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)

Limitations in the Use of CRP Levels in Infants

Many researchers have evaluated serum CRP for its predictive value in identifying infants with suspected sepsis. A CRP level measured at the onset of signs of infection has an overall sensitivity between 35% to 94% and a specificity between 60% and 96% in diagnosing sepsis.^[11,15,25] These broad ranges reflect variations in the population studied and the definition of sepsis, as well as different evaluation strategies, differences in defining abnormal serum cutoff levels, various methods of measuring CRP, and the number and timing of samples collected. Each variation in approach can influence the sensitivity and specificity of CRP levels in identifying sepsis. Table 3 provides an overview of the findings of relevant studies.

The timing of CRP measurement(s) is critical to achieve the highest sensitivity. A single CRP level drawn early in the course of disease has a low sensitivity between 35% and 96% in detecting the presence or absence of infection because the sampling time may precede a measurable rise in CRP levels; this rise may lag 12 to 24 hours after the onset of symptoms.^{[11,15,20,22,26,49]} It cannot be overemphasized that a single CRP level, obtained at the onset of illness, lacks sufficient sensitivity to be useful in prospectively excluding the diagnosis of sepsis.^[11]

Further, serum CRP testing is not suitable as a sole diagnostic test in determining sepsis because it can be elevated for reasons other than infection. Increased CRP levels can occur in infants for up to 3 days of life from noninfectious causes.^[23,29] The following factors have been reported to cause elevated CRP levels:

Maternal fever during labor^[37,40]
Prolonged rupture of membranes^[37,40]
Stressful delivery, fetal distress, or bot.^[37]
Perinatal asphyxia/shock^[26,37,40]
Periventricular and intraventricular hemorrhag.^[26]
Pneumothorace.^[26]
Meconium aspiration pneumonitis^{[15,26,37,40]}

CRP is not considered accurate in the preterm population. Levels do not always rise above 10 mg/L in preterm infants or those infants with overwhelming sepsis, resulting in a false-negative test result.^{[19,23,49,56,57]} Some authors hypothesize that the immature liver function of premature infants decreases their ability to generate and secrete CRP into the serum and/or there may be decreased ability of CRP to actually bind to phosphocholine and activate the complement system.^[56]

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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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