Hydroxyurea Affects T-Lymphocyte Subsets in Sickle Cell Disease.
Authors: Sivasubramaniam Devaki , Bekoe Osei , Motwani Bharat , Allen Sandra , Feldman Lori , Beaman Kenneth , Gilman-Sachs Alice , Feldman Lawrence E. 
Published: October 2019

Abstract
Hydroxyurea (HU) is now widely used in the treatment of sickle cell disease (SCD). The effect of this agent on T-lymphocytes in this disease has not been extensively studied. In other diseases such as human immunodeficiency virus (HIV) disease, HU was found to have a variable effect on T-cell subsets. We previously reported (Blood2002; 100: 363) a case of a sickle cell disease patient who was HIV- negative who was found to have low CD4 count on HU that normalized after stopping this agent. We have since conducted a case-controlled study in our sickle cell disease clinic in an attempt to analyze the effects of HU on CD4 count and other T-lymphocyte subsets. Written informed consent was obtained from 15 SCD patients. All patