**1. Introduction**

During the last decades advances in neonatal intensive care have led to an impressive decrease of neonatal mortality and morbidity. However, infectious episodes in the early postnatal period still remain serious and potentially life-threatening events with a mortality rate of up to 50% in very premature infants. [1, 2] The signs and symptoms of neonatal sepsis can be clinically indistinguishable from various noninfectious conditions such as respiratory distress syndrome or maladaptation. Therefore rapid diagnosis is crucial for preventing the child from an adverse outcome. The current practice of starting empirical antibiotic therapy in all neonates showing infection-like symptoms results in their exposure to adverse drug effects, nosocomial complications, and in the emergence of resistant strains. [3]

Sepsis results from the complex interaction between the invading microorganism and the host immune, inflammatory, and coagulation response. [4, 5] Inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-15, IL-18, MIF) and growth factors (IL-3, CSFs), and their secondary mediators, including nitric oxide, thromboxanes, leukotrienes, platelet-activating factor, prostaglandins, and complement, cause activation of the coagulation cascade, the complement cascade, and the production of prostaglandins, leukotrienes, proteases and oxidants. [6]

Laboratory sepsis markers represent a helpful tool in the evaluation of a child with clinical signs and complement the evaluation of a neonate with a potential infection. During the last decades efforts were done to improve laboratory sepsis diagnosis and a variety of the above mentioned markers and more were studied with different success. Despite the promising results for some of them current evidence suggests that none of them can consistently diagnose 100% of infected cases. C-reactive protein (CRP) is the most extensively acute phase reactant studied so far and despite the ongoing rise (and fall) of new infection markers it still remains the preferred index in many neonatal intensive care units.

© 2013 Hofer et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Hofer et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

There is great interest in rapid diagnostic tests that are able to safely distinguish infected from uninfected newborns, especially in the early phase of the disease. [7] In fact, a delayed start of the antibiotic treatment may be no more able to stop the fulminant clinical course with development of septic shock and death within hours after the first clinical symptoms. [8] In the era of multi-resistant microorganisms, it is as well important to avoid the unnecessary use of antibiotics in sepsis-negative infants.

The Role of C-Reactive Protein in the Diagnosis of Neonatal Sepsis 47

initiates the release of prostaglandins, leucotriens, and histamine, which results in vasodilatation, elevated vascular permeability, sensibilization of nozizeptors, and attraction

Activated fibroblasts, leukocytes, and endothelial cells produce pro-inflammatory cytokines including IL-1, TNF- α, and IL-6. They are responsible for the development of fever, lethargy, arthralgia, and headache, they activate the vascular endothelial cells, regulate proliferation of T-and B-lymphocytes, activate macrophages, have pro-coagulatory effects on endothelial cells, and they induce the production of acute-phase-proteins in the

Acute-phase-proteins form a heterogeneous group and include components of the complement system, coagulation factors, protease inhibitors, metal binding proteins, CRP, and other proteins that increase or decrease by more than 25% during an inflammatory

The production of CRP in the hepatocytes is mainly induced by IL-6 but can be further increased by synergy with IL-1. [14] ] Some authors have aimed to determine the normal serum CRP concentration in healthy adults: In 1981 Shine et al. [15] evaluated serum concentration of CRP determined by radioimmunoassay in 468 sera from normal adult volunteer blood donors and reported on a median concentration of 0.8 mg/l with a 90th percentile of less than 3.0 mg/l. More recently, Rifai and Ridker [16] used three different high-sensitivity techniques to determine CRP distributions in their cohort consisting of 22 thousand healthy adults from the Unites States. The median CRP values for men and women were 1.5 and 1.52 mg/l, the 90th percentiles were 6.05 and 6.61 mg/l, respectively. Similarly, Imhof et al [17] examined CRP values from 13 thousand apparently healthy men and women from different populations in Europe. The reported median concentration in the

single cohorts ranged from 0.6 to 1.7 mg/l, the 90th percentiles from 3.2 to 8.0 mg/l.

**4. Serial CRP determinations are of high sensitivity in diagnosis of** 

During the acute-phase-response the hepatic synthesis rate increases within hours and can reach levels 1000 fold. [10, 12] CRP levels remain high as long as the inflammation or tissue damage persists and then decrease rapidly. The half life time of CRP is 19 hours under all conditions, which shows the synthesis rate alone is responsible for the actual serum

CRP passes the placenta only in very low quantities, therefore, any elevation in the neonate always represents endogenous synthesis. [19] De novo hepatic synthesis starts very rapidly after a single stimulus with serum concentrations rising above 5 mg/l by about 6 hours and

In diagnosis of early onset sepsis previous studies reported on widely differing sensitivities and specificities of CRP ranging from 29% to 100% and from 6% to 100%, respectively. [11,

and activation of further inflammatory cells.

hepatocytes of the liver.

reaction. [11-13]

concentration. [18]

**neonatal sepsis** 

peaking around 48 hours. [20]
