Publications by authors named "Anders Larsson"

626 Publications

Plasma endostatin correlates with hypoxia and mortality in COVID-19-associated acute respiratory failure.

Biomark Med 2021 Oct 20. Epub 2021 Oct 20.

Department of Surgical Sciences, Anaesthesiology & Intensive Care Medicine, Uppsala University, Uppsala, 751 85, Sweden.

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. To investigate if plasma endostatin is associated to hypoxia, inflammation and 30-day mortality in patients with severe COVID-19 infection. 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. Plasma endostatin levels correlated with; PaO/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. Our results suggest that plasma endostatin is an early biomarker for disease severity in COVID-19.
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http://dx.doi.org/10.2217/bmm-2021-0111DOI Listing
October 2021

The association between BMI and 90-day mortality in patients with and without diabetes seeking care at the emergency department.

Ups J Med Sci 2021 16;126. Epub 2021 Sep 16.

Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden.

Background: The impact of body mass index (BMI) on mortality varies with age and disease states. The aim of this research study was to analyse the associations between BMI categories and short- and long-term mortality in patients with or without diabetes seeking care at the emergency department (ED) with acute dyspnoea.

Population And Methods: Patients aged ≥18 years at ED during daytime on weekdays from March 2013 to July 2018 were included. Participants were triaged according to the Medical Emergency Triage and Treatment System-Adult score (METTS-A), and blood samples were collected. Totally, 1,710 patients were enrolled, with missing values in 113, leaving 1,597 patients, 291 with diabetes and 1,306 without diabetes. The association between BMI and short-term (90-day) and long-term (mean follow-up time 2.1 years) mortality was estimated by Cox regression with normal BMI (18.5-24.9) as referent category, with adjustment for age, sex, METTS-A scoring, glomerular filtration rate, smoking habits and cardiovascular comorbidity in a fully adjusted model. The Bonferroni correction was also used.

Results: Regarding long-term mortality, patients with diabetes and BMI category ≥30 kg/m had a fully adjusted Hazard Ratio (HR) of 0.40 (95% confidence interval [CI]: 0.23-0.69), significant after the Bonferroni correction. Amongst patients without diabetes, those with underweight had an increased risk but only of borderline significance, whilst risks in those with overweight or obesity did not differ from reference.Regarding short-term mortality, risks did not differ from reference amongst patients with or without diabetes.

Conclusions: We found divergent long-term mortality risks in patients with and without diabetes, with lower risk in obese patients (BMI ≥ 30 kg/m) with diabetes, but no increased risk for patients without diabetes and overweight (BMI: 25-29.9 kg/m) and obesity.
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http://dx.doi.org/10.48101/ujms.v126.7590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494247PMC
September 2021

Soluble TNF receptors predict acute kidney injury and mortality in critically ill COVID-19 patients: A prospective observational study.

Cytokine 2021 Oct 5;149:155727. Epub 2021 Oct 5.

Hedenstierna Laboratory, CIRRUS, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Uppsala University, Uppsala, Sweden; Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, Uppsala University, Uppsala, Sweden. Electronic address:

Background: Although pneumonia is the hallmark of coronavirus disease 2019 (COVID-19), multiple organ failure may develop in severe disease. TNFα receptors in their soluble form (sTNFR) are involved in the immune cascade in other systemic inflammatory processes such as septic shock, and could mediate the inflammatory activation of distant organs. The aim of this study is to analyse plasma levels of sTNFR 1 and 2 in association with organ failure and outcome in critically ill patients with COVID-19.

Methods: After informed consent, we included 122 adult patients with PCR-confirmed COVID-19 at ICU admission. Demographic data, illness severity scores, organ failure and survival at 30 days were collected. Plasma sTNFR 1 and 2 levels were quantified during the first days after ICU admission. Twenty-five healthy blood donors were used as control group.

Results: Levels of sTNFR were higher in severe COVID-19 patients compared to controls (p < 0.001). Plasma levels of sTNFR were associated to illness severity scores (SAPS 3 and SOFA), inflammation biomarkers such as IL-6, ferritin and PCT as well as development of AKI during ICU stay. sTNFR 1 higher than 2.29 ng/mL and? sTNFR 2 higher than 11.7 ng/mL were identified as optimal cut-offs to discriminate survivors and non-survivors 30 days after ICU admission and had an area under the curve in receiver operating characteristic curve of 0.75 and 0.67 respectively.

Conclusion: Plasma levels of sTNFR 1 and 2 were higher in COVID-19 patients compared to controls and were strongly associated with other inflammatory biomarkers, severity of illness and acute kidney injury development during ICU stay. In addition, sTNFR 1 was an independent predictor of 30-day mortality after adjustment for age and respiratory failure.
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http://dx.doi.org/10.1016/j.cyto.2021.155727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491926PMC
October 2021

Longitudinal change in c-terminal fibroblast growth factor 23 and outcomes in patients with advanced chronic kidney disease.

BMC Nephrol 2021 Oct 2;22(1):329. Epub 2021 Oct 2.

Vascular Research Group, Manchester Academic Health Sciences Centre, University of Manchester, Salford Royal NHS Foundation Trust, Salford, UK.

Background: Fibroblast growth factor23 (FGF23) is elevated in CKD and has been associated with outcomes such as death, cardiovascular (CV) events and progression to Renal Replacement therapy (RRT). The majority of studies have been unable to account for change in FGF23 over time and those which have demonstrate conflicting results. We performed a survival analysis looking at change in c-terminal FGF23 (cFGF23) over time to assess the relative contribution of cFGF23 to these outcomes.

