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- Asif, Sana, M.D, PhD student, et al.
(författare)
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Immuno-Modulatory Effects of Dexamethasone in Severe COVID-19 : A Swedish Cohort Study
- 2023
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Dexamethasone (Dex) has been shown to decrease mortality in severe coronavirus disease 2019 (COVID-19), but the mechanism is not fully elucidated. We aimed to investigate the physiological and immunological effects associated with Dex administration in patients admitted to intensive care with severe COVID-19. A total of 216 adult COVID-19 patients were included-102 (47%) received Dex, 6 mg/day for 10 days, and 114 (53%) did not. Standard laboratory parameters, plasma expression of cytokines, endothelial markers, immunoglobulin (Ig) IgA, IgM, and IgG against SARS-CoV-2 were analyzed post-admission to intensive care. Patients treated with Dex had higher blood glucose but lower blood lactate, plasma cortisol, IgA, IgM, IgG, D-dimer, cytokines, syndecan-1, and E-selectin and received less organ support than those who did not receive Dex (Without-Dex). There was an association between Dex treatment and IL-17A, macrophage inflammatory protein 1 alpha, syndecan-1 as well as E-selectin in predicting 30-day mortality. Among a subgroup of patients who received Dex early, within 14 days of COVID-19 debut, the adjusted mortality risk was 0.4 (95% CI 0.2-0.8), i.e., 40% compared with Without-Dex. Dex administration in a cohort of critically ill COVID-19 patients resulted in altered immunological and physiologic responses, some of which were associated with mortality.
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- Asif, Sana, M.D, PhD student, et al.
(författare)
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Plasma endostatin correlates with hypoxia and mortality in COVID-19-associated acute respiratory failure
- 2021
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Ingår i: Biomarkers in Medicine. - : Future Medicine. - 1752-0363 .- 1752-0371. ; 15:16, s. 1509-1517
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Tidskriftsartikel (refereegranskat)abstract
- Background: The contribution of endothelial injury in the pathogenesis of COVID-19-associated acute respiratory distress syndrome (ARDS) and resulting respiratory failure remains unclear. Plasma endostatin, an endogenous inhibitor of angiogenesis and endothelial dysfunction is upregulated during hypoxia, inflammation and progress of pulmonary disease.Aim: To investigate if plasma endostatin is associated to hypoxia, inflammation and 30-day mortality in patients with severe COVID-19 infection.Method: Samples for blood analysis and plasma endostatin quantification were collected from adult patients with ongoing COVID-19 (n = 109) on admission to intensive care unit (day 1). Demographic characteristics and 30-day mortality data were extracted from medical records. The ability of endostatin to predict mortality was analyzed using receiving operating characteristics and Kaplan-Meier analysis with a cutoff at 46.2 ng/ml was used to analyze the association to survival.Results: Plasma endostatin levels correlated with; PaO2/FiO2 (r = -0.3, p < 0.001), arterial oxygen tension (r = -0.2, p = 0.01), lactate (r = 0.2, p = 0.04), C-reactive protein (r = 0.2, p = 0.04), ferritin (r = 0.2, p = 0.09), D-dimer (r = 0.2, p = 0.08) and IL-6 (r = 0.4, p < 0.001). Nonsurvivors at 30 days had higher plasma endostatin levels than survivors (72 ± 26 vs 56 ± 16 ng/ml, p = 0.01). Receiving operating characteristic curve (area under the curve 0.7) showed that plasma endostatin >46.2 ng/ml predicts mortality with a sensitivity of 92% and specificity of 71%. In patients with plasma endostatin >46.2 ng/ml probability of survival was lower (p = 0.02) in comparison to those with endostatin <46.2 ng/ml.Conclusion: Our results suggest that plasma endostatin is an early biomarker for disease severity in COVID-19.
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5. |
- Bülow Anderberg, Sara, et al.
(författare)
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Increased levels of plasma cytokines and correlations to organ failure and 30-day mortality in critically ill Covid-19 patients
- 2021
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Ingår i: Cytokine. - : Springer Nature. - 1043-4666 .- 1096-0023. ; 138
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The infection caused by SARS CoV-2 has been postulated to induce a cytokine storm syndrome that results in organ failure and even death in a considerable number of patients. However, the inflammatory response in Corona virus disease-19 (Covid-19) and its potential to cause collateral organ damage has not been fully elucidated to date. This study aims to characterize the acute cytokine response in a cohort of critically ill Covid-19 patients.METHOD: 24 adults with PCR-confirmed Covid-19 were included at time of admission to intensive care a median of eleven days after initial symptoms. Eleven adult patients admitted for elective abdominal surgery with preoperative plasma samples served as controls. All patients were included after informed consent was obtained. 27 cytokines were quantified in plasma. The expression of inflammatory mediators was then related to routine inflammatory markers, SAPS3, SOFA score, organ failure and 30-day mortality.RESULTS: A general increase in cytokine expression was observed in all Covid-19 patients. A strong correlation between respiratory failure and IL-1ra, IL-4, IL-6, IL-8 and IP-10 expression was observed. Acute kidney injury development correlated well with increased levels of IL-1ra, IL-6, IL-8, IL-17a, IP-10 and MCP-1. Generally, the cohort demonstrated weaker correlations between cytokine expression and 30-day mortality out of which IL-8 showed the strongest signal in terms of mortality.CONCLUSION: The present study found that respiratory failure, acute kidney injury and 30-day mortality in critically ill Covid-19 patients are associated with moderate increases of a broad range of inflammatory mediators at time of admission.
