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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."

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]

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]

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]

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.