Methods: We measured cFGF23 on plasma samples from 388 patients with CKD 3-5 who had serial measurements of cFGF23, with a mean of 4.2 samples per individual. We used linear regression analysis to assess the annual rate of change in cFGF23 and assessed the relationship between time-varying cFGF23 and the outcomes in a cox-regression analysis.

Results: Across our population, median baseline eGFR was 32.3mls/min/1.73m, median baseline cFGF23 was 162 relative units/ml (RU/ml) (IQR 101-244 RU/mL). Over 70 months (IQR 53-97) median follow-up, 76 (19.6%) patients progressed to RRT, 86 (22.2%) died, and 52 (13.4%) suffered a major non-fatal CV event. On multivariate analysis, longitudinal change in cFGF23 was significantly associated with risk for death and progression to RRT but not non-fatal cardiovascular events.

Conclusion: In our study, increasing cFGF23 was significantly associated with risk for death and RRT.
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http://dx.doi.org/10.1186/s12882-021-02528-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487581PMC
October 2021

The Accuracy of Hemoglobin A1c and Fructosamine Evaluated by Long-Term Continuous Glucose Monitoring in Patients with Type 2 Diabetes Undergoing Hemodialysis.

Blood Purif 2021 Sep 28:1-9. Epub 2021 Sep 28.

Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Introduction: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD.

Methods: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m2) completed the study period of 17 weeks. CGM (Ipro2®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM.

Findings: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0-1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: -0.1-[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (-7.3 mmol/mol, 95% CI: -10.0-[-4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64).

Discussion: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.
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http://dx.doi.org/10.1159/000519050DOI Listing
September 2021

Plasma calprotectin in the emergency department: a potential clinical biomarker for patients with infectious diseases.

Scand J Clin Lab Invest 2021 Sep 23:1-5. Epub 2021 Sep 23.

Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden.

Increased levels of plasma calprotectin are reported in patients with infectious diseases. However, the clinical usefulness of calprotectin as a biomarker to identify patients with infectious diseases in the emergency department (ED) setting has not been investigated. To study the ability of calprotectin to discriminate patients with acute infectious diseases and dyspnea from patients with other causes of acute dyspnea in the ED setting. Patients aged ≥18 years seeking ED during daytime on weekdays between March 2013 and July 2018, with acute dyspnea, were included. Participants ( = 1287) were triaged according to Medical Emergency Triage and Treatment System-Adult score (METTS-A) or Rapid Emergency Triage and Treatment System (RETTS), and blood samples were collected. The association between calprotectin and other markers of infectious diseases, i.e. biomarkers (CRP, leucocytes) and body temperature, was studied. The predictive value of calprotectin for the outcome of acute infection was evaluated with receiver operating characteristic (ROC) analysis. Univariate cross-sectional regression showed significant associations between calprotectin and leucocytes, CRP and body temperature. Patients with severe infections including pneumonia ( = 119) had significantly higher concentrations of calprotectin compared to patients with heart failure ( = 162) or chronic obstructive pulmonary disease ( = 183). When tested for the outcome of acute infection ( = 109), the area under the ROC curve (AUROC) was for CRP 0.83 and for calprotectin 0.78. Plasma calprotectin identifies infectious diseases in ED patients with acute dyspnea, and the clinical usefulness of Calprotectin in the ED has to be further studied.
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http://dx.doi.org/10.1080/00365513.2021.1980223DOI Listing
September 2021

Strong Associations between Plasma Osteopontin and Several Inflammatory Chemokines, Cytokines, and Growth Factors.

Biomedicines 2021 Jul 28;9(8). Epub 2021 Jul 28.

School of Health and Social Sciences, Dalarna University, 791 88 Falun, Sweden.

Osteopontin is a member of the proinflammatory cytokine network, a complex system that involves many chemokines, cytokines, and growth factors. The aim of the present study was to study the associations between osteopontin and a large number of chemokines, cytokines, and growth factors. We analyzed plasma and urine osteopontin in 652 men from the Uppsala Longitudinal Study of Adult Men (ULSAM) study cohort and compared the levels with the levels of eighty-five chemokines, cytokines, and growth factors. We found significant associations between plasma osteopontin and 37 plasma biomarkers in a model adjusted for age, and 28 of those plasma biomarkers were significant in a model also adjusting for cardiovascular risk factors. There were no significant associations after Bonferroni adjustment between urine osteopontin and any of the studied plasma cytokine biomarkers. This study shows that circulating osteopontin participates in a protein-protein interaction network of chemokines, cytokines, and growth factors. The network contains responses, pathways, and receptor binding interactions relating to cytokines, regulation of the immune system, and also regulation of apoptosis and intracellular signal transduction.
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http://dx.doi.org/10.3390/biomedicines9080908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389577PMC
July 2021

The Aging Kidney-As Influenced by Heavy Metal Exposure and Selenium Supplementation.

Biomolecules 2021 07 22;11(8). Epub 2021 Jul 22.

Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria, 09042 Monserrato-Cagliari, Italy.

