Widespread vaccination, hybrid immunity, and reduced pathogenicity with circulating Omicron variants have decreased the rate of severe coronavirus disease 2019 (COVID-19) outcomes in the general population. Certain patients with COVID-19 remain at high risk for severe outcomes. Clinicians must individualize treatments based on expected benefits and relative harms for patients with mild-to-moderate COVID-19. Guideline-directed therapy for severe and critical COVID-19 has remained static over the last couple of years. Data on immunomodulatory agents have improved our understanding of the management of severe and critical COVID-19, yet uncertainty remains on the role and timing of these agents in the Omicron era.

The urokinase-type plasminogen activator receptor (uPAR) system, which includes protease, receptor and inhibitors, is essential for key cellular functions like immune activation, cell migration, and tissue remodeling. Soluble uPAR (suPAR), released into circulation, serves as a valuable biomarker for systemic inflammation and immune activation. Elevated suPAR levels are associated with disease severity in conditions such as infections, sepsis, cardiovascular diseases, renal injury, cancer, and autoimmune diseases providing prognostic value especially in acute settings. Recent advancements in diagnostic methods, have enhanced the accuracy of suPAR measurement in serum and plasma. New rapid tests, such as suPARnostic Quick Triage, as well as turbidimetric assays, further expand its clinical applicability. In this review, we discuss the suPAR biomarker, focusing on its biochemical structure, biological functions, measurement methods and areas of clinical interest in different fields of medicine.

Differences in recurrent pericarditis with normal vs. elevated C-reactive protein (CRP) are unknown.

We studied 448 patients with recurrent or incessant pericarditis. CRP levels <10 mg/L were considered normal. Forty-one patients with normal CRP were tested for interleukin 6 (IL-6), serum amyloid A (SAA) and soluble urokinase plasminogen activator receptor (suPAR).

Among the cohort (median age 43 years, 48.4% females), 336 patients (75%) had elevated CRP, while 112 (25%) had normal levels. CRP-negative patients were younger (38.6 vs. 43.5 years, p=0.007) and predominantly female (67.9% vs. 42.0%, p<0.001). They presented less often with fever (23.2% vs. 74.1%, p<0.001), pleural involvement (7.1% vs. 61.6% p<0.001), and neutrophilic leucocytosis (WBC 6760 vs. 12315/µL, p<0.001). Pericardiocentesis was performed rarely in CRP-negative patients (2.7% vs. 13.4%, p=0.001). Recurrence rates were similar (5.4 vs. 5.5/100 months-patient, p=0.918). Among CRP-negative patients, 53 (47.3%) had an incessant course characterized by persistent symptoms (pain and tachycardia); abnormal instrumental findings included ECG changes (28.6%), mild pericardial effusion (86.6%), and cardiac magnetic resonance evidence of effusion/oedema/late gadolinium enhancement (43.7%). Anakinra was administered to 48 CRP-positive (14.3%) and 10 CRP-negative patients (8.9%), leading to good responses with discontinuation of NSAIDs and corticosteroids in 39/48 (81.2%) and 5/10 (50.0%), respectively. Among the 41 CRP-negative patients tested, IL-6 and suPAR levels were always normal, while SAA was elevated in 17.1%.

Pericarditis with normal CRP exhibits distinct clinical and laboratory features, often presenting with an incessant course. Although rarely elevated, SAA may help to identify inflammation beyond CRP.

Following several waves of the COVID-19 pandemic, we are now facing a lower but persistent rate of SARS-CoV-2 infections, with seasonal resurgences often coinciding with other respiratory tract infections.

We aimed to identify early clinico-biological variables predictive of an unfavorable outcome in patients with primary SARS-CoV-2 infection. We also evaluated the role of suPAR, an innovative biomarker, in predicting disease severity.

We included 255 patients with PCR-confirmed primary SARS-CoV-2 infection and with a 30-day follow-up minimum. Blood samples were collected within the first 24 h of hospitalization to measure suPAR levels. Comprehensive data from medical records were analyzed to assess their predictive value in stratifying patients into seven severity groups, with groups 1 to 3 representing severe COVID-19 (death, intubation, ECMO, or non-invasive ventilation).

Early plasma suPAR levels were significantly associated with severe disease progression, as evidenced by ANOVA and logistic regression models, highlighting suPAR as a persistent predictive factor for unfavorable outcomes.

Our findings suggest that a single suPAR measurement, performed early after a positive PCR test for SARS-CoV-2, holds strong predictive value for patient outcomes. This biomarker, alongside pulse oximetry and CT scan results, could be instrumental in early patient triage during seasonal COVID-19 resurgences.

