The Role of C-Reactive Protein in the Evaluation and Management of Infants With Suspected Sepsis

Joan M. Hengst, RNC, MSN, ARNP

Adv Neonatal Care. 2003;3(1)

The Biologic Structure and Function of CRP

Tillet and Francis first discovered CRP in 1930 at Rockefeller University while examining the serum of adult patients diagnosed with acute pneumococcal pneumonia.^[28] They observed a precipitation reaction between CRP and the C-polysaccharide cell wall of the pneumococcal bacteria. This reaction later was determined to be the result of CRP binding to C-polysaccharide in the presence of calcium, forming CRP-ligand complexes.^{[29,30,31,32,33,34]} CRP's unique binding characteristics have led to the identification of elevated CRP levels in over 70 different infectious and noninfectious disorders associated with acute and chronic inflammatory disorders in adults, children, and infants.^[12,29,35]

Understanding the biochemical structure and function of CRP is important to ensure appropriate use. CRP is a member of the pentraxin family of proteins, which are nonspecific, acute-phase reactant proteins composed of 5 identical 23-kDa polypeptide subunits arranged in a cyclic pentameter shape.^{[30,31,33,34]} Each of these subunits (Fig 1) contains one binding site for a phosphocholine molecule and 2 binding sites for calcium.^{[30,31,32,33,34]}

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Pentameter structure of CRP, including calcium and phosphocholine binding sites. These sites enable CRP to recognize and bind to a variety of microorganisms, cellular debris, and nuclear material from damaged cells. Data from Kushner.[34]

These binding sites allow CRP to recognize and bind to a variety of biologic substrates, including phosphocholine and phospholipid components of damaged cell walls and chromatin and nuclear antigens resulting in the formation of CRP-ligand complexes.^{[13,30,31,32,33]} CRP-ligand complexes can activate the complement system, thereby facilitating phagocytosis and the removal of materials released from damaged cells as well as potentially toxic materials from invading microorganisms.^{[31,32,33,36]} CRP-ligand complexes also bind directly to neutrophils, macrophages, and other phagocytic cells, stimulating an inflammatory response and the release of cytokines.^[31,32] Figure 2 illustrates the functions of CRP within the immune system.

(Enlarge Image)

Key functions of CRP within the innate immune system include the ability to (1) recognize and bind to phosphocholine exposed in damaged cell walls and found in many bacteria, fungi, and parasites; (2) act like an opsonin, marking bacteria, damaged cell walls, and nuclear debris for phagocytosis; (3) bind to Cl, the first component of the classical pathway of the complement system that triggers phagocytic activity; and (4) bind to polymorphonuclear leukocytes (PMNs) and monocytes, which stimulate the production of inflammatory cytokines. Data from DuClos.[31]

The fetus is able to produce CRP and other acute-phase reactant proteins as early as 4 to 5 weeks of gestation.^[10,12] Paired mother and infant sampling shows that CRP does not cross the placenta, and although maternal risk factors can exert an effect on the fetus, there is no correlation between maternal and infant CRP levels at birth.^{[37,38,39,40]}

An acute-phase inflammatory response occurs as the human body mounts a systemic response to tissue injury caused by infectious, noninfectious, chemical, physical, or immunologic toxins.^[32,33,34] CRP, serum amyloid A, haptoglobin, and fibrinogen are all positive acute-phase proteins regulated by cytokines, which are known to increase by at least 25% during the inflammatory response.^[32] Interleukin-1 (IL-1), interleukin-6 (IL-6), and tissue necrosis factor (TNF)- are the major cytokines that stimulate the liver to synthesize CRP and other positive acute-phase proteins (Fig 3).^[32,33]

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Stimulation and synthesis of positive acute-phase reactants during inflammation. Inflammation caused by infection or tissue damage stimulates the circulating inflammation-associated cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-. These cytokines stimulate hepatocytes to increase the synthesis and release of positive acute-phase proteins, including CRP. IL-6 is the major cytokine stimulus for CRP production.

CRP is the most sensitive of the acute-phase proteins, with levels rising as much as 1,000-fold during the acute inflammatory processes.^[29,32,34] Levels begin to rise within 4 to 6 hours of the onset of signs of infection or tissue injury and peak 24 to 48 hours later. They rapidly disappear as the infection or inflammatory process resolves.^{[11,22,23,26]}

The degree of CRP response or rise in serum may be dependent on the amount of tissue damage present. For example, elevated CRP levels from 150 to 350 mg/L have been reported in cases of invasive bacterial meningitis, whereas smaller rises from 20 to 40 mg/L occur in acute viral infections and from noninfectious causes.^[29,41] CRP is a useful serum marker to assess and monitor the presence, severity, and course of the inflammatory response in infectious and noninfectious disorders, including acute myocardial infarction, angina, malignancies, rheumatoid arthritis, inflammatory bowel disease, burns, and trauma, and after surgical procedures.^{[29,35,41,42]}

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Cite this: The Role of C-Reactive Protein in the Evaluation and Management of Infants With Suspected Sepsis - Medscape - Feb 01, 2003.

Abstract and Introduction
Diagnostic Testing and Sepsis
The Biologic Structure and Function of CRP
Laboratory Methods to Measure CRP
Controversies Surrounding the Use of CRP in Infants
Sensitivity, Specificity, and Clinical Utility of CRP Levels
Limitations in the Use of CRP Levels in Infants
The Clinical Application of CRP Testing in Infants With Suspected Sepsis
References

Table 1. Essential terms used in describing neonatal sepsis
Term	Definition
Infection	The body's response to the invasion of any microorganism, including bacterial, fungal, protozoan, or viral agent, that causes clinical signs of infection.^[3]
Clinical signs of infection	Generalized signs and symptoms seen with any infectious process, including respiratory distress, lethargy or irritability, poor muscle tone, feeding intolerance, apnea, bradycardia, tachycardia, pallor, cyanosis, poor perfusion, and temperature instability.^[3,6]
Maternal risk factors	Factors, when present, that increase the risk for infection in the infant. These include prolonged rupture of membranes (PROM) >18 hr, maternal fever, chorioamnionitis, maternal vaginal culture positive for group B streptococcus, history of a previous infant with group B streptococcus disease, and premature delivery <37 weeks gestation, and are associated with an increased risk of early-onset sepsis in the infant.^[2,3,5]
Sepsis	A bacterial bloodstream infection identified by one or more positive blood cultures in the presence of clinical signs of infection.
Early-onset sepsis	Sepsis that occurs within the first 3 days of life. It is associated with birth canal organisms acquired in utero or during delivery. Group B streptococcus remains the primary causative agent. One or more maternal risk factors are usually present. Term and preterm infants often present with respiratory distress, which can progress quickly to multisystem involvement within the first 24 hours.^[2,3,5,6]
Late-onset sepsis	Sepsis that occurs after the first 3-5 days of life and is associated with nosocomially acquired microorganisms. It occurs more frequently in premature and LBW infants and often includes meningitis. Coagulase-negative staphylococci are the primary causing bacteria.^[9] Presentation of signs of infection are slow and insidious.^[3,4,6]

Table 2. Comparison of CRP testing methods
Test Type	What Is Measured	How the Test Is Performed	How the Results Are Reported
Qualitative	The presence or absence of CRP-antibody complexes within a given amount of serum sample.	A measured amount of serum is added to a slide or test tube, mixed with a latex reagent, and examined for any signs of agglutination.	Positive: Presence of any agglutination indicates a concentration of CRP >6 mg/L or >10 mg/L
Qualitative		A latex reagent usually consists of a uniform-sized polystyrene or plastic beads coated with anti-human CRP antibodies. CRP binds to the antibody forming a CRP-antibody complex, which precipitates.	Negative: Absence of agglutination indicates a concentration of CRP <6 mg/L or <10 mg/L
Semiquantitative	An approximate amount of CRP-antibody complexes within a given amount of serum sample.	Serial serum/saline dilutions are mixed with a latex reagent and examined for the presence of agglutination. The highest dilution in which agglutination is visualized corresponds to the approximate amount of CRP.	The highest dilution in which agglutination occurs is reported as an approximate titer of CRP in mg/dL or mg/L 1:6 ratio = 6 to 12 mg/L 1:12 ratio = 12 to 24 mg/L 1:24 ratio = 24 to 48 mg/L 1:48 ratio >48 mg/L
Quantitative	The amount of CRP-antibody complexes within a serum sample.	Diluted serum samples are mixed with a reagent containing monoclonal antibodies that react specifically to CRP. The resulting CRP-antibody complexes are then measured.	Both quantitative methods are reported as an amount in mg/L or mg/dL
	Directly measures CRP-antibody complexes marked with an enzyme or fluorescent tracer.	Enzyme-linked multiplied immunoassay (ELISA), immunofluorescence CRP binds to fixed monoclonal anti-CRP-antibodies marked with an enzyme or fluorescent tracer. Enzyme marked CRP-antibody complexes are measured by a handheld or fully automated analyzer spectrophotometer. Fluorescent marked CRP-antibody complexes are visualized and measured via a fluorescent microscope.
	Directly measures the amount of agglutination or precipitation caused by the presence of CRP-antibody complexes.	Immunoturbidity, nephelometry, or radial immunodiffusion A beam of light from an infrared light emitting diode or detector is passed through a test tube containing CRP-antibody complexes. The amount of light scattered is measured from different angles using a nephelometer device or handheld turbidimeter or automated analyzer. The amount of CRP is proportional to the amount of light scattered.

Table 3. Studies evaluating the sensitivity and specificity of CRP in infants
Author(s) and Sample	Testing Method	Cutoff Value	Samples Collected	Test and Timing	Sensitivity	Specificity	Comments
Russel et al.^[25] n = 56 premature and term infants	Quantitative rate nephelometry	>8 mg/L	Serial: daily	CRP	71%	72%
				I:T Ratio	34%	73%
Pourcyrous et al.^[15] n = 187 premature and term infants	Quantitative immuno-nephelometry	≥9 mg/L	Serial: at least 2 initial and 12 to 24 hours later			91%
Kawamura et al.^[23] n = 108 term and n = 240 preterm infants with suspected sepsis	Quantitative laser nephelometry	>10 mg/L	Serial: at least 3 levels		Preterm: 61.5%	Preterm: 95%	Infected infants' levels peaked at 48 hours
					Term: 75%	Term: 97.8%
Franz et al.^[20] n = 223 preterm infants	Quantitative nephelometry	≥10 mg/L	Serial: 2 levels initial and 12-60 hours later	CRP and IL-8	93%	100%
				CRP alone	41%	41%
Benitz et al.^[11] n = 1,002 EOS and n = 184 LOS preterm and term infants	Qualitative rate nephelometry	>10 mg/L	Serial: 3 levels First level on admission, and the next 2 mornings (at least 8 hours apart between level 1 and level 2)	Initial CRP 1 for EOS	35%	90%
				Initial CRP 1 for LOS	61.5%	92.5%
				CRP 2 and 3 for EOS	88.9%	97.6%
				CRP 2 and 3 for LOS	96.4%	71.8%
Berger et al.^[26] n = 195 term and preterm infants	Qualitative immunoassay	>20 mg/L	Serial: 3 levels Initial level and then every 12-24 hours	CRP	75%	86%	Infected infants' levels peaked 24 hours after positive culture
				I:T Ratio	78%	73%

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The Role of C-Reactive Protein in the Evaluation and Management of Infants With Suspected Sepsis

The Biologic Structure and Function of CRP

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