The aging process in the kidneys has been well studied. It is known that the glomerular filtration rate (GFR) declines with age in subjects older than 50-60 years. However, there is still insufficient knowledge regarding the response of the aged kidney to environmental toxicants such as mercury, cadmium, and lead. Here, we present a review on the functional decline and proposed mechanisms in the aging kidney as influenced by metal pollutants. Due to the prevalence of these toxicants in the environment, human exposure is nearly unavoidable. Further, it is well known that acute and chronic exposures to toxic metals may be detrimental to kidneys of normal adults, thus it may be hypothesized that exposure of individuals with reduced GFR will result in additional reductions in renal function. Individuals with compromised renal function, either from aging or from a combination of aging and disease, may be particularly susceptible to environmental toxicants. The available data appear to show an association between exposure to mercury, cadmium and/or lead and an increase in incidence and severity of renal disease in elderly individuals. Furthermore, some physiological thiols, as well as adequate selenium status, appear to exert a protective action. Further studies providing improved insight into the mechanisms by which nephrotoxic metals are handled by aging kidneys, as well as possibilities of therapeutic protection, are of utmost importance.
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http://dx.doi.org/10.3390/biom11081078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391790PMC
July 2021

HGF, CSF-1, CD40 and 11 other inflammation-related proteins are associated with pain in diabetic neuropathy: exploration and replication serum data from the Pain in Neuropathy Study (PiNS).

Pain 2021 Aug 24. Epub 2021 Aug 24.

Pain and Rehabilitation Center, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden Department of Surgical Sciences, Uppsala University, Uppsala, Sweden Pain Research, Dept Surgery and Cancer, Faculty of Medicine, Imperial College London, United Kingdom Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Abstract: One in five diabetic patients suffers from chronic pain with neuropathic characteristics, but the pathophysiological mechanisms underlying the development of neuropathic pain in diabetic distal symmetrical polyneuropathy (DSP) patients are poorly understood. Systemic low-grade inflammation has been implicated, but there is still a considerable knowledge gap concerning its scope and meaning in this context. The aim of the study was to establish the broad inflammatory signature of painful diabetic DSP in serum samples from the Pain in Neuropathy Study (PiNS), an observational cross-sectional multicentre study in which participants underwent deep phenotyping. In the present two-cohorts exploration-replication study (180 participants in each cohort), serum samples from PiNS participants were analyzed with the Olink INFLAMMATION panel (Olink Bioscience, Uppsala, Sweden) which enables the simultaneous measurement of 92 inflammation-related proteins (mainly cytokines, chemokines and growth factors). In both the exploration and the replication cohort, we identified a high-inflammation subgroup where 14 inflammation-related proteins in particular were associated with more neuropathy and higher pain intensity. The top 3 proteins were HGF, CSF-1 and CD40 in both cohorts. In the exploratory cohort, additional clinical data were available, showing an association of inflammation with insomnia and self-reported psychological distress. Hence, this cross-sectional exploration-replication study seems to confirm that low-grade systemic inflammation is related to the severity of neuropathy and neuropathic pain in a subgroup of diabetic DSP patients. The pathophysiological relevance of these proteins for the development of neuropathic pain in diabetic DSP patients must be explored in more depth in future studies.
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http://dx.doi.org/10.1097/j.pain.0000000000002451DOI Listing
August 2021

Strong Associations Between Early Tubular Damage and Urinary Cytokine, Chemokine, and Growth Factor Levels in Elderly Males and Females.

J Interferon Cytokine Res 2021 08;41(8):283-290

Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.

Acute tubular necrosis is associated with high mortality rates and it is important to develop new biomarkers for tubular damage. The aim of this study was to investigate the effect of early tubular damage on a large number of urinary cytokines, chemokines, and growth factors. We selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The tubular damage markers cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) were analyzed in the urine samples and urinary cytokine levels were analyzed with 2 multiplex assays (proximity extension assay). After adjustment for sex, body mass index, estimated glomerular filtration rate, smoking, and multiplicity testing using the false discovery rate approach, there remained 26 cytokines that correlated significantly with urine cystatin C, 27 cytokines that correlated with NGAL, and 66 cytokines that correlated with KIM-1. Tubular damage shows a strong association with urinary cytokines, chemokines, and growth factors. Our findings indicate that multiplex proteomics could be a promising new approach to explore the complex effects of tubular damage.
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http://dx.doi.org/10.1089/jir.2021.0065DOI Listing
August 2021

A screening method to spot biomarkers that may warn of serious events in a chronic disease - illustrated by cardiological CLARICOR trial data.

Clin Chem Lab Med 2021 Oct 12;59(11):1852-1860. Epub 2021 Aug 12.

Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: To develop a crude screening method for detecting biomarkers which frequently exhibit a rise (or fall) in level prior to a serious event (e.g. a stroke) in patients with a chronic disease, signalling that the biomarker may have an alarm-raising or prognostic potential. The subsequent assessment of the marker's clinical utility requires costly, difficult longitudinal studies. Therefore, initial screening of candidate-biomarkers is desirable.

Methods: The method exploits a cohort of patients with biomarkers measured at entry and with recording of first serious event during follow-up. Copying those individual records onto a common timeline where a specific event occurs on the same day (Day 0) for all patients, the baseline biomarker level, when plotted against the patient's entry time on the revised timeline, will have a positive (negative) regression slope if biomarker levels generally rise (decline) the closer one gets to the event. As an example, we study 1,958 placebo-treated patients with stable coronary artery disease followed for nine years in the CLARICOR trial (NCT00121550), examining 11 newer biomarkers.

Results: Rising average serum levels of cardiac troponin T and of N-terminal pro-B-type natriuretic peptide were seen prior to a fatal cardiovascular outcome. C-reactive protein rose prior to non-cardiovascular death. Glomerular filtration rate, seven lipoproteins, and nine newer cardiological biomarkers did not show convincing changes.