This review explores the crucial role of established and emerging biomarkers in the diagnosis, management, and understanding of post-COVID-19 conditions. With COVID-19 affecting multiple organ systems, biomarkers have been instrumental in identifying ongoing inflammation and tissue damage, facilitating early diagnosis and prognostication. Specifically, markers like C-reactive protein (CRP), interleukin-6 (IL-6), and novel entities such as soluble urokinase plasminogen activator receptor (suPAR) and neutrophil extracellular traps (NETs) provide insights into the pathophysiological mechanisms and predict long-term outcomes. This review highlights the integration of these biomarkers into clinical workflows and their implications for personalized medicine, emphasizing their potential in guiding therapeutic interventions and monitoring recovery. Future directions suggest a focus on longitudinal studies to explore biomarker trajectories and their interaction with therapeutic outcomes, aiming to enhance the management of post-COVID-19 conditions and refine public health strategies.

Patients admitted to the emergency department (ED) are a highly diverse group in terms of the risk of death. In overcrowded EDs, it becomes crucial to quickly and reliably estimate the risk of death or significant health deterioration. For this purpose, the concentration of soluble urokinase plasminogen activator receptor (suPAR) in plasma has been studied in recent years in various patient populations. In the present study, we tested the hypothesis that measuring suPAR upon the ED admission of critically ill patients can identify those at the highest mortality risk. To verify this hypothesis, we analyzed the relationship between suPAR plasma concentration, other biochemical parameters, and Early Warning Scores (EWSs) on admission and survival to hospital discharge. The study group consisted of 61 ED patients with priority 1 in the Manchester Triage System (MTS), excluding patients with illness caused by environmental factors. Positive correlations between suPAR and inflammatory parameters such as CRP and PCT, as well as the warning scales MEWS, MEDS, and qSOFA, were confirmed. Plasma suPAR concentration on admission was found to be a promising predictor of in-hospital mortality. The study indicated the potential prognostic value of suPAR as the mortality risk predictor for a specific population of critically ill ED patients.

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2, has led to significant morbidity and mortality worldwide, with severe complications often involving coagulation dysfunction and thromboembolic events. Identifying reliable biomarkers for early detection and monitoring of these complications is crucial for improving patient outcomes. The soluble urokinase plasminogen activator receptor (suPAR) has emerged as a potential biomarker in this context, given its role in inflammation and immune response. Elevated suPAR levels correlate with disease severity and inflammatory markers, making it a valuable indicator of the complex interplay between inflammation and coagulation observed in COVID-19. Elevated suPAR levels have been linked to an increased risk of thromboembolic events, such as deep vein thrombosis and pulmonary embolism. Combining suPAR measurement with other coagulation markers, such as D-dimer, enhances the predictive accuracy for thrombotic complications. Furthermore, higher suPAR levels are associated with increased disease severity, intensive care requirements, and higher mortality rates, underscoring its significance in risk stratification and therapeutic decision-making. The integration of suPAR measurement into routine clinical practice for COVID-19 could significantly aid in early diagnosis, risk assessment, and monitoring of therapeutic interventions. By providing insights into the patient's inflammatory and coagulation status, suPAR can guide the timely initiation of anticoagulant therapy and other treatments aimed at reducing thromboembolic complications. As research continues to validate suPAR's utility across diverse populations and clinical settings, it holds promise for becoming an integral component of clinical management strategies to mitigate the morbidity and mortality associated with COVID-19.

The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19.

Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status.

Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs.

This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

EU Horizon 2020 (grant number 101015736).

Anakinra was approved by the European Medicines Agency and received Emergency Use Authorization by the United States Food and Drug Administration for patients with COVID-19 pneumonia at risk for severe respiratory failure (SRF) with blood levels of soluble urokinase plasminogen activator receptor (suPAR) ≥ 6 ng/mL. We report the final results of the phase II open-label single-arm SAVE trial in a large population.

Patients with COVID-19 pneumonia and suPAR levels ≥ 6 ng/mL received subcutaneous anakinra 100 mg once daily for 10 days. The primary outcome was the incidence of SRF by day 14. Secondary outcomes were 30-day mortality, incidence of SRF according to time delay for start of treatment, safety, and associations with the inflammatory burden of the host.

From March 2020 to March 2022, a total of 992 patients were enrolled. The incidence of SRF was 18.8%, similar to the results of the phase III pivotal SAVE-MOREtrial. The overall 30-day mortality was 9.5%. Participants were divided into 4 subgroups according to time delay between symptoms onset and start of anakinra. The incidence of SRF was similar for all subgroups. Serious adverse events were reported in 15.4%; only 3 were possibly related to anakinra. The most common adverse event was increased liver function tests. A post hoc comparison with the pivotal phase III trial showed similar anakinra outcomes among patient subgroups by levels of inflammatory mediators and D-dimers.

Results support the efficacy of anakinra as being similar to that of the pivotal registrational trial for COVID-19 pneumonia. The lack of a comparator group is a limitation.

ClinicalTrials.gov, NCT04357366.

The aim of this study is to investigate the early prognostic efficacy of plasma soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor 1 (sTNFR1), and soluble tumor necrosis factor receptor 2 (sTNFR2) in complicated acute kidney injury (AKI) in patients with coronavirus disease 2019 (COVID-19), and to analyze the relevant factors contributing to complicated AKI in these patients.

