Intubation Decision Based on Illness Severity and Mortality in COVID-19: An International Study.

OBJECTIVES: To evaluate the impact of intubation timing, guided by severity criteria, on mortality in critically ill COVID-19 patients, amidst existing uncertainties regarding optimal intubation practices. DESIGN: Prospective, multicenter, observational study conducted from February 1, 2020, to November 1, 2022. SETTING: Ten academic institutions in the United States and Europe. PATIENTS: Adults (≥ 18 yr old) confirmed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hospitalized specifically for COVID-19, requiring intubation postadmission. Exclusion criteria included patients hospitalized for non-COVID-19 reasons despite a positive SARS-CoV-2 test. INTERVENTIONS: Early invasive mechanical ventilation (EIMV) was defined as intubation in patients with less severe organ dysfunction (Sequential Organ Failure Assessment [SOFA] < 7 or Pa o2 /F io2 ratio > 250), whereas late invasive mechanical ventilation (LIMV) was defined as intubation in patients with SOFA greater than or equal to 7 and Pa o2 /F io2 ratio less than or equal to 250. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mortality within 30 days of hospital admission. Among 4464 patients, 854 (19.1%) required mechanical ventilation (mean age 60 yr, 61.7% male, 19.3% Black). Of those, 621 (72.7%) were categorized in the EIMV group and 233 (27.3%) in the LIMV group. Death within 30 days after admission occurred in 278 patients (42.2%) in the EIMV and 88 patients (46.6%) in the LIMV group ( p = 0.28). An inverse probability-of-treatment weighting analysis revealed a statistically significant association with mortality, with patients in the EIMV group being 32% less likely to die either within 30 days of admission (adjusted hazard ratio [HR] 0.68; 95% CI, 0.52-0.90; p = 0.008) or within 30 days after intubation irrespective of its timing from admission (adjusted HR 0.70; 95% CI, 0.51-0.90; p = 0.006). CONCLUSIONS: In severe COVID-19 cases, an early intubation strategy, guided by specific severity criteria, is associated with a reduced risk of death. These findings underscore the importance of timely intervention based on objective severity assessments.

SuPAR, biomarkers of inflammation, and severe outcomes in patients hospitalized for COVID-19: The International Study of Inflammation in COVID-19.

Severe coronavirus disease 2019 (COVID-19) is a hyperinflammatory syndrome. The biomarkers of inflammation best suited to triage patients with COVID-19 are unknown. We conducted a prospective multicenter observational study of adult patients hospitalized specifically for COVID-19 from February 1, 2020 to October 19, 2022. Biomarkers measured included soluble urokinase plasminogen activator receptor (suPAR), C-reactive protein, interleukin-6, procalcitonin, ferritin, and D-dimer. In-hospital outcomes examined include death and the need for mechanical ventilation. Patients admitted in the United States (US, n = 1962) were used to compute area under the curves (AUCs) and identify biomarker cutoffs. The combined European cohorts (n = 1137) were used to validate the biomarker cutoffs. In the US cohort, 356 patients met the composite outcome of death (n = 197) or need for mechanical ventilation (n = 290). SuPAR was the most important predictor of the composite outcome and had the highest AUC (0.712) followed by CRP (0.642), ferritin (0.619), IL-6 (0.614), D-dimer (0.606), and lastly procalcitonin (0.596). Inclusion of other biomarkers did not improve discrimination. A suPAR cutoff of 4.0 ng/mL demonstrated a sensitivity of 95.4% (95% CI: 92.4%-98.0%) and negative predictive value (NPV) of 92.5% (95% CI: 87.5%-96.9%) for the composite outcome. Patients with suPAR < 4.0 ng/mL comprised 10.6% of the cohort and had a 0.8% probability of the composite outcome. Applying this cutoff to the validation cohort yielded a sensitivity of 93.8% (90.4%-96.7%) and NPV of 95.5% (93.1%-97.8%) for the composite outcome. Among commonly measured biomarkers, suPAR offered stronger discriminatory ability and may be useful in triaging low-risk patients with COVID-19.

Social isolation, loneliness, and inflammation: A multi-cohort investigation in early and mid-adulthood.