Conclusions: For early detection of biomarkers with an alarm-raising potential in chronic diseases, we proposed the described easy procedure. Using only baseline biomarker values and clinical course of participants with coronary heart disease, we identified the same cardiovascular biomarkers as those previously found containing prognostic information using longitudinal or survival analysis.
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http://dx.doi.org/10.1515/cclm-2021-0333DOI Listing
October 2021

High expression of neutrophil and monocyte CD64 with simultaneous lack of upregulation of adhesion receptors CD11b, CD162, CD15, CD65 on neutrophils in severe COVID-19.

Ther Adv Infect Dis 2021 Jan-Dec;8:20499361211034065. Epub 2021 Jul 31.

Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden.

Background And Aims: The pronounced neutrophilia observed in patients with coronavirus disease 2019 (COVID-19) infections suggests a role for these leukocytes in the pathology of the disease. Monocyte and neutrophil expression of CD64 and CD11b have been reported as early biomarkers to detect infections. The aim of this study was to study the expression of receptors for IgG (CD64) and adhesion molecules (CD11b, CD15s, CD65, CD162, CD66b) on neutrophils and monocytes in patients with severe COVID-19 after admission to an intensive care unit (ICU).

Methods: The expression of receptors was analyzed using flow cytometry. EDTA blood from 23 patients with confirmed COVID-19 infection was sampled within 48 h of admission to the ICU. Leukocytes were labeled with antibodies to CD11b, CD15s, CD65s, CD162, CD64, and CD66b. Expression of receptors was reported as mean fluorescence intensity (MFI) or the percentage of cells expressing receptors.

Results: Results are presented as comparison of COVID-19 patients with the healthy group and the receptor expression as MFI. Neutrophil receptors CD64 (2.5 0.5) and CD66b (44.5 34) were increased and CD15 decreased (21.6 28.3) when CD65 (6.6 4.4), CD162 (21.3 21.1) and CD11b (10.5 12) were in the same range. Monocytes receptors CD64 (30.5 16.6), CD11b (18.7 9.8), and CD162 (38.6 36.5) were increased and CD15 decreased (10.3 17.9); CD65 were in the same range (2.3 1.96).

Conclusion: Monocytes and neutrophils are activated during severe COVID-19 infection as shown by strong upregulation of CD64. High monocyte and neutrophil CD64 can be an indicator of a severe form of COVID19. The adhesion molecules (CD11b, CD162, CD65, and CD15) are not upregulated on otherwise activated neutrophils, which might lead to relative impairment of tissue migration. Low adhesion profile of neutrophils suggests immune dysfunction of neutrophils. Monocytes maintain upregulation of some adhesion molecules (CD11b, CD162) suggesting the persistence of an increased ability to migrate into tissues, even during a severe stage of COVID-19. Future research should focus on CD64 and CD11b kinetics in the context of prognosis.
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http://dx.doi.org/10.1177/20499361211034065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326822PMC
July 2021

Evolution of NETosis markers and DAMPs have prognostic value in critically ill COVID-19 patients.

Sci Rep 2021 08 3;11(1):15701. Epub 2021 Aug 3.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands.

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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http://dx.doi.org/10.1038/s41598-021-95209-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333321PMC
August 2021

A model-based source separation algorithm for lung perfusion imaging using electrical impedance tomography.

Physiol Meas 2021 08 27;42(8). Epub 2021 Aug 27.

Medical Information Technology, RWTH Aachen University, Pauwelsstr. 20, 52074 Aachen, Germany.

. Electrical impedance tomography (EIT) for lung perfusion imaging is attracting considerable interest in intensive care, as it might open up entirely new ways to adjust ventilation therapy. A promising technique is bolus injection of a conductive indicator to the central venous catheter, which yields the indicator-based signal (IBS). Lung perfusion images are then typically obtained from the IBS using the maximum slope technique. However, the low spatial resolution of EIT results in a partial volume effect (PVE), which requires further processing to avoid regional bias.. In this work, we repose the extraction of lung perfusion images from the IBS as a source separation problem to account for the PVE. We then propose a model-based algorithm, called gamma decomposition (GD), to derive an efficient solution. The GD algorithm uses a signal model to transform the IBS into a parameter space where the source signals of heart and lung are separable by clustering in space and time. Subsequently, it reconstructs lung model signals from which lung perfusion images are unambiguously extracted.. We evaluate the GD algorithm on EIT data of a prospective animal trial with eight pigs. The results show that it enables lung perfusion imaging using EIT at different stages of regional impairment. Furthermore, parameters of the source signals seem to represent physiological properties of the cardio-pulmonary system.. This work represents an important advance in IBS processing that will likely reduce bias of EIT perfusion images and thus eventually enable imaging of regional ventilation/perfusion (V/Q) ratio.
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http://dx.doi.org/10.1088/1361-6579/ac0e84DOI Listing
August 2021

[GFR estimation in children - age-adjusted creatinine makes the adult Lund-Malmö equation applicable in children and facilitates automatic GFR reporting from the clinical laboratory].

Lakartidningen 2021 06 21;118. Epub 2021 Jun 21.

professor, institutionen för laboratoriemedicin, Lunds universitet.

