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

Linder, Adam MD, PhD1; Arnold, Ryan MD2; Boyd, John H. MD3; Zindovic, Marko MS1; Zindovic, Igor MD1; Lange, Anna MD4; Paulsson, Magnus MD5; Nyberg, Patrik MD, PhD6; Russell, James A. MD3; Pritchard, David PhD7; Christensson, Bertil MD, PhD1; Åkesson, Per MD, PhD1

doi: 10.1097/CCM.0000000000001265
Clinical Investigations

Objectives: Early identification of patients with infection and at risk of developing severe disease with organ dysfunction remains a difficult challenge. We aimed to evaluate and validate the heparin-binding protein, a neutrophil-derived mediator of vascular leakage, as a prognostic biomarker for risk of progression to severe sepsis with circulatory failure in a multicenter setting.

Design: A prospective international multicenter cohort study.

Setting: Seven different emergency departments in Sweden, Canada, and the United States.

Patients: Adult patients with a suspected infection and at least one of three clinical systemic inflammatory response syndrome criteria (excluding leukocyte count).

Intervention: None.

Measurements and Main Results: Plasma levels of heparin-binding protein, procalcitonin, C-reactive protein, lactate, and leukocyte count were determined at admission and 12–24 hours after admission in 759 emergency department patients with suspected infection. Patients were defined depending on the presence of infection and organ dysfunction. Plasma samples from 104 emergency department patients with suspected sepsis collected at an independent center were used to validate the results. Of the 674 patients diagnosed with an infection, 487 did not have organ dysfunction at enrollment. Of these 487 patients, 141 (29%) developed organ dysfunction within the 72-hour study period; 78.0% of the latter patients had an elevated plasma heparin-binding protein level (> 30 ng/mL) prior to development of organ dysfunction (median, 10.5 hr). Compared with other biomarkers, heparin-binding protein was the best predictor of progression to organ dysfunction (area under the receiver operating characteristic curve = 0.80). The performance of heparin-binding protein was confirmed in the validation cohort.

Conclusion: In patients presenting at the emergency department, heparin-binding protein is an early indicator of infection-related organ dysfunction and a strong predictor of disease progression to severe sepsis within 72 hours.

1Department of Clinical Sciences, Division of Infection Medicine, Klinikgatan 1, Skåne University Hospital, Lund University, Lund, Sweden.

2Value Institute and Department of Emergency Medicine, Christiana Care Health System, Newark, DE.

3Centre for Heart Lung Innovation, Division of Critical Care Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada.

4Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden.

5Department of Translational Medicine, Lund University, Lund, Sweden.

6Department of Emergency Medicine, Linköping University Hospital, Linköping, Sweden.

7Axis-Shield Diagnostics, Dundee, GB, United Kingdom.

Clinical trial number: ClinicalTrials.gov NCT01392508 (the IMproved PREdiction of Severe Sepsis in the Emergency Department study).

Drs. Linder, Arnold, Christensson, Pritchard, and Åkesson conceived and designed the study. Dr. Linder, Dr. Arnold, Mr. M. Zindovic, Dr. I. Zindovic, Dr. Lange, Dr. Paulsson, Dr. Nyberg, Dr. Boyd, and Dr. Russell did sample and collected data. All the authors analyzed and interpreted the data. Drs. Linder, Arnold, Boyd, Russell, Christensson, Pritchard, and Åkesson drafted the article for important intellectual content.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the Swedish Government Funds for Clinical Research (ALF), the University Hospital in Lund, and by Axis-Shield Diagnostics, Dundee, United Kingdom.

Presented, in part, at the 6th International Sepsis Forum, Rio de Janeiro, Brazil, November 2013.

Dr. Linder has a patent with Hansa Medical (inventor of HBPassay). Dr. Arnold received support from Axis Shield Diagnostics. His institution received support for travel from Axis Shield Diagnostics. Drs. I. Zindovic, Lange, Paulsson, and Nyberg received grant support and compensation for costs for biochemical analyses from Axis-Shield Diagnostics. Dr. Russell served as a board member for Cyon Therapeutics; consulted for Cubist Pharmaceutical, Ferring Pharmaceutical, Grifols, Leading Biosciences, Cytovale, and Sirius Genomics; has patents (owned by the University of British Columbia that are related to PCSK9 inhibitor[s] and sepsis and related to the use of vasopressin in septic shock. He is an inventor on these patents); and has stock in Cyon Therapeutics. His institution received grant support from Sirius Genomics and Ferring Pharmaceutical. Dr. Pritchard is employed by Axis-Shield Diagnostics. Dr. Christensson has a patent with Hansa Medical (inventor of HBPassay). Dr. Åkesson has a patent with Hansa Medical (inventor of HBPassay). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: adam.linder@med.lu.se

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