Accepted wisdom in the assessment of a person with HIV is that the erythrocyte sedimentation rate (ESR) is not a useful test. Although initially considered as an indicator of disease progression [1,2], later studies disagreed  or demonstrated only a negligible fall in CD4 cell count with rising ESR .
Although the use of ESR to predict the development of AIDS is still under investigation in the developing world , it is considered less helpful in countries with easy access to CD4 cell monitoring. The ESR does not predict acute illness in HIV  and when measured, it is not uncommon to discover values in triple figures in otherwise asymptomatic individuals with normal CD4 cell counts: in one recent study, 27% of Tanzanian patients with an ESR more than 120 mm/h still had a CD4 cell count greater than 200/μl . As such, it is rare to find recent data on ESR levels in HIV-positive people except from Africa [5,7,8], and it has not been published as an independent variable in any of the large prospective cohort studies.
I would argue that this approach is short-sighted, especially given what we have learned regarding cardiovascular disease in the last decade, across many disciplines. Indeed, a chronically elevated ESR is potentially very informative:
1. It reflects immune activation, correlating well with cytokines, including interleukin-6 and tumour necrosis factor-α, a finding documented both in other chronic inflammatory conditions [9,10] and in heart failure patients . These molecules are known to be associated with endothelial damage, consistent with the presumed inflammatory nature of atherosclerosis ; predictably, both ESR and pro-inflammatory cytokines show a positive relationship with soluble endothelial markers, including E-selectin, von Willebrand factor (vWF), and soluble intercellular adhesion molecule-1 (sICAM-1) [10,13,14]. Inflammatory cytokines [14,15] and endothelial markers [14,16–18] have consistently been shown to be elevated in HIV-positive patients, though their levels have not been stratified by ESR to my knowledge.
2. It also reflects altered plasma viscosity, enhanced red cell aggregation, and impaired microvascular blood flow. These phenomena, and their relationship to sedimentation rate, have been extensively studied in the context of HIV infection in the accessible retinal bed [19–22] and are also suggested by in-vitro evidence .
It is, thus, perhaps not surprising to find the following clinical evidence:
1. ESR independently predicts carotid atherosclerosis in both rheumatoid arthritis patients and healthy controls [24,25].
2. Current ESR  or ‘cumulative ESR’  predicts arterial stiffness in rheumatoid arthritis.
3. ESR has consistently and repeatedly been shown to be an independent predictor of cardiovascular mortality both in patients with chronic inflammatory conditions [28,29] and without [25,30–34].
It would thus seem sensible to pay more attention to the ESR, especially now that cardiovascular disease potentially represents the greatest life-shortening threat to our patients. In terms of how to ‘treat’, the most obvious and attractive answer would be antiretroviral therapy, which reduces markers of immune activation , reduces serum markers of endothelial activation , and improves measurable endothelial function . We await with interest the results of the Strategic Timing of Antiretroviral Treatment (START) study (clinicaltrials.gov reference NCT00867048), but I would postulate that the long-term advantage of early initiation of therapy would be greatest in the population with most immune activation and most impaired microvascular blood flow. It would seem logical from the evidence above that this is the group with significantly elevated ESR readings (it should be noted that not all HIV-positive patients have elevated ESRs , and ethnic or environmental differences may contribute to this : in fact, chronic immune activation may be of greatest concern in Africa). If this is indeed the case, then we would have a preexisting, cheap, and simple test to help guide these treatment decisions – rather than having to introduce high-sensitivity CRP (hsCRP) or cytokine assays into routine laboratories.
There may be other treatment options: the Medical Research Council are currently investigating the use of the immunomodulatory drug hydroxychloroquine in antiretroviral-naive patients (clinicaltrials.gov reference NCT01067417), and this may be of particular benefit in those with excessive immune activation and viscosity. Other immunomodulators such as pentoxifyllene might also be considered. Another important drug class to consider would be statins. Despite the potential for drug interactions, their beneficial effect both on endothelial function and in reducing inflammation – including ESR – has been well documented [37,38]. Improvements in endothelial function have been specifically demonstrated in HIV-positive patients taking pravastatin [39,40]. Together with my belief that lipid targets should be lower in HIV-positive people than the general population (more akin to high-risk groups such as diabetic patients, as has been suggested for those with chronic rheumatological conditions ) and the opportunity for ‘learning compliance’ with a daily tablet before the commencement of antiretrovirals, I would suggest that statins should be prescribed to antiretroviral-naive patients far more commonly than they are in current practice.
Whichever strategy is adopted, the greatest risk appears to be leaving a high ESR ‘untreated’. Many of our colleagues in rheumatology or hematology with greater experience of this parameter and its consequences would not even entertain such an idea.
In conclusion, I would urge those conducting large cohort studies to start measuring the ESR again: perhaps, we will find that it is a useful test after all.
D.M.L.'s salary is provided via a Clinical Training Fellowship from the Wellcome Trust. Many thanks to Dr Moses Kapembwa for his expert review of the manuscript.
