Introduction

The erythrocyte sedimentation rate (sedimentation rate, sed rate, ESR) serves as a routine hematology test used to detect and monitor increased inflammatory activity in response to conditions such as autoimmune disorders, infections, or tumors. Although not specific to a single disease, ESR supports the evaluation of inflammation when interpreted alongside other diagnostic tests.

Clinicians have long used the ESR as a general indicator of illness because of its reproducibility and low cost. Multiple techniques for performing the test have emerged over several decades. The reference method endorsed by the International Committee for Standardization in Haematology (ICSH) derives from Westergren’s original description nearly a century ago.[1] More recent laboratory systems incorporate automated readers and closed blood collection tubes to reduce biohazard exposure and shorten processing time.[2]

The Westergren method measures the distance, in millimeters, that red blood cells (RBCs) in anticoagulated whole blood settle in a standardized, upright tube over an hour under the influence of gravity. This specialized tube, known as the Westergren tube, is now manufactured from either glass or plastic, with an internal diameter of 2.5 mm and a length ranging from 190 to 300 mm.[3]

John Hunter (1728-1793), a British surgeon, first observed changes in blood sedimentation associated with illness, as described in his posthumous publication A Treatise on the Blood, Inflammation, and Gun-Shot Wounds.[4] Edmund Faustyn Biernacki (1866-1911), a Polish physician, refined the clinical application of ESR near the end of the 19th century.[5] In 1897, Biernacki published his findings in both Gazeta Lekarska in Poland and Deutsche Medizinische Wochenschrift in Germany, and developed an instrument for measurement. His work did not gain early recognition in English-speaking medical literature. In many parts of the world, the ESR is still referred to as the "Biernacki reaction."

Biernacki’s clinical application of the ESR was further developed by Robert Fahraeus in 1918 and Alf Vilhelm Albertsson Westergren in 1921.[6] Dr. Westergren defined the standard measurement method still used in clinical practice today.[7] Fahraeus and Westergren are often credited jointly for the test, historically known as the Fahraeus-Westergren test (FW test, Westergren test), which employs a standardized tube and sodium citrate-anticoagulated blood.

The Westergren method, as endorsed by the ICSH, has provided consistent reproducibility for nearly a century. This method has enabled the establishment of comparable reference values both within individual laboratories and across institutions worldwide. The ICSH adopted the Westergren method as the gold standard for ESR measurement in 1973. Even after the introduction of automated analyzers, the ICSH and the Clinical and Laboratory Standards Institute reaffirmed the Westergren method as the reference standard in 2011.[8]

Pathophysiology

The ESR test measures the rate at which RBCs, or erythrocytes, in a whole blood sample fall to the bottom of the Westergren tube. This process of falling is called "sedimentation."[9] RBCs typically fall at a faster rate in people with inflammatory conditions, such as infections, cancer, or autoimmune disorders. These conditions increase the concentration of proteins in the blood. The elevated protein content causes RBCs to clump and settle more rapidly. A group of RBCs clumped together forms a stack, similar to a stack of coins, known as a rouleau (plural: rouleaux).[10] Rouleaux formation occurs because of the particular discoid shape of RBCs. The flat surfaces of the RBCs allow them to make contact with one another and stick together.[11]

RBCs typically carry a net negative surface charge due to sialic acid residues on their membranes, which generates electrostatic repulsion that helps maintain their dispersion in plasma. This repulsion is quantified by the ζ potential, representing the electrical potential at the boundary layer around RBCs and influenced by a surrounding cloud of positive ions in plasma. Plasma proteins such as fibrinogen and globulins, which are predominantly negatively charged, promote RBC aggregation by adsorbing onto the RBC surface or forming bridges between cells. This interaction reduces the ζ potential and diminishes electrostatic repulsion, thereby facilitating rouleaux formation.

