Heparin-Binding Protein Measurement Improves the Prediction of Severe Infection With Organ Dysfunction in the Emergency Department

Abstract Background: The pathophysiology of severe COVID-19 has been implicated to involve neutrophil activation in the blood and in the lungs and endothelial dysfunction. Heparin binding protein (HBP) is a neutrophil protein that plays an important role in bacterial sepsis and is a promising biomarker in severe infections. Syndecans and glypicans are potential markers of sheeding of the glycocalyx and endothelial dysfunction.The primary aims of this study were to assess whether HBP or syndecans and glypicans are involved in the pathophysiology of COVID-19 and if so, whether they can be used to predict severe disease preferably using a point-of-care test (POC) that can substitute more time-consuming analysis with enzyme-linked immunosorbent assay (ELISA).Methods: A prospective convenience sample study of biomarkers. The main cohort consisted of patients admitted to hospital with a confirmed COVID-19 diagnosis. Samples and clinical data were collected at admission, during admission and at discharge and samples were analyzed with ELISA kit (Axis-Shield Diagnostics) for measuring HBP concentration and a novel dry immunofluorescence analyzer (Jet-iStar 800) (Joinstar) for point-of-care testing.Results: Thirty-five COVID-19 patients were prospectively enrolled in the study. HBP was significantly elevated in COVID-19 patients with organ dysfunction (n= 23) compared to those without organ dysfunction (n=6), 24.7 ng/mL (95% CI 17.3-48.4) vs 10.6 ng/mL (95% CI 6.2-17.1 ng/mL), p=0.03. Syndecan-1 and Glypican-4 were not significantly elevated in patients with organ dysfunction. Syndecan-1, 62.1 ng/mL (44.4-102.0) vs 57.5 ng/mL (95% CI 46.0- 63.7), p=0.44 and glypican-4, 3292.4 pg/mL (95% CI 1707.5- 6790.6) vs 3962.7 pg/mL (95% CI 2653.6- 5823.5), p=0.80. The point-of-care (POC) HBP test showed good correlation to the standard ELISA with an R-value of 0.83. HBP measured by the POC device predicted development of COVID-induced organ dysfunction within 72 hours with an AUC of 0.88.Conclusions: The neutrophil-derived HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.

Download Full-text

Heparin-Binding Protein Performs Better for Detecting Sepsis Among Patients Presenting With Signs of Systemic Infection Compared With Procalcitonin, C-Reactive Protein, and Lactate Level, and Heparin-Binding Protein Is Sufficient for Both Ruling in and Out Sepsis With Organ Dysfunction: Beware of Potential Confounding Factors!

Critical Care Medicine ◽

10.1097/ccm.0000000000005005 ◽

2021 ◽

Vol 49 (7) ◽

pp. e733-e734

Author(s):

Patrick M. Honore ◽

Sebastien Redant ◽

Thierry Preseau ◽

Keitiane Kaefer ◽

Leonel Barreto Gutierrez ◽

...

Keyword(s):

Organ Dysfunction ◽

Lactate Level ◽

Binding Protein ◽

Systemic Infection ◽

Confounding Factors ◽

Heparin Binding ◽

C Reactive Protein ◽

Reactive Protein ◽

Heparin Binding Protein

Download Full-text

Heparin-Binding Protein as a Prognostic Biomarker of Sepsis and Disease Severity at the Emergency Department

Shock ◽

10.1097/shk.0000000000001332 ◽

2019 ◽

Vol 52 (6) ◽

pp. e135-e145 ◽

Cited By ~ 7

Author(s):

Fredrik Kahn ◽

Jonas Tverring ◽

Lisa Mellhammar ◽

Nils Wetterberg ◽

Anna Bläckberg ◽

...

