Introduction

C-reactive protein (CRP) was discovered by Tillett and Francis in 1930. The name CRP arose because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the "c" carbohydrate antigen of the capsule of pneumococcus.

CRP is a pentameric protein synthesized by the liver, whose level rises in response to inflammation. CRP is an acute-phase reactant protein that is primarily induced by the IL-6 action on the gene responsible for the transcription of CRP during the acute phase of an inflammatory/infectious process. There is some question about whether dysregulation of the role of CRP in the clearance of apoptotic cells and cellular debris plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but this has not been definitively demonstrated. It has been demonstrated to have some protective properties in animal studies on lung tissue in alveolitis by reducing neutrophil-mediated damage to the alveoli and protein leakage into the lung.

CRP has both proinflammatory and anti-inflammatory properties. It plays a role in the recognition and clearance of foreign pathogens and damaged cells by binding to phosphocholine, phospholipids, histone, chromatin, and fibronectin. It can activate the classic complement pathway and also activate phagocytic cells via Fc receptors to expedite the removal of cellular debris and damaged or apoptotic cells and foreign pathogens. This can become pathologic, however, when it is activated by autoantibodies displaying the phosphocholine arm in auto-immune processes, such as idiopathic thrombocytopenic purpura (ITP). It can also worsen tissue damage in certain cases by activation of the complement system and thus inflammatory cytokines.[1][2][3]

As compared to the erythrocyte sedimentation rate, which is an indirect test for inflammation, the levels of CRP rise and fall rapidly with the onset and removal of the inflammatory stimulus, respectively. Persistently elevated CRP levels can be seen in chronic inflammatory conditions such as chronic infections or inflammatory arthritides such as rheumatoid arthritis.

There are numerous causes of an elevated C-reactive protein.  These include acute and chronic conditions, and these can be infectious or non-infectious in etiology. However, markedly elevated levels of CRP are most often associated with an infectious cause[4] (an example of pathogen-associated molecular pattern recognition).  Trauma can also cause elevations in CRP (alarmin response). More modest elevations tend to be associated with a broader spectrum of etiologies, ranging from sleep disturbances to periodontal disease.

Specimen Collection

A blood specimen is taken from a peripheral venous draw. A phlebotomist performs the procedure in most cases. The phlebotomist secures a snug rubber band around the upper arm, and the patient pumps his or her fist several times. The phlebotomist palpates the vein to confirm the location and cleanses the area with an alcohol prep pad. Once the area air dries, the practitioner introduces a needle into the vein and draws a vial of blood. He or she removes the band from the patient's arm and then removes the needle and applies pressure to the venipuncture site until hemostasis occurs, usually within one minute. A bandage is applied over the site.

The patient's medications should be reviewed, as these can affect the outcome of the test. Fasting is not required before the blood draw. There are no special procedures required. Complications include oozing at the draw site, bruising or mild tenderness at the site, or very rarely, infection at the venipuncture site. Other bodily fluids, such as synovial fluid, can be tested for in this manner but frequently are not.

Immunoassays and laser nephelometry are the methods to quantify CRP levels and are cheap, accurate, and fast. To detect lower levels of CRP (0.3 to 1.0 mg/L), high-sensitivity CRP methods are recommended as the usual CRP detection tests are less precise. High-sensitivity CRP only denotes the assay process used, allowing for detection of lower levels of CRP and not a different, or more specific, differential diagnosis.

Indications

This test is performed when the physician suspects acute or chronic inflammation (e.g., SLE or rheumatoid arthritis [RA]) or infection. The utility of the hs-CRP for cardiac screening is debatable. There is some correlation between cardiovascular risk and elevated hs-CRP, but the application of this is still controversial especially given the poor specificity of this test, and it is currently undergoing more evaluation.[5][6][7]

Normal and Critical Findings

Lab values vary, and there is no standard at present.  However, in general, the result is reported in either mg/dL or mg/L. Hs-CRP is usually reported in mg/dL. When used for cardiac risk stratification, hs-CRP levels less than 1 mg/dL are considered low risk. Levels between 1 mg/dL and 3 mg/dL are considered a moderate risk, and a level greater than 3 mg/dL is considered high risk for the development of cardiovascular disease.[8][9] 

Interpretation of CRP levels:

Less than 0.3 mg/dL: Normal (level seen in most healthy adults).

0.3 to 1.0 mg/dL: Normal or minor elevation (can be seen in obesity, pregnancy, depression, diabetes, common cold, gingivitis, periodontitis, sedentary lifestyle, cigarette smoking, and genetic polymorphisms).

1.0 to 10.0 mg/dL: Moderate elevation (Systemic inflammation such as RA, SLE, or other autoimmune diseases, malignancies, myocardial infarction, pancreatitis, bronchitis).

More than 10.0 mg/dL: Marked elevation (Acute bacterial infections, viral infections, systemic vasculitis, major trauma).

More than 50.0 mg/dL: Severe elevation (Acute bacterial infections).

Interfering Factors

Certain medications, such as non-steroidal anti-inflammatory drugs (NSAIDs), will falsely decrease CRP levels. Statins, as well, have been known to reduce CRP levels falsely. Recent injury or illness can falsely elevate levels, particularly when using this test for cardiac risk stratification. Magnesium supplementation also can decrease CRP levels.

As mentioned above, mild elevations in CRP can be seen without any systemic or inflammatory disease. Females and elderly patients have higher levels of CRP. Obesity, insomnia, depression, smoking, and diabetes can all contribute to mild elevations in CRP, and the results shall be interpreted with caution in individuals with these comorbidities.

Complications

Given the highly variable causality of elevated CRP, marginal elevations in the CRP can be difficult to interpret and should not be used as an isolated test result interpreted as appropriate for the clinical picture. It is useful in suggesting infection versus inflammation if the levels are extremely high, but levels between 1 mg/dL and 10 mg/dL can be difficult to interpret accurately. Chronic conditions, such as inflammatory arthritis or SLE, can make these levels elevated chronically, making it harder to determine if there is any significance to an elevated hs-CRP level when using it as a predictive marker for cardiovascular disease.

Clinical Significance

Very high levels of CRP, greater than 50 mg/dL, are associated with bacterial infections about 90% of the time. In multiple studies, CRP has been used as a prognostic factor in acute and chronic infections, including hepatitis C, dengue, and malaria. [10][11][12] On the other hand, mild elevations may or may not be clinically relevant. Clinical correlation is strongly recommended while interpreting the results of the CRP test.