Association of Anisocytosis with Markers of Immune Activation and Exhaustion in Treated HIV

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Sadeer G. Al-Kindi
David A. Zidar
Grace A. McComsey
Chris T. Longenecker


Background: Treated HIV infection is associated with heightened inflammation which can contribute to increased risk of cardiovascular disease (CVD). We have previously shown that anisocytosis, as measured by red cell distribution width (RDW), is independently associated with prevalent CVD in people living with HIV (PLHIV). In this study, we sought to identify immune correlates of RDW in PLHIV receiving antiretroviral therapy.

Methods: We performed a cross-sectional and longitudinal analysis of 147 virally-suppressed PLHIV, who had LDL <130 mg/dL and evidence of heightened inflammation, in a randomized trial of statin therapy. A complete blood count and biomarkers of inflammation and immune activation/exhaustion were measured in peripheral blood at entry and after 24 and 48 weeks. Associations with RDW were estimated using linear regression and linear mixed models.

Results: The median age (IQR) for the cohort at enrollment was 46 (40–53) years; 78% were male and 68% were African American. The median RDW for the cohort was 13.4% (12.9–14.0). Compared with the lowest RDW tertile, patients in the highest tertile were less likely to be male, and more likely to be African American, have lower hemoglobin, lower mean corpuscular volume, and higher platelet counts (all P<0.05). At baseline, RDW weakly correlated with C-reactive protein (r=0.196), d-dimer (r=0.214), fibrinogen (r=0.192), interleukin-6 (r=0.257), CD4+DR+38+ T cells (r=0.195), and CD4+PD1+ T cells (r=0.227), all P<0.05. Only IL-6, CD4+38+DR+ T cells, and CD4+PD1+ T_cells remained associated after adjustment for clinical factors known to affect RDW in the general population. Over 48 weeks, RDW did not change and there was no significant effect of statin (P=0.45). After adjustment for clinical parameters, RDW remained positively associated with CD4+38+DR+ and CD4+PD1+ T cells across all time points (P=0.05).

Conclusion: In this population of treated HIV+ subjects, anisocytosis was associated with biomarkers of inflammation and T-cell activation/exhaustion over time and independent of clinical confounders. Therefore, RDW may be a useful prognostic biomarker of cardiovascular risk that partially reflects chronic inflammation and immune exhaustion in PLHIV receiving antiretroviral therapy. 


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1. Huttner A, Harbarth S, Carlet J, Cosgrove S, Goossens H, Holmes A, Jarlier V, Voss A, Pittet D. Antimicrobial resistance: a global view from the 2013 World Healthcare-Associated Infections Forum. Antimicrob Resist Infect Control. 2013;2:31. PubMed PMID: 24237856. Pubmed Central PMCID: PMC4131211. doi: 10.1186/2047-2994-2-31

2. World Health Organization. Antimicrobial resistance: global report on surveillance. : WHO; 2014 [cited 2016 March 27]. Available from:

3. Prestinaci F, Pezzotti P, Pantosti A. Antimicrobial resistance: a global multifaceted phenomenon. Pathog Glob Health. 2015;109(7):309-18. PubMed PMID: 26343252. Pubmed Central PMCID: PMC4768623. doi: 10.1179/2047773215Y.0000000030

4. Alsan M, Schoemaker L, Eggleston K, Kammili N, Kolli P, Bhattacharya J. Out-of-pocket health expenditures and antimicrobial resistance in low-income and middle-income countries: an economic analysis. Lancet Infect Dis. 2015;15(10):1203-10. PubMed PMID: 26164481. Pubmed Central PMCID: PMC4609169. doi: 10.1016/S1473-3099(15)00149-8

5. Kristiansson C, Grape M, Gotuzzo E, Samalvides F, Chauca J, Larsson M, Bartoloni A, Pallecchi L, Kronvall G, Petzold M. Socioeconomic factors and antibiotic use in relation to antimicrobial resistance in the Amazonian area of Peru. Scand J Infect Dis. 2009;41(4):303-12. PubMed PMID: 19253090. doi: 10.1080/00365540902783301

6. Azmi IJ, Khajanchi BK, Akter F, Hasan TN, Shahnaij M, Akter M, Banik A, Sultana H, Hossain MA, Ahmed MK, Faruque SM, Talukder KA. Fluoroquinolone resistance mechanisms of Shigella flexneri isolated in Bangladesh. PLoS One. 2014;9(7):e102533. PubMed PMID: 25028972. Pubmed Central PMCID: PMC4100904. doi: 10.1371/journal.pone.0102533

7. Bowen A, Hurd J, Hoover C, Khachadourian Y, Traphagen E, Harvey E, Libby T, Ehlers S, Ongpin M, Norton JC, Bicknese A, Kimura A, Centers for Disease Control and Prevention. Importation and domestic transmission of Shigella sonnei resistant to ciprofloxacin - United States, May 2014-February 2015. MMWR Morb Mortal Wkly Rep. 2015;64(12):318-20. PubMed PMID: 25837241.