Age-adjustment of creatinine, i.e. recalculation of childhood levels of creatinine to corresponding levels at 18 years of age and applied in the adult revised Lund-Malmö GFR equation led to markedly improved accuracy in Swedish children (n=1 718) at measured GFR <75 mL/min/1.73 m2 (n=318) and preserved high accuracy at ≥75 mL/min/1.73 m2 (n=1 400). The adjusted LMR equation performed as well as dedicated paediatric equations based on height. The proposed adjustment strategy has four strengths: (i) the original coefficients of the adult GFR equation can be used, (ii) the same equation can be used across the entire lifespan without artificial changes in estimated GFR when switching from paediatric to adult care, (iii) the lack of height factor makes it easier to automatically report estimated GFR by the laboratories and (iv) age-adjusted creatinine values imply that well-established creatinine reference intervals for adults can also be used for children.
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June 2021

Increased levels of the cardiovascular disease risk biomarkers GDF15 and myostatin in patients with chronic lymphocytic leukemia.

Growth Factors 2020 Jun-Jul;38(3-4):189-196

Department of Medical Sciences, Division of Hematology, University Hospital, Uppsala, Sweden.

Individuals suffering from cancer, including hematological malignancies, are at increased risk of cardiovascular disease (CVD). Elevated levels of several biomarkers in blood are associated with an increased risk of CVD. The aim of this study was to investigate whether a subset of such CVD risk biomarkers was elevated in patients with untreated chronic lymphocytic leukemia (CLL). Blood plasma and serum from 139 CLL patients and 71 healthy age-matched controls were analyzed for 11 proposed CVD risk biomarkers. The CLL cohort displayed a more heterogeneous pattern of biomarker expression compared to controls. The majority, eight out of 11, analyzed CVD risk biomarkers differed significantly in concentrations between CLL patients and controls. Increased levels of the biomarkers GDF15 and myostatin have not previously been reported in CLL. Further prospective studies are warranted to investigate whether these biomarkers predict future cardiovascular events in patients with CLL.
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http://dx.doi.org/10.1080/08977194.2021.1932870DOI Listing
June 2021

Lung-protective ventilation increases cerebral metabolism and non-inflammatory brain injury in porcine experimental sepsis.

BMC Neurosci 2021 04 29;22(1):31. Epub 2021 Apr 29.

Centre for Clinical Research Sörmland, Uppsala University, Uppsala, Sweden.

Background: Protective ventilation with lower tidal volumes reduces systemic and organ-specific inflammation. In sepsis-induced encephalopathy or acute brain injury the use of protective ventilation has not been widely investigated (experimentally or clinically). We hypothesized that protective ventilation would attenuate cerebral inflammation in a porcine endotoxemic sepsis model. The aim of the study was to study the effect of tidal volume on cerebral inflammatory response, cerebral metabolism and brain injury. Nine animals received protective mechanical ventilation with a tidal volume of 6 mL × kg and nine animals were ventilated with a tidal volume of 10 mL × kg. During a 6-h experiment, the pigs received an endotoxin intravenous infusion of 0.25 µg × kg × h. Systemic, superior sagittal sinus and jugular vein blood samples were analysed for inflammatory cytokines and S100B. Intracranial pressure, brain tissue oxygenation and brain microdialysis were sampled every hour.

Results: No differences in systemic or sagittal sinus levels of TNF-α or IL-6 were seen between the groups. The low tidal volume group had increased cerebral blood flow (p < 0.001) and cerebral oxygen delivery (p < 0.001), lower cerebral vascular resistance (p < 0.05), higher cerebral metabolic rate (p < 0.05) along with higher cerebral glucose consumption (p < 0.05) and lactate production (p < 0.05). Moreover, low tidal volume ventilation increased the levels of glutamate (p < 0.01), glycerol (p < 0.05) and showed a trend towards higher lactate to pyruvate ratio (p = 0.08) in cerebral microdialysate as well as higher levels of S-100B (p < 0.05) in jugular venous plasma compared with medium-high tidal volume ventilation.

Conclusions: Contrary to the hypothesis, protective ventilation did not affect inflammatory cytokines. The low tidal volume group had increased cerebral blood flow, cerebral oxygen delivery and cerebral metabolism together with increased levels of markers of brain injury compared with medium-high tidal volume ventilation.
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http://dx.doi.org/10.1186/s12868-021-00629-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082058PMC
April 2021

Dietary Supplementation with Selenium and Coenzyme Q Prevents Increase in Plasma D-Dimer While Lowering Cardiovascular Mortality in an Elderly Swedish Population.

Nutrients 2021 Apr 17;13(4). Epub 2021 Apr 17.

Norwegian Institute of Public Health, N-0403 Oslo, Norway.

A low intake of selenium is associated with increased cardiovascular mortality. This could be reduced by supplementation with selenium and coenzyme Q. D-dimer, a fragment of fibrin mirroring fibrinolysis, is a biomarker of thromboembolism, increased inflammation, endothelial dysfunction and is associated with cardiovascular mortality in ischemic heart disease. The objective was to examine the impact of selenium and coenzyme Q on the level of D-dimer, and its relationship to cardiovascular mortality. D-dimer was measured in 213 individuals at the start and after 48 months of a randomised double-blind placebo-controlled trial with selenium yeast (200 µg/day) and coenzyme Q (200 mg/day) ( = 106) or placebo ( = 107). The follow-up time was 4.9 years. All included individuals were low in selenium (mean 67 μg/L, SD 16.8). The differences in D-dimer concentration were evaluated by the use of T-tests, repeated measures of variance and ANCOVA analyses. At the end, a significantly lower D-dimer concentration was observed in the active treatment group in comparison with those on placebo ( = 0.006). Although D-dimer values at baseline were weakly associated with high-sensitive CRP, while being more strongly associated with soluble tumour necrosis factor receptor 1 and sP-selectin, controlling for these in the analysis there was an independent effect on D-dimer. In participants with a D-dimer level above median at baseline, the supplementation resulted in significantly lower cardiovascular mortality compared to those on placebo ( = 0.014). All results were validated with a persisting significant difference between the two groups. Therefore, supplementation with selenium and coenzyme Q in a group of elderly low in selenium and coenzyme Q prevented an increase in D-dimer and reduced the risk of cardiovascular mortality in comparison with the placebo group. The obtained results also illustrate important associations between inflammation, endothelial function and cardiovascular risk.
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http://dx.doi.org/10.3390/nu13041344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073286PMC
April 2021