Keyword(s):

Emergency Department ◽

Disease Severity ◽

Prognostic Biomarker ◽

Binding Protein ◽

Heparin Binding ◽

Heparin Binding Protein

Download Full-text

Heparin-binding protein: a key player in the pathophysiology of organ dysfunction in sepsis

Journal of Internal Medicine ◽

10.1111/joim.12604 ◽

2017 ◽

Vol 281 (6) ◽

pp. 562-574 ◽

Cited By ~ 26

Author(s):

J. Fisher ◽

A. Linder

Keyword(s):

Organ Dysfunction ◽

Binding Protein ◽

Protein A ◽

Heparin Binding ◽

Heparin Binding Protein

Download Full-text

An Exploratory, Observational Cohort Study on the Dynamics of Heparin Binding Protein in Cardiothoracic Surgery Using Cardiopulmonary Bypass

10.21203/rs.3.rs-74892/v1 ◽

2020 ◽

Author(s):

Niklas Sterner ◽

Jane Fisher ◽

Louise Thelaus ◽

Carolin Ketteler ◽

Špela Lemež ◽

...

Keyword(s):

Cardiac Surgery ◽

Cardiopulmonary Bypass ◽

Organ Dysfunction ◽

Binding Protein ◽

Surgical Trauma ◽

Heparin Binding ◽

Postoperative Infections ◽

Heparin Binding Protein ◽

Heparin Administration ◽

Protamine Administration

Abstract BackgroundSurgical trauma and cardiopulmonary bypass (CPB) cause an inflammatory response, difficult to differentiate from postoperative infections. Heparin-binding protein (HBP) is released from neutrophils and has been shown to predict infection-related organ dysfunction and disease progression to severe sepsis. In order to explore the potential of HBP as a biomarker for postoperative infections and asess possible confounding effects of concomitant medications, this study aimed to investigate the pre-, intra- and postoperative dynamics of HBP in cardiac surgery with CPB.Methods Thirty patients undergoing cardiac surgery with CPB were included, of which 15 underwent coronary artery bypass grafting (CABG) surgery and 15 underwent complex procedures with longer CPB duration. Ten patients undergoing lung surgery without CPB were also included as a conventional surgery reference group. HBP was measured at nine different perioperative time points.Results Our results showed that HBP levels were not affected by surgical trauma by itself. An increase in HBP levels was observed immediately following heparin administration and further increased during CPB. Prior to protaminization, we measured higher peak HBP-levels in the complex group (345.7 (287.8-472.6) ng/mL) compared with the CABG group (152.7 (85.3-204.0) ng/mL, p<0.001). HBP decreased rapidly following cessation of CPB and simultaneous protamine administration. Delay of protamine administration revealed that protamine, and not the cessation of CPB is primarily responsible for the rapidly reduced HBP concentration. At the arrival to the ICU, the median HBP levels were 24.8 (15.6-38.1) ng/mL for CABG patients compared with 50.5 (36.5-104.6) ng/mL for complex surgery patients (p=0.004). One day after surgery, HBP levels in all three groups were below the proposed cutoff of 30 ng/mL, previously found to predict development of organ dysfunction during infection, while other biomarkers for infections remained elevated.ConclusionsHBP levels are elevated by administration of heparin and the use of CPB but reduced by protamine administration. At postoperative day one, HBP levels were below the threshold for infection with organ dysfunction, indicating that postoperative HBP measurement may be a better screening tool for postoperative infections than other biomarkers of infections that remain elevated after surgery.

Download Full-text

Heparin binding protein in severe COVID-19—A prospective observational cohort study

PLoS ONE ◽

10.1371/journal.pone.0249570 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249570

Author(s):

Lisa Mellhammar ◽

Louise Thelaus ◽

Sixten Elén ◽

Jane Fisher ◽

Adam Linder

Keyword(s):

