Heparin-binding Protein Levels Research Articles

Should heparin-binding protein levels be routinely monitored in patients with severe sepsis and septic shock?

Heparin-binding protein (HBP), also known as azurocidin, has multiple functions in the inflammatory process, especially during severe infections. Beside its antimicrobial properties, HBP may induce vascular leakage leading to extravascular efflux, which is an important pathophysiologic event in the development of septic shock. Not surprisingly, high HBP plasma levels are found in severe sepsis patients and in septic shock patients as well as in serious infections associated with endothelial damage. In the present issue of Critical Care, Linder and colleagues demonstrate new aspects of HBP daily monitoring in ICU patients. The authors observed that high HBP plasma levels are associated with an increased mortality rate in both septic and nonseptic critically ill patients, indicating that HBP may be a reliable prognostic biomarker. However, there are some limitations hindering rapid translation of these interesting findings into the daily routine. First, the group of nonseptic critically ill patients (n = 28) enrolled in the study was rather small as compared with the septic group (n = 151). Moreover, 50% of nonseptic patients developed infection while hospitalized in the ICU, and to classify them as truly nonseptic patients is problematic. Second, there is a lack of a routine diagnostic method for HBP analysis. Nevertheless, if the results of the present study are validated in large clinical trials in different ICU populations and cost-effectiveness data become available, the serial HBP measurements will have a promising future.

Elevated urine levels of heparin-binding protein in children with urinary tract infection

Urinary tract infection (UTI) is a common infection diagnosis in children, and efficient diagnosis and treatment are important to avoid serious complications. In this study we investigated whether urinary levels of neutrophil-derived heparin-binding protein (HBP) can be used as a marker of UTI in children. These results were compared to those of dipstick analysis, interleukin-6 (IL-6) analysis in urine, and bacterial culturing. Seventy-eight children aged 0-18 years with fever and/or symptoms indicating UTI were enrolled in a prospective consecutive study. Urine samples were cultured and analyzed with dipstick, and concentrations of HBP and IL-6 were measured. Fifteen patients were classified as having UTI, 30 patients had fever but were diagnosed with a non-urinary tract infection, and 33 patients had neither UTI nor fever. Using a urine HBP (U-HBP) cut-off level of 32 ng/mL, the sensitivity and specificity for detecting UTI were 93.3 and 90.3 %, respectively. Receiver operating characteristic curves demonstrated that U-HBP levels were a higher specificity indicator of UTI than urine white blood cell counts or urine IL-6 levels; they also showed a higher sensitivity than the results of the urine nitrite test. All patients with significant growth of clinically relevant bacteria had elevated U-HBP levels. The results indicate that rapid analysis of U-HBP can provide helpful guidance in the management of children with suspected UTI.

Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock

IntroductionRapid detection of, and optimized treatment for, severe sepsis and septic shock is crucial for successful outcome. Heparin-binding protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcome in patients with severe infections. Our aim was to study the systemic release and dynamics of HBP in the plasma of patients with severe sepsis and septic shock in the ICU.MethodsA prospective study was conducted of two patient cohorts treated in the ICU at Karolinska University Hospital Huddinge in Sweden. A total of 179 patients was included, of whom 151 had sepsis (126 with septic shock and 25 patients with severe sepsis) and 28 a non-septic critical condition. Blood samples were collected at five time points during six days after admission.ResultsHBP levels were significantly higher in the sepsis group as compared to the control group. At admission to the ICU, a plasma HBP concentration of ≥15 ng/mL and/or a HBP (ng/mL)/white blood cell count (109/L) ratio of >2 was found in 87.2% and 50.0% of critically ill patients with sepsis and non-septic illness, respectively. A lactate level of >2.5 mmol/L was detected in 64.9% and 56.0% of the same patient groups. Both in the sepsis group (n = 151) and in the whole group (n = 179), plasma HBP concentrations at admission and in the last measured sample within the 144 hour study period were significantly higher among 28-day non-survivors as compared to survivors and in the sepsis group, an elevated HBP-level at baseline was associated with an increased case-fatality rate at 28 days.ConclusionsPlasma HBP levels were significantly higher in patients with severe sepsis or septic shock compared to patients with a non-septic illness in the ICU. HBP was associated with severity of disease and an elevated HBP at admission was associated with an increased risk of death. HBP that rises over time may identify patients with a deteriorating prognosis. Thus, repeated HBP measurement in the ICU may help monitor treatment and predict outcome in patients with severe infections.