Physiological and inflammatory consequences of high and low respiratory rate in acute respiratory distress syndrome.

Acta Anaesthesiol Scand 2021 Sep 1;65(8):1013-1022. Epub 2021 May 1.

Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Using protective mechanical ventilation strategies with low tidal volume is usually accompanied by an increment of respiratory rate to maintain adequate alveolar ventilation. However, there is no robust data that support the safety of a high respiratory rate concerning ventilator-induced lung injury. Several experimental animal studies have explored the effects of respiratory rate over lung physiology, using a wide range of frequencies and different models. Clinical evidence is scarce and restricted to the physiological impact of increased respiratory rate. Undoubtedly, the respiratory rate can influence respiratory mechanics in various ways as a factor of multiplication of the power of ventilation, and gas exchange, and also on alveolar dynamics. In this narrative review, we present our point of view over the main experimental and clinical evidence available regarding the effect of respiratory rate on ventilator-induced lung injury development.
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http://dx.doi.org/10.1111/aas.13830DOI Listing
September 2021

Albumin Urinary Excretion Is Associated with Increased Levels of Urinary Chemokines, Cytokines, and Growth Factors Levels in Humans.

Biomolecules 2021 03 8;11(3). Epub 2021 Mar 8.

Department of Medical Sciences, Uppsala University, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.
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http://dx.doi.org/10.3390/biom11030396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000571PMC
March 2021

Addition of cystatin C predicts cardiovascular death better than creatinine in intensive care.

Heart 2021 Apr 1. Epub 2021 Apr 1.

Department of Medical Sciences/Clinical Chemistry, Uppsala University, Uppsala, Sweden.

Objective: Decreased kidney function increases cardiovascular risk and predicts poor survival. Estimated glomerular filtration rate (eGFR) by creatinine may theoretically be less accurate in the critically ill. This observational study compares long-term cardiovascular mortality risk by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; Caucasian, Asian, paediatric and adult cohort (CAPA) cystatin C equation and the CKD-EPI combined creatinine/cystatin C equation.

Methods: The nationwide study includes 22 488 intensive care patients in Uppsala, Karolinska and Lund University Hospitals, Sweden, between 2004 and 2015. Creatinine and cystatin C were analysed with accredited methods at admission. Reclassification and model discrimination with C-statistics was used to compare creatinine and cystatin C for cardiovascular mortality prediction.

Results: During 5 years of follow-up, 2960 (13 %) of the patients died of cardiovascular causes. Reduced eGFR was significantly associated with cardiovascular death by all eGFR equations in Cox regression models. In each creatinine-based GFR category, 17%, 19% and 31% reclassified to a lower GFR category by cystatin C. These patients had significantly higher cardiovascular mortality risk, adjusted HR (95% CI), 1.55 (1.38 to 1.74), 1.76 (1.53 to 2.03) and 1.44 (1.11 to 1.86), respectively, compared with patients not reclassified. Harrell's C-statistic for cardiovascular death for cystatin C, alone or combined with creatinine, was 0.73, significantly higher than for creatinine (0.71), p<0.001.

Conclusions: A single cystatin C at admission to the intensive care unit added significant predictive value to creatinine for long-term cardiovascular death risk assessment. Cystatin C, alone or in combination with creatinine, should be used for estimating GFR for long-term risk prediction in critically ill.
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http://dx.doi.org/10.1136/heartjnl-2020-318860DOI Listing
April 2021

Cystatin C predicts long term mortality better than creatinine in a nationwide study of intensive care patients.

Sci Rep 2021 Mar 15;11(1):5882. Epub 2021 Mar 15.

Department of Medical Sciences/Clinical Chemistry, Uppsala University, 751 85, Uppsala, Sweden.

Decreased glomerular filtration rate (GFR) is linked to poor survival. The predictive value of creatinine estimated GFR (eGFR) and cystatin C eGFR in critically ill patients may differ substantially, but has been less studied. This study compares long-term mortality risk prediction by eGFR using a creatinine equation (CKD-EPI), a cystatin C equation (CAPA) and a combined creatinine/cystatin C equation (CKD-EPI), in 22,488 patients treated in intensive care at three University Hospitals in Sweden, between 2004 and 2015. Patients were analysed for both creatinine and cystatin C on the same blood sample tube at admission, using accredited laboratory methods. During follow-up (median 5.1 years) 8401 (37%) patients died. Reduced eGFR was significantly associated with death by all eGFR-equations in Cox regression models. However, patients reclassified to a lower GFR-category by using the cystatin C-based equation, as compared to the creatinine-based equation, had significantly higher mortality risk compared to the referent patients not reclassified. The cystatin C equation increased C-statistics for death prediction (p < 0.001 vs. creatinine, p = 0.013 vs. combined equation). In conclusion, this data favours the sole cystatin C equation rather than the creatinine or combined equations when estimating GFR for risk prediction purposes in critically ill patients.
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http://dx.doi.org/10.1038/s41598-021-85370-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961058PMC
March 2021

Inspiratory Efforts, Positive End-Expiratory Pressure, and External Resistances Influence Intraparenchymal Gas Redistribution in Mechanically Ventilated Injured Lungs.