Patients with COVID-19 hospitalized at the Affiliated Baiyun Hospital of Guizhou Medical University from March 2022 to March 2024 were selected as study participants. A total of 589 patients met the inclusion and exclusion criteria, 68 patients complicated with AKI were classified as AKI group, and the remaining 521 cases were divided into proportion sampling method and randomly selected 200 samples, which were classified as non-AKI group. Additionally, 50 healthy controls were enrolled as the control group. Logistic regression analysis was conducted to identify the relevant factors associated with complicated AKI in patients with COVID-19. Receiver operating characteristic (ROC) curves were plotted to evaluate the prognostic efficacy of plasma suPAR, sTNFR1, and sTNFR2 indicators for complicated AKI in patients with COVID-19.

Among the patients with COVID-19 in the AKI group, 43 were males (63.20 %), with a median age of 79.00 (interquartile range: 75.00, 83.00) years, while the non-AKI group comprised 83 males (41.50 %), with a median age of 73.00 (interquartile range: 60.00, 80.75) years. Comparison of the sex and age between the two groups indicated that males and elderly patients had increased risks of complicated AKI (P < 0.05). Plasma levels of suPAR, sTNFR1, and sTNFR2 in the AKI group were significantly higher than those in the non-AKI group (P < 0.05). Logistic regression analysis indicated that suPAR and sTNFR2 were independent factors influencing complicated AKI in patients with COVID-19 (P < 0.05). The ROC curve for a single indicator showed that suPAR had the highest prognostic efficacy for complicated AKI, with an area under the curve (AUC) of 0.813, a sensitivity of 79.4 %, and a specificity of 74.0 %. The combined use of suPAR and sTNFR2 for risk assessment yielded the highest AUC of 0.838, with a sensitivity of 66.2 % and a specificity of 87.5 %. The combined risk assessment using all three indicators (suPAR, sTNFR1, and sTNFR2) had an AUC of 0.837, with a sensitivity of 64.7 % and a specificity of 89.0 %.

Elderly patients had increased risks of complicated AKI. Indicators such as suPAR, sTNFR1, and sTNFR2 can assist in assessing the risk in patients with COVID-19 complicated AKI, with suPAR demonstrating the highest prognostic efficacy as a single indicator. The combined detection of suPAR, sTNFR1, and sTNFR2 offers greater prognostic value than using any single indicator.

Introduction Efficient and practical healthcare based on prognostic indicators can reduce morbidity and mortality in hospitalized COVID-19 patients. Soluble urokinase plasminogen activator receptor (suPAR) predicts clinical outcomes and respiratory failure in SARS-CoV-2 patients, but additional research is needed. Among other characteristics, we aimed to evaluate the predictive value of suPAR in COVID-19 patients. Methods This observational study was conducted at the All India Institute of Medical Sciences in New Delhi between January and April 2022. Patients within the age range from 18 to 85 years with mild, moderate, or severe COVID-19 infections were included in the study. Twenty-one patients (group 1) had positive RT-PCR throat and nasal swabs. Nine patients (group 2) with fever but without COVID-19 were recruited as controls. Ninety patient samples were tested for suPAR on days 1, 5, and 10 utilizing suPARnostic AUTO Flex ELISA kits (ViroGates, Denmark). Results The median age was 59 years in both groups. COVID-19 was mild in six patients (29%), moderate in seven patients (33%), and severe in eight patients (38%). At a median follow-up of 10 days, 8 out of 21 patients (38%) in group 1 died, while none in group 2 died. Patients' median suPAR levels were 4.35 ng/ml on day 1, 4.68 ng/ml on day 5, and 4.37 ng/ml on day 10. In the control group, suPAR levels were 1.6 ng/ml on day 1, 1.7 ng/ml on day 5, and 2.02 ng/ml on day 10. The suPAR levels were statistically significant on day 1 (p = 0.004), day 5 (p = 0.04), and day 10 (p = 0.007) between the patient and the control groups. Conclusion Patients who died had higher suPAR levels on days 1 (p = 0.007), 5 (p = 0.01), and 10 (p = 0.03) than survivors. The suPAR cut-off ≥ 3.64 (AUC = 0.82) predicts mortality with 88% sensitivity and 73% specificity.

Background/Objectives: This retrospective study analyzed soluble urokinase plasminogen activator receptor (suPAR) plasma levels alongside routine inflammatory markers, including the neutrophil-to-lymphocyte count ratio, C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and D-dimers in COVID-19 patients hospitalized during the Omicron wave of the pandemic. Methods: We measured plasma suPAR levels using a suPARnostic® Quick Triage kit. We divided COVID-19 patients into two groups based on the severity of SARS-CoV-2 infection according to the National Institutes of Health (NIH) criteria. The logistic regression analysis tested the predictive value of the biomarkers. Results: We evaluated 160 consecutive COVID-19 patients hospitalized between January and August 2022. The cohort exhibited a high incidence of comorbidities, with an in-hospital mortality rate of 5.6%. Upon admission, the median suPAR plasma levels were not significantly different between patients with mild COVID-19 (n = 110) and those with moderate/severe disease (n = 50), with 7.25 ng/mL and 7.55 ng/mL, respectively. We observed significant differences (p < 0.01) between the groups for CRP and IL-6 levels that were higher in moderate/severe disease than in mild infection. Additionally, suPAR plasma levels were above the normal range (0-2.00 ng/mL) in all patients, with a significant positive correlation identified between suPAR levels and serum IL-6, PCT, and creatinine levels. Conclusions: These findings indicate that COVID-19 during the Omicron wave is strongly associated with elevated suPAR levels; however, these levels do not directly correlate with the severity of SARS-CoV-2 infection.