8. Kim JS, Kim JJ, Kim SJ, Jeon SE, Seo KY, Choi JK, Kim NO, Hong S, Chung GT, Yoo CK, Kim YT, Cheun HI, Bae GR, Yeo YH, Ha GJ, Choi MS, Kang SJ, Kim J. Outbreak of Ciprofloxacin-Resistant Shigella sonnei Associated with Travel to Vietnam, Republic of Korea. Emerg Infect Dis. 2015;21(7):1247-50. PubMed PMID: 26079171. Pubmed Central PMCID: PMC4480405. doi: 10.3201/eid2107.150363

9. Taneja N. Changing epidemiology of shigellosis and emergence of ciprofloxacin-resistant Shigellae in India. J Clin Microbiol. 2007;45(2):678-9. PubMed PMID: 17122011. Pubmed Central PMCID: PMC1829036. doi: 10.1128/JCM.02247-06

10. Chung The H, Rabaa MA, Pham Thanh D, De Lappe N, Cormican M, Valcanis M, Howden BP, Wangchuk S, Bodhidatta L, Mason CJ, Nguyen Thi Nguyen T, Vu Thuy D, Thompson CN, Phu Huong Lan N, Voong Vinh P, Ha Thanh T, Turner P, Sar P, Thwaites G, Thomson NR, Holt KE, Baker S. South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study. PLoS Med. 2016;13(8):e1002055. PubMed PMID: 27483136. Pubmed Central PMCID: PMC4970813. doi: 10.1371/journal.pmed.1002055

11. Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, Wu Y, Sow SO, Sur D, Breiman RF, Faruque AS, Zaidi AK, Saha D, Alonso PL, Tamboura B, Sanogo D, Onwuchekwa U, Manna B, Ramamurthy T, Kanungo S, Ochieng JB, Omore R, Oundo JO, Hossain A, Das SK, Ahmed S, Qureshi S, Quadri F, Adegbola RA, Antonio M, Hossain MJ, Akinsola A, Mandomando I, Nhampossa T, Acacio S, Biswas K, O'Reilly CE, Mintz ED, Berkeley LY, Muhsen K, Sommerfelt H, Robins-Browne RM, Levine MM. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet. 2013;382(9888):209-22. PubMed PMID: 23680352. doi: 10.1016/S0140-6736(13)60844-2

12. Platts-Mills JA, Babji S, Bodhidatta L, Gratz J, Haque R, Havt A, McCormick BJ, McGrath M, Olortegui MP, Samie A, Shakoor S, Mondal D, Lima IF, Hariraju D, Rayamajhi BB, Qureshi S, Kabir F, Yori PP, Mufamadi B, Amour C, Carreon JD, Richard SA, Lang D, Bessong P, Mduma E, Ahmed T, Lima AA, Mason CJ, Zaidi AK, Bhutta ZA, Kosek M, Guerrant RL, Gottlieb M, Miller M, Kang G, Houpt ER, Investigators M-EN. Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED). Lancet Glob Health. 2015;3(9):e564-75. PubMed PMID: 26202075. doi: 10.1016/S2214-109X(15)00151-5

13. Ferdous F, Das SK, Ahmed S, Farzana FD, Malek MA, Das J, Latham JR, Faruque AS, Chisti MJ. Diarrhoea in slum children: observation from a large diarrhoeal disease hospital in Dhaka, Bangladesh. Trop Med Int Health. 2014;19(10):1170-6. PubMed PMID: 25039966. doi: 10.1111/tmi.12357

14. Stoll BJ, Glass RI, Huq MI, Khan MU, Holt JE, Banu H. Surveillance of patients attending a diarrhoeal disease hospital in Bangladesh. Br Med J (Clin Res Ed). 1982;285(6349):1185-8. PubMed PMID: 6812801. Pubmed Central PMCID: PMC1500105.

15. (CLSI) CaLSI. Performance Standards for Antimicrobial Susceptibility Testing; 20th Informational Supplement(June 2010, Updated), CLSI document M100-S20-U, CLSI, Clinical and Laboratory Standard Institute, Fort Wayne, Ind, USA. 2010.

16. Nilsson P, Laurell MH. Impact of socioeconomic factors and antibiotic prescribing on penicillin- non-susceptible Streptococcus pneumoniae in the city of Malmo. Scand J Infect Dis. 2005;37(6-7):436-41. PubMed PMID: 16012003. doi: 10.1080/00365540510037795

17. Walson JL, Marshall B, Pokhrel BM, Kafle KK, Levy SB. Carriage of antibiotic-resistant fecal bacteria in Nepal reflects proximity to Kathmandu. J Infect Dis. 2001;184(9):1163-9. PubMed PMID: 11598839. doi: 10.1086/323647

18. Miranda A, Avila B, Diaz P, Rivas L, Bravo K, Astudillo J, Bueno C, Ulloa MT, Hermosilla G, Del Canto F, Salazar JC, Toro CS. Emergence of Plasmid-Borne dfrA14 Trimethoprim Resistance Gene in Shigella sonnei. Front Cell Infect Microbiol. 2016;6:77. PubMed PMID: 27489797. Pubmed Central PMCID: PMC4951496. doi: 10.3389/fcimb.2016.00077

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