Front Physiol 2020 9;11:618640. Epub 2021 Feb 9.

Hedenstierna Laboratory, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background: Potentially harmful lung overstretch can follow intraparenchymal gas redistribution during mechanical ventilation. We hypothesized that inspiratory efforts characterizing spontaneous breathing, positive end-expiratory pressure (PEEP), and high inspiratory resistances influence inspiratory intraparenchymal gas redistribution.

Methods: This was an experimental study conducted on a swine model of mild acute respiratory distress syndrome. Dynamic computed tomography and respiratory mechanics were simultaneously acquired at different PEEP levels and external resistances, during both spontaneous breathing and controlled mechanical ventilation. Images were collected at two cranial-caudal levels. Delta-volume images (ΔVOLs) were obtained subtracting pairs of consecutive inspiratory images. The first three ΔVOLs, acquired for each analyzed breath, were used for the analysis of inspiratory pendelluft defined as intraparenchymal gas redistribution before the start of inspiratory flow at the airway opening. The following ΔVOLs were used for the analysis of gas redistribution during ongoing inspiratory flow at the airway opening.

Results: During the first flow-independent phase of inspiration, the pendelluft of gas was observed only during spontaneous breathing and along the cranial-to-caudal and nondependent-to-dependent directions. The pendelluft was reduced by high PEEP ( < 0.04 comparing PEEP 15 and PEEP 0 cm HO) and low external resistances ( < 0.04 comparing high and low external resistance). During the flow-dependent phase of inspiration, two patterns were identified: (1) characterized by large gas redistribution areas; (2) characterized by small, numerous areas of gas redistribution. was observed at low PEEP, high external resistances, and it characterized controlled mechanical ventilation ( < 0.01, comparing high and low PEEP during controlled mechanical ventilation).

Conclusions: Low PEEP and high external resistances favored inspiratory pendelluft. During the flow-dependent phase of the inspiration, controlled mechanical ventilation and low PEEP and high external resistances favored larger phenomena of intraparenchymal gas redistribution (gas displacing) endangering lung stability.
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http://dx.doi.org/10.3389/fphys.2020.618640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900494PMC
February 2021

Imaging atelectrauma in Ventilator-Induced Lung Injury using 4D X-ray microscopy.

Sci Rep 2021 Feb 19;11(1):4236. Epub 2021 Feb 19.

Synchrotron Radiation for Biomedicine Laboratory (STROBE, INSERM UA7), Grenoble, France.

Mechanical ventilation can damage the lungs, a condition called Ventilator-Induced Lung Injury (VILI). However, the mechanisms leading to VILI at the microscopic scale remain poorly understood. Here we investigated the within-tidal dynamics of cyclic recruitment/derecruitment (R/D) using synchrotron radiation phase-contrast imaging (PCI), and the relation between R/D and cell infiltration, in a model of Acute Respiratory Distress Syndrome in 6 anaesthetized and mechanically ventilated New-Zealand White rabbits. Dynamic PCI was performed at 22.6 µm voxel size, under protective mechanical ventilation [tidal volume: 6 ml/kg; positive end-expiratory pressure (PEEP): 5 cmHO]. Videos and quantitative maps of within-tidal R/D showed that injury propagated outwards from non-aerated regions towards adjacent regions where cyclic R/D was present. R/D of peripheral airspaces was both pressure and time-dependent, occurring throughout the respiratory cycle with significant scatter of opening/closing pressures. There was a significant association between R/D and regional lung cellular infiltration (p = 0.04) suggesting that tidal R/D of the lung parenchyma may contribute to regional lung inflammation or capillary-alveolar barrier dysfunction and to the progression of lung injury. PEEP may not fully mitigate this phenomenon even at high levels. Ventilation strategies utilizing the time-dependence of R/D may be helpful in reducing R/D and associated injury.
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http://dx.doi.org/10.1038/s41598-020-77300-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895928PMC
February 2021

Bedside monitoring of lung volume available for gas exchange.

Intensive Care Med Exp 2021 Jan 11;9(1). Epub 2021 Jan 11.

Nuffield Division of Anaesthetics, University of Oxford, Oxford, UK.

Background: Bedside measurement of lung volume may provide guidance in the personalised setting of respiratory support, especially in patients with the acute respiratory distress syndrome at risk of ventilator-induced lung injury. We propose here a novel operator-independent technique, enabled by a fibre optic oxygen sensor, to quantify the lung volume available for gas exchange. We hypothesised that the continuous measurement of arterial partial pressure of oxygen (PaO) decline during a breath-holding manoeuvre could be used to estimate lung volume in a single-compartment physiological model of the respiratory system.

Methods: Thirteen pigs with a saline lavage lung injury model and six control pigs were studied under general anaesthesia during mechanical ventilation. Lung volumes were measured by simultaneous PaO rate of decline (V) and whole-lung computed tomography scan (V) during apnoea at different positive end-expiratory and end-inspiratory pressures.