The effect of the COVID-19 pandemic on healthcare systems emphasized the need for rapid and effective triage tools to identify patients at risk of severe or fatal infection. Measuring host response markers of inflammation and endothelial activation at clinical presentation may help to inform appropriate triage and care practices in patients with SARS-CoV-2 infection.

We enrolled patients with COVID-19 across five GeoSentinel clinical sites (in Italy, Belgium, Canada, and the United States) from September 2020 to December 2021, and analyzed the association of plasma markers, including soluble urokinase-type plasminogen activator receptor (suPAR), soluble tumor necrosis factor receptor-1 (sTREM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), complement component C5a (C5a), von Willebrand factor (VWF-a2), and interleukin-1 receptor antagonist (IL-1Ra), with 28-day (D28) mortality and 7-day (D7) severity (discharged, hospitalized on ward, or died/admitted to the ICU).

Of 193 patients, 8.9% (16 of 180) died by D28. Higher concentrations of suPAR were associated with increased odds of mortality at D28 and severity at D7 in univariable and multivariable regression models. The biomarkers sTREM-1 and IL-1Ra showed bivariate associations with mortality at D28 and severity at D7. IL-6, VWF, C5a, and IL-8 were not as indicative of progression to severe disease or death. Conclusions: Our findings confirm previous studies' assertions that point-of-care tests for suPAR and sTREM-1 could facilitate the triage of patients with SARS-CoV-2 infection, which may help guide hospital resource allocation.

Background/Objectives: The incidence of acute kidney injury (AKI) has been steadily increasing. Despite its high prevalence, there is no pathogenetically rational therapy for AKI. This deficiency stems from the poor understanding of the pathogenesis of AKI. Renal ischemia/hypoxia is one of the leading causes of clinical AKI. This study investigates whether αMUPA mice, overexpressing the urokinase plasminogen activator (uPA) gene are protected against ischemic AKI, thus unraveling a potential renal damage treatment target. Methods: We utilized an in vivo model of I/R-induced AKI in αMUPA mice and in vitro experiments of uPA-treated HEK-293 cells. We evaluated renal injury markers, histological changes, mRNA expression of inflammatory, apoptotic, and autophagy markers, as compared with wild-type animals. Results: the αMUPA mice exhibited less renal injury post-AKI, as was evident by lower SCr, BUN, and renal NGAL and KIM-1 along attenuated adverse histological alterations. Notably, the αMUPA mice exhibited decreased levels pro-inflammatory, fibrotic, apoptotic, and autophagy markers like TGF-β, IL-6, STAT3, IKB, MAPK, Caspase-3, and LC3. By contrast, ACE-2, p-eNOS, and PGC1α were higher in the kidneys of the αMUPA mice. In vitro results of the uPA-treated HEK-293 cells mirrored the in vivo findings. Conclusions: These results indicate that uPA modulates key pathways involved in AKI, offering potential therapeutic targets for mitigating renal damage.

The COVID-19 pandemic has brought attention to a newly identified syndrome of multisystem inflammation. This potentially fatal complication of the disease was initially observed in children and later in adults. It affects primarily unvaccinated patients and may manifest within a timeframe of 2-12 weeks following infection. Soluble urokinase plasminogen activator receptor (suPAR), a novel biomarker, highlights the severity of inflammation and the degree of immune system activation. Herein, we report a case of a patient with multisystem inflammatory syndrome in adults (MIS-A) and markedly elevated suPAR levels, successfully treated with interleukin-1 (IL-1) receptor antagonist. A 59-year-old female was admitted to our hospital due to febrile illness (up to 40°C) with chills, vomiting, non-bloody diarrhea, and abdominal pain for four days prior to her admission. She tested positive for SARS-CoV-2 12 weeks before her presentation. During hospitalization, the patient deteriorated clinically with multiorgan involvement and hemodynamically instability, with concomitant markedly elevated inflammatory markers. Extensive workup with high suPAR levels led to post-COVID-19 MIS-A diagnosis, and treatment with dexamethasone and an interleukin-1 receptor antagonist (IL-1ra), anakinra, was administered. The subcutaneous injection of anakinra effectively and safely deterred MIS-A. Further research is needed to investigate the role of interleukin-1 inhibitors for the management of this potentially life-threatening condition.