Social isolation and loneliness have been associated with poor health and increased risk for mortality, and inflammation might explain this link. We used data from the Danish TRIAGE Study of acutely admitted medical patients (N = 6,144, mean age 60 years), and from two population-representative birth cohorts: the New Zealand Dunedin Longitudinal Study (N = 881, age 45) and the UK Environmental Risk (E-Risk) Longitudinal Twin Study (N = 1448, age 18), to investigate associations of social isolation with three markers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer inflammation marker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to index systemic chronic inflammation. In the TRIAGE Study, socially isolated patients (those living alone) had significantly higher median levels of suPAR (but not CRP or IL-6) compared with patients not living by themselves. Social isolation prospectively measured in childhood was longitudinally associated with higher CRP, IL-6, and suPAR levels in adulthood (at age 45 in the Dunedin Study and age 18 in the E-Risk Study), but only suPAR remained associated after controlling for covariates. Dunedin Study participants who reported loneliness at age 38 or age 45 had elevated suPAR at age 45. In contrast, E-Risk Study participants reporting loneliness at age 18 did not show any elevated markers of inflammation. In conclusion, social isolation was robustly associated with increased inflammation in adulthood, both in medical patients and in the general population. It was associated in particular with systemic chronic inflammation, evident from the consistently stronger associations with suPAR than other inflammation biomarkers.

qSOFA combined with suPAR for early risk detection and guidance of antibiotic treatment in the emergency department: a randomized controlled trial.

BACKGROUND: Sepsis guidelines suggest immediate start of resuscitation for patients with quick Sequential Organ Failure Assessment (qSOFA) 2 or 3. However, the interpretation of qSOFA 1 remains controversial. We investigated whether measurements of soluble urokinase plasminogen activator receptor (suPAR) may improve risk detection when qSOFA is 1. METHODS: The study had two parts. At the first part, the combination of suPAR with qSOFA was analyzed in a prospective cohort for early risk detection. At the second part, the double-blind, randomized controlled trial (RCT) SUPERIOR evaluated the efficacy of the suPAR-guided medical intervention. SUPERIOR took place between November 2018 and December 2020. Multivariate stepwise Cox regression was used for the prospective cohort, while univariate and multivariate logistic regression was used for the RCT. Consecutive admissions at the emergency department (ED) with suspected infection, qSOFA 1 and suPAR ≥ 12 ng/mL were allocated to single infusion of placebo or meropenem. The primary endpoint was early deterioration, defined as at least one-point increase of admission Sequential Organ Failure Assessment (SOFA) score the first 24 h. RESULTS: Most of the mortality risk was for patients with qSOFA 2 and 3. Taking the hazard ratio (HR) for death of patients with qSOFA = 1 and suPAR < 12 ng/mL as reference, the HR of qSOFA = 1 and suPAR ≥ 12 ng/mL for 28-day mortality was 2.98 (95% CI 2.11-3.96). The prospective RCT was prematurely ended due to pandemia-related ED re-allocations, with 91 patients enrolled: 47 in the placebo and 44 in the meropenem arm. The primary endpoint was met in 40.4% (n = 19) and 15.9% (n = 7), respectively (difference 24.5% [5.9-40.8]; odds ratio 0.14 [0.04-0.50]). One post hoc analysis showed significant median changes of SOFA score after 72 and 96 h equal to 0 and - 1, respectively. CONCLUSIONS: Combining qSOFA 1 with the biomarker suPAR improves its prognostic performance for unfavorable outcome and can help decision for earlier treatment. Trial registration EU Clinical Trials Register (EudraCT, 2018-001008-13) and Clinical-Trials.gov (NCT03717350). Registered 24 October 2018.

Overall and inter-individual effect of four different drug classes on soluble urokinase plasminogen activator receptor in type 1 and type 2 diabetes.

AIM: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. METHODS: We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed. RESULTS: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001). CONCLUSIONS: We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels.

Circulating suPAR associates with severity and in-hospital progression of COVID-19.