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6. |
- Bülow Anderberg, Sara
(författare)
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Inflammatory aspects of acute kidney injury development during severe infections
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute kidney injury is common in intensive care. In this setting sepsis, by definition a dysregulated inflammatory response secondary to infection, is the most common cause. Sepsis associated acute kidney injury is in turn linked to worse outcome. The syndrome is considered to be the result of multiple mechanisms elicited by the inflammatory response and not merely hypoperfusion. COVID-19 has become an additional cause of acute kidney injury in critically ill patients. The present thesis focused on investigating contributing aspects of the inflammatory response in regard to acute kidney injury development in sepsis and COVID-19.The innate immune response recognizes invading pathogens through preserved molecular structures. When detected small and short-acting immunomodulatory molecules, cytokines, are produced shaping the reaction. Neutrophils are quickly mobilized. They engage in degranulation and expulsion of extracellular traps aiming at eradicating pathogens but may in doing so cause collateral tissue damage. Neutrophils are proposed contributors to renal dysfunction during sepsis and COVID-19.We investigated the effect of hydrocortisone, a glucocorticoid, on renal function and neutrophil infiltration in an ovine sepsis model with associated renal impairment. The observed reduction in glomerular filtration and tubular sodium transport efficiency during sepsis was ameliorated. Neutrophil infiltration which was observed post mortem in renal tissue was not reduced by hydrocortisone.The progression of organ dysfunction and by extension also acute kidney injury during severe COVID-19 was early on considered caused by a hyperinflammatory state. We analysed plasma cytokine concentrations in patients admitted to intensive care because of respiratory failure secondary to COVID-19. Only a moderate increase of theses mediators was found. The majority of the cytokines analysed were in turn associated with acute kidney injury development.Human neutrophil lipocalin is a neutrophil granular protein. It was used to first evaluate neutrophil reactivity by measuring its concentration after ex vivo stimulation and second systemic activity by estimating its concentration in plasma. In turn the association with renal dysfunction in severe COVID-19 was explored. Increased concentrations in both instances were linked to a greater risk of developing severe acute kidney injury.Lastly, the effect of dexamethasone, another glucocorticoid, on AKI development and neutrophil extracellular markers including histones and myeloperoxidase-DNA in critical COVID-19 was investigated. Dexamethasone was associated with lower AKI incidence and reduced extracellular trap formation.
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- Bülow Anderberg, Sara, et al.
(författare)
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Systemic Human Neutrophil Lipocalin Associates with Severe Acute Kidney Injury in SARS-CoV-2 Pneumonia
- 2021
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:18
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils have been suggested mediators of organ dysfunction in COVID-19. The current study investigated if systemic neutrophil activity, estimated by human neutrophil lipocalin (HNL) concentration in peripheral blood, is associated with acute kidney injury (AKI) development. A total of 103 adult patients admitted to intensive care, with PCR-confirmed SARS-CoV-2 infection, were prospectively included (Clinical Trials ID: NCT04316884). HNL was analyzed in plasma (P-HNL Dimer) and in whole blood (B-HNL). The latter after ex vivo activation with N-formyl-methionine-leucine-phenylalanine. All patients developed respiratory dysfunction and 62 (60%) were treated with invasive ventilation. Sixty-seven patients (65%) developed AKI, 18 (17%) progressed to AKI stage 3, and 14 (14%) were treated with continuous renal replacement therapy (CRRT). P-HNL Dimer was higher in patients with invasive ventilation, vasopressors, AKI, AKI stage 3, dialysis, and 30-day mortality (p < 0.001-0.046). B-HNL performed similarly with the exception of mild AKI and mortality (p < 0.001-0.004). The cohort was dichotomized by ROC estimated cutoff concentrations of 13.2 mu g/L and 190 mu g/L for P-HNL Dimer and B-HNL respectively. Increased cumulative risks for AKI, AKI stage 3, and death were observed if above the P-HNL cutoff and for AKI stage 3 if above the B-HNL cutoff. The relative risk of developing AKI stage 3 was nine and 39 times greater if above the cutoffs in plasma and whole blood, respectively, for CRRT eight times greater for both. In conclusion, systemically elevated neutrophil lipocalin, interpreted as increased neutrophil activity, was shown to be associated with an increased risk of severe AKI, renal replacement therapy, and mortality in COVID-19 patients with respiratory failure.
