Clinical Laboratory in Emergency MedicineThe C-reactive protein1
Introduction
C-reactive protein (CRP) was first detected in 1930 by Tillet and Frances, who identified a substance in the sera of patients acutely infected with pneumococcal pneumonia that formed a precipitate when combined with polysaccharide C of Streptococcus pneumoniae (1). Subsequently, it was found that this reaction was not unique to pneumococcal pneumonia but could be found with a variety of other acute infections. This was early evidence of the body’s chemical response to inflammatory states and led to the characterization of other so-called “acute phase proteins” 2, 3. Like many acute phase proteins, CRP is normally present in trace levels in serum but increases rapidly and dramatically in response to a variety of infectious or inflammatory conditions 4, 5, 6. Since its discovery, CRP has been studied as a screening device for occult inflammation, as a marker of disease activity, and as a diagnostic tool (7). Recently, more rapid and precise methods of quantifying CRP have led to a renewed interest in its value in clinical medicine 8, 9. This article will focus on the potential use of CRP as an adjunct diagnostic test in the emergency department (ED).
Section snippets
Biochemistry/physiology
C-reactive protein is synthesized by hepatocytes. It is a pentameric protein consisting of five noncovalently bonded identical subunits with an overall molecular weight of approximately 118,00 daltons. In response to infection or tissue inflammation, CRP production is stimulated by cytokines, particularly IL-6, IL-1, and tumor necrosis factor 4, 10.
Levels in healthy individuals are normally less than 10 mg/L; however, in disease states, this level increases in the first 6 to 8 h and can reach
Measurement
Until the late 1970s, CRP was measured using qualitative or semi-quantitative laboratory techniques, most commonly latex agglutination, which precluded its use as a differential diagnostic test because any degree of inflammation produced positive results 12, 15. Presently, accurate and rapid quantitative measures of CRP are obtained using laser nephelometry, rate immunonephelometry or turbidimetry, and enzyme immunoassay. Nephelometric assays, which measure the formation of antigen-antibody
Application of CRP in the ED
Numerous studies conclude that CRP aids in the diagnosis of invasive bacterial disease, implying a role in the ED; however, there are a great deal of conflicting data regarding the use of CRP for diagnostic purposes 6, 17, 18, 19, 20, 21. Some argue that as a nonspecific indicator of inflammation, CRP, by definition, cannot accurately differentiate among the many sources of potential tissue destruction (16). In addition, conclusive data have not been reproduced consistently. Young cites several
Appendicitis
C-reactive protein has been studied in a variety of surgical conditions, mostly as an indicator of postoperative complications 22, 23, 24. Preoperatively, elevated CRP levels have been reported to aid in the diagnosis of acute appendicitis. The overall sensitivity of CRP in the studies we reviewed ranges from 40–87%, with a specificity of 53–82% 25, 26, 27, 28, 29.
Early in the course of appendicitis, the white blood cell count has shown the best diagnostic sensitivity among laboratory tests 30,
Cholecystitis
Juvonen found that a CRP level > 30 mg/L had a sensitivity of 78% in 108 patients with histologically diagnosed cholecystitis. In the same study, ultrasound had a sensitivity of 79%. When positive ultrasound findings were combined with a CRP > 30 mg/L, sensitivity was reported as 97% (42). C-reactive protein was found to be a more sensitive marker than ESR, white blood cell count, or fever in identifying acute cholecystitis. The study included 18 patients with elevated CRPs or ultrasound
Pancreatitis
C-reactive protein has been used to diagnose and predict the severity of pancreatitis 43, 44. Wilson found that peak CRP levels ≥ 210 mg/L discriminated between patients with clinically mild and severe pancreatitis with a sensitivity of 83% and a specificity of 85% (45). Heath obtained similar results, with peak concentrations > 150 mg/L predicting severe attacks (46). In these studies, pancreatitis was diagnosed by serum amylase and was graded on severity based on clinical impression. While
Pelvic inflammatory disease
C-reactive protein has been studied along with ESR in the diagnosis and prediction of severity of pelvic inflammatory disease (PID). Lehtinen concludes that both CRP and ESR should be routinely used to augment the clinical diagnosis of PID. However, in this study, no statistical significance was found between CRP levels in women presenting with endometritis only and no PID at all. The overall sensitivity and specificity of CRP in the diagnosis of PID was 74% and 67%, respectively, using a
Pneumonia
In the diagnosis of pneumonia, CRP is not useful for discriminating between bacterial and viral infections 51, 52. However, it has been found useful as a marker for antibiotic treatment failure or the development of infectious complications 53, 54. This has been shown in both the non-HIV and HIV populations (55). Although higher CRP levels usually correspond to bacterial pneumonia, especially due to S. pneumoniae, the ED management should be based on traditional parameters and on the overall
Urinary tract infection
Most data on CRP in urinary tract infection come from the pediatric literature. In all patients with clinically obvious pyelonephritis (14 of 14), Jodal found CRP levels > 25 mg/L, while all patients with uncomplicated infection (10 of 10) had CRP levels < 25 mg/L (21). C-reactive protein is not a useful marker to help distinguish between simple and complicated urinary tract infection in patients without clinical signs of acute pyelonephritis 21, 57. False positives may occur in acute cystitis
Meningitis
Serum CRP has been reported to accurately diagnose bacterial meningitis and to correspond with resolution of symptoms after successful antibiotic treatment 60, 61, 62. Recent studies have focused on cerebrospinal fluid (CSF) CRP to distinguish bacterial from viral meningitis 60, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72. Sensitivities of CSF CRP in diagnosing bacterial meningitis have been reported as high as 97–100% on initial lumbar puncture 63, 64, 66. In some cases, CSF CRP was a more
Neonatal sepsis and pediatric infections
In the neonatal period, CRP has been studied extensively for its ability to detect early infection 75, 76, 77, 78, 79, 80. Berger found that after the first 3 days of life, CRP is the single best test in early detection of neonatal septicemia, and that serial measurements parallel the course of infection and the efficacy of antibiotic treatment (75). Forest found that serial CRP values lead to increased accuracy of detecting bacterial infection in neonates. In this study, all neonates with
Summary
We regularly encounter equivocal presentations of disease in the ED. In these situations, we often turn to the clinical laboratory to help confirm or disprove our suspicions. The measurement of C-reactive protein has enjoyed periodic emphasis over the years as a measure of general illness and as an adjunct to physical examination and other laboratory data. Unfortunately, the nonspecific nature of the acute phase response prevents CRP from being a useful discriminatory diagnostic test. Based on
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Clinical Laboratory in Emergency Medicine is coordinated by Jonathan S. Olshaker, MD, of the University of Maryland Medical Center, Baltimore, Maryland