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

Adam Linder, Ryan Arnold, John H Boyd, Marko Zindovic, Igor Zindovic, Anna Lange, Magnus Paulsson, Patrik Nyberg, James A Russell, David Pritchard, Bertil Christensson, Per Åkesson, Adam Linder, Ryan Arnold, John H Boyd, Marko Zindovic, Igor Zindovic, Anna Lange, Magnus Paulsson, Patrik Nyberg, James A Russell, David Pritchard, Bertil Christensson, Per Åkesson

Abstract

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.

Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.
Flow chart of patients in the study cohort and subsequent patient outcomes.
Figure 2.
Figure 2.
Diagnostic accuracy of biomarker testing for infection-related organ dysfunction, that is, severe sepsis. Receiver operating characteristic curves are shown comparing heparin-binding protein (HBP), procalcitonin (PCT), C-reactive protein (CRP), lactate, and leukocyte count in discriminating between patients with infection who progressed to organ dysfunction and those who did not. The highest biomarker value before onset of organ dysfunction was used. The area under the receiver operating characteristic curve values (95% CI) for the progression to organ dysfunction were as follows: HBP, 0.80 (0.76–0.85); PCT, 0.70 (0.64–0.75); WBC, 0.72 (0.66–0.77); CRP, 0.70 (0.65–0.75); and lactate, 0.64 (0.58–0.69). HBP was significantly better than all the other markers in discriminating between patients who progressed to organ dysfunction and those who did not (p < 0.01).
Figure 3.
Figure 3.
Analysis of infected patients progressing to organ dysfunction after enrollment. Plasma heparin-binding protein (HBP) levels and times from plasma sampling to the development of organ dysfunction are indicated. Each dot represents one of the 141 patients. Patients with organ dysfunction detected at 24 hr or later after sampling are marked at 24 hr.
Figure 4.
Figure 4.
Analysis of peak biomarker values in infected patients. Two plasma samples were collected in the study: one at enrollment and one after 12–24 hr. The maximal value obtained for each biomarker was used to calculate the median values (line), interquartile range (boxes), and the 10–90% ranges (whiskers) for patients in each patient group. CRP = C-reactive protein, HBP = heparin-binding protein, PCT = procalcitonin.

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