Anisocytosis is Associated With Short-Term Mortality in COVID-19 and May Reflect Proinflammatory Signature in Uninfected Ambulatory Adults
Article Sidebar
Main Article Content
Abstract
Background
Red cell distribution width (RDW), a measure of anisocytosis, is observed in chronic inflammation and is a prognostic marker in critically ill patients without COVID-19, but data in COVID-19 are limited.
Methods
Between March 12 and April 19, 2020, 282 individuals with confirmed COVID-19 and RDW available within 7 days prior to COVID-19 confirmation were evaluated. Individuals were grouped by quartiles of RDW. Association between quartiles of RDW and mortality was assessed using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. The association between RDW and all-cause mortality was further assessed using a Cox proportional hazards model. Plasma cytokine levels in uninfected ambulatory adults without cardiovascular disease (n=38) were measured and bivariate Spearman correlations and principle components analysis were used to identify relationships between cytokine concentrations with RDW.
Results
After adjusting for age, sex, race, cardiovascular disease, and hemoglobin, there was an association between RDW and mortality (Quartile 4 vs Quartile 1: HR 4.04 [1.08-15.07]), with each 1% increment in RDW associated with a 39% increased rate of mortality (HR 1.39 [1.21-1.59]). Remote RDW was also associated with mortality after COVID-19 infection. Among uninfected ambulatory adults without cardiovascular disease, RDW was associated with elevated pro-inflammatory cytokines (TNF-α, IL8, IL6, IL1b), but not regulatory cytokines (TGFb).
Conclusions
Anisocytosis predicts short-term mortality in COVID-19 patients, often predates viral exposure, and may be related to a pro-inflammatory phenotype. Additional study of whether the RDW can assist in the early identification of pending cytokine storm is warranted.
Downloads
Article Details
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. Epub 2020/01/28. doi: 10.1016/S0140-6736(20)30183-5. PubMed PMID: 31986264; PMCID: PMC7159299.
2. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, Hlh Across Speciality Collaboration UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. Epub 2020/03/21. doi: 10.1016/S0140-6736(20)30628-0. PubMed PMID: 32192578; PMCID: PMC7270045.
3. Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest. 2020;130(5):2202-5. Epub 2020/03/29. doi: 10.1172/JCI137647. PubMed PMID: 32217834; PMCID: PMC7190904.
4. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620-9. Epub 2020/03/29. doi: 10.1172/JCI137244. PubMed PMID: 32217835; PMCID: PMC7190990.
5. Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020;178:104791. Epub 2020/04/11. doi: 10.1016/j.antiviral.2020.104791. PubMed PMID: 32275914; PMCID: PMC7138382.
6. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. Epub 2020/03/15. doi: 10.1016/S0140-6736(20)30566-3. PubMed PMID: 32171076; PMCID: PMC7270627.
7. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z, Feng Z, Zhang Y, Wu Y, Chen Y. Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827. Epub 2020/05/20. doi: 10.3389/fimmu.2020.00827. PubMed PMID: 32425950; PMCID: PMC7205903.
8. Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med. 2020;217(6). Epub 2020/05/01. doi: 10.1084/jem.20200678. PubMed PMID: 32353870; PMCID: PMC7191310.
9. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, Swedberg K, Wang D, Yusuf S, Michelson EL, Granger CB, Investigators C. Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank. J Am Coll Cardiol. 2007;50(1):40-7. Epub 2007/07/03. doi: 10.1016/j.jacc.2007.02.067. PubMed PMID: 17601544.
10. Al-Kindi SG, Kim CH, Morris SR, Freeman ML, Funderburg NT, Rodriguez B, McComsey GA, Dalton JE, Simon DI, Lederman MM, Longenecker CT, Zidar DA. Brief Report: Elevated Red Cell Distribution Width Identifies Elevated Cardiovascular Disease Risk in Patients With HIV Infection. J Acquir Immune Defic Syndr. 2017;74(3):298-302. Epub 2016/11/10. doi: 10.1097/QAI.0000000000001231. PubMed PMID: 27828877; PMCID: PMC5303143.
11. Luo R, Hu J, Jiang L, Zhang M. Prognostic Value of Red Blood Cell Distribution Width in Non-Cardiovascular Critically or Acutely Patients: A Systematic Review. PLoS One. 2016;11(12):e0167000. Epub 2016/12/10. doi: 10.1371/journal.pone.0167000. PubMed PMID: 27936006; PMCID: PMC5147853.
12. Bazick HS, Chang D, Mahadevappa K, Gibbons FK, Christopher KB. Red cell distribution width and all-cause mortality in critically ill patients. Crit Care Med. 2011;39(8):1913-21. Epub 2011/05/03. doi: 10.1097/CCM.0b013e31821b85c6. PubMed PMID: 21532476; PMCID: PMC4427349.
