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)

Controversies Surrounding the Use of CRP in Infants

There is not an established standard of practice for the use of CRP in infants, and a variety of approaches are described in the literature. Some authors advocate the use of serial CRP levels as an early diagnostic tool for confirming the presence of sepsis,^[20,25,26] whereas others view it as a screening tool to rule out the presence of sepsis.^{[11,15,22,23,49]} Further, some authors advocate the use of CRP to monitor therapy and determine the length of antibiotic treatment^{[20,21,22,26,49]}; others do not use it at all.

Ideally, a clinical laboratory test that is considered reliable and diagnostic must have a high level of sensitivity and specificity in identifying what it is measuring.^[4] In other words, a test used to diagnose sepsis in the infant must always indicate abnormal results in those infants who have sepsis (sensitivity) and indicate normal results in infants who are not infected (specificity).^[4] Because neonatal sepsis has a reported mortality rate between 5% and 50%,^[4,5] it is critical that practitioners identify all infants with sepsis (high sensitivity), even if the trade-off is overdiagnosis and treatment of infants who are not infected (low specificity).^[29]

Initial criteria for normal and abnormal CRP levels were developed in adult populations. Recent studies of healthy asymptomatic adults have documented CRP levels ranging from 0.08 to 6.1 mg/L.^[48,50,51] Generally, CRP levels <10 mg/L are considered normal in adults and children.^{[12,29,35,37,50]} Emerging evidence that serum CRP levels as low as 2 mg/L may suggest a chronic or low-grade systemic inflammatory response and may be a useful risk predictor of cardiovascular and peripheral vascular disease in adults is beginning to challenge this norm.^{[51,52,53,54]}

CRP levels in healthy full-term and preterm infants may range from 2 to 5 mg/L during the first few days of life.^{[26,37,39,55]} During the neonatal period, an established upper normal CRP level of 10 mg/L has been identified in many studies.^{[11,12,15,20,21,22,23,26,38,39,49,55]} Other research teams have used upper normal reference levels ranging from 6 to 20 mg/L as cutoff levels to indicate the presence of sepsis or infection.^[15,25,41] Conflicting values have added to the confusion and uncertainty in using CRP in clinical practice.

Benitz et al evaluated CRP levels in 1,186 term and preterm infants and constructed receiver-operator characteristic curves for serial serum CRP levels.^[11] These data provide strong statistical evidence to establish 10 mg/L as the appropriate threshold level, that is, the level at which the test has the maximum ability to identify infants with proven or probable sepsis. The study also confirms that serial CRP levels drawn 12 to 24 hours after the onset of signs and symptoms of infection are superior to a single level.^[11]

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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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