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)

Sensitivity, Specificity, and Clinical Utility of CRP Levels

When combined with other tests, elevated CRP levels lend support to a diagnosis of sepsis while awaiting culture results.^[15,20] Sepsis screening panels augment, but do not replace, a thorough history, physical examination, and other clinical data.^[12,20,26] The use of combinations of tests, such as CRP, leukocyte indices, I:T ratios, elastase -proteinase inhibitor complexes, and IL-6, IL-8, and TNF levels, is under investigation.^[12,24,39] Studies examining the use of 2 tests, serial CRP and IL-8 levels, in infants being evaluated for late-onset sepsis revealed that if both levels were elevated, a sensitivity of 93% to 100% and specificity of 80% to 83% was achieved.^[20] This adds to the current body of evidence supporting the use of a combination of tests, along with the infant's history and physical examination, to improve the overall sensitivity and specificity of tests used to identify infection.^[7,26]

Infants suspected of sepsis often present with nonspecific subtle symptoms. They are treated initially with broad-spectrum antibiotics until culture results are available. As many as 20% to 30% of LBW infants are exposed to antenatal antibiotics;^[5,7,21] 79% of these infants are started on antibiotics within 24 hours of birth.^[7,11] Approximately 6% to 47% of infants with clinical signs of infection and a negative blood culture continue on antibiotics for an average of 2 to 5 days.^[5,7]

A CRP level that returns to the normal range (<10 mg/L) may indicate that the duration of antibiotic treatment has been sufficient, allowing earlier discontinuation of antibiotics.^[21,22,49] Several authors suggest that 2 CRP levels <10 mg/L have a negative predictive value of 99% in accurately identifying infants not infected or with a resolved infection.^[11,21,49]

In the face of increasing numbers of resistant organisms to antibiotics.^[5] using serial CRP levels to identify infants not likely to be infected has the potential to decrease overuse of antibiotics and slow the rate of antimicrobial resistance.^{[4,5,11,29,49]} CRP has a high predictive value when it remains normal 24 to 48 hours after the onset of signs of infection and is useful in retrospectively excluding the diagnosis of sepsis in infants receiving antibiotic therapy.^{[3,11,15,21,23]}

Serial measurements of CRP levels drawn every 24 to 48 hours after the onset of signs of infection have an increased sensitivity between 78.9% and 98%, specificity of 84% to 97%, and a negative predictive value of 99% in detecting sepsis.^{[11,15,21,23,26]} A high negative predictive value indicates that CRP levels drawn between 24 and 48 hours can identify infants who are unlikely to be infected.^{[11,15,22,26]}

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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

Sensitivity, Specificity, and Clinical Utility of CRP Levels

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