13. Lorente L, Martin MM, Abreu-Gonzalez P, Sole-Violan J, Ferreres J, Labarta L, Diaz C, Gonzalez O, Garcia D, Jimenez A, Borreguero-Leon JM. Red blood cell distribution width during the first week is associated with severity and mortality in septic patients. PLoS One. 2014;9(8):e105436. Epub 2014/08/26. doi: 10.1371/journal.pone.0105436. PubMed PMID: 25153089; PMCID: PMC4143268.
14. Al-Kindi SG, Zidar DA, McComsey GA, Longenecker CT. Association of Anisocytosis with Markers of Immune Activation and Exhaustion in Treated HIV. Pathog Immun. 2017;2(1):138-50. Epub 2017/07/18. doi: 10.20411/pai.v2i1.199. PubMed PMID: 28713869; PMCID: PMC5505669.
15. Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, Ghali JK, Lenihan DJ, Oren RM, Wagoner LE, Schwartz TA, Adams KF, Jr. Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure. J Card Fail. 2010;16(3):230-8. Epub 2010/03/09. doi: 10.1016/j.cardfail.2009.11.003. PubMed PMID: 20206898; PMCID: PMC3894681.
16. Esmaili H. Determining the Association between RDW and Traditional Markers of Inflammation. Annual Research & Review in Biology. 2014;4(15):2547-52. doi: 10.9734/arrb/2014/9651.
17. Lippi G, Targher G, Montagnana M, Salvagno GL, Zoppini G, Guidi GC. Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch Pathol Lab Med. 2009;133(4):628-32. Epub 2009/04/28. doi: 10.1043/1543-2165-133.4.628. PubMed PMID: 19391664.
18. Gong J, Ou J, Qiu X, Jie Y, Chen Y, Yuan L, Cao J, Tan M, Xu W, Zheng F, Shi Y, Hu B. A Tool for Early Prediction of Severe Coronavirus Disease 2019 (COVID-19): A Multicenter Study Using the Risk Nomogram in Wuhan and Guangdong, China. Clin Infect Dis. 2020;71(15):833-40. Epub 2020/04/17. doi: 10.1093/cid/ciaa443. PubMed PMID: 32296824; PMCID: PMC7184338.
19. Wang C, Deng R, Gou L, Fu Z, Zhang X, Shao F, Wang G, Fu W, Xiao J, Ding X, Li T, Xiao X, Li C. Preliminary study to identify severe from moderate cases of COVID-19 using combined hematology parameters. Ann Transl Med. 2020;8(9):593. Epub 2020/06/23. doi: 10.21037/atm-20-3391. PubMed PMID: 32566620; PMCID: PMC7290538.
20. Patel KV, Semba RD, Ferrucci L, Newman AB, Fried LP, Wallace RB, Bandinelli S, Phillips CS, Yu B, Connelly S, Shlipak MG, Chaves PH, Launer LJ, Ershler WB, Harris TB, Longo DL, Guralnik JM. Red cell distribution width and mortality in older adults: a meta-analysis. J Gerontol A Biol Sci Med Sci. 2010;65(3):258-65. Epub 2009/11/03. doi: 10.1093/gerona/glp163. PubMed PMID: 19880817; PMCID: PMC2822283.
21. Zidar DA, Al-Kindi SG, Liu Y, Krieger NI, Perzynski AT, Osnard M, Nmai C, Anthony DD, Lederman MM, Freeman ML, Bonomo RA, Simon DI, Dalton JE. Association of Lymphopenia With Risk of Mortality Among Adults in the US General Population. JAMA Netw Open. 2019;2(12):e1916526. Epub 2019/12/04. doi: 10.1001/jamanetworkopen.2019.16526. PubMed PMID: 31790569; PMCID: PMC6902755.
22. Cooper AC, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Increased expression of erythropoiesis inhibiting cytokines (IFN-gamma, TNF-alpha, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy. J Am Soc Nephrol. 2003;14(7):1776-84. Epub 2003/06/24. doi: 10.1097/01.asn.0000071514.36428.61. PubMed PMID: 12819237.
23. Scharte M, Fink MP. Red blood cell physiology in critical illness. Crit Care Med. 2003;31(12 Suppl):S651-7. Epub 2004/01/16. doi: 10.1097/01.CCM.0000098036.90796. ED. PubMed PMID: 14724462.
24. Zhang Z, Chew GM, Shikuma CM, Gangcuangco LMA, Souza SA, Shiramizu B, Nakamoto BK, Gong T, Mannem SR, Mitchell BI, Kallianpur KJ, Ndhlovu LC, Chow DC. Red blood cell distribution width as an easily measurable biomarker of persistent inflammation and T cell dysregulation in antiretrovirally treated HIV-infected adults. HIV Clin Trials. 2018;19(5):172-6. Epub 2018/11/14. doi: 10.1080/15284336.2018.1514821. PubMed PMID: 30422099; PMCID: PMC6324948.