In inflammatory conditions, elevated plasma protein levels enhance rouleaux formation, causing RBCs to aggregate and settle more rapidly, which increases the ESR.[12] The settling of these aggregates in the Westergren tube occurs at a constant rate, making the ESR a physical measure of RBC aggregation influenced by plasma protein interactions rather than a direct assay of a single inflammatory marker.[13]

Rouleaux formation, and thus the ESR, depends on the concentrations of immunoglobulins and acute-phase proteins (APPs) such as prothrombin, plasminogen, fibrinogen, C-reactive protein (CRP), α-1 antitrypsin, haptoglobin, and complement proteins, which are present in several inflammatory conditions.[14] APPs comprise a class of approximately 30 distinct, chemically unrelated plasma proteins that are innately regulated in response to infection and inflammation.[15] The liver produces APPs under functional control by the body in response to tissue damage or insult. These proteins act as inhibitors or mediators of the inflammatory response.[16]

The first APP identified was CRP, detected in the 1930s during the analysis of plasma from patients with acute pneumococcal pneumonia.[17] CRP and many other APPs may rise in response to ongoing tissue injury, whether acute or chronic.[18] The term "acute phase" remains in use to describe these proteins that change in concentration during defined disease processes, regardless of duration. The fluctuating levels of APPs in inflammation increase the adhesive properties of RBCs, promote the formation of RBC stacks (rouleaux), and raise the ESR.[19]

Although many inflammatory illnesses increase the ESR, other conditions can lower its value. These diminishing factors may exist either as isolated disease processes that reduce the ESR or coexisting conditions associated with increased ESR, resulting in a lower than expected value despite a significant underlying inflammatory state.[20] Polycythemia, an increased number of RBCs, raises blood viscosity and can reduce the ESR by slowing the rate at which RBC rouleaux settle in the Westergren tube.[21] Some hemoglobinopathies, such as sickle cell disease, lower the ESR due to abnormal RBC shapes that impair rouleaux formation. Spherocytosis, characterized by sphere-shaped rather than disc-shaped RBCs, also disrupts rouleaux formation and can further reduce the ESR.[22]

Specimen Requirements and Procedure

The Westergren method involves a simple blood draw that requires only a few minutes to perform.[23] A trained healthcare professional, such as a phlebotomist, collects the blood sample. The skin overlying the selected vein is cleansed, after which a needle is inserted into the vein to draw blood. The needle is removed upon completion, and the puncture site is covered with a dressing to achieve hemostasis.[24]

Blood is typically collected in a black-top ESR vacuum tube that contains a 3.2% sodium citrate anticoagulant. Whole blood collected in a lavender tube containing ethylenediaminetetraacetic acid (EDTA) is also acceptable. The sample must remain in the original ESR-designated tube and cannot be shared with other tests due to the required volume.[25]

The blood sample is then transported to the laboratory. A technician transfers the anticoagulated whole blood to a vertical test tube (Westergren tube), which is inserted into the vacuum tube. RBCs gradually settle to the bottom under the influence of gravity when allowed to stand vertically for an hour. A clear, straw-colored fluid appears at the top of the tube. This fluid is plasma, the acellular portion of blood remaining after the sedimentation of RBCs and other formed elements, such as platelets.

The test result is based on the height of the plasma column, measured in millimeters after 1 hour. Results are reported in millimeters per hour (mm/hr).[26]

Diagnostic Tests

ESR can be measured using either the Westergren, Wintrobe, micro-ESR, or automated method.[27] Historically, the Westergren method was the most commonly used approach for determining the ESR. Technical factors, including the volume of blood drawn into the tube, ambient vibrations, temperature, time from specimen collection, anticoagulant use, and tube orientation, can influence the results. RBC size, shape, and concentration can also alter the ESR. Plasma characteristics significantly affect the ESR as well.[28]

The Westergren method has classically been used to measure the ESR based on the distance RBCs settle to the bottom of an elongated tube with a 2.5 mm internal bore. The tube is graduated downward in millimeters, from 0 to 200, which allows clear plasma to remain at the top once RBCs have settled under the influence of gravity after an hour.

Several other methods have been described, including the Linzenmeier, Graphic or Cutler, Wintrobe Landsberg, and Landau techniques. Only the Westergren and Wintrobe methods remain in common use. The Wintrobe approach uses a shorter tube, only 100 mm in length, with a narrower internal bore than the standard Westergren tube. This method is considered less sensitive than the Westergren technique.[29]

Although the Westergren method remains widely used for determining the ESR, it is time-consuming and susceptible to error. Faster and more reliable alternatives have been developed, including methods that use centrifuges and automated systems capable of producing results within 5 minutes.[30]

The micro-ESR method requires the use of capillary tubes and enables quicker test completion compared to standard techniques. Four drops of capillary blood obtained via fingerstick are mixed with a 3.8% sodium citrate solution in a 4:1 ratio on a slide. The mixture is drawn into a 7.5 cm heparin-free microhematocrit capillary tube. Results are recorded after 20 minutes and mathematically adjusted to estimate conventional ESR values. Other automated systems for measuring the ESR have become available. A study found that fewer laboratories now use the unmodified Westergren technique and that automated results may differ from standard values by as much as 142%.[31]

Several new automated and semi-automated techniques have been introduced for determining the ESR. These methods offer improved safety, faster turnaround, and greater accuracy. ICSH has evaluated the reliability and reproducibility of more than a dozen methods and issued recommendations for manufacturers regarding the validation of new ESR systems. Recent studies demonstrate that automated ESR measurements closely correlate with those obtained using the Westergren method.[32] Many automated analyzers do not measure sedimentation directly but instead calculate a derived rate based on early-stage RBC aggregation during rouleaux formation. Responsibility for the validation and verification of these new procedures rests with manufacturers and healthcare institutions.

Interfering Factors

Technical factors such as seasonal variations in room temperature, time elapsed from specimen collection, tube orientation and inclination, and environmental vibration can influence ESR results. Elevated room temperature decreases blood viscosity and increases the ESR.[33] Exposure to direct sunlight can also raise the ESR. Tube tilt and vibration elevate the ESR value, with an angle of 3° from vertical increasing the ESR by as much as 30%. Inadequate filling of the ESR tube introduces air bubbles, which can further increase the measured value.[34]

Delays in processing the blood sample cause RBCs to lose their biconcave shape, reducing the ESR. Testing should be initiated within 2 hours of sample collection. Clotted blood disrupts rouleaux formation and lowers the ESR.[35] Tubes with inconsistent internal bore diameters are highly sensitive to RBC aggregation and may contribute to variability in ESR measurements. Icteric samples from patients with liver disease produce dark yellow plasma that is visually difficult to distinguish from the sedimented RBCs. Hemolyzed samples release hemoglobin into the plasma, turning it red and obscuring visual separation from the RBC layer.[36]

Results, Reporting, and Critical Findings

As with other laboratory investigations, the reference range for ESR should be established by the laboratory performing the test. ESR values are generally higher in female than in male individuals and tend to increase with age.[37] Reference values using the Westergren method are as follows:

• Men younger than 50 years: 15 mm/hr or lower
• Women younger than 50 years: 20 mm/hr or lower
• Men older than 50 years: 20 mm/hr or lower
• Women older than 50 years: 30 mm/hr or lower
• Children: 10 mm/hr or lower [38]

Reference ranges must be interpreted alongside clinical presentation and additional laboratory data. An abnormal ESR alone does not establish a diagnosis.