BACKGROUND: COVID-19 disease progression is characterized by hyperinflammation and risk stratification may aid in early aggressive treatment and advanced planning. The aim of this study was to assess whether suPAR and other markers measured at hospital admission can predict the severity of COVID-19. METHODS: The primary outcome measure in this international, multi-centre, prospective, observational study with adult patients hospitalized primarily for COVID-19 was the association of WHO Clinical Progression Scale (WHO-CPS) with suPAR, ferritin, CRP, albumin, LDH, eGFR, age, procalcitonin, and interleukin-6. Admission plasma suPAR levels were determined using the suPARnostic® ELISA and suPARnostic® Turbilatex assays. RESULTS: Seven hundred and sixty-seven patients, 440 (57.4%) males and 327 (42.6%) females, were included with a median age of 64 years. Log-suPAR levels significantly correlated with WHO-CPS score, with each doubling of suPAR increasing the score by one point (p < .001). All the other markers were also correlated with WHO-CPS score. Admission suPAR levels were significantly lower in survivors (7.10 vs. 9.63, 95% CI 1.47-3.59, p < .001). A linear model (SALGA) including suPAR, serum albumin, serum lactate dehydrogenase, eGFR, and age can best estimate the WHO-CPS score and survival. Combining all five parameters in the SALGA model can improve the accuracy of discrimination with an AUC of 0.80 (95% CI: 0.759-0.836). CONCLUSIONS: suPAR levels significantly correlated with WHO-CPS score, with each doubling of suPAR increasing the score by one point. The SALGA model may serve as a quick tool for predicting disease severity and survival at admission.

Using soluble urokinase plasminogen activator receptor to stratify patients for medication review in the emergency department.

AIMS: To investigate whether the association between levels of medication use (including polypharmacy and potentially inappropriate medications [PIMs]) and health outcomes such as readmission and mortality is dependent on baseline soluble urokinase plasminogen activator receptor (suPAR). METHODS: This registry-based cohort study included medical patients admitted to the emergency department at Copenhagen University Hospital Hvidovre, Denmark. Patients were grouped according to their admission suPAR levels: low (0-3 ng/mL), intermediate (3-6 ng/mL), or high (>6 ng/mL). Hyper-polypharmacy was defined as ≥10 prescribed medications. PIMs were identified based on the EU(7)-PIM list, and data on admissions and mortality were obtained from national registries. Risk of 90-day readmission and mortality was assessed by Cox regression analysis adjusted for sex, age and Charlson comorbidity index. Results were reported as hazard ratios within 90 days of index discharge. RESULTS: In total, 26 291 patients (median age 57.3 y; 52.7% female) were included. Risk of 90-day readmission and mortality increased significantly for patients with higher suPAR or higher number of medications. Among patients with low suPAR, patients with ≥10 prescribed medications had a hazard ratio of 2.41 (95% confidence interval = 2.09-2.78) for 90-day readmission and 8.46 (95% confidence interval = 2.53-28.28) for 90-day mortality compared to patients with 0 medications. Patients with high suPAR generally had high risk of readmission and mortality, and the impact of medication use was less pronounced in this group. Similar, but weaker, association patterns were observed between suPAR and PIMs. CONCLUSION: The association between levels of medication use and health outcomes is dependent on baseline suPAR.

Soluble urokinase plasminogen activator receptor and functionally relevant coronary artery disease: a prospective cohort study.

BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker associated with anatomical CAD burden and cardiovascular outcomes including myocardial infarction (MI) and death. We aimed to validate previous findings of the prognostic value of suPAR and to evaluate its diagnostic potential for functional relevant CAD (fCAD). METHODS: Consecutive patients with suspected fCAD were enrolled. Adjudication of fCAD was performed blinded to suPAR concentrations by myocardial perfusion single-photon emission tomography (MPI-SPECT) and coronary angiography. Prognostic outcome measures included all-cause death, cardiovascular death, and incident MI during 2-year follow-up. RESULTS: Among consecutive 968 patients, suPAR concentrations were higher in patients with fCAD compared to those without (3.45 vs. 3.20 ng/mL, p = 0.007), but did not provide acceptable diagnostic accuracy (area under the curve [AUC]: 0.56, 95%CI 0.52-0.60). SuPAR correlated with high-sensitivity cardiac-troponin T (Spearman's rho (ρ) 0.393, p < 0.001), NT-proBNP (ρ = 0.327, p < 0.001), age (ρ = 0.364, p < 0.001) and very weakly with coronary atherosclerosis (ρ = 0.123, p < 0.001). Prognostic discrimination of suPAR was moderate for cardiovascular death (AUC = 0.72, 95%CI 0.62-0.81) and all-cause death (AUC = 0.72, 95%CI 0.65-0.79) at 2-years. SuPAR remained a significant predictor for all-cause death in multivariable Cox regression (HR = 1.96, p = 0.001). CONCLUSIONS: SuPAR was an independent predictor of all-cause death, without diagnostic utility for fCAD. CLINICAL TRIAL REGISTRATION: NCT01838148.

