Discipline - Haematology
Erythrocyte sedimentation rate (ESR)
First added in 2020
Aid to diagnosis
To detect inflammation as an indicator of various conditions when C-reactive protein (CRP) is not available
Venous whole blood
Summary of evidence evaluation
Some guidelines recommend measuring either CRP or ESR as part of the initial diagnostic workup for juvenile idiopathic arthritis, GCA, polymyalgia rheumatica and prosthetic joint infections, or for monitoring disease for GCA. But there is little evidence behind these recommendations, and they are rated as weak. The DAS28 disease activity score for RA includes either CRP or ESR, but other scores exist which seem to perform as well. Systematic reviews exist of the accuracy of ESR for inflammation and joint infection which show some diagnostic relationship between ESR and these diseases, but one which is weak. CRP has similar, sometimes superior, performance. The sensitivity and specificity noted for different conditions are, respectively: 78% and 68% for orthopaedic infections; 77% and 59% for other inflammatory infections; 79% and 81% for prosthetic joint infection; and 84% and 30% for GCA (single study). There were no real studies of impact, although the studies cited did give some evidence on other uses of ESR. There was evidence that discrepant high ESR and low CRP results had some diagnostic value in diseases of the immune system such as lupus, and that ESR was related to disease activity in lupus. In summary, although ESR is recommended in guidelines to aid in the diagnosis of several diseases (including RA, juvenile idiopathic arthritis, bone infections, prosthetic joint infections, GCA, SLE and polymyalgia rheumatica), such recommendations are mainly based on expert opinion with little supporting evidence. There is no strong evidence supporting ESR as an essential test, although there are strong opinions that its use, despite its limitations, is helpful in the workup, diagnosis and monitoring of several different diseases. Evidence of the accuracy of ESR suggests high rates of false positives and false negatives in all applications, similar to those of CRP. Evidence showing the utility and impact of measuring ESR either for diagnosis or for monitoring is not available. The full evidence review for this test category is available online at: https://www.who.int/medical_devices/diagnostics/selection_in-vitro/selection_in-vitro-meetings/new-prod-categories_3
Summary of SAGE IVD deliberations
SAGE IVD noted that the evidence provided suggests that ESR may be inaccurate and that there is little evidence of the test’s clinical utility and impact. But despite the test’s limited sensitivity and specificity overall, a marked elevation of ESR > 100 mm/h is strongly associated with an underlying infection, neoplasm or rheumatic disease. ESR is included in the guidelines of several inflammatory conditions and is a well-established test that is embedded in clinical practice around the world. It is used in most laboratories as a non-specific marker for inflammation for a broad range of infectious and autoimmune diseases. In particular, the test is regularly used to aid the diagnosis of conditions such as GCA and polymyalgia rheumatica; it is also often used to monitor rheumatic diseases, including RA and SLE; and it is sometimes used to aid the prognosis of conditions like Hodgkin’s lymphoma. ESR is a very simple test that has minimal requirements (it can even be done without a kit), which means that access to it can be ensured in resource-constrained environments. Importantly, SAGE IVD emphasized that in most cases, CRP is more sensitive than ESR, with a more robust reference range. This means that in most cases, CRP should remain the preferred choice of test, with ESR providing an alternative only in settings where CRP is not available. But SAGE IVD members highlighted two examples – SLE and low-grade bone and joint infections – where ESR may be the preferred method, because in both cases there is evidence that the condition elevates ESR without causing a rise in CRP.
SAGE IVD recommendation
SAGE IVD recommended including the erythrocyte sedimentation rate (ESR) test category in the third EDL: • as a general IVD for use in community settings and health facilities without laboratories (EDL 3, Section I.a Haematology); • using a Westergren method; • to detect inflammation as an indicator of various conditions when CRP is not available.
Details of submission from 2020
Disease condition and impact on patients The ESR – with or without a concurrent CRP test – contributes to the diagnosis and management of certain infections and diseases of the immune system, including orthopaedic infections (1), rheumatoid arthritis (RA) (2) and systemic lupus erythematosus (SLE), as well as less common conditions, including giant cell arteritis (GCA) and polymyalgia rheumatica. RA and SLE typically present in young adulthood and are lifelong diseases causing significant disability and substantial socioeconomic impact. Does the test meet a medical need? The ESR was the mainstay of laboratory testing for inflammation during the 20th century. In inflammation, there is increased production of fibrinogen and other plasma proteins, which cause erythrocytes to adhere to each other, increasing the rate at which erythrocytes sediment when blood is placed in a vertical tube. The ESR is therefore an indirect measure of inflammation. Factors other than inflammation also have a substantial influence on the rate at which erythrocytes sediment (3, 4). How the test is used In certain infections, particularly orthopaedic infections, an elevated ESR may be an early clue to infection, justifying microbiological investigations that, if positive, provide a specific diagnosis. In disorders of the immune system, an elevated ESR, with or without CRP, provides objective evidence of significant inflammation. But it is too non-specific for final diagnosis, as ESR can be raised in many immune and infectious diseases. In certain immune disorders, CRP may not be as elevated as clinically expected because of a Type I interferon response (5). In these cases, ESR still has a role in assessment, often alongside CRP. But diagnosing and monitoring immune diseases is much more complex than infectious disorders, and so also includes clinical assessment, often with scoring systems, imaging and other blood tests. In the case of GCA, biopsy is also part of the diagnostic algorithm. In many cases, if CRP is not available to diagnose or monitor infection, then ESR may be used. Elevated ESR is a non-specific finding, however, and diagnosis depends on infection-specific tests.