1. Schwartländer B, Bek B, Skarabis H, Koch J, Burkowitz J, Koch MA. Improvement of the predictive value of CD4+ lymphocyte count by beta 2 microglobulin, immunoglobulin A and erythrocyte sedimentation rate. The Multicentre Cohort Study Group. AIDS 1993; 7:813–821.
2. Lefrère JJ, Salmon D, Doinel C, Rouger P, Courouce AM, Lambin P, et al. Sedimentation rate as a predictive marker in HIV infection. AIDS 1988; 2:63–64.
3. Vázquez EG, de Górgolas M, Guerrero ML. Relation between erythrocyte sedimentation rate, clinical and immune status and virus load in nonhospitalized HIV-infected patients. Rev Esp Quimioter 2001; 14:264–268.
4. Kapiga SH, Mwakagile D, Spiegelman D, Msamanga GI, Hunter D, Fawzi WW. Predictors of CD4+ lymphocyte count among HIV-seropositive and HIV-seronegative pregnant women in Dar es Salaam, Tanzania. East Afr Med J 2000; 77:206–211.
5. Peters PJ, Zulu I, Kancheya NG, Lakhi S, Chomba E, Vwalika C, et al, Rwanda Zambia HIV Research Group. Modified Kigali combined staging predicts risk of mortality in HIV-infected adults in Lusaka, Zambia. AIDS Res Hum Retroviruses 2008; 24:919–924.
6. Arango CA, Midani S, Alvarez A, Kubilis PS, Rathore MH. Usefulness of acute phase reactants in the diagnosis of acute infections in HIV-infected children. South Med J 1999; 92:209–213.
7. Morpeth SC, Crump JA, Shao HJ, Ramadhani HO, Kisenge PR, Moylan CA, et al. Predicting CD4 lymphocyte count <200 cells/mm(3) in an HIV type 1-infected African population. AIDS Res Hum Retroviruses 2007; 23:1230–1236.
8. Ndakotsu MA, Salawu L, Durosinmi MA. Relation between erythrocyte sedimentation rate, clinical and immune status in HIV-infected patients. Niger J Med 2009; 18:208–210.
9. Kaufmann J, Franke S, Kientsch-Engel R, Oelzner P, Hein G, Stein G. Correlation of circulating interleukin 16 with proinflammatory cytokines in patients with rheumatoid arthritis. Rheumatology (Oxford) 2001; 40:474–475.
10. Foster W, Carruthers D, Lip GY, Blann AD. Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: effect of intensive anti-inflammatory treatment. J Thromb Thrombolysis 2010; 29:437–442.
11. Sharma R, Rauchhaus M, Ponikowski PP, Varney S, Poole-Wilson PA, Mann DL, et al. The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2000; 36:523–528.
12. Patterson CC, Smith AE, Yarnell JW, Rumley A, Ben-Shlomo Y, Lowe GD. The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: the Caerphilly Study. Atherosclerosis 2010; 209:551–557.
13. Wållberg-Jonsson S, Cvetkovic JT, Sundqvist KG, Lefvert AK, Rantapää-Dahlqvist S. Activation of the immune system and inflammatory activity in relation to markers of atherothrombotic disease and atherosclerosis in rheumatoid arthritis. J Rheumatol 2002; 29:875–882.
14. de Larrañaga GF, Petroni A, Deluchi G, Alonso BS, Benetucci JA. Viral load and disease progression as responsible for endothelial activation and/or injury in human immunodeficiency virus-1-infected patients. Blood Coagul Fibrinolysis 2003; 14:15–18.
15. Haissman JM, Vestergaard LS, Sembuche S, Erikstrup C, Mmbando B, Mtullu S, et al. Plasma cytokine levels in Tanzanian HIV-1-infected adults and the effect of antiretroviral treatment. J Acquir Immune Defic Syndr 2009; 52:493–497.
16. Sfikakis PP, Tzavara V, Sipsas N, Kosmopoulou O, Sfikakis P, Kordossis T. Levels of the circulating cell adhesion molecule E-selectin and disease progression in HIV infection. Infection 1995; 23:207–211.
17. Kristoffersen US, Kofoed K, Kronborg G, Giger AK, Kjaer A, Lebech AM. Changes in circulating markers of endothelial function in HIV patients starting combination antiretroviral therapy [abstract]. Presented at: 15th Conference on Retroviruses and Opportunistic Infections (CROI); Boston, MA; 2008.
18. Wolf K, Tsakiris DA, Weber R, Erb P, Battegay M, Swiss HIV Cohort Study. Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with human immunodeficiency virus type 1. J Infect Dis 2002; 185:456–462.
19. Kim A, Dadgostar H, Holland GN, Wenby R, Yu F, Terry BG, et al. Hemorheologic abnormalities associated with HIV infection: altered erythrocyte aggregation and deformability. Invest Ophthalmol Vis Sci 2006; 47:3927–3932.
20. Lim MC, Cumberland WG, Minassian SL, Ransome SS, Cornish MJ, Terry BG, et al. Decreased macular leukocyte velocity in human immunodeficiency virus-infected individuals. Am J Ophthalmol 2001; 132:711–719.
21. Dejaco-Ruhswurm I, Kiss B, Rainer G, Krepler K, Wedrich A, Dallinger S, et al. Ocular blood flow in patients infected with human immunodeficiency virus. Am J Ophthalmol 2001; 132:720–726.
