**3. CRP is part of the acute-phase-response**

The acute-phase-response is a physiological and metabolic reaction to an acute tissue injury of different etiology (trauma, surgery, infection, acute inflammation, etc) which aims to neutralize the inflammatory agent and to promote the healing of the injured tissue. [11]

After a trauma or the invasion of microorganisms an acute localized inflammatory reaction is initiated by activation of local resident cells. The contact with bacterial endo-or exotoxins initiates the release of prostaglandins, leucotriens, and histamine, which results in vasodilatation, elevated vascular permeability, sensibilization of nozizeptors, and attraction and activation of further inflammatory cells.

46 Neonatal Bacterial Infection

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

CRP was first described in 1930 by Tillet and Francis at Rockefeller University. [9] They observed a precipitation reaction between serum from patients suffering acute pneumococcal pneumonia and the extracted polysaccharide fraction C from the pneumococcal cell wall. This reaction could not be observed when using serum of neither healthy controls nor the same pneumonia patients after they had recovered. In view of the fact that the polysaccharide fraction was a protein the C-reactive component in the serum was named C-reactive protein. [9] By the 1950s CRP had been detected in more than 70 disorders including acute bacterial, viral, and other infections, as well as non-infectious diseases such as acute myocardial infarction, rheumatic disorders, and malignancies. [10] All of these disorders of disparate etiology had in common the theme of inflammation

CRP is composed by five identical subunits arranged in a cyclic pentameter shape. The whole protein has a diameter of 102 Å (1 Ångström = 10-10 m) and a molecular weight of 118 000 Daltons. [12] All subunits have the same orientation; therefore the whole protein has two faces, a 'recognition' face exhibiting five phosphocholin-binding sites and an 'effector' face containing complement and Fc-receptor-binding sites. [12] The principal ligand to CRP with the highest binding affinity is phosphocholin, which is found in lipopolysaccharid and cell walls of many bacteria and micro-organisms as well as in the outer leaflet of most

After binding to a macromolecular ligand CRP is recognized by the component C1q of the complement system and activates it on the classical pathway. CRP-ligand complexes bind to the Fc-receptor on neutrophil granulocytes, macrophages, etc as well and thus promote phagocytosis of the pathogen. CRP further activates monocytes and macrophages and stimulates the production of pro-inflammatory cytokines such as Interleukin-1 and Tumor

The acute-phase-response is a physiological and metabolic reaction to an acute tissue injury of different etiology (trauma, surgery, infection, acute inflammation, etc) which aims to neutralize the inflammatory agent and to promote the healing of the injured tissue. [11]

After a trauma or the invasion of microorganisms an acute localized inflammatory reaction is initiated by activation of local resident cells. The contact with bacterial endo-or exotoxins

unnecessary use of antibiotics in sepsis-negative infants.

**2. Structure and function of CRP** 

and/or tissue injury. [11]

biological membranes. [12]

necrosis factor α. [12, 13]

**3. CRP is part of the acute-phase-response** 

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 hepatocytes of the liver.

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 reaction. [11-13]

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.

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 concentration. [18]