Organ Dysfunction ◽

Binding Protein ◽

Point Of Care ◽

Severe Disease ◽

University Hospital ◽

Enzyme Linked Immunosorbent Assay ◽

Heparin Binding ◽

Convenience Sample ◽

Point Of Care Test ◽

Heparin Binding Protein

Background and aims Neutrophil-derived heparin binding protein (HBP; also known as azurocidin or CAP-37) is a key player in bacterial sepsis and a promising biomarker in severe infections. The aims of this study were to assess whether HBP is involved in the pathophysiology of COVID-19 and, if so, whether it can be used to predict severe disease preferably using a point-of-care test. Methods This was a prospective convenience sample study of biomarkers in patients admitted to Skåne University hospital in Sweden with a confirmed COVID-19 diagnosis. Plasma samples and clinical data were collected within 72h after admission, during hospital stay and at discharge. Plasma HBP concentrations samples were measured both with enzyme-linked immunosorbent assay (ELISA) and with a novel dry immunofluorescence analyzer (Joinstar) point-of-care test. Results Thirty-five COVID-19 patients were enrolled in the study. Twenty-nine patients had blood samples taken within 72h after admission. We compared the highest HBP value taken within 72h after admission in patients who eventually developed organ dysfunction (n = 23) compared to those who did not (n = 6), and found that HBP was significantly elevated in those who developed organ dysfunction (25.0 ng/mL (interquartile range (IQR) 16.6–48.5) vs 10.6 ng/mL (IQR 4.8–21.7 ng/mL), p = 0.03). Point-of-care test measurements correlated well with ELISA measurements (R = 0.83). HBP measured by the POC device predicted development of COVID-induced organ dysfunction with an AUC of 0.88 (95% confidence interval (CI) 0.70–1.0). Conclusions HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.

Download Full-text

Dynamics of heparin binding protein in cardiothoracic surgery using cardiopulmonary bypass – exploring its potential as a marker for postoperative infections.

10.21203/rs.3.rs-26369/v1 ◽

2020 ◽

Author(s):

Niklas Sterner ◽

Jane Fisher ◽

Louise Thelaus ◽

Carolin Ketteler ◽

Spela Lemez ◽

...

Keyword(s):

Cardiac Surgery ◽

Cardiopulmonary Bypass ◽

Organ Dysfunction ◽

Binding Protein ◽

Surgical Trauma ◽

Heparin Binding ◽

Postoperative Infections ◽

Heparin Binding Protein ◽

Heparin Administration ◽

Protamine Administration

Abstract Background Surgical trauma and cardiopulmonary bypass (CPB) cause an inflammatory response, difficult to differentiate from postoperative infections. Heparin-binding protein (HBP) is released from neutrophils and has been shown to predict infection-related organ dysfunction and disease progression to severe sepsis. The aim of this study was to investigate the pre-, intra- and postoperative dynamics of HBP in cardiac surgery using CPB, in order to explore the usefulness of HBP as a biomarker for postoperative infections. Methods and Results Thirty patients undergoing cardiac surgery with CPB were included, of which 15 underwent coronary artery bypass grafting (CABG) surgery and 15 underwent complex procedures with longer CPB time. A reference group of ten patients undergoing lung surgery without CPB was also included. HBP was measured at nine different time points during surgery. Our results showed that HBP levels were not affected by surgical trauma itself. An increase in HBP levels was observed immediately following heparin administration and further increased during CPB. Prior to protaminization, we measured higher peak in HBP-levels in the complex group 345.7 (287.8-472.6) ng/mL compared with the CABG group 152.7 (85.3-204.0) ng/mL, p <0.001. HBP decreased rapidly following end of CPB and simultaneous protamine administration. Delay of protamine administration revealed that protamine, and not the cessation of CPB is primarily responsible for the rapidly reduced HBP concentration. At the arrival to the ICU, the median HBP levels were 24.8 (15.6-38.1) ng/mL for CABG patients compared with 50.5 (36.5-104.6) ng/mL for complex surgery patients ( p =0.004). One day after surgery HBP levels in all three groups were below the proposed cutoff of 30 ng/mL previously found to predict development organ dysfunction during infection. There was a statistically significant correlation between CPB duration and peak HBP concentration (r=0.598, p =0.002). Conclusions HBP levels are elevated by administration of heparin and the use of CPB. However, at postoperative day one, HBP levels normalized regardless of surgical complexity, indicating that postoperative HBP measurement may be used as a screening tool for postoperative infections in cardiac surgery.

Download Full-text