Sepsis is a heterogeneous syndrome often misdiagnosed. Point-of-care (POC) diagnostic tests are commonly used to guide decision and include host biomarkers and molecular diagnostics.

The diagnostic and prognostic accuracy of established and emerging biomarkers for sepsis, including procalcitonin (PCT) soluble urokinase plasminogen activator receptor (suPAR), presepsin, TRAIL/IP-10/CRP, MxA, and MxA-CRP, are analyzed in this review. The clinical utility of the two prevalent molecular techniques for pathogens identification using polymerase chain reaction (PCR) assays is also presented: FILMARRAY and QIAstat-Dx RP.

The rising benefits of the combined use of POC biomarkers with molecular diagnostics in daily clinical routine appear to outperform conventional practices in terms of reduced turnaround time, timely diagnosis, and prompt administration of the appropriate treatment. Yet, this must be further demonstrated in future investigations. However, the cost-effectiveness of POC tests and the high rate of false positive and negative results, indicate the need for a comprehensive clinical evaluation.

Elevated soluble urokinase plasminogen activator receptor (suPAR) has been associated with a poor prognosis in serious infections. The aim of this study was to evaluate the clinical value of suPAR in children with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C).

Serum suPAR was measured using the suPARnostic AUTO Flex enzyme-linked immunosorbent assay in hospitalized children with COVID-19, MIS-C, bacterial pneumonia, and healthy controls.

A total of 211 children with a mean (±SD) age of 6.9 ± 4.96 years were tested; with COVID-19: 59 (28%), MIS-C: 36 (17%), pneumonia: 78 (37%) and healthy controls: 38 (18%). In the acute phase, the levels of suPAR (mean ± SD) were: MIS-C: 8.11 ± 2.80 ng/mL, COVID-19: 4.91 ± 1.90 ng/mL, pneumonia: 4.25 ± 1.44 ng/mL and controls: 2.09 ± 0.47 ng/mL ( P < 0.001). Children with acute COVID-19 and a severe or moderate clinical presentation had higher values than those with mild symptoms: 5.79 ± 1.58 versus 5.40 ± 1.94 versus 3.19 ± 0.73 ng/mL, respectively ( P < 0.001). In the MIS-C group, children hospitalized in the intensive care unit and in need of mechanical ventilation had higher suPAR than those who were not admitted to an intensive care unit: 9.32 ± 3.06 versus 7.13 ± 2.19 ng/mL, respectively ( P = 0.023). In children with COVID-19 or MIS-C, a correlation was detected between suPAR values and length of hospitalization ( rs = 0.418, P < 0.001).

The findings suggest that suPAR may be a valuable biomarker of disease severity in children with COVID-19 or MIS-C. This could facilitate the identification of children in need of intensive anti-inflammatory treatment, as it has been shown in adults with severe COVID-19.

We aimed to evaluate heparin-binding protein (HBP) as a marker of prognosis of unfavorable outcome in COVID-19 pneumonia. This was a post hoc analysis of the SAVE clinical trial investigating anakinra treatment, guided by suPAR (soluble urokinase plasminogen activator receptor) levels ≥6 ng/mL, for the prevention of severe respiratory failure in hospitalized patients with COVID-19 pneumonia. Baseline HBP plasma levels were measured in 534 patients by fluorescence dry quantitative immunoassay using the Jet-iStar 800 analyzer. Concentrations higher than 35 ng/mL predicted 30-day mortality with a moderate specificity of 53.3% and negative predictive value 78.1%; sensitivity was low (29.0%). After multivariate Cox analysis, HBP higher than 35 ng/mL was an independent predictor of 30-day unfavorable outcome (adjusted hazard ratio, 1.77; 95% CI, 1.06-2.94; P = 0.028) and these patients were also at greater risk of death after 90 days (hazard ratio, 1.85; 95% CI, 1.25-2.74; P = 0.002). The cutoff was not predictive of development of severe respiratory failure, septic shock or acute kidney injury. Among patients with baseline HBP levels higher than 35 ng/mL, anakinra treatment was associated with decreased mortality (7.2%) versus comparators (18.1%; P < 0.001). Results confirm that HBP may be an early biomarker of poor outcome among preselected patients at risk from COVID-19 pneumonia.ClinicalTrials.gov registration NCT04357366.

Sepsis, a dysregulated host immune response to an infectious agent, significantly increases morbidity and mortality for hospitalized patients worldwide. This chapter reviews (1) the basic principles of infectious diseases, pathophysiology and current definition of sepsis, (2) established sepsis biomarkers such lactate, procalcitonin and C-reactive protein, (3) novel, newly regulatory-cleared/approved biomarkers, such as assays that evaluate white blood cell properties and immune response molecules, and (4) emerging biomarkers and biomarker panels to highlight future directions and opportunities in the diagnosis and management of sepsis.

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.

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.

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.

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.

