Chapter 12 Erythrocyte Sedimentation Rate
Introduction
The erythrocyte sedimentation rate (ESR), the rate at which erythrocytes settle out of nonclotted blood in 1 hour, has been one of the most widely performed laboratory tests in the past 65 years. Used primarily to detect occult processes and monitor inflammatory conditions, the ESR test has changed little since 1918 when Fahraeus discovered that erythrocytes of pregnant women sedimented in plasma more rapidly than they did in nonpregnant women. Since its incorporation into standard laboratory diagnosis, the ESR has been shrouded with medical myths and is often misinterpreted or misused. This chapter provides a rational guideline for its use as a nonspecific measure of inflammatory, infectious, neoplastic, and cardiovascular diseases.1–4
Erythrocyte Aggregation
Normally, erythrocytes settle quite slowly as the gravitational force of the erythrocyte’s mass is counteracted by the buoyant force of the erythrocyte’s volume. However, when erythrocytes aggregate, they sediment relatively rapidly because the proportional increase in their total mass exceeds the proportional increase in their volume.1–4
Therefore, the major determinant in the sedimentation rate of erythrocytes is erythrocyte aggregation, which usually occurs along a single axis (rouleaux formation). The aggregation of erythrocytes is largely determined by electrostatic forces. Under normal circumstances, erythrocytes have a negative charge and therefore repel each other. However, many plasma proteins are positively charged and neutralize the surface charge of erythrocytes, thereby reducing repulsive forces and promoting aggregation.1–3
The relative contribution of the various “acute phase” reactant proteins to aggregation is shown in Table 12-1. One protein that has no direct effect on the ESR in physiologic concentrations, but which is associated with certain inflammatory, degenerative, and neoplastic diseases, is C-reactive protein (CRP). Its major function is facilitation of the complement system. Like ESR, measurement of CRP is used in the monitoring of patients with chronic inflammatory conditions.1 An elevated CRP provides evidence of an inflammatory process despite a normal ESR. Therefore, when used in conjunction with the ESR, it greatly increases the sensitivity in detecting inflammatory and/or infectious processes, especially when variables such as anemia confound the ESR.
TABLE 12-1 Relative Contribution of Acute-Phase Reactant Proteins to Erythrocyte Aggregation
| BLOOD CONSTITUENT | RELATIVE CONTRIBUTION |
|---|---|
| Fibrinogen | 10 |
| β-Globulin | 5 |
| α-Globulin | 2 |
| Albumin | 1 |
The ESR is also elevated in patients with proteinemias (myeloma, macroglobulinemia, cryoglobulinemia, and cold agglutinin disease).1–4 Disorders of erythrocytes such as various anemias will alter the ESR and may interfere with accurate interpretation.1–4 Because the ESR is directly proportional to the mass of the erythrocyte and inversely proportional to its surface area, large erythrocytes sediment more rapidly than smaller cells. Therefore, in macrocytic anemia, there is an increased ESR, and in microcytic anemia, there is a decreased ESR.
Although the usefulness of ESR determination has decreased as new methods of evaluating disease have been developed, it remains quite helpful in the diagnosis of some diseases, such as temporal arteritis and polymyalgia rheumatica. Perhaps more useful is its ability to monitor these conditions as well as others, including chronic inflammatory diseases such as rheumatoid arthritis (RA), Hodgkin’s disease, and other cancers. Although the use of the ESR as a screening test to identify patients who have serious disease is not supported by the literature, it does provide a general gauge of inflammatory processes in the body. It is well accepted that an extreme elevation of the ESR is strongly associated with serious underlying disease, most often infection, collagen vascular disease, or metastatic malignancy. Recently, there has been a growing appreciation of the value of the ESR as a marker for atherosclerosis and coronary artery disease.5,6 In addition, as a sign of chronic low-grade inflammation, it may be helpful as a marker for other conditions as well. For example, in a study of 49,321 Swedish males aged 18 to 20 years, screened for general health and for mental and physical capacity at compulsory conscription examination before military service, there was an inverse correlation between ESR and performance on an IQ test.7 This result indicated that low-grade inflammation, as indicated by the ESR, was associated with reduced cognitive abilities at ages 18 to 20 years.
Procedures
Westergren Method
In the standard Westergren method, the following procedure is used:
