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HAPS Executive
Locked Bag 1
Hunter Region Mail Centre
NSW 2310, Australia

Phone: (02) 4921 4000
Fax: (02) 4921 4400

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Phone: +61 2 4921 4000
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C-Reactive Protein

(Download  C-Reactive Protein.pdf)

Acute Phase Response

Inflammation is a protective reaction of vascular connective tissue to damaging stimuli, including infection. The inflammatory response is associated with vasodilatation, increased vascular permeability, recruitment of inflammatory cells (especially neutrophils in acute inflammation), the release of inflammatory mediators from these cells (including vasoactive amines, prostanoids, and reactive oxygen intermediates), and cytokine release. The macrophage-derived cytokines IL-1 and IL-6 are primarily responsible for the acute phase response, a protective change in plasma protein production by hepatocytes. The responses of some of the more important acute phase proteins are indicated in Table 1.

Erythrocyte Sedimentation Rate

The erythrocyte sedimentation rate (ESR) is an index of the acute phase response, mainly reflecting the concentrations of fibrinogen and the a-globulins, but also those of immunoglobulins that are not acute phase reactants. These proteins all have half-lives of days to weeks, and there is a significant lag time between changes at the clinical level and variations in the ESR. This, plus the influence of various other factors on the ESR (including diurnal variation, anaemia, food intake, and red cell morphology) makes it an imprecise guide to disease activity in most cases.

C-Reactive Protein

C-Reactive Protein (CRP) belongs to the pentraxin family of proteins, so-called because it has five identical subunits, encoded by a single gene on chromosome 1, which associate to form a stable disc-like pentameric structure. It was so named because it reacts with the somatic C polysaccharide of Streptococcus pneumoniae, and was first discovered in 1930 by Tillet and Frances. In the presence of calcium, CRP specifically binds to phosphocholine moieties. This gives CRP a host-defensive role, as phosphocholine is found in microbial polysaccharides (where CRP-binding activates the classical complement pathway and opsonises ligands for phagocytosis), the pro-inflammatory platelet-activating factor (PAF) (which is neutralised), and polymorphs (which are down-regulated).

CRP is exclusively made in the liver and is secreted in increased amounts within 6 hours of an acute inflammatory stimulus. The plasma level can double at least every 8 hours, reaching a peak after about 50 hours. After effective treatment or removal of the inflammatory stimulus, levels can fall almost as rapidly as the 5-7-hour plasma half-life of labelled exogenous CRP. The only condition that interferes with the "normal" CRP response is severe hepatocellular impairment.

The commonest conditions associated with major elevations of CRP levels are shown in Table 2.

Despite unequivocal evidence of active inflammatory disease and/or tissue damage, the conditions listed in Table 3 are usually associated with only minor elevations of CRP levels, and in many cases the CRP remains normal despite severe disease. The mechanism of this "selective" failure of the acute-phase CRP response is currently unknown. Differential diagnosis and management of fever in patients with systemic lupus erythematosus, interpreted in the clinical context, are improved by CRP measurement, with elevation favouring intercurrent infection over a lupus flare.

Clinical Utility of CRP

Screening for inflammatory disease

While an elevated CRP value is not specific for any condition, it is a very sensitive index of ongoing inflammation, and so provides a valuable adjunct to a careful clinical assessment. In differentiating between bacterial and viral infections, the CRP level is of some use. A very high CRP (>100 mg/L) is more likely to occur in bacterial than viral infection, and a normal CRP is unlikely in the presence of bacterial infection. However, intermediate CRP levels (10-50 mg/L) may be seen in both bacterial and viral conditions.

Monitoring the extent and activity of disease

Once a diagnosis has been established, CRP may be used to monitor the patient's response to therapy. The possiblity of intercurrent infection must always be kept in mind, especially when immunosuppressants are being administered. Infections usefully monitored by CRP levels include pyelonephritis, pelvic infections, meningitis, and endocarditis. Serial CRP measurements are important adjuncts to the use of temperature charts in clinical practice, as CRP levels are not affected by drug therapy or thermoregulatory factors. In rheumatoid arthritis, CRP levels correspond well to disease activity and treatment efficacy.

Detection and management of intercurrent infection

In conditions such as lupus and ulcerative colitis, where a major diagnostic dilemma is often posed between a disease flare and superinfection, elevation of the CRP above usual baseline levels for a particular patient may provide a valuable clue to the presence of infection.

CRP or ESR?

CRP is superior to ESR in terms of rapidity of response and specificity for inflammation. The CRP is also more precise and reproducible and a quicker test to perform than the ESR. However, ESR measurements remain helpful in certain clinical situations:

Detection of paraproteinaemias, which often don't elicit an acute phase response; and Monitoring of disease activity in Hodgkin's disease and the Polymyalgia Rheumatica-Giant Cell Arteritis syndrome.

Normal Ranges

The median normal concentration of CRP is 0.8mg/L, with 90% of apparently healthy individuals having a value less than 3mg/L and 99% less than 12mg/L. Higher values are abnormal and indicate the presence of organic disease. In pregnancy, the normal range is < 20mg/L.

Specimen Collection

Serum (5mL) should be collected in a non-anticoagulated tube. CRP testing is routinely provided Monday to Friday by the Hunter Immunology Unit (HIU). Urgent tests are provided 24 hours a day by contacting on-call staff after routine hours. For further information, contact the HIU staff on:

Phone: (049) 236 188
Fax: (049) 236 623

References

1. Pepys MB. The acute phase response and C-reactive protein. The Oxford Textbook of Medicine 1996 Ed. 3, Vol. 2. pp. 1527-1533
2. Young B, Gleeson M, Cripps AW. C-reactive protein: A critical review. Pathology 1991; 23: pp. 118-124
3. Janeway C, Travers P. Immunobiology. 1994; 9:18
4. Seldon M. Erythrocyte Sedimentation Rate. HAPS Newsletter September 1995.

Written by:                 Dr Glenn Reeves, Immunology HAPS
Written:                      November 1998

Last Reviewed:         10.5.2001