Soluble Urokinase Receptor Levels Are Not Affected by the Systemic Inflammatory Response to Anesthesia and Operative Trauma.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is an emerging biomarker of the level of chronic systemic inflammation and the general condition of the patient. We aimed to investigate the impact of general anesthesia and major surgery on perioperative suPAR and C-reactive protein (CRP) levels. METHODS: This study included patients undergoing elective major noncardiac surgery with an expected duration of ≥2 h under general anesthesia. Inclusion criteria were age ≥18 years and American Society of Anesthesiologists' physical status I-IV. Blood was drawn 30 min prior to induction of anesthesia (preoperatively), as well as 30 min after emergence from anesthesia (postoperatively). Plasma suPAR levels were determined using the suPARnostic® Quick Triage lateral flow assay. CRP measurements were performed by particle-enhanced immunoturbidimetric assay. RESULTS: The difference in preoperative and postoperative suPAR levels was not statistically significant (7.7 [5.28-10.4] ng/mL vs. 7.15 [5.68-9.8] ng/mL, p = 0.462). CRP levels increased significantly during surgery (0.81 [0.24-2.1] mg/dL vs. 5.76 [2.2-8.75] mg/dL, p < 0.001). No correlation was observed between CRP and suPAR levels, both preoperatively (rho = 0.127; p = 0.208) and postoperatively (rho = 0.017; p = 0.87). A statistically significant increase was also observed in postoperative white blood cell count (7.576 vs. 10.711, p < 0.001). CONCLUSION: General anesthesia and operative trauma did not affect perioperative suPAR levels despite the activation of systemic inflammatory response.

Evaluation of commercially available immuno-magnetic agglutination in comparison to enzyme-linked immunosorbent assays for rapid point-of-care diagnostics of COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Fast, accurate, and simple blood-based assays for quantification of anti-SARS-CoV-2 antibodies are urgently needed to identify infected individuals and keep track of the spread of disease. METHODS: The study included 33 plasma samples from 20 individuals with confirmed COVID-19 by real-time reverse-transcriptase polymerase chain reaction and 40 non-COVID-19 plasma samples. Anti-SARS-CoV-2 immunoglobulin M (IgM)/immunoglobulin A (IgA) or immunoglobulin G (IgG) antibodies were detected by a microfluidic quantitative immunomagnetic assay (IMA) (ViroTrack Sero COVID IgM + IgA/IgG Ab, Blusense Diagnostics) and compared to an enzyme-linked immunosorbent assay (ELISA) (EuroImmun Medizinische Labordiagnostika). RESULTS: Of the 33 plasma samples from the COVID-19 patients, 28 were positive for IgA/IgM or IgG by IMA and 29 samples were positive by ELISA. Sensitivity for only one sample per patient was 68% for IgA + IgM and 75% IgG by IMA and 80% by ELISA. For samples collected 14 days after symptom onset, the sensitivity of both IMA and ELISA was around 91%. The specificity of the IMA reached 100% compared to 95% for ELISA IgA and 97.5% for ELISA IgG. CONCLUSION: IMA for COVID-19 is a rapid simple-to-use point-of-care test with sensitivity and specificity similar to a commercial ELISA.

Linking stressful life events and chronic inflammation using suPAR (soluble urokinase plasminogen activator receptor).