Results: A total of 146 volume measurements was completed (range 134 to 1869 mL). A linear correlation between V and V was found both in control (slope = 0.9, R = 0.88) and in saline-lavaged pigs (slope = 0.64, R = 0.70). The bias from Bland-Altman analysis for the agreement between the V and V was - 84 mL (limits of agreement ± 301 mL) in control and + 2 mL (LoA ± 406 mL) in saline-lavaged pigs. The concordance for changes in lung volume, quantified with polar plot analysis, was - 4º (LoA ± 19°) in control and - 9° (LoA ± 33°) in saline-lavaged pigs.

Conclusion: Bedside measurement of PaO rate of decline during apnoea is a potential approach for estimation of lung volume changes associated with different levels of airway pressure.
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http://dx.doi.org/10.1186/s40635-020-00364-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835652PMC
January 2021

Severe acute kidney injury associated with progression of chronic kidney disease after critical COVID-19.

Crit Care 2021 01 25;25(1):37. Epub 2021 Jan 25.

Anesthesia and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University Hospital, Uppsala University, Entrance 78, etg 4, 75185, Uppsala, Sweden.

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http://dx.doi.org/10.1186/s13054-021-03461-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829656PMC
January 2021

Bronchially instilled IgY-antibodies did not decrease pulmonary p. aeruginosa concentration in experimental porcine pneumonia.

Acta Anaesthesiol Scand 2021 05 10;65(5):656-663. Epub 2021 Feb 10.

Hedenstierna laboratory, CIRRUS, Anesthesiology and Intensive Care, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Background: P. aeruginosa possesses antibiotic resistance, making treatment difficult. Polyclonal anti-P. aeruginosa IgY-antibodies (Pa-IgY) have antibacterial effects, but have not been studied in large animal pneumonia.

Objectives: To test if Pa-IgY decreases the concentration of P. aeruginosa in bronchoalveolar lavage in experimental porcine pneumonia over 27 hours.

Method: Norwegian landrace pigs were anesthetized, mechanically ventilated, and subject to invasive monitoring. The animals were randomized to receive either P. aeruginosa (control, n = 12) or P aeruginosa + Pa-IgY antibodies with a repeated dose of Pa-IgY after 12 hours (intervention, n = 12) in the right lower pulmonary lobe. Bronchoalveolar lavage (BAL) cultures and physiological measurements were obtained repeatedly for 27 hours after which the pigs were sacrificed.

Results: BAL bacterial concentration increased in both groups and peaked at 10  ± 10  CFU/mL in the intervention group vs 10 .  ± 10  CFU/mL in the control group (n.s.). BAL bacterial concentration decreased during the experiment to 10  ± 10 .  CFU/mL in the intervention group vs 10  ± 10 in the control group (n.s.). The intervention group had lower heart rate (P < .001), lower cardiac index (P < .01), and lower arterial lactate (P < .001) compared to the control group. The core temperature was lower in the intervention group than in the control group (P < .001).

Conclusion: The chosen dose of Pa-IgY did not decrease concentrations of P. aeruginosa in BAL over 27 hours. We conclude that it is unlikely that there is a large effect of this specific dose and route of administration of Pa-IgY in this type of model.
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http://dx.doi.org/10.1111/aas.13784DOI Listing
May 2021

Impact of synthetic surfactant CHF5633 with SP-B and SP-C analogues on lung function and inflammation in rabbit model of acute respiratory distress syndrome.

Physiol Rep 2021 01;9(1):e14700

Division for Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.

Acute respiratory distress syndrome (ARDS) is associated with diffuse inflammation, alveolar epithelial damage, and leakage of plasma proteins into the alveolar space, which together contribute to inactivation of pulmonary surfactant and respiratory failure. Exogenous surfactant delivery is therefore considered to hold potential for ARDS treatment, but clinical trials with natural derived surfactant or synthetic surfactant containing a surfactant protein C (SP-C) analogue have been negative. Synthetic surfactant CHF5633, containing analogues of SP-B and SP-C, may be effective against ARDS. The aim here was to compare treatment effects of CHF5633 and animal-derived surfactant poractant alfa in animal model of ARDS. ARDS was induced in adult New Zealand rabbits by mild lung lavages followed by injurious ventilation until respiratory failure (P/F ratio <26.7 kPa). The animals were then treated with intratracheal bolus of 200 mg/kg CHF5633 or poractant alfa (Curosurf ), or air as control. The animals were subsequently ventilated for an additional 4 hr and respiratory parameters were recorded regularly. Postmortem, histological analysis, degree of lung edema, and levels of the cytokines TNFα, IL-6, and IL-8 in lung homogenates were evaluated. Both surfactant preparations improved lung function, reduced the levels of pro-inflammatory cytokines, and degree of lung edema to very similar degrees versus the controls. No significant differences in any of the analyzed parameters were observed between the CHF5633- and poractant alfa-treated groups. This study indicates that single dose of CHF5633 improves lung function and attenuates inflammation as effectively as poractant alfa in experimental ARDS caused by injurious ventilation.
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http://dx.doi.org/10.14814/phy2.14700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786196PMC
January 2021

Increased levels of plasma cytokines and correlations to organ failure and 30-day mortality in critically ill Covid-19 patients.

Cytokine 2021 02 14;138:155389. Epub 2020 Dec 14.

Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden; Department of Medical Cell Biology, Integrative Physiology, Uppsala University, Uppsala, Sweden.

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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http://dx.doi.org/10.1016/j.cyto.2020.155389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833204PMC
February 2021
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