1. Dilute venous blood 4:1 with anticoagulant sodium citrate.
2. Put in a 200-mm long, 2.5-mm internal diameter, glass tube (Westergren tube).
3. Allow to stand in a vertical position for 1 hour.
4. At the end of 1 hour, the distance from the meniscus to the top of the column of erythrocytes is recorded as the ESR.
The modified Westergren method uses ethylenediaminetetraacetic acid rather than sodium citrate as an anticoagulant and is more convenient because the same tube of blood can be used for other hematologic studies. The standard and modified methods give identical results.1–4
Wintrobe Method
The second most commonly used method is the Wintrobe method. This method is performed with a 100-mm tube (Wintrobe tube) containing oxalate as the anticoagulant. It is more sensitive than the Westergren method in the “normal” to “mildly elevated” range; however, in the more highly elevated ESR, the short tube leads to relatively insensitive readings due to packing of cells.2
Interpretation
Several factors may result in false-positive or false-negative ESR values; the more significant of these are listed in Box 12-2. In addition, it is important to recognize that in acute disease, the change in sedimentation rate may lag behind the temperature elevation and leukocytosis for 6 to 24 hours, and in unruptured acute appendicitis the rate may be normal. In convalescence, the increased rate tends to persist longer than the fever or leukocytosis. Box 12-3 lists the most common clinical implications of changes in the ESR. An ESR value exceeding 100 mm/h has a 90% predictive value for serious underlying disease—most often infection, collagen vascular disease, or metastatic tumor.1
BOX 12-2 Factors Interfering with the Erythrocyte Sedimentation Rate
False Increase
• Elevated levels of fibrinogen, globulins, and cholesterol
• Running a refrigerated blood sample before it has returned to room temperature
• Tilted erythrocyte sedimentation rate tube
• Certain drugs: dextran, methyldopa, methysergide, oral contraceptive agents, penicillamine, procainamide, theophylline, trifluperidol, vitamin A
False Decrease
Data from references 1 and 4.
Elevated Erythrocyte Sedimentation Rate
Asymptomatic Patients
The presence of an elevated ESR as the only manifestation of a disease process is quite rare. However, when present, it can be highly significant. For example, in one study of 17 patients whose increased ESR was the sole initial clue to disease, two had tuberculosis, one had colon cancer, one had systemic lupus erythematosus, three had ankylosing spondylitis (diagnoses that typically become apparent only after several years of observation), and four men had a persistently elevated ESR several years before a myocardial infarction. The remaining patients developed myeloma, prostate cancer, psoriasis, benign monoclonal gammopathy, and pancreatic cancer.2
Although the ESR generally makes a small contribution to disease detection in asymptomatic persons, the presence of an elevated ESR as the only clue to illness in an asymptomatic person indicates the need for a careful diagnostic workup; it may be the first sign of an occult malignancy or a chronic inflammatory disease. Laboratory evaluation for an asymptomatic patient with an elevated ESR should include complete blood cell count with differentials, blood urea nitrogen and creatinine, alkaline phosphatase measurement, serum protein electrophoresis, urinalysis, guaiac tests of stool, and chest radiograph.2
An ESR that exceeds 100 mm/h is definitely associated with infection, malignancy, or connective tissue disease. Rarely does disease remain undiagnosed when the ESR is greatly elevated.1–4 If, after further clinical evaluation, an elevated ESR cannot be explained, the ESR should be repeated in 1 month.
As a Predictor of Coronary Artery Disease
An elevated ESR in white men aged 45 to 64 years was found to be an independent risk factor for coronary heart disease in the National Health and Nutrition Examination Survey-I.5 The risk was highest when the ESR was greater than 22 mm/h. Subsequent studies and the growing awareness that atherosclerosis is associated with chronic inflammation has given support to the use of the ESR as a prognostic indicator for the risk of coronary artery disease.6,8 It was hypothesized and later shown that an elevated ESR reflected an elevated blood fibrinogen level (see Chapter 148 for further discussion of fibrinogen). The association of an elevated ESR as a harbinger of coronary artery disease precedes an elevated CRP, and can be viewed as an easy-to-use and inexpensive method that indirectly indicates fibrinogen level and aids in the early detection of microinflammation and eventual atherosclerotic burden, even in apparently healthy people.9,10
Erythrocyte Sedimentation Rate in Cancer
Malignancy is quite common in symptomatic patients with an elevated ESR. In one study, 70 (8.8%) of 790 clinic patients with an elevated ESR had cancer.1 However, of the 70 patients with malignancy and an increased ESR, 68 had local signs that led directly to the diagnosis. Thus occult malignancy was present in only 2 of the 790 patients. In addition, the ESR is often normal in patients with cancer, indicating that the ESR should not be relied on as a test to exclude occult malignancy in patients with vague symptoms.