Increased plasma levels of heparin-binding protein in patients with shock: a prospective, cohort study

Heparin-binding protein (HBP) is a potent inducer of increased vascular permeability. The purpose of this study was to examine plasma levels of HBP in patients with shock. Fifty-three consecutive patients with septic and non-septic shock at a mixed-bed intensive care unit were included, as well as 20 age-matched controls. Patients with local infections but without signs of shock served as infectious controls. Enzyme-linked immunosorbent assay was used to determine plasma levels of HBP. There were no differences in serum HBP levels between healthy controls and those with local infections, including urinary tract infections, pneumonia and gastroenteritis, without shock. Levels of HBP were higher in patients with non-septic shock and septic shock than healthy controls. However, there was no difference in serum HBP levels between patients with septic shock and those with non-septic shock. Moreover, HBP levels were not different between patients with low and high APACHE II scores. Plasma levels of HBP were similar in surviving and non-surviving patients with shock. HBP is elevated in patients with shock from septic and non-septic etiologies. Future investigations are required to define the functional role of HBP in patients with shock.

Evaluation of potential biomarkers for the discrimination of bacterial and viral infections

Timely knowledge of the bacterial etiology and localization of infection are important for empirical antibiotic therapy. Thus, the goal of this study was to evaluate routinely used biomarkers together with novel laboratory parameters in the diagnosis of infection. In this prospective study, 54 adult patients with bacterial infections admitted to the Department of Infectious Diseases were included. For comparison, 27 patients with viral infections were enrolled. In these patients, white blood cell (WBC) counts, differential blood counts, serum levels of procalcitonin (PCT), IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α, IFN-γ, soluble CD14 (sCD14), heparin-binding protein (HBP), cortisol (Cort), and monocyte surface expression of TLR2, TLR4, HLA-DR, and CD14 were analyzed. Also, these biomarkers were evaluated in 21 patients with acute community-acquired bacterial pneumonia (CABP), as well as in 21 patients with pyelonephritis and urosepsis. The highest sensitivity and specificity (expressed as the area under the curve [AUC]) for bacterial infection were observed in serum concentration of PCT (0.952), neutrophil and lymphocyte counts (0.852 and 0.841, respectively), and serum levels of HBP (0.837), IL-6 (0.830), and Cort (0.817). In addition, the serum levels of IFN-γ and Cort were significantly higher and IL-8 levels were lower in CABP when compared to pyelonephritis or urosepsis. From the novel potential biomarkers, only PCT demonstrated superiority over the routine parameters in the differentiation of bacterial from viral infections. However, some of the novel parameters should be further evaluated in larger and better characterized cohorts of patients in order to find their clinical applications.

Heparin-binding protein: A diagnostic marker of acute bacterial meningitis*

The early detection of bacterial meningitis is crucial for successful outcome. Heparin-binding protein, a potent inducer of increased vascular permeability, is released from activated neutrophils in severe sepsis. In this study we investigated whether heparin-binding protein levels in cerebrospinal fluid could be used as a diagnostic marker for acute bacterial meningitis. One prospective and one retrospective patient cohort from two university hospitals in Sweden were analyzed. Cerebrospinal fluid samples were collected from 174 patients with suspected central nervous system infection. Thirty-seven patients with acute community-acquired bacterial meningitis, four patients with neurosurgical bacterial meningitis, 29 patients with viral meningitis or encephalitis, seven patients with neuroborreliosis, and 97 control patients were included. None. Cerebrospinal fluid samples were analyzed for the concentrations of heparin-binding protein, lactate, protein, glucose, neutrophils, and mononuclear cells. Heparin-binding protein levels were significantly higher (p < .01) in patients with acute bacterial meningitis (median 376 ng/mL, range 12-858 ng/mL) than in patients with viral central nervous system infection (median 4.7 ng/mL, range 3.0-41 ng/mL) or neuroborreliosis (median 3.6 ng/mL, range 3.2-10 ng/mL) or in control patients with a normal cerebrospinal fluid cell count (median 3.5 ng/mL, range 2.4-8.7 ng/mL). In the prospectively studied group, a heparin-binding protein concentration exceeding 20 ng/mL gave a sensitivity of 100%, a specificity of 99.2%, and positive and negative predictive values of 96.2% and 100%, respectively, in diagnosing acute bacterial meningitis. The area under the receiver-operating characteristic curve for heparin-binding protein was 0.994, which was higher than for the other investigated parameters. Elevated cerebrospinal fluid levels of heparin-binding protein distinguish between patients with acute bacterial meningitis and patients with other central nervous system infections.

