The Role of Biomarkers in Management of Sepsis

Clinical management of critically ill patients with severe infection and sepsis can be improved by shortening the time to diagnostic and treatment decision (i.e. differentiation between bacterial vs. viral vs. fungal infection and vs. noninfectious etiologies). Furthermore, site-of-care decisions can be improved (e.g., early discharge or escalation of care) by an early risk stratification and the provision of prognostic information. Repeatedly measured biomarkers also help monitoring patients for tailoring therapy to individual needs of patients (antibiotic stewardship). In this context, the use of the host-response and blood infection marker procalcitonin (PCT) has gained much attention and has already been approved for guidance of antimicrobial therapies in patients with respiratory infection and sepsis. PCT is a precursor hormone of calcitonin that is not detectable in healthy individuals. However, the production of PCT is upregulated in response to bacterial infections and can decrease rapidly during recovery. Thus, PCT provides important additional information, which are able to supplement clinical and diagnostic parameters. This in turn, has not only a high impact on decisions regarding treatment of patients with suspected infections or sepsis, but can also influence the duration of antibiotic treatment courses. The use of PCT is evolving in the management of sepsis and several interventional studies and systematic reviews have analysed and summarised the effects of PCT guided strategies on antibiotic use and health outcomes. However, there is no universal consensus on the optimal use of PCT in the setting of sepsis. 

In healthy individuals, serum PCT is not detectable, since the protein is not released into the blood in absence of systemic inflammation. In case of a sepsis caused by bacterial infections, however, PCT synthesis is induced in practically all tissues and therefore detectable in the blood. PCT synthesis is triggered by bacterial toxins, such as endotoxin and cytokines e.g., interleukin (IL)-1beta, interleukin-6 and tumor necrosis factor (TNF)-alpha. Due to cytokines released during viral infections that inhibit the production of TNF-alpha, PCT synthesis is not induced in most viral infections. Moreover, PCT has a wide biological range, a short time to induction after bacterial stimulation and a long half-life. Thus, PCT has good discriminatory properties for the differentiation between bacterial and viral inflammations with rapidly available results. PCT per se cannot isolate or detect specific pathogens, but the level of PCT may be useful to estimate the probability of a severe bacterial infection.

Despite decades of research efforts, there is still no sepsis specific treatment option available. Crucial for a successful treatment and positive outcomes, is an early diagnosis and differentiation from non-infectious causes, in order to rapidly start with antimicrobial therapy and fluid resuscitation. However, due to the fact that clinical signs for a definite or suspected sepsis can be heterogeneous and often ambiguous, its diagnosis and treatment remains challenging. To date, no gold standard exists for the detection of sepsis caused by bloodstream infections. The use of conventional diagnostic approaches such as blood cultures and inflammatory blood markers C-reactive protein (CRP), white blood count (WBC)] in patients with a clinical suspected infection or sepsis is restricted by some limitations. The use of blood cultures for the identification of pathogens, can provide information about type of microorganism and susceptibility towards antibiotic therapy. However, only a small part of the analysed cultures results positive and in around 40–90% of patients with an assumed systemic infection, the results are negative blood culture with no growing pathogens. Moreover, the long time to results limits initial treatment decision making and contamination leads to suboptimal specificity of the obtained results. In order to improve diagnostic work-up, additional tests are appropriate, which are able to facilitate an early and reliable diagnosis³. 

Neonatal sepsis accounts for 0.97% of all disability-adjusted life years worldwide, demonstrating higher percentages compared to colon and rectum cancer, asthma or breast cancer. Neonatal sepsis has a high mortality of 11–19%2 and is associated with brain injury as well as poor neurodevelopmental and growth outcomes in early childhood. These adverse outcomes call for early detection and rapid intervention. Since sepsis is a systemic inflammatory response to infection, isolation of bacteria from blood is considered the gold standard. Due to the low obtainable blood volume in very low-birthweight infants (VLBW infants, birth weight < 1500 gm) of around 0.5–1 ml, the high percentage of low-level bacteraemia and the long duration to a positive blood culture, several parameters have been tested for their accuracy in diagnosing neonatal sepsis including procalcitonin, lipopolysaccharide-binding protein, presepsin and interleukin-6.

IL-6 is a multifunctional cytokine participating in immune response, haemopoiesis and acute-phase reactions. In response to infection, IL-6 enhances the production of IgM, IgG and IgA as well as the proliferation of helper T-cells and thereby plays a crucial role in host defence mechanisms. After exposure to bacterial endotoxins, IL-6 concentrations rise before acute-phase reactants including C-reactive protein (CRP). IL-6 can be determined in cord blood or serum yielding different diagnostic accuracy. Cord blood IL-6 has a sensitivity of 87–100% for early-onset sepsis. Serum IL-6 has a sensitivity of 75–85% and a specificity of 72.8–88% for the diagnosis of early-onset sepsis and a sensitivity of 80–93.8% and a specificity of 80–96% for late-onset sepsis, thereby outperforming CRP. Serum IL-6 concentrations quickly fall to undetectable values during antibiotic treatment. The high sensitivity and negative predictive value of IL-6 make it a suitable candidate for diagnosing neonatal sepsis in combination with the high specific CRP.