Stressful life events have been linked to declining health, and inflammation has been proposed as a physiological mechanism that might explain this association. Using 828 participants from the Dunedin Longitudinal Study, we tested whether people who experienced more stressful life events during adulthood would show elevated systemic inflammation when followed up in midlife, at age 45. We studied three inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer biomarker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to index systemic chronic inflammation. Stressful life events were not associated with CRP or IL-6. However, people who experienced more stressful life events from age 38 to 44 had elevated suPAR at age 45, and had significantly greater increases in suPAR from baseline to follow-up across the same period. When examining stressful life events across the lifespan, both adverse childhood experiences (ACEs) and adult stressful life events were independently associated with suPAR at age 45. ACEs moderated the association of adult stressful life events and suPAR at age 45-children with more ACEs showed higher suPAR levels after experiencing stressful life events as adults. The results suggest systemic chronic inflammation is one physiological mechanism that could link stressful life events and health, and support the use of suPAR as a useful biomarker for such research.

Sex- and age-related differences in the predictive capability of circulating biomarkers: from the MONICA 10 cohort.

OBJECTIVES: The purpose of this study was to assess whether high-sensitivity C-reactive protein (hs-CRP), N-terminal pro-brain natriuretic peptide (NT-proBNP), and soluble urokinase plasminogen activator receptor (suPAR) differed in their ability to predict cardiovascular outcomes beyond traditional risk factors in younger and older men and women without known cardiovascular disease. Design. Prospective population-based cohort study of 1951 individuals from the MONItoring of trends and determinants in Cardiovascular disease (MONICA) study, examined 1993-1994. Participants were stratified into four groups based on sex and age. Subjects aged 41 or 51 years were classified as younger; those aged 61 or 71 years were classified as older. The principal endpoint was death from cardiovascular causes. Predictive capabilities of biomarkers were tested using Cox proportional-hazards regression, Harrell's concordance-index, net reclassification improvement, and classification and regression tree (CART) analysis. Results. Median follow-up was 18.5 years, during which 19/597 younger men, 100/380 older men, 12/607 younger women, and 46/367 older women had died from a cardiovascular cause. NT-proBNP was independently associated with death from cardiovascular causes among all participants (p ≤ .02) except younger women (p = .70), whereas hs-CRP was associated with this endpoint in men (p ≤ .007), and suPAR in older men only (p < .001). None of the biomarkers improved discrimination ability beyond traditional risk factors (p ≥ .07). However, NT-proBNP enhanced reclassification in men and older women. CART-analysis showed that NT-proBNP was generally of greater value among men, and suPAR among women. Conclusions. Hs-CRP, NT-proBNP, and suPAR displayed different associations with cardiovascular death among apparently healthy younger and older men and women.

Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI.

BACKGROUND: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown. METHODS: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI. RESULTS: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups. CONCLUSIONS: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.

Soluble Urokinase Plasminogen Activator Receptor as a Decision Marker for Early Discharge of Patients with COVID-19 Symptoms in the Emergency Department.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (The Covid-19 pandemic) strains health care capacity. Better risk stratification, with discharge of patients with a predicted mild disease trajectory, can ease this burden. Elevated blood-soluble urokinase plasminogen activator receptor (suPAR) has previously been shown to be associated with risk of intubation in confirmed COVID-19 patients. OBJECTIVE: To evaluate whether point-of-care measures of suPAR in patients presenting to the emergency department (ED) with symptoms of COVID-19 can identify patients that can be safely discharged. METHODS: Observational cohort study including all patients in the ED with symptoms of COVID-19 from March 19 to April 3, 2020. SuPAR was measured at first presentation. Review of electronic patient records 14 days after admission was used to assess disease trajectory. Primary endpoints were mild, moderate, severe, or very severe trajectory. The predictive value of suPAR, National Early Warning Score (NEWS), C-reactive protein (CRP), and duration of symptoms was calculated using receiver operating characteristics (ROC). RESULTS: Of 386 patients, 171 (44%) had a mild disease trajectory, 79 (20%) a moderate, 63 (16%) a severe, and 73 (19%) a very severe disease trajectory. Low suPAR was a strong marker of mild disease trajectory. Results suggest a cut-off for discharge for suPAR < 2.0 ng/mL if suPAR is used as a single parameter, and <3.0 ng/mL when combined with NEWS ≤ 4 and CRP < 10 mg/L. CONCLUSION: suPAR is a potential biomarker for triage and safe early discharge of patients with COVID-19 symptoms in the ED. suPAR can be used even before SARS-CoV-2 status is known.