Clinical Significance

Several factors may influence the ESR. Female individuals generally exhibit slightly higher ESR values than male patients. Pregnancy and advancing age are also associated with increased ESR. Additional contributing factors include anemia, RBC abnormalities, tilted ESR tubes, elevated specimen temperature, and dilution errors.[39]

The ESR lacks both sensitivity and specificity as a general screening tool. Elevated values may occur in a wide range of clinical conditions, limiting this variable's utility as a stand-alone laboratory parameter. Some patients with malignant neoplasms, severe infections, or active inflammatory disease may demonstrate normal ESR levels.[40] Nevertheless, an elevated ESR should prompt further evaluation for potential underlying pathology, which may include the following:

• Anemia
• Arteritis
• Infections, including those involving bone or joints
• Kidney disease
• Low serum albumin
• Systemic lupus erythematosus
• Lymphoma, including lymphoplasmacytic lymphoma
• Multiple myeloma
• Polymyalgia rheumatica
• RBC abnormalities
• Rheumatoid arthritis
• Systemic vasculitis
• Thyroid disease

Any process that elevates fibrinogen levels, such as pregnancy, infection, diabetes mellitus, end-stage renal disease, heart disease, or malignancy, may also increase the ESR. Extremely high ESR values, defined as over 100 mm/hr, are often associated with serious underlying disease. Such conditions may include infection, multiple myeloma, lymphoplasmacytic lymphoma (Waldenström macroglobulinemia), giant cell arteritis, polymyalgia rheumatica, or hypersensitivity vasculitis.

A study reported an average ESR exceeding 90 mm/hr in patients with temporal arteritis, with values greater than 30 mm/hr observed in 99% of cases.[41] An ESR over 100 mm/hr is associated with a low false-positive rate for a significant underlying condition.[42] Infection accounts for most cases of extreme ESR elevation, followed by collagen vascular disease and metastatic malignancies.[43] In oncologic settings, ESR elevation often correlates with poor prognosis in several cancer types.[44][45]

An increased ESR may serve as a helpful adjunct in the identification of coronary artery disease.[46][47] This association is likely related to the inflammatory pathophysiology of atherosclerotic disease.[48] In the setting of ischemic stroke, ESR may correlate with the extent of brain injury, severity of atherosclerosis, and short-term clinical outcomes.[49][50]

Polymyalgia rheumatica and giant cell arteritis are inflammatory conditions that typically affect individuals older than 50 years.[51] ESR is useful in diagnosing both conditions. However, normal ESR values should not be used to exclude these diagnoses.[52] In rheumatoid arthritis, systemic lupus erythematosus, and osteoarthritis, ESR levels are frequently used to support the diagnosis. However, ESR does not always correlate with clinical measures of disease activity.[53] Some patients with active rheumatoid arthritis and histologic evidence of synovial inflammation may present with a normal ESR.[54]

Periprosthetic joint infection is a serious complication following total hip or knee arthroplasty. ESR demonstrates low sensitivity in this context, with reported values ranging from 42% to 94%.[55]

An isolated ESR measurement has variable sensitivity and is insufficient to exclude septic arthritis. When used in combination with clinical findings such as inability to bear weight and elevated temperature, ESR may provide useful diagnostic information, particularly when applying a low threshold value above 15 mm/hr.[56] An elevated ESR may assist in the diagnosis and follow-up of individuals with osteomyelitis. Optimal ESR threshold values for diagnostic purposes vary across studies.[57][58] In confirmed cases of osteomyelitis, ESR may also help monitor therapeutic response or identify relapse.[59]

In oncology, ESR elevation correlates with metastasis and worse prognosis in patients with cutaneous malignant melanoma.[60] Higher ESR values have similarly been associated with poor outcomes in breast, prostate, colorectal, and hematologic malignancies, including Hodgkin lymphoma and chronic lymphocytic leukemia.

In pediatric populations, ESR may serve as an indicator of invasive bacterial infection.[61] A study reported a sensitivity of 94% for detecting bacterial bone or joint infection at admission using an ESR threshold of 20 mm/hr.[62]

In addition to conditions that raise the ESR, the healthcare team must also consider factors that reduce its value. This consideration is particularly important in cases where ESR-lowering factors coexist with conditions that typically increase the ESR, potentially obscuring clinically significant findings. One such factor is polycythemia, which increases blood viscosity and slows erythrocyte sedimentation.[63] Hemoglobinopathies such as sickle cell disease can also reduce ESR by altering RBC morphology, impairing rouleaux formation.[64]

Regular alcohol consumption is inversely associated with ESR. Individuals who consume low, moderate, or high amounts of alcohol tend to exhibit lower ESR values than abstainers or occasional drinkers. Similarly, habitual physical activity at moderate to high levels has been linked to lower ESR measurements compared to sedentary individuals.

Timely sample handling is critical. Blood should be tested within 2 hours of collection, as prolonged standing leads to erythrocyte spherocytosis, which inhibits stacking. Morphologic abnormalities such as anisocytosis and poikilocytosis further interfere with rouleaux formation, thereby decreasing the ESR. Certain medications, including valproic acid, statins, and nonsteroidal anti-inflammatory drugs, are known to reduce ESR levels.[65][66]

Quality Control and Lab Safety

For nonwaived tests, laboratory regulations require, at a minimum, the analysis of at least 2 levels of control materials every 24 hours. Laboratories may analyze control materials more frequently to maintain result accuracy. Control materials should also be analyzed after calibration or maintenance of an instrument to verify appropriate method performance.

Laboratories may implement an individualized quality control plan to reduce the frequency of control testing when manufacturer recommendations are less stringent than regulatory requirements, such as once a month.[67] This approach involves a formal risk assessment across all phases of testing, followed by a targeted plan to minimize the likelihood of analytical error.[68] The Westgard multirule system is commonly applied to interpret control runs. Corrective and preventive measures must be taken before proceeding with patient testing if any rule violation occurs.[69]

Participation in an external performance verification program, also known as proficiency testing, is required under federal regulations established by the Centers for Medicare and Medicaid Services (CMS) through the Clinical Laboratory Improvement Amendments (CLIA).[70] This process provides an objective measure of laboratory accuracy and consistency in comparison with other laboratories performing similar assays. CMS and accreditation agencies monitor participation and scored performance. The proficiency testing process should be incorporated into the laboratory’s comprehensive oversight program to support ongoing performance evaluation and regulatory compliance.[71]

All specimens, control materials, and calibrators should be regarded as potentially infectious. Standard precautions must be observed when laboratory reagents are handled. All waste materials should be disposed of in accordance with local regulatory guidelines. Gloves, a laboratory coat, and safety glasses should be worn when human blood specimens are handled. Plastic pipette tips, sample cups, and gloves that come into contact with blood must be discarded in designated biohazard containers.[72] All disposable glassware should be placed into approved sharps containers. Work surfaces must be covered with disposable absorbent bench paper, which should be replaced weekly or immediately after contamination with blood. All work surfaces must be decontaminated on a weekly basis.[73]

Enhancing Healthcare Team Outcomes

Elevated ESR values do not always indicate an underlying condition requiring treatment. A result outside the reference range is not necessarily a cause for concern. Mild elevations may occur due to laboratory variability, pregnancy, menstruation, or increasing age. Although the ESR may support the presence of an inflammatory state, it is not specific for any single disease process. The test must be interpreted in conjunction with clinical findings and additional diagnostic studies. As a screening tool in asymptomatic individuals, the ESR has limited value due to low sensitivity and specificity.

The ESR may be used as a general indicator of illness when clinical findings suggest a possible disease. Extremely high values, exceeding 100 mm/hr, are typically associated with identifiable causes such as malignancy, infection, or temporal arteritis. Mild-to-moderate elevations without an obvious cause may warrant additional testing in the appropriate clinical context. However, no evidence supports extensive diagnostic workup or invasive procedures when an elevated ESR occurs in the absence of concerning history, physical findings, or corroborative test results. Repeat testing after several months may be considered for asymptomatic individuals with a persistently elevated ESR. Persistent elevation may justify further investigation to rule out occult pathology.

Close coordination among the interprofessional team is essential for the appropriate interpretation of the ESR. Such collaboration also supports diagnostic decisions, treatment strategies, and specialist referrals.

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Disclosure: Kevin Tishkowski declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Zubair declares no relevant financial relationships with ineligible companies.