Diseases of the pericardium encompass a spectrum of conditions, including acute and recurrent pericarditis, where inflammation plays a pivotal role in the pathogenesis and clinical manifestations. Anti-inflammatory therapy indeed forms the cornerstone of treating these conditions: NSAIDs, colchicine, and corticosteroids (as a second-line treatment) are recommended by current guidelines. However, these medications come with several contraindications and are not devoid of adverse effects. In recent years, there has been an increased focus on the role of the inflammasome and potential therapeutic targets. Recurrent pericarditis also shares numerous characteristics with other autoinflammatory diseases, in which interleukin-1 antagonists have already been employed with good efficacy and safety. The objective of this review is to summarize the available studies on the use of anti-IL-1 drugs both in acute and recurrent pericarditis.

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.

Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β.

To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay.

A single-centre, non-pharmacological, diagnostic study was performed.

A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment.

CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.

Plasma soluble urokinase-type Plasminogen Activator Receptor (suPAR) predicts disease aggressiveness in renal cell carcinoma (ccRCC), but its prognostic accuracy has not been investigated. To investigate the prognostic accuracy of preoperative plasma suPAR in patients who received curative treatment for initially localized ccRCC.

We retrospectively analyzed plasma samples stored in the Danish National Biobank between 2010 and 2015 from 235 patients with ccRCC at any stage. Relationships with outcome analyzed using univariate and multiple logistic Cox regression analysis.

There were 235 patients with ccRCC. The median follow-up period was 7.7 years. In univariate analysis suPAR ≥ 6 ng/mL was significantly associated with overall survival (OS) and recurrence-free survival (RFS). Patients with elevated suPAR were more likely to recur, with a Hazard Ratio (HR) of 2.3 for RFS. In multiple logistic regression, suPAR ≥ 6 ng/mL remained a negative predictor of OS and RFS. Limitations include retrospective study design, wide confidence intervals, and tumor subtype heterogeneity bias.

ccRCC patients with high plasma suPAR concentrations are at an elevated risk of disease recurrence and see lower OS. suPAR is a promising surveillance tool to more precisely follow up with ccRCC patients and detect future recurrences. In this study, we showed that new type of liquid marker in blood plasma, called suPAR, is associated to a higher risk of kidney cancer recurrence when elevated above 6ng/mL. We also showed suPAR to independently be able to predict patients overall and recurrence free survival in patient with any stage of kidney cancer.

Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, transgenic mice expressing D2D3 protein developed progressive kidney disease marked by microalbuminuria, elevated serum creatinine, and glomerular hypertrophy. D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored β cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired β cell proliferation and inhibited the bioenergetics of β cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus.

The soluble urokinase plasminogen activator receptor (suPAR) has been proposed as a biomarker for risk stratification of patients presenting with acute infections. However, most studies evaluating suPAR have used platform-based assays, the accuracy of which may differ from point-of-care tests capable of informing timely triage in settings without established laboratory capacity. Using samples and data collected during a prospective cohort study of 425 patients presenting with moderate Covid-19 to two hospitals in India, we evaluated the analytical performance and prognostic accuracy of a commercially-available rapid diagnostic test (RDT) for suPAR, using an enzyme-linked immunosorbent assay (ELISA) as the reference standard. Our hypothesis was that the suPAR RDT might be useful for triage of patients presenting with moderate Covid-19 irrespective of its analytical performance when compared with the reference test. Although agreement between the two tests was limited (bias = -2.46 ng/mL [95% CI = -2.65 to -2.27 ng/mL]), prognostic accuracy to predict supplemental oxygen requirement was comparable, whether suPAR was used alone (area under the receiver operating characteristic curve [AUC] of RDT = 0.73 [95% CI = 0.68 to 0.79] vs. AUC of ELISA = 0.70 [95% CI = 0.63 to 0.76]; p = 0.12) or as part of a published multivariable prediction model (AUC of RDT-based model = 0.74 [95% CI = 0.66 to 0.83] vs. AUC of ELISA-based model = 0.72 [95% CI = 0.64 to 0.81]; p = 0.78). Lack of agreement between the RDT and ELISA in our cohort warrants further investigation and highlights the importance of assessing candidate point-of-care tests to ensure management algorithms reflect the assay that will ultimately be used to inform patient care. Availability of a quantitative point-of-care test for suPAR opens the door to suPAR-guided risk stratification of patients with Covid-19 and other acute infections in settings with limited laboratory capacity.