In a prospective follow-up of 300 patients with prostate cancer, an ESR greater than 37 mm/h was associated with a higher incidence of disease progression and death. These findings paralleled other prognostic indicators such as tumor, node, and metastasis staging, grade, performance status, and age, but also indicated that ESR provided additional value in the monitoring of these patients, and presumably others with invasive cancer.3
Temporal Arteritis and Polymyalgia Rheumatica
Determination of the ESR is of critical importance in the diagnosis and management of patients with temporal arteritis, a condition that can result in blindness due to obstruction of the ophthalmic arteries. When the clinical evidence for temporal arteritis is limited, a normal ESR reduces the probability of the disease to less than 1%. When the clinical evidence is strong, it is extremely rare to have a normal ESR. Achievement of a normal ESR by using anti-inflammatory agents, such as cortisone or the natural medicines (e.g., Curcuma longa, Fish oils, Ginkgo biloba), greatly reduces the risk of developing blindness.1,2
Inflammatory Arthritis
The ESR is sometimes used to distinguish inflammatory arthritis from other causes of joint symptoms. This is particularly true in the differentiation of RA, which has an elevated ESR, and osteoarthritis, which typically has a normal ESR. Because ESR is not a specific indicator of RA, it is not appropriate to place much value on it as an independent diagnostic predictor of RA. An elevated ESR in patients with joint symptoms simply indicates an active inflammatory process.1,2
Suspected Infection
Leukocytosis and fever are better indicators than the ESR of an acute infectious process, since the ESR is typically normal during the first stages of infection. However, the ESR is of some value in the differentiation of an intact versus ruptured appendix. Researchers demonstrated that only 2 of 25 patients with nonruptured appendicitis had an ESR of greater than 20 mm/h. In contrast, 67% of patients with ruptured appendixes had an elevated ESR.1 CRP, however, has emerged as a more accurate measure. The value of CRP for surgical indication of appendicitis is 4.95 mg/dL.11 CRP has also been shown to correlate better with joint sepsis than ESR.11
Monitoring of Disease Activity
The ESR is well recognized as an aid in monitoring the activity of such inflammatory diseases as temporal arteritis, polymyalgia rheumatica, and RA.1–3 In general, improvements in ESR levels generally reflect clinical improvement and vice versa.
Temporal Arteritis and Polymyalgia Rheumatica
The ESR is the most widely used test for assessing disease activity in patients with temporal arteritis and polymyalgia rheumatica because these conditions have few specific clinical indicators of disease activity. However, both the ESR and clinical status need to be monitored in these patients and appropriate therapy instituted if the ESR increases or if there is a worsening in the clinical picture.1,2,12
Rheumatoid Arthritis
Although 5% to 10% of patients with RA have a normal ESR; the ESR generally parallels disease activity. Therefore, monitoring the patient’s ESR provides invaluable feedback on therapeutic effect. An isolated elevated ESR is not useful for prognosis, but sustained extreme elevation of the ESR is associated with a poor prognosis.1–3 It is important to note that in a meta-analysis of 63 clinical trials or observational studies of RA treatment, the authors concluded that ESR was more sensitive to change than CRP and was the preferred measure of the acute phase response in RA in clinical practice.13
Summary
The ESR is a simple, valuable, and useful laboratory procedure. Although it is a nonspecific indicator of inflammation, an elevated ESR (i.e., greater than 80 mm/h) indicates the presence of significant disease in more than 95% of individuals. The ESR should never be used as the sole diagnostic test. Clinical presentation, comprehensive history, laboratory investigation, and other diagnostic procedures should always be considered when interpreting ESR results. The ESR may be used as a nonspecific gauge of therapeutic efficacy and as a monitoring tool in several inflammatory conditions, including temporal arteritis, polymyalgia rheumatica, RA, certain malignancies, and atherosclerosis.
1. Brigden M.L. Clinical utility of the erythrocyte sedimentation rate. Am Fam Physician. 1999;60:1443–1450.
2. Sox H.C., Jr., Liang M.H. The erythrocyte sedimentation rate. Guidelines for rational use. Ann Intern Med. 1986;104:515–523.
3. Bedell S.E., Bush B.T. Erythrocyte sedimentation rate, from folklore to facts. Am J Med. 1985;78:1001–1009.
4. Saadeh C. The erythrocyte sedimentation rate: old and new clinical applications. South Med J. 1998;91:220–225.
5. Gillum R.F., Mussolino M.E., Makuc D.M. Erythrocyte sedimentation rate and coronary heart disease: the NHANES I Epidemiologic Follow-up Study. J Clin Epidemiol. 1995;48:353–361.
6. Erikssen G., Liestol K., Bjornholt J.V., et al. Erythrocyte sedimentation rate: a possible marker of atherosclerosis and a strong predictor of coronary heart disease mortality. Eur Heart J. 2000;21:1614–1620.
7. Karlsson H., Ahlborg B., Dalman C. Association between erythrocyte sedimentation rate and IQ in Swedish males aged 18-20. Brain Behav Immun. 2010;24(6):868–873.
8. Danesh J., Collins R., Peto R. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J. 2000;21:515–520.
9. Natali A., L’Abbate A., Ferrannini E. Erythrocyte sedimentation rate, coronary atherosclerosis, and cardiac mortality. Eur Heart J. 2003;24(7):639–648.
10. Steinvil A., Shapira I., Arbel Y., et al. Determinants of the erythrocyte sedimentation rate in the era of microinflammation: excluding subjects with elevated C-reactive protein levels. Am J Clin Pathol. 2008;129(3):486–491.
11. Ernst A.A., Weiss S.J., Tracy L.A. Usefulness of CRP and ESR in predicting septic joints. South Med J. 2010;103(6):522–526.
12. Cantini F., Salvarani C., Olivieri I., et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study. Semin Arthritis Rheum. 2000;30:17–24.
13. Ward M.M. Relative sensitivity to change of the erythrocyte sedimentation rate and serum C-reactive protein concentration in rheumatoid arthritis. J Rheumatol. 2004;31:884–895.