Heparin‐Binding Protein: An Early Marker of Circulatory Failure in Sepsis

The early detection of circulatory failure in patients with sepsis is important for successful treatment. Heparin-binding protein (HBP), released from activated neutrophils, is a potent inducer of vascular leakage. In this study, we investigated whether plasma levels of HBP could be used as an early diagnostic marker for severe sepsis with hypotension. A prospective study of 233 febrile adult patients with a suspected infection was conducted. Patients were classified into 5 groups on the basis of systemic inflammatory response syndrome criteria, organ failure, and the final diagnosis. Blood samples obtained at enrollment were analyzed for the concentrations of HBP, procalcitonin, interleukin-6, lactate, C-reactive protein, and the number of white blood cells. Twenty-six patients were diagnosed with severe sepsis and septic shock, 44 patients had severe sepsis without septic shock, 100 patients had sepsis, 43 patients had an infection without sepsis, and 20 patients had an inflammatory response caused by a noninfectious disease. A plasma HBP level > or = 15 ng/mL was a better indicator of severe sepsis (with or without septic shock) than any other laboratory parameter investigated (sensitivity, 87.1%; specificity, 95.1%; positive predictive value, 88.4%; negative predictive value, 94.5%). Thirty-two of the 70 patients with severe sepsis were sampled for up to 12 h before signs of circulatory failure appeared, and in 29 of these patients, HBP plasma concentrations were already elevated. In febrile patients, high plasma levels of HBP help to identify patients with an imminent risk of developing sepsis with circulatory failure.

Heparin binding protein is increased in chronic leg ulcer fluid and released from granulocytes by secreted products of Pseudomonas aeruginosa.

Recently it was demonstrated by Gautam, et al. that release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, induced endothelial hyperpermeability and neutrophil efflux. Here, we show that chronic leg ulcer fluid, in contrast to wound fluid from acute wounds, contains highly increased levels of HBP. Immunohistochemistry demonstrated the presence of HBP in chronic ulcer tissues. Furthermore, secreted products of Pseudomonas aeruginosa were found to induce release of HBP from human neutrophils. Our data suggest a possible link between bacterial presence and HBP-release in chronic ulcers. Thus, targeting HBP offers an interesting option for reduction of endothelial barrier dysfunction in chronic ulcers.

The air we breathe

<b>Introduction.</b> The Organ Care System (OCS) is a sophisticated platform to preserve, evaluate and recondition donated lungs for transplantation (LTx). The impact of OCS on inflammatory response is not known. Here we focus on leukocyte responses and release of neutrophil-derived permeability and oxidative stress mediators. <b>Methods.</b> Neutrophil kinetics were retrospectively evaluated in 269 patients receiving standard-LTx (n=248) or OCS-LTx (n=21) between 2010 and 2015. In a subset of 40 patients, plasma levels of Myeloperoxidase (MPO) and Heparin Binding Protein (HBP) were measured by ELISA at baseline and at 0, 6, 12, 24, 48, and 72 hours. <b>Results.</b> Total leukocyte and neutrophil counts and CRP levels were significantly lower in the OCS group on day 1 and 2. Figure 1 shows plasma levels of HBP and MPO demonstrating lower mediator release at several time points in the OCS group. Postoperative gas exchange, duration of ventilation, ITU and hospital stay were similar between groups. Patient with severe grade3 Primary Graft Dysfunction (PGD) had higher HBP at T0 after LTx compared to patients with no PGD (p= 0.038). <b>Conclusions.</b> Recipients of OCS lungs exhibit lower leucocytosis and neutrophilia and lesser inflammatory mediator release with similar clinical outcomes compared to standard LTx. PGD is associated with increased HBP release suggesting HBP as a potential biomarker of lung injury.