22. Engstrom RE Jr, Holland GN, Hardy WD, Meiselman HJ. Hemorheologic abnormalities in patients with human immunodeficiency virus infection and ophthalmic microvasculopathy. Am J Ophthalmol 1990; 109:153–161.
23. Monsuez JJ, Dufaux J, Vittecoq D, Flaud P, Vicaut E. Hemorheology in asymptomatic HIV-infected patients. Clin Hemorheol Microcirc 2000; 23:59–66.
24. Del Rincón I, Williams K, Stern MP, Freeman GL, O'Leary DH, Escalante A. Association between carotid atherosclerosis and markers of inflammation in rheumatoid arthritis patients and healthy subjects. Arthritis Rheum 2003; 48:1833–1840.
25. Natali A, L'Abbate A, Ferrannini E. Erythrocyte sedimentation rate, coronary atherosclerosis, and cardiac mortality. Eur Heart J 2003; 24:639–648.
26. Maki-Petaja KM, Hall FC, Booth AD, Wallace SM, Yasmin, Bearcroft PW, et al. Rheumatoid arthritis is associated with increased aortic pulse-wave velocity, which is reduced by antitumor necrosis factor-alpha therapy. Circulation 2006; 114:1185–1192
27. Crilly MA, Kumar V, Clark HJ, Scott NW, Macdonald AG, Williams DJ. Arterial stiffness and cumulative inflammatory burden in rheumatoid arthritis: a dose-response relationship independent of established cardiovascular risk factors. Rheumatology (Oxford) 2009; 48:1606–1612.
28. Turesson C, Jacobsson LT, Matteson EL. Cardiovascular co-morbidity in rheumatic diseases. Vasc Health Risk Manag 2008; 4:605–614.
29. Maradit-Kremers H, Nicola PJ, Crowson CS, Ballman KV, Gabriel SE. Cardiovascular death in rheumatoid arthritis: a population-based study. Arthritis Rheum 2005; 52:722–732.
30. Erikssen G, Liestol K, Bjornholt JV, Stormorken H, Thaulow E, Erikssen J. Erythrocyte sedimentation rate: a possible marker of atherosclerosis and a strong predictor of coronary heart disease mortality. Eur Heart J 2000; 21:1614–1620.
31. Danesh J, Collins R, Peto R, Lowe GD. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000; 21:515–520.
32. Timmer JR, Ottervanger JP, Hoorntje JC, De Boer MJ, Suryapranata H, van't Hof AW, et al, Zwolle Myocardial Infarction study group. Prognostic value of erythrocyte sedimentation rate in ST segment elevation myocardial infarction: interaction with hyperglycaemia. J Intern Med 2005; 257:423–429.
33. Skretteberg PT, Bodegård J, Kjeldsen SE, Erikssen G, Thaulow E, Sandvik L, Erikssen JE. Interaction between inflammation and blood viscosity predicts cardiovascular mortality. Scand Cardiovasc J 2010; 44:107–112.
34. Godsland IF, Bruce R, Jeffs JA, Leyva F, Walton C, Stevenson JC. Inflammation markers and erythrocyte sedimentation rate but not metabolic syndrome factor score predict coronary heart disease in high socioeconomic class males: the HDDRISC study. Int J Cardiol 2004; 97:543–550.
35. Torriani F, Komarow L, Cotter B, Murphy R, Fichtenbaum C, Currier J, et al. Control of HIV viral replication is associated with rapid improvement in endothelial function sustained over 24 weeks: A5152 s, a substudy of A5142 [abstract]. Presented at: 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention; Sydney, Australia; 2007.
36. Modjarrad K, Zulu I, Karita E, Kancheya N, Funkhouser E, Allen S. Predictors of HIV serostatus among HIV discordant couples in Lusaka, Zambia and female antenatal clinic attendants in Kigali, Rwanda. AIDS Res Hum Retroviruses 2005; 21:5–12.
37. Akalin A, Temiz G, Akcar N, Sensoy B. Short term effects of atorvastatin on endothelial functions and oxidized LDL levels in patients with type 2 diabetes. Endocr J 2008; 55:861–866.
38. Abou-Raya A, Abou-Raya S, Helmii M. Statins as immunomodulators in systemic sclerosis. Ann N Y Acad Sci 2007; 1110:670–680.
39. Hürlimann D, Chenevard R, Ruschitzka F, Flepp M, Enseleit F, Béchir M, et al. Effects of statins on endothelial function and lipid profile in HIV infected persons receiving protease inhibitor-containing antiretroviral combination therapy: a randomised double blind crossover trial. Heart 2006; 92:110–112.
40. Stein JH, Merwood MA, Bellehumeur JL, Aeschlimann SE, Korcarz CE, Underbakke GL, et al. Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors. Am Heart J 2004; 147:E18.
41. Wajed J, Ahmad Y, Durrington PN, Bruce IN. Prevention of cardiovascular disease in systemic lupus erythematosus: proposed guidelines for risk factor management. Rheumatology (Oxford) 2004; 43:7–12.
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