SuPAR is associated with death and adverse cardiovascular outcomes in patients with suspected coronary artery disease.

BACKGROUND: The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with presence and severity of coronary artery disease (CAD) and incident death and myocardial infarction (MI). We sought to validate this finding in a further cohort of patients with suspected CAD. METHODS: Plasma suPAR was available in 1635 patients (73% with CAD) undergoing coronary angiography at a single regional Danish hospital between 2003 and 2005. Patients were followed for adverse cardiovascular outcomes of death, cardiac death and MI over a median follow-up of 4.2 years. RESULTS: In multivariate Cox models, adjusted for established cardiovascular risk factors, the biomarkers C-reactive protein, troponin-T and N-terminal-pro brain natriuretic peptide and the number of stenotic vessels, suPAR was independently associated with the combined endpoint of death/MI, hazard ratio (HR) 1.88; cardiovascular death, HR 2.01; and non-fatal MI, HR 1.53; (all p ≤ .037) per doubling of suPAR concentration. A plasma cutoff for suPAR ≥ 3.5 ng/mL was also significantly associated with death/MI, HR 1.51; p = .005. The C-statistic for the multivariate model predicting death/MI improved from 0.712 to 0.730 (p for difference .008) after inclusion of suPAR. However, suPAR was not associated with presence or extent of CAD (p > .05). CONCLUSION: These results validate previous findings that demonstrate suPAR to be an independent predictor of death/MI in patients with suspected or known CAD, however suPAR was not associated with presence or extent of CAD in our cohort. Probably because suPAR reflects end organ damage rather than the degree of atherosclerosis. BRIEF SUMMARY: We demonstrate that the inflammatory biomarker soluble urokinase plasminogen activator receptor is an independent predictor of death/myocardial infarction in patients with suspected or known coronary artery disease, but is not associated with the presence or severity of coronary artery disease.

Validation of suPAR turbidimetric assay on Cobas® (c502 and c702) and comparison to suPAR ELISA.

suPAR is a plasma marker of chronic inflammation, and an elevated suPAR is consistently associated with worse outcome in a variety of clinical conditions. Quantification of suPAR is useful for determining patient risk in triage, but there is no fast automatized method for quick determination of suPAR. We developed and validated a rapid latex particle-enhanced turbidimetric immunoassay for quantification of plasma suPAR on the c502 and the c702 Roche Cobas® 8000 measurment systems. The turbidimetric assay was validated against the suPARnostic® ELISA (ViroGates, Denmark). This validation demonstrates suPAR can be analysed by turbidimetry giving very similar results (<15% difference) compared to the ELISA method and the observed correlations (n = 103) were strong, r > 0.95. Roche Cobas® 8000 instruments demonstrated repeatability and repoducibility, CV % at 3.4-4.1 and 5.7-11.4, respectively. The estimated limit of detection was 1.30 µg/L and 1.31 µg/L for the Cobas® c502 and c702, respectively. Dilution tests showed linearity of suPAR from 1.8 to 26.5 µg/L. The acceptable concentrations of Bilirubin, Intralipid and Hemoglobin, were 350 µmol/L, 3.3 g/L and 1.4 g/L, respectively. suPAR can be quantified reproducibly within 10 min using a turbidimetry assay. This assay is faster than ELISA with similar results, making it suitable for clinical routine analysis.

Soluble Urokinase Plasminogen Activator Receptor Is Predictive of Non-AIDS Events During Antiretroviral Therapy-mediated Viral Suppression.

BACKGROUND: Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events. METHODS: Participants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference. RESULTS: At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. CONCLUSIONS: Elevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.

Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial.