Since December 2019, many drugs have been evaluated or advocated as potential treatments of SARS-CoV-2 induced disease (COVID-19), including many repositioned drugs and some others specifically developed for these diseases. They can be roughly classified into three categories according to their main mechanism of action (passive immunization, direct antivirals, and anti-inflammatory treatments), and their use depends on the stage of the disease. Despite often promising preclinical data, most of the treatments evaluated failed to show a significant clinical benefit. In addition, a few others have seen their effectiveness affected by the occurrence of SARS-CoV-2 variants and sub-variants. Herein, the aim of this article is to take stock of the data available as of the 14th of July 2022, concerning the specific healing options evaluated for patients suffering from COVID-19. We focus particularly on healing treatments of COVID-19 and do not deal with preventive treatments such as vaccine. Associated therapies such as venous thromboembolism prophylaxis are not detailed since they are covered in a specific chapter of this issue. Passive immunization, especially through monoclonal antibodies, showed a positive impact on the clinical evolution, whether in outpatients or inpatients without oxygen supply. However, their effectiveness strongly depends on the type of SARS-CoV-2 variant, and often decreases or even vanishes with the most recent variants. Among direct antiviral treatments, ritonavir-boosted nirmatrelvir appears to currently be the cornerstone in the management of early infections, but its use may be limited by drug interactions. Remdesivir remains as an alternative in this situation, even though it is potentially less convenient. Anti-inflammatory treatments have often been shown to be the most effective in inpatients with oxygen supply. Dexamethasone is now a cornerstone of management of these patients. Added tocilizumab seems beneficial in the case of hyper inflammation. JAK inhibitors and anakinra have also gained an interest in some studies. As a conclusion of this narrative review, the best treatment strategy has yet to be defined and is likely to evolve in the future, not only because many other drugs are still under development and evaluation, but also because of the viral epidemics and epidemiology evolution.

This review summarizes current progress in the development of biomarkers to guide immunotherapy in oncology, rheumatology, and critical illness.

An extensive literature search was performed about biomarkers classifying patients' immune responses to guide immunotherapy in oncology, rheumatology, and critical illness. Surface markers, such as programmed death-ligand 1 (PD-L1), genetic biomarkers, such as tumor mutation load, and circulating tumor DNA are biomarkers associated with the effectiveness of immunotherapy in oncology. Genomics, metabolomics, and proteomics play a crucial role in selecting the most suitable therapeutic options for rheumatologic patients. Phenotypes and endotypes are a promising approach to detect critically ill patients with hyper- or hypo-inflammation. Sepsis trials using biomarkers such as ferritin, lymphopenia, HLA-DR expression on monocytes and PD-L1 to guide immunotherapy have been already conducted or are currently ongoing. Immunotherapy in COVID-19 pneumonia, guided by C-reactive protein and soluble urokinase plasminogen activator receptor (suPAR) has improved patient outcomes globally. More research is needed into immunotherapy in other critical conditions.

Targeted immunotherapy has improved outcomes in oncology and rheumatology, paving the way for precision medicine in the critically ill. Transcriptomics will play a crucial role in detecting the most suitable candidates for immunomodulation.

C-reactive protein (CRP) has been one of the most investigated inflammatory-biomarkers during the ongoing COVID-19 pandemics caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The severe outcome among patients with SARS-CoV-2 infection is closely related to the cytokine storm and the hyperinflammation responsible for the acute respiratory distress syndrome and multiple organ failure. It still remains a challenge to determine which of the hyperinflammatory biomarkers and cytokines are the best predictors for disease severity and mortality in COVID-19 patients. Therefore, we evaluated and compared the outcome prediction efficiencies between CRP, the recently reported inflammatory modulators (suPAR, sTREM-1, HGF), and the classical biomarkers (MCP-1, IL-1β, IL-6, NLR, PLR, ESR, ferritin, fibrinogen, and LDH) in patients confirmed with SARS-CoV-2 infection at hospital admission. Notably, patients with severe disease had higher serum levels of CRP, suPAR, sTREM-1, HGF and classical biomarkers compared to the mild and moderate cases. Our data also identified CRP, among all investigated analytes, to best discriminate between severe and non-severe forms of disease, while LDH, sTREM-1 and HGF proved to be excellent mortality predictors in COVID-19 patients. Importantly, suPAR emerged as a key molecule in characterizing the Delta variant infections.

Lifeways of worldwide people have changed dramatically amid the coronavirus disease 2019 (COVID-19) pandemic, and public health is at stake currently. In the early stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, fibrinolytic system is mostly inhibited, which is responsible for the development of hypofibrinolysis, promoting disseminated intravascular coagulation, hyaline membrane formation, and pulmonary edema. Whereas the common feature and risk factor at advanced stage is a large amount of fibrin degradation products, including D-dimer, the characteristic of hyperfibrinolysis. Plasmin can cleave both SARS-CoV-2 spike protein and γ subunit of epithelial sodium channel (ENaC), a critical element to edematous fluid clearance. In this review, we aim to sort out the role of fibrinolytic system in the pathogenesis of COVID-19, as well as provide the possible guidance in current treating methods. In addition, the abnormal regulation of ENaC in the occurrence of SARS-CoV-2 mediated hypofibrinolysis and hyperfibrinolysis are summarized, with the view of proposing an innovative view of epithelial ion transport in preventing the dysfunction of fibrinolytic system during the progress of COVID-19.

