteers (4 women, 11 men).

Interventions: 

Endotoxin (2 ng/kg) was administered intravenously. Thirty minutes thereafter the volunteers were given glucocorticoids (2 mg/kg) intravenously and inhaled nitric oxide 30 ppm or placebo (nitrogen) administered through a nasal cannula. Blood samples and clinical signs were collected before and up to 5.5 hrs after the endotoxin infusion.

Measurements and Main Result: 

Following endotoxin body temperature and heart rate increased significantly compared with baseline. There were no differences observed between the treatments. Endotoxin challenge also markedly elevated the plasma levels of tumor necrosis factor-α, interleukin (IL)-6, IL-10, and IL1-ra concentrations during the study period. No difference between placebo/glucocorticoids and inhaled nitric oxide/glucocorticoids treatment was seen in the cytokine response.

Conclusions: 

In a human experimental inflammatory model using endotoxin, inhaled nitric oxide and glucocorticoids in low doses given after the endotoxin challenge did not modify the inflammatory cascade as monitored in this study.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2008
Keywords
cytokines, inflammation, nitric oxide, receptor for advanced glycation end products, sepsis, volunteers
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-540360 (URN)10.1097/ccm.0b013e318186f5b2 (DOI)000260694200013 ()
Available from: 2024-10-14 Created: 2024-10-14 Last updated: 2024-10-15Bibliographically approved
2. Immunomodulation by a combination of nitric oxide and glucocorticoids in a human endotoxin model
Open this publication in new window or tab >>Immunomodulation by a combination of nitric oxide and glucocorticoids in a human endotoxin model
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2011 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 55, no 1, p. 20-27Article in journal (Refereed) Published
Abstract [en]

Background: Inflammatory reactions arise in reaction to a variety of pathogenic insults. The combination of inhaled nitric oxide (iNO) and glucocorticoids (GC) may attenuate endotoxin-induced inflammatory responses. It has been shown that the combination of iNO (30 p.p.m.) and steroids blunted the inflammatory response in a porcine endotoxin model, but not in humans. Therefore, we investigated whether a clinically ‘maximal’ dose of iNO in combination with GC could modulate the systemic inflammatory response in a human endotoxin model.

Methods: A double-blind, cross-over, placebo-controlled randomized study including 15 healthy Caucasian volunteers (five females, 10 males). Performed at the Intensive Care Unit in a university hospital. iNO 80 p.p.m. or placebo (nitrogen) was started 2 h before administration of endotoxin (2 ng/kg). Thirty minutes later, GC (2 mg/kg, hydrocortisone) was administered intravenously. Blood samples and clinical signs were collected before and up to 24 h after the endotoxin injection.

Results: Body temperature and heart rate increased significantly subsequent to endotoxin challenge. The plasma levels of IFN–γ, IL-1β, IL-2, 4 5, 6, 8, 10, 12, 13 and TNFα were markedly elevated. However, HMGB-1 and sRAGE were unaffected. No difference between placebo/GC and iNO/GC treatment was observed in the clinical or cytokine response, neither was there any difference between the first and the second exposure to endotoxin.

Conclusions: Pre-treatment with iNO 80 p.p.m. along with GC (2 mg/kg) administrated after the endotoxin challenge could not modulate the systemic inflammatory response in this model of human experimental inflammation.

Place, publisher, year, edition, pages
John Wiley & Sons, 2011
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-540362 (URN)10.1111/j.1399-6576.2010.02297.x (DOI)000284898500004 ()
Available from: 2024-10-14 Created: 2024-10-14 Last updated: 2024-10-15Bibliographically approved
3. The Evolution of Blood Cell Phenotypes, Intracellular and Plasma Cytokines and Morphological Changes in Critically Ill COVID-19 Patients
Open this publication in new window or tab >>The Evolution of Blood Cell Phenotypes, Intracellular and Plasma Cytokines and Morphological Changes in Critically Ill COVID-19 Patients
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2022 (English)In: Biomedicines, E-ISSN 2227-9059, Vol. 10, no 5, article id 934Article in journal (Refereed) Published
Abstract [en]

Background: Severe coronavirus disease 2019 (COVID-19) causes a strong inflammatory response. To obtain an overview of inflammatory mediators and effector cells, we studied 25 intensive-care-unit patients during the timeframe after off-label chloroquine treatment and before an introduction of immunomodulatory drugs.

Material and methods: Blood samples were weekly examined with flow cytometry (FCM) for surface and intracytoplasmic markers, cytokine assays were analyzed for circulating interleukins (ILs), and blood smears were evaluated for morphological changes. Samples from healthy volunteers were used for comparison. Organ function data and 30-day mortality were obtained from medical records.

Results: Compared to that of the healthy control group, the expression levels of leukocyte surface markers, i.e., the cluster of differentiation (CD) markers CD2, CD4, CD8, CD158d, CD25, CD127, and CD19, were lower (p < 0.001), while those of leukocytes expressing CD33 were increased (p < 0.05). An aberrant expression of CD158d on granulocytes was found on parts of the granulocyte population. The expression levels of intracellular tumor necrosis factor alpha (TNF alpha) and IL-1 receptor type 2 in leukocytes were higher (p < 0.001) as well as plasma levels of TNF alpha, IL-2, IL-6, IL-8, IL-10 (p < 0.001), interferon gamma (IFN gamma) (p < 0.01), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (p < 0.05). The expression levels of CD33+ leukocytes and circulating IL-6 were higher (p < 0.05) among patients with arterial oxygen partial pressure-to-fractional inspired oxygen (PaO2/FiO(2)) ratios below 13.3 kPa compared to in the remaining patients. The expression levels of TNF alpha, IL-2, IL-4, IL-6, IL-8, and IL-10 were higher in patients treated with continuous renal replacement therapy (CRRT) (p < 0.05), and the levels of the maximum plasma creatinine and TNF alpha Spearman's rank-order correlation coefficient (rho = 0.51, p < 0.05) and IL-8 (rho = 0.44, p < 0.05) correlated. Blood smears revealed neutrophil dysplasia with pseudo-Pelger forms being most common.

Conclusion: These findings suggest that patients with severe COVID-19, in addition to augmented ILs, lymphopenia, and increased granulocytes, also had effects on the bone marrow.

Place, publisher, year, edition, pages
MDPIMDPI AG, 2022
Keywords
severe COVID-19, flow cytometry, immunophenotype, morphology, intensive care
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-476610 (URN)10.3390/biomedicines10050934 (DOI)000801756400001 ()35625671 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20210089Swedish Heart Lung Foundation, 20190639Swedish Heart Lung Foundation, 20190637Swedish Research Council, 2014-02569Swedish Research Council, 2014-07606Knut and Alice Wallenberg Foundation, KAW 2020.0182Knut and Alice Wallenberg Foundation, KAW 2020.0241
Note

Correction in: Biomedicines, Volume 11, Issue 11, 2965, 2023

DOI: 10.3390/biomedicines11112965

Available from: 2022-06-21 Created: 2022-06-21 Last updated: 2024-12-03Bibliographically approved
4. Characterisation of sex differences in a cohort of critically ill COVID-19 patients
Open this publication in new window or tab >>Characterisation of sex differences in a cohort of critically ill COVID-19 patients
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(English)Manuscript (preprint) (Other academic)
National Category
Anesthesiology and Intensive Care
Research subject
Anaesthesiology and Intensive Care
Identifiers
urn:nbn:se:uu:diva-540364 (URN)
Available from: 2024-10-14 Created: 2024-10-14 Last updated: 2024-10-17

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