Heparin Binding Protein in Early Sepsis Diagnosis

Study Overview
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Brief Summary
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The primary objective of this study is to use heparin-binding protein (HBP) concentration to indicate the presence, or outcome, of sepsis over 72 hours after ED admission. The secondary objectives of this study are to separately evaluate the performance of HBP to predict outcome in patients with suspected infection over 12-24 hours after ED admission.

Detailed Description
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The purpose of this prospective, non-interventional, multi-centre clinical study is to assess the clinical validity of the Heparin Binding Protein (HBP) assay for indicating the presence, or outcome, of severe sepsis (including septic shock), over 72 hours, in patients with suspected infection following emergency department admission. Sepsis is an increasingly common cause of morbidity and mortality, with approximately 150,000 people in Europe and 215,000 people in the US dying of severe sepsis each year. Deaths attributable to sepsis continue to rise due to an increase in incidence of the disease, which can be attributed to numerous factors including the aging population, the increased number of immuno-compromised patients, the increased use of invasive surgery and the increased incidence of microbial resistance. The sepsis syndrome was first described in the 1992 publication by Bone et al detailing the conclusions of the ACCP/SCCM Consensus Conference held in 1991, which first introduced the Systemic Inflammatory Response Syndrome (SIRS) classification system. Systemic Inflammatory Response Syndrome (SIRS) is considered to be present when patients have 2 or more of the following clinical findings: body temperature, >38ºC or <36ºC heart rate, >90 beats per minute respiratory rate of >20 breaths per minute or a PaCO2 of <32mm Hg white cell count of >12,000 cells per µL or <4,000 per µL, or >10% immature (band) forms According to the suggested definitions, sepsis is defined as SIRS plus confirmed infection, severe sepsis is defined as sepsis associated with organ dysfunction, hypoperfusion, or hypotension and septic shock is defined as sepsis-induced hypotension, persisting despite adequate fluid resuscitation. Diagnosis of sepsis traditionally relies on identification of the above symptoms, as well as culturing techniques to confirm and identify the infection. This method of diagnosis is, however, far from ideal as it has been demonstrated that SIRS criteria are poorly predictive of subsequent events in the sepsis cascade and that approximately one half of severe sepsis cases are culture negative. In addition, the assay time for culture-based diagnosis is 24 to 48 hours, where it has been shown that diagnosis of severe sepsis and septic shock as early as possible is important, as each hour of delay in effective antimicrobial administration is associated with an average decrease in survival of 7.6%. Although the majority of severe sepsis patients receive treatment in an intensive care unit (ICU), it is estimated that up to two thirds of those patients initially present to the emergency department (ED), and that approximately 20% of patients with confirmed infection who present to the ED with uncomplicated sepsis progress to severe sepsis or septic shock within 72 hours. This high incidence of early progression to severe sepsis and septic shock among patients presenting to the ED highlights the time-sensitive nature of diagnosis, especially in patients who initially do not appear critically ill. Therefore early intervention to prevent subsequent or worsening clinical deterioration is key to the successful treatment of patients. However, two major impediments to the effectiveness of sepsis treatment strategies are a failure to recognise the early stages of the disease and underestimation of its severity, as it is difficult to determine which of the patients with signs of infection on initial evaluation have, or will develop, more serious illness. Several outcome prediction models, including Acute Physiology and Chronic Health Evaluation (APACHE) IV, the Simplified Acute Physiology Score (SAPS) III, the Logistic Organ Dysfunction Score (LODS), and the Mortality Probability Model (MPM) III have therefore been developed for use in clinical practice. Moreover patients admitted in the ED with at least two of three clinical signs (hypotension, tachypnea, altered mental status) are highly possible to suffer from sepsis. These three clinical signs are the qSOFA score. Data from the Hellenic Sepsis Study Group put into question if the qSOFA score can predict sepsis in the ED with sensitivity that exceeds 65% (15, 16). There is, therefore, still an unmet need for a diagnostic tool that can identify those patients at risk of developing more severe disease, and although a number of laboratory measures or novel sepsis biomarkers have been proposed for clinical use, there is currently no single accepted biomarker or combination of biomarkers for use in patients with suspected sepsis. The recent publication by Linder et al(17) has shown that measurement of heparin binding protein (HBP), also known as azurocidin or CAP37, in febrile patients presenting to the ED shows a close correlation between increased plasma HBP levels and the development of severe sepsis with hypotension or shock. In this prospective study of 233 febrile adult patients with suspected infection, 26 were diagnosed with severe sepsis with septic shock, 44 with severe sepsis without septic shock, 100 with sepsis, 43 with infection without SIRS and 20 with SIRS without infection. Using a cut-off of 15ng/mL, HBP showed a sensitivity in diagnosing severe sepsis (with or without septic shock) of 87.1%, a specificity of 95.1%, a positive predictive value (PPV) of 88.4% and a negative predictive value (NPV) of 94.5%, which exceeded those values obtained for the other tested markers. Receiver-operating characteristic (ROC) curves also demonstrated that HBP was the best predictor of severe sepsis, with an area under the curve (AUC) value of 0.95. It is therefore hypothesised that HBP may be used for the early identification of patients at risk of developing severe sepsis and septic shock. In addition, it was observed that 20 of the patients with severe sepsis were monitored with serial plasma sample collection during the course of the disease, and that the 18 of these patients who survived had HBP levels that decreased rapidly when the clinical signs improved and the blood pressures were normalised. It is therefore further hypothesised that a decrease in HBP levels may be used to predict survival.

Official Title
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Prospective Multi-centre Clinical Study to Assess the Clinical Validity of the Heparin Binding Protein Assay to Indicate the Presence and Outcome of Sepsis in Patients With Suspected Infection Following Emergency Department Admission

Conditions
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Sepsis, Infection

Intervention / Treatment
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* Diagnostic Test: Biomarker


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Male or female Written informed consent Suspected infection Presence of at least ONE of the following: Temperature > 38°C Temperature < 36°C Heart rate > 90 bpm Respiratory rate > 20/min Self reported fever/chills Exclusion Criteria: None

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Biomarker<br>Blood sampling | Diagnostic Test: Biomarker<br>* Measument of heparin-binding protein in the serum of patients<br>* Other names: Heparin Binding Protein;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ΗΒΡ for sepsis diagnosis | Sensitivity of ΗΒΡ for sepsis diagnosis. Every value over 90% is considered satisfactory. | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic performance of HBP for sepsis | Specificity, positive predictive value and negative predictive value of HBP to diagnose sepsis | 72 hours | 
| Diagnostic performance of HBP for septic shock | Specificity, positive predictive value and negative predictive value of HBP to diagnose septic shock | 72 hours | 
| Diagnostic performance of HBP for early death | Sensitivity, specificity, positive predictive value and negative predictive value of HBP to predict unfavorable outcome | 72 hours | 
| Diagnostic performance of HBP for death | Sensitivity, specificity, positive predictive value and negative predictive value of HBP to predict unfavorable outcome | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heparin binding protein, Mortality