The erythrocyte sedimentation rate (often called the ESR or the "Sed Rate") is one of the oldest laboratory tests still in use. It expresses the rate at which cells sediment in blood that has been anticoagulated with sodium citrate or ethylenediaminetetraacetic acid (EDTA). The erythrocyte sedimentation rate reflects the relative density of the cells with respect to the plasma, and it is influenced by, among other things, the ability of the cells to form rouleaux. The surface attraction between erythrocytes is in turn affected by the proportions and types of proteins in the plasma. For example, increased fibrinogen and alpha, beta, and gamma globulins decrease the negative charges that normally keep red cells apart. This causes increased rouleaux and more rapid sedimentation1. Plasma viscosity, hematocrit, and cell shape also influence the sedimentation rate. The test is quite nonspecific, and an increased erythrocyte sedimentation rate can be seen in inflammatory bowel disease, rheumatoid arthritis and other inflammatory arthropathies, cardiac disease, cancer and lymphoma, gout, hepatitis, cirrhosis, systemic lupus erythematosus, and pregnancy, among other conditions. Blood that has been anticoagulated with heparin, either in vivo or in vitro, also may have an elevated erythrocyte sedimentation rate.
In 1930, Tillett and Francis identified a protein that precipitated with the C-polysaccharide antigen of the pneumococcus bacterium2. C-reactive protein is now known to be an "acute phase reactant" that is produced in the liver and has a biologic activity similar to immunoglobulins in that it binds membranes of microorganisms and cancer cells. In so doing, it opsonizes those membranes and activates complement to help initiate an inflammatory reaction prior to the production of specific antibodies. Similar to the erythrocyte sedimentation rate, the C-reactive protein level is elevated in a number of inflammatory disorders, including inflammatory bowel disease, inflammatory arthropathies, lymphoma, and infections. It increases and normalizes more rapidly than the erythrocyte sedimentation rate does, and a persistent, mild increase in the C-reactive protein level is associated with an increased risk of coronary artery disease and stroke.
While these two laboratory tests are quite nonspecific, they are rather sensitive, so many previous studies have documented their utility as screening tests for diagnosing orthopaedic infections3-5. In the July 2007 issue of The Journal, Greidanus and coauthors describe a prospective study intended to quantify how good these tests really are in diagnosing periprosthetic infections.
From 1997 to 2001, the authors measured the serum C-reactive protein level and the erythrocyte sedimentation rate in all patients who were scheduled to undergo revision knee arthroplasty at one center. Each consenting patient then underwent aspiration of the affected knee, and that aspirated fluid specimen was divided into three samples for microbiologic culture. Each patient also had three cultures obtained from the knee at the time that the implants were removed. Knees that had at least two positive fluid cultures or two positive operative cultures were considered to be infected; knees that had fewer positive cultures were considered not infected. The sensitivity and specificity of each test was then calculated with use of the culture results as the so-called gold standard. In addition, the authors used receiver-operating-characteristic curve analysis to identify the optimal cutoff points (i.e., threshold values) for distinguishing positive from negative results in their hospital. The results confirmed that these are both good screening tests, and that used together they are even better, but there are several important caveats to be considered when looking at the results of this study.
First, one might argue that the use of two positive culture results to define infection is an imperfect "gold standard." But of more importance is the very nature of the test population itself. Of the original 201 patients, twenty-six were excluded because they had an underlying disease or condition known to be associated with elevated erythrocyte sedimentation rate and/or C-reactive protein level. Some of these patients had rheumatoid arthritis, but we do not know the exact reasons for excluding the other patients. This is important, because anyone attempting to reproduce these results would need to use the same exclusion criteria. Nineteen patients who presented for second-stage revision for a known knee infection were also excluded, and eleven patients who were receiving antibiotics were excluded from the primary data set but were analyzed separately.
Of the remaining 151 knees, forty-five (approximately 30%) were diagnosed as infected. This extremely high prevalence of infection accurately reflects the referred patient base of the authors, but it is much higher than that seen by most orthopaedic surgeons and has important implications concerning the predictive value of the test results for C-reactive protein levels and erythrocyte sedimentation rates. A laboratory test with a relatively high frequency of false-positive results may seem like a good test when it is used in a population with a high prevalence of disease; however, if that same test is applied to a population with a low prevalence of disease, a high proportion of the results may be false-positives.
For example, with use of the cutoff values for erythrocyte sedimentation rate that the authors calculated from the receiver-operating-characteristic curves (sensitivity = 93%, specificity = 83%, prevalence = 29.8%), the negative predictive value is 96% and the positive predictive value is 71%. As these results are based in part on the exclusion criteria of this study, it is difficult to extrapolate how accurate these tests would be when applied to a population with a lower prevalence of infection, but if we lower the prevalence to, for example, 2%, the negative predictive value increases a little to 99.8% but the positive predictive value drops sharply from 70% to 10%.
Similarly, changing the prevalence of infection from 30% to 2% slightly increases the negative predictive value of the C-reactive protein test results from 95% to 99% but markedly decreases the positive predictive value from 73% to 12%.
What these additional calculations emphasize is an observation made by the authors as well as by previous investigators6: the erythrocyte sedimentation rate and the C-reactive protein level are both good screening tests, not confirmatory tests. An elevated erythrocyte sedimentation rate or C-reactive protein level in a patient who has had knee arthroplasty and who has knee pain but who does not have an underlying inflammatory or neoplastic disorder should raise suspicion of infection and should prompt further investigation, especially aspiration and culture of knee fluid. On the other hand, both the erythrocyte sedimentation rate test and the C-reactive protein level test are associated with too many false-positives to be considered confirmatory tests, especially when used in the usual orthopaedic practice that has a low prevalence of infections.
Finally, the cutoff points calculated by the authors from their receiver-operating-characteristic curves may be helpful in optimizing the accuracy of their tests, but it is useful to remember that these tests give continuous, not binary results, and that following the changes in erythrocyte sedimentation rate and C-reactive protein values over time for any given patient can also provide helpful information.
*The author did not receive any outside funding or grants in support of his research for or preparation of this work. Neither he nor a member of his immediate family received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the author, or a member of his immediate family, is affiliated or associated.
1. McPherson RA, Pincus MR, editors. Henry's Clinical Diagnosis and Management by Laboratory Methods. 21st ed. Philadelphia: Saunders; 2006. p 465.
2. Tillett WS, Francis T Jr. Serological reactions in pneumonia with non-protein somatic fraction of pneumococcus. J Exp Med. 1930;52:561-71.
3. Carlsson AS. Erythrocyte sedimentation rate in infected and non-infected total hip arthroplasties. Acta Orthop Scand. 1978;49:287-90.
4. White J, Kelly M, Dunsmuir R. C-reactive protein level after total hip and total knee replacement. J Bone Joint Surg Br. 1998;80:909-11.
5. Spangehl MJ, Masri BA, O'Connell JX, Duncan CP. Prospective analysis of preoperative and intraoperative investigations for the diagnosis of infection at the sites of two hundred and two revision total hip arthroplasties. J Bone Joint Surg Am. 1999;81:672-83.
6. Parvizi J, Ghanem E, Menashe S, Barrack RL, Bauer TW. Periprosthetic infection: what are the diagnostic challenges? J Bone Joint Surg Am. 2006;88:138-47.