Public health relevance
Rheumatoid arthritis is a chronic disease that typically presents in young adulthood and is prevalent in around 0.25% of the world population. In 2010, it had a burden of 4.8 million disability-adjusted life years (DALYs) (6). Juvenile idiopathic arthritis affects around 10 in 100 000 people, although estimates vary widely (7). Some patients continue to be affected in adulthood. SLE affects approximately 0.1% of the global population (8). It is a chronic disease that typically presents in teenagers or young adults. In South Korea, people with SLE have a standardized mortality ratio 2.6 times greater than the general population (9). GCA and polymyalgia rheumatica affect 0.1–0.3% and 0.6% of the US population, respectively (10). Onset is in older adults and the conditions are chronic; they may occur in all racial groups but are best recognized in Europeans. Other non-organ-specific systemic autoimmune diseases are less common, and diagnosis is challenging. Presenting features may overlap the above conditions. There is limited evidence about ESR in these conditions. Around 1–2% of recipients of hip and knee replacements experience prosthetic joint infections (11).
WHO or other clinical guidelines relevant to the test
The American College of Rheumatology (ACR) recommends using ESR (or CRP) as a disease activity measure in its DAS 28-ESR score, where the ESR contributes a sizeable proportion of the information in the final score (2). The Royal Australian College of General Practitioners recommends the use of ESR (or CRP) in diagnosing idiopathic juvenile arthritis. The European League against Rheumatism (EULAR) updated its guidelines for large vessel vasculitis (GCA and Takayasu arteritis) in 2018 (12), giving the use of ESR and CRP a 3b level of evidence and indicating that this dual measurement is useful in diagnosis. The EULAR/ACR guidelines for polymyalgia rheumatica recommended assessing ESR and/or CRP for monitoring disease progress (13). Armstrong et al. (14) compiled a set of “unified” guidelines for the diagnosis of prosthetic joint infections, which indicated that 92% of patients who went to surgery had a pre-operative ESR and CRP.
Evidence for diagnostic accuracy
Lapic et al. (15) analysed 29 studies comparing the clinical accuracy of ESR and CRP. The studies included 16 on orthopaedic infections, 3 on rheumatic conditions (RA, GCA and Takayasu’s disease) and 10 on miscellaneous conditions (mostly infective). Overall clinical accuracy was reasonable, CRP performed somewhat better than ESR, and combined use of CRP and ESR was often better than either alone. Carli et al. (16) did a systematic review of articles on periprosthetic joint infection and found that serum markers including ESR and CRP performed moderately well, although in their view synovial examination was preferable. Berbari et al. (17) did a meta-analysis on the performance of inflammatory markers in assessing prosthetic joint infections. CRP performed somewhat better than ESR though both were satisfactory. The combination of CRP and ESR was not assessed. Interestingly, the three studies on interleukin-6 (IL-6) showed it performed better than either CRP or ESR. IL-6 has been considered as a routine diagnostic test, but it is more expensive and technically more complex than CRP or ESR.
Evidence for clinical usefulness and impact
Gwinnutt et al. (18) reviewed studies on factors predicting outcome in inflammatory arthritis. They found that ESR performed better than CRP, but they concluded that clinical assessment was more informative than laboratory markers. Dejaco et al. (19) reviewed studies on prognostic factors in polymyalgia rheumatica, and found evidence from some but not all studies that a high ESR at the time of diagnosis is a poor prognostic factor. Clinical utility in SLE has also been demonstrated. Feldman et al. (20) provide supportive evidence for the fact that diseases of the immune system such as SLE may be discordant, with high ESR and low CRP. Other studies provide data on usefulness in SLE for monitoring disease activity (11, 21).
Evidence for economic impact and/or cost–effectiveness
Although the ESR is a long-established test, there is limited literature on its cost–effectiveness. A 2015 Canadian review (22) assessed the value of testing both ESR and CRP compared with testing either alone and found it reduced the rate of misdiagnosis in prosthetic joint infection. The cost of the combined test per misdiagnosis avoided, compared with the cost of CRP alone, was Can$ 240.62. The benefits, opportunities, costs and risks of various diagnostic approaches to prosthetic joint infection were assessed in a US study on Medicare patients (23). The study found that the most effective strategy was to start with both ESR and CRP, and then follow these with arthrocentesis in patients testing positive for both.
