High Sensitivity C-Reactive Protein (hsCRP)

Introduction
Over 50% of coronary events occur in individuals with low to moderate low density lipoprotein (LDL) cholesterol.1 The search for additional predictive risk factors has recently focused on the role of inflammation in the development of atherosclerosis. High sensitivity C-reactive protein, or hsCRP, is a systemic marker of inflammation and an effective marker for long-term risk assessment.2

Alere Cholestech LDX System Brief

Why High Sensitivity CRP?

Low level increases in CRP have been reported in various conditions and disease states that are thought to be associated with inflammation.2,5-7 The most prominently studied utility has been for cardiovascular disease, where CRP has been reported to predict cardiovascular outcomes independently of other conventional markers of risk.2,8,9 Increases in CRP are nonspecific and should be interpreted in the context of a complete clinical evaluation. If elevated values are observed in an apparently healthy individual, the test should be repeated in order to help rule out a recent response to undetected infection or tissue injury. Conventional CRP assays that can accommodate very large increases have not been optimized for the highly sensitive detection of the low level increases characterizing these clinical applications. CRP levels in apparently healthy individuals can be below 0.2 mg/L,10 requiring high sensitivity or hsCRP assays.

recommended the following interpretation of hsCRP results: < 1 mg/L Low Risk 13 mg/L Average Risk > 3 mg/L High Risk

What is CRP?
C-reactive protein (CRP) is an acute phase reactant that responds as a sensitive, though nonspecific, marker of systemic inflammation. The pentameric, globular protein is synthesized by the liver in response to stimuli from circulating inflammatory cytokines. CRP has traditionally been used as a systemic marker of infection and tissue injury.3 An expanding body of research now indicates that CRP likely plays a direct, active inflammatory role in blood vessels, leading to the development of atherosclerosis.4 Within 2448 hours of an infectious or noninfectious stimulus, CRP levels may rise up to 3000-fold over circulating levels seen in apparently healthy individuals, typically less than 10 mg/L.3 CRP levels in conditions characterized by chronic inflammation, such as rheumatoid arthritis and certain other rheumatic disorders, are likewise characterized by significant elevations. Conventional CRP assays have therefore been optimized to facilitate measurement of dynamic increases in concentration. But this is achieved at the expense of sensitivity to detect low level increases due to more subtle causes of inflammation.

Increases in CRP are nonspecific, however, and should be interpreted in the context of a complete clinical evaluation. HsCRP values > 10 mg/L observed in an apparently healthy individual should be repeated in order to help rule out a recent response to undetected infection or tissue injury.9

Standardization of hsCRP
The CDC is coordinating a project to standardize hsCRP assays. Alere participated in the first phase of this project which concluded that it was feasible to use Certified Reference Material (CRM) 470 as a secondary reference material for hsCRP assays (CRM 470 has since been replaced by ERM-DA472).11 The second phase of the standardization project involves working with manufacturers to ensure accurate calibrator value assignment and to normalize assay results. Alere standardizes the Alere Cholestech LDX hsCRP assay using diluted ERM-DA472, and intends to adjust its process in accord with CDC recommendations.

How are hsCRP Results Interpreted?

HsCRP values range between 0.3 and 8.6 mg/L in healthy men and between 0.2 and 9.1 mg/L in healthy women who are not taking hormone replacement therapy.10 Low grade inflammation may occur in apparently healthy individuals, placing them at increased risk of the conditions noted above. In a scientific statement,9 the Centers for Disease Control and Prevention (CDC) and the American Heart Association (AHA)

Differences Among hsCRP Methods

A variety of methods are employed by the various manufacturers of hsCRP assays. These include several immunoturbidometric approaches, chemiluminescence, particle-enhanced

immunonephelometry, and the lateral flow immunoassay technique of the Alere Cholestech LDX hsCRP assay. Like Alere, most manufacturers claim to standardize their assays using CRM470 or ERM-DA472. However, differences in standardization are clearly evident,11,12 likely as a result of differences in assay methodologies and manufacturing processes.

System is giving accurate results. Ensure that sample type is set to Serum mode in the Configuration menu. Controls should be tested: With each new lot of cassettes With every new shipment of cassettes, even if the lot has been received previously When reagents may have been stored or handled in a way that can degrade their performance As otherwise required by your laboratorys standard quality control procedures As otherwise required by federal, state and local guidelines Note that if you will be running fingerstick or whole blood samples after you have tested Quality Control materials, be sure to change the sample type in the Conguration menu to Whole Blood mode. The quality control results should be in range before testing patient samples. Refer to the Alere Cholestech LDX System User Manual if they are not. Please call Alere Product Support to report any problems or if you have any questions about quality control.

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Schmidt R, Schmidt H, Curb JD, Masaki K et al. Early inammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 2002; 52:168-74. Danesh J, Whincup P, Walker M, Lennon L et al. Low grade inammation and coronary heart disease: prospective study and updated metaanalyses. BMJ 2000; 321:199-204.

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9. Pearson TA, Mensah GA, Alexander RW, Anderson JL et al. Markers of inammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003; 107:499- 511. 10. Rifai N, Ridker PM. Population distributions of C-reactive protein in apparently healthy men and women in the United States: implication for clinical interpretation. Clin Chem 2003; 49:666-9. 11. Kimberly MM, Vesper HW, Caudill SP, Cooper GR et al. Standardization of immunoassays for measurement of high-sensitivity C-reactive protein. Phase I: evaluation of secondary reference materials. Clin Chem 2003; 49:611-6. 12. Roberts WL, Moulton L, Law TC, Farrow G et al. Evaluation of nine automated high-sensitivity C-reactive protein methods: implications for clinical and epidemiological applications. Part 2. Clin Chem 2001; 47:418-25.

Testing hsCRP on the Alere Cholestech LDX System

Alere Cholestech LDX hsCRP is an in vitro diagnostic test for the quantitative determination C-reactive protein in whole blood or serum. Measurement of CRP is useful as an aid in the detection and evaluation of infection, tissue injury, inflammatory disorders, and associated diseases. Alere Cholestech LDX hsCRP tests are for use in laboratories certified for moderate complexity testing Instructions for running the hsCRP test will be found in the package insert in each box of hsCRP cassettes. Please read the hsCRP package insert before running an hsCRP test and note the following: Fingerstick samples are collected using an Alere Cholestech LDX 50 L Capillary Tube. Please note that this is a different volume/capillary tube than any other Alere Cholestech LDX test that you might already perform. Fingerstick samples must be applied to the cassette within 5 minutes after collection. Place the cassette into the drawer of the analyzer immediately after dispensing the sample into the well. After pressing Run, hsCRP results will be displayed in 7 minutes (results will be displayed in 4 minutes for serum or plasma samples). Hematocrit levels between 30% and 55% do not affect results.

CPT Code
hsCRP 86141

References
1. Wilson PW, DAgostino RB, Levy D, Belanger AM et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97:1837-47.

2. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107:363-9. 3. Pepys MB. C-reactive protein fty years on. Lancet 1981; 1:653-7. 4. Szmitko PE, Wang CH, Weisel RD, de Almeida JR et al. New markers of inammation and endothelial cell activation: Part I. Circulation 2003; 108:1917-23. Wasunna A, Whitelaw A, Gallimore R, Hawkins PN, Pepys MB. C-reactive protein and bacterial infection in preterm infants. Eur J Pediatr 1990; 149:424-7. Spector TD, Hart DJ, Nandra D, Doyle DV et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 1997; 40:723-7.

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Quality Control
Quality control should be run routinely to show that your Alere Cholestech LDX

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