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.

In the present issue of Critical Care, Linder and colleagues present a new study in which they assess the clinical importance of serial measurements of heparin-binding protein (HBP) plasma levels in critically ill septic and nonseptic patients [1]. Th ey found that HBP plasma levels are signifi cantly higher in patients with severe sepsis and septic shock in comparison with patients with a nonseptic critical condition. Th e authors also demonstrated that HBP plasma levels obtained at admission to the ICU and during the last individual sampling are higher in nonsurvivors as compared with survivors in both the septic group and the whole study group. Moreover, the high baseline HBP plasma levels in septic patients were associated with an increased 28-day mortality rate. Altogether, these results indicate that serial HBP measurements might be very helpful in stratifi cation of ICU patients. However, there are some issues that should be raised before the study results can be translated into the daily routine.
Th e study was designed to compare HBP plasma levels in patients with severe sepsis and septic shock with levels in patients with noninfectious critical illness. However, these two groups of patients were not equal in size. Also, a signifi cant proportion of patients from the nonseptic group developed infection and was treated with antibiotics. Th is raises the question of whether the comparison between septic and nonseptic ICU patients is hindered by this treatment. Nevertheless, the study design is logical because fi nding a biomarker that would predict development of any shock state is highly desirable. Previous studies have demonstrated signifi cant predictive values of elevated levels of lactate, cortisol and IL-6 in the blood of patients with diff erent etiologies of shock [2][3][4]. However, these biomarkers have some limita tions: lactate levels are less infl uenced by arterial sampling, endogenous cortisol levels are downregulated by corticosteroids used in the treatment of septic shock or by relative adrenal insuffi ciency, and IL-6 analysis is not generally available in regular hospital laboratories [5].

Abstract
Heparin-binding protein (HBP), also known as azurocidin, has multiple functions in the infl ammatory process, especially during severe infections. Beside its antimicrobial properties, HBP may induce vascular leakage leading to extravascular effl ux, 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 fi ndings 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 diff erent ICU populations and cost-eff ectiveness data become available, the serial HBP measurements will have a promising future.
Other routinely measured biomarkers -such as procalcitonin, C-reactive protein, neutrophil and lymphocyte counts -have only a limited value in prognostic scoring of the critically ill patients and are mostly used in the early diagnostics of bacterial etiology of critical illness [6][7][8].
It is worth noting that HBP mediates multiple actions during the infectious process. Notably, HBP has antibacterial activity, which includes a direct microbicidal eff ect, and also helps neutrophils to migrate into the focus of infection. Similarly to HBP, C-reactive protein and IL-6 play an active role during the immune responses against infections: C-reactive protein is an infl ammation opsonin, and the major function of IL-6 is amplifi cation as well as downregulation of infl ammatory reactions, depending on the concentrations [9,10]. Regarding procalcitonin, there are only limited data from animal studies -which demonstrate that immunoneutralization of procalcitonin improved sur vival in experimental porcine sepsis [11]. Additionally, elevated cortisol levels in peripheral blood during sepsis are considered an integral part of com pensatory anti-infl ammatory res ponse syndrome, leading to downregulation of exagger ated systemic immune responses [12]. From the func tional point of view, in compari son with the above mentioned biomarkers, HBP there fore plays the most complex role in severe sepsis and septic shock -high lighting its potential for clinical use.
In conclusion, the serial measurements of HBP plasma levels can be a useful tool for close monitoring of critically ill septic patients. Th e results of Linder and colleagues therefore warrant evaluation in diff erent ICU populations. However, availability of a routine diagnostic method for HBP analysis is essential to confi rm these interesting data.

Competing interests
The authors declare that they have no competing interests.