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8. |
- Gradin, Anna, et al.
(författare)
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Urinary cytokines correlate with acute kidney injury in critically ill COVID-19 patients
- 2021
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Ingår i: Cytokine. - : Springer Nature. - 1043-4666 .- 1096-0023. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Acute kidney injury is common in COVID-19 patients admitted to the ICU. Urinary biomarkers are a non-invasive way of assaying renal damage, and so far, urinary cytokines are not fully investigated. The current study aimed to assess urinary cytokine levels in COVID-19 patients.METHODS: Urine was collected from COVID-19 patients (n = 29) in intensive care and compared to a preoperative group of patients (n = 9) with no critical illness. 92 urinary cytokines were analyzed in multiplex using the Olink Target 96 inflammation panel and compared to clinical characteristics, and urinary markers of kidney injury.RESULTS: There were strong correlations between proinflammatory cytokines and between urinary cytokines and urinary kidney injury markers in 29 COVID-19 patients. Several cytokines were correlated to kidney injury, 31 cytokines to AKI stage and 19 cytokines correlated to maximal creatinine.CONCLUSIONS: Urinary inflammatory cytokines from a wide range of immune cell lineages were significantly upregulated during COVID-19 and the upregulation correlated with acute kidney injury as well as urinary markers of kidney tissue damage.
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- Huckriede, Joram, et al.
(författare)
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Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Coronavirus disease 19 (COVID-19) presents with disease severities of varying degree. In its most severe form, infection may lead to respiratory failure and multi-organ dysfunction. Here we study the levels and evolution of the damage associated molecular patterns (DAMPS) cell free DNA (cfDNA), extracellular histone H3 (H3) and neutrophil elastase (NE), and the immune modulators GAS6 and AXL in relation to clinical parameters, ICU scoring systems and mortality in patients (n = 100) with severe COVID-19. cfDNA, H3, NE, GAS6 and AXL were increased in COVID-19 patients compared to controls. These measures associated with occurrence of clinical events and intensive care unit acquired weakness (ICUAW). cfDNA and GAS6 decreased in time in patients surviving to 30 days post ICU admission. A decrease of 27.2 ng/mL cfDNA during ICU stay associated with patient survival, whereas levels of GAS6 decreasing more than 4.0 ng/mL associated with survival. The presence of H3 in plasma was a common feature of COVID-19 patients, detected in 38% of the patients at ICU admission. NETosis markers cfDNA, H3 and NE correlated well with parameters of tissue damage and neutrophil counts. Furthermore, cfDNA correlated with lowest p/f ratio and a lowering in cfDNA was observed in patients with ventilator-free days.
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10. |
- Luther, Tomas, et al.
(författare)
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COVID-19 patients in intensive care develop predominantly oliguric acute kidney injury
- 2021
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Ingår i: Acta Anaesthesiologica Scandinavica. - : John Wiley & Sons. - 0001-5172 .- 1399-6576. ; 65:3, s. 364-372
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Acute kidney Injury (AKI) is a syndrome of reduced glomerular filtration rate and/or reduced urine flow associated with mortality in corona virus disease 2019 (COVID-19). AKI is often associated with renal tissue damage, which may lead to chronic kidney disease. Biomarkers of tissue damage may identify patients of particular risk.METHODS: In a prospective observational study of 57 patients admitted to intensive care, AKI incidence and characteristics was evaluated according to KDIGO criteria and related to days after admission. Urinary albumin, Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM-1) and Plasma Tissue Inhibitor of MetalloProteinase 2 (TIMP-2) were analysed in 52 patients at admission.RESULTS: The majority (n=51, 89%) of patients developed AKI, and 27 (47%) patients had predominantly oliguric AKI where oliguria was more severe than plasma Creatinine increase. Severe oliguria within first 2 days after admission was common (n=37, 65%) while stage 2 and 3 AKI due to Creatinine occurred later than day 2 in 67% (12/18) of cases. Renal replacement therapy was started in 9 (16%) patients, and 30-day mortality was 28%. Urinary biomarkers were increased in a majority of patients, but did not robustly predict KDIGO stage. Most patients had microalbuminuria, and severe albuminuria (albumin Creatinine ratio > 30 mg/mmol) was found in n=9 (17%) patients.CONCLUSIONS: A majority of patients with COVID-19 admitted to the ICU develop AKI. The functional deficit is often low urinary volume, and initial levels of biomarkers are generally increased without clear relation to final AKI stage.
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