BACKGROUND: Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. METHODS: Seventy CAD patients, BMI 28-40 kg/m2 and age 45-75 years were randomised to (1) 12 weeks' aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks' AIT twice weekly or (2) a low energy diet (LED) (800-1000 kcal/day) for 8-10 weeks followed by 40 weeks' weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. RESULTS: Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO2peak 20.7 mL O2/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (- 8.4; - 6.1) and waist circumference by 6.6 cm (- 7.7; - 5.5) compared to 1.7 kg (- 0.7; - 2.6) and 3.3 cm (- 5.1; - 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO2peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. CONCLUSIONS: Both interventions were feasible. Both groups obtained improvements in VO2peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).

The biomarkers suPAR and blood eosinophils are associated with hospital readmissions and mortality in asthma - a retrospective cohort study.

INTRODUCTION: Prognostic biomarkers in asthma are needed. The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with asthma control and with prognosis in acutely admitted medical patients. We investigated if suPAR and blood eosinophil counts at the time of admission for asthma are associated with readmission and mortality. METHODS: Our cohort comprised 1341 patients (median age 45.3, IQR 30.1-63.1) acutely admitted with a diagnosis of asthma to Hvidovre Hospital, Denmark (November 2013 to March 2017). Patients had suPAR and blood eosinophils measured at admission. Outcomes were 365-day readmission and all-cause mortality. Logistic regression analysis adjusted for age, sex, C-reactive protein, and Charlson comorbidity score was used to assess the association of the two biomarkers with readmission and all-cause mortality. RESULTS: Compared to event-free patients, patients who were either readmitted (n = 452, 42.3%) or died (n = 57, 5.3%) had significantly higher suPAR concentrations (p < 0.0001) and lower eosinophil counts (p = 0.0031) at admission. The highest odds of readmission or mortality were observed for patients in either the 4th suPAR quartile (p < 0.0001) or with eosinophil counts < 150 cells/µL at admission. Increasing levels of suPAR were associated with 365-day readmission (OR 1.3 [1.0-1.6]; p = 0.05) and mortality (OR 2.9 [1.7-5.1]; p = 0.0002). Eosinophil count > 300 cells/µL was significantly associated with lower odds of readmission (OR 0.64 [0.5-0.9]; p = 0.005) and lower mortality (OR 0.7 [0.6-0.9]; p = 0.0007). CONCLUSIONS: In patients acutely admitted with asthma, elevated suPAR concentrations together with blood eosinophil count < 150 cells/µL at the time of hospital admission were associated with both 365-day all-cause readmission and mortality.

Cumulative childhood risk is associated with a new measure of chronic inflammation in adulthood.

BACKGROUND: Childhood risk factors are associated with elevated inflammatory biomarkers in adulthood, but it is unknown whether these risk factors are associated with increased adult levels of the chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR). We aimed to test the hypothesis that childhood exposure to risk factors for adult disease is associated with elevated suPAR in adulthood and to compare suPAR with the oft-reported inflammatory biomarker C-reactive protein (CRP). METHODS: Prospective study of a population-representative 1972-1973 birth cohort; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38 years. Main childhood predictors were poor health, socioeconomic disadvantage, adverse childhood experiences (ACEs), low IQ, and poor self-control. Main adult outcomes were adulthood inflammation measured as suPAR and high-sensitivity CRP (hsCRP). RESULTS: Participants with available plasma samples at age 38 were included (N = 837, 50.5% male). suPAR (mean 2.40 ng/ml; SD 0.91) was positively correlated with hsCRP (r 0.15, p < .001). After controlling for sex, body mass index (BMI), and smoking, children who experienced more ACEs, lower IQ, or had poorer self-control showed elevated adult suPAR. When the five childhood risks were aggregated into a Cumulative Childhood Risk index, and controlling for sex, BMI, and smoking, Cumulative Childhood Risk was associated with higher suPAR (b 0.10; SE 0.03; p = .002). Cumulative Childhood Risk predicted elevated suPAR, after controlling for hsCRP (b 0.18; SE 0.03; p < .001). CONCLUSIONS: Exposure to more childhood risk factors was associated with higher suPAR levels, independent of CRP. suPAR is a useful addition to studies connecting childhood risk to adult inflammatory burden.