The pulmonary endothelium is a highly regulated organ that performs a wide range of functions under physiological and pathological conditions. Since endothelial dysfunction has been demonstrated to play a direct role in sepsis and acute respiratory distress syndrome, its role in COVID-19 has also been extensively investigated. Indeed, apart from the COVID-19-associated coagulopathy biomarkers, new biomarkers were recognised early during the pandemic, including markers of endothelial cell activation or injury. We systematically searched the literature up to 10 March 2023 for studies examining the association between acute and long COVID-19 severity and outcomes and endothelial biomarkers.

Urokinase receptors regulate the interplay between inflammation, immunity, and blood clotting. The soluble urokinase plasminogen activator system is an immunologic regulator affecting endothelial function and its related receptor; the soluble urokinase plasminogen activator receptor (suPAR) has been reported to impact kidney injury. This work aims to measure serum levels of suPAR in COVID-19 patients and correlate the measurements with variable clinicolaboratory parameters and patient outcomes. In this prospective cohort study, 150 COVID-19 patients and 50 controls were included. The circulating suPAR levels were quantified by Enzyme-linked immunosorbent assay (ELISA). Routine COVID-19 laboratory assessments, including CBC, CRP, LDH, serum creatinine, and estimated glomerular filtration rates, were performed. The need for oxygen therapy, CO-RAD score, and survival rates was assessed. Bioinformatic analysis and molecular docking were run to explore the urokinase receptor structure/function and to characterize molecules as potential anti-suPAR therapeutic targets, respectively. We found higher circulating suPAR levels in COVID-19 patients vs. controls (p < 0.001). Circulating suPAR levels positively correlated with COVID-19 severity, the need for O2 therapy, the total leukocytes count, and the neutrophils to lymphocyte ratio, while they were negatively correlated with the O2 saturation level, albumin, blood calcium, lymphocytic count, and GFR. In addition, the suPAR levels were associated with poor prognostic outcomes such as a high incidence of acute kidney injury (AKI) and mortality rate. Kaplan-Meier curves showed a lower survival rate with higher suPAR levels. The logistic regression analysis confirmed the significant association of suPAR levels with the occurrence of AKI related to COVID-19 and with increased mortality probability within three months of COVID-19 follow-up. Some compounds that can act similarly to uPAR were discovered and tested by molecular docking to identify the possible ligand-protein interactions. In conclusion, higher circulating suPAR levels were associated with COVID-19 severity and could be considered a putative predictor of AKI development and mortality.

Acute kidney injury (AKI) secondary to sepsis results in poor outcomes and conventional kidney function indicators lack diagnostic value. Soluble urokinase plasminogen activator receptor (suPAR) is an innate immune-derived molecule implicated in inflammatory organ damage. We characterized the diagnostic ability of longitudinal serum suPAR levels to discriminate severity and course of sepsis-induced AKI (SI-AKI) in 200 critically ill patients meeting Sepsis-3 criteria. The pathophysiologic relevance of varying suPAR levels in SI-AKI was explored in a polymicrobial sepsis model in WT, (s)uPAR-knockout, and transgenic suPAR-overexpressing mice. At all time points studied, suPAR provided a robust classification of SI-AKI disease severity, with improved prediction of renal replacement therapy (RRT) and mortality compared with established kidney biomarkers. Patients with suPAR levels of greater than 12.7 ng/mL were at highest risk for RRT or death, with an adjusted odds ratio of 7.48 (95% CI, 3.00-18.63). suPAR deficiency protected mice against SI-AKI. suPAR-overexpressing mice exhibited greater kidney damage and poorer survival through inflamed kidneys, accompanied by local upregulation of potent chemoattractants and pronounced kidney T cell infiltration. Hence, suPAR allows for an innate immune-derived and kidney function-independent staging of SI-AKI and offers improved longitudinal risk stratification. suPAR promotes T cell-based kidney inflammation, while suPAR deficiency improves SI-AKI.

Chronic kidney disease (CKD) patients face an unacceptably high morbidity and mortality, mainly from cardiovascular diseases. Diabetes mellitus, arterial hypertension and dyslipidemia are highly prevalent in CKD patients. Established therapeutic protocols for the treatment of diabetes mellitus, arterial hypertension, and dyslipidemia are not as effective in CKD patients as in the general population. The role of non-traditional risk factors (RF) has gained interest in the last decades. These entail the deranged clinical spectrum of secondary hyperparathyroidism involving vascular and valvular calcification, under the term "CKD-mineral and bone disorder" (CKD-MBD), uremia per se, inflammation and oxidative stress. Each one of these non-traditional RF have been addressed in various study designs, but the results do not exhibit any applied clinical benefit for CKD-patients. The "crusade" against cardiorenal morbidity and mortality in CKD-patients is in some instances, derailed. We propose a therapeutic paradigm advancing from isolated treatment targets, as practiced today, to precision medicine involving patient phenotypes with distinct underlying pathophysiology. In this regard we propose two steps, based on current stratification management of corona virus disease-19 and sepsis. First, select patients who are expected to have a high mortality, i.e., a prognostic enrichment. Second, select patients who are likely to respond to a specific therapy, i.e., a predictive enrichment.