Ethical issues, equity and human rights issues
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Lupus. 2016;25(11):1173–1179. doi:10.1177/0961203316651742. 6. Cross M, Smith E, Hoy D, Carmona L, Wolfe F, et al. The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1316–1322. doi:10.1136/annrheumdis-2013-204627. 7. Thierry S, Fautrel B, Lemelle I, Guillemin F. Prevalence and incidence of juvenile idiopathic arthritis: a systematic review. Joint Bone Spine. 2014;81(2):112–117. doi:10.1016/j.jbspin.2013.09.003. 8. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology. 2017;56(11):1945–1961. doi:10.1093/rheumatology/kex260. 9. Lee YH, Choi SJ, Ji JD, Song GC. Overall and cause-specific mortality in systemic lupus erythematosus: an updated meta-analysis. Lupus. 2016;25(7):727–734. doi:10.1177/0961203315627202. 10. Crowson CS, Matteson EL. Contemporary prevalence estimates for giant cell arteritis and polymyalgia rheumatica. 2015. Semin Arthritis Rheum. 2017;47(2):253–256. doi:10.1016/j.semarthrit.2017.04.001. 11. Tande AJ, Patel R. Prosthetic joint infection. Clin Microbiol Rev. 2014;27(2):302–345. doi:10.1128/CMR.00111-13. 12. Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, et al. 2018 update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020;79(1):19–30. doi:10.1136/annrheumdis-2019-215672. 13. Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, et al. 2015 recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2015;74(10):1799–1807. doi:10.1136/annrheumdis-2015-207492. 14. Armstrong MD, Carli AV, Abdelbary H, Poitras S, Lapner P, et al. Tertiary care centre adherence to unified guidelines for management of periprosthetic joint infections: a gap analysis. Can J Surg. 2018;61(1):34–41. doi:10.1503/cjs.008617. 15. Lapic I, Padoan A, Bozzato D, Plebani M. Erythrocyte sedimentation rate and C-reactive protein in acute inflammation. Am J Clin Pathol. 2020;153(1):14–29. doi:10.1093/ajcp/aqz142. 16. Carli AV, Abdelbary H, Ahmadzai N, Cheng W, Shea B, et al. Diagnostic accuracy of serum, synovial, and tissue testing for chronic periprosthetic joint infection after hip and knee replacements: a systematic review. J Bone Joint Surg Am. 2019;101(7):635–649. doi:10.2106/JBJS.18.00632. 17. Berbari E, Mabry T, Tsaras G, Spangehl M, Erwin PJ, et al. Inflammatory blood laboratory levels as markers of prosthetic joint infection: a systematic review and meta-analysis. J Bone Joint Surg Am. 2010;92(11):2102–2109. doi:10.2106/JBJS.I.01199. 18. Gwinnutt JM, Sharp CA, Symmons DP, Lunt M, Verstappen SM. Baseline patient reported outcomes are more consistent predictors of long-term functional disability than laboratory, imaging or joint count data in patients with early inflammatory arthritis: a systematic review. Semin Arthritis Rheum. 2018;48(3): 384–398. doi:10.1016/j.semarthrit.2018.03.004. 19. Dejaco C, Singh YP, Perel P, Hutchings A, Camellino D, et al. Current evidence for therapeutic interventions and prognostic factors in polymyalgia rheumatica: a systematic literature review informing the 2015 European League Against Rheumatism/American College of Rheumatology recommendations for the management of polymyalgia rheumatica. Ann Rheum Dis. 2015;74(10):1808–1817. doi:10.1136/annrheumdis-2015-207578. 20. Feldman M, Aziz B, Kang GN, Opondo MA, Belz RK, et al. C-reactive protein and erythrocyte sedimentation rate discordance: frequency and causes in adults. Transl Res. 2013;161(1):37–43. doi:10.1016/j.trsl.2012.07.006. 21. Stojan G, Fang H, Magder L, Petri M. Erythrocyte sedimentation rate is a predictor of renal and overall SLE disease activity. Lupus. 2013;22(8):827–834. doi:10.1177/0961203313492578. 22. Assasi N, Blackhouse G, Campbell K, Hopkins RB, Levine M, et al. Comparative value of erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) testing in combination versus individually for the diagnosis of undifferentiated patients with suspected inflammatory disease or serious infection: a systematic review and economic analysis. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2015. 23. Diaz-Ledezma C, Lichstein PM, Dolan JG, Parvizi J. Diagnosis of periprosthetic joint infection in Medicare patients: multicriteria decision analysis. Clin Orthop Relat Res. 2014;472(11):3275–3284. doi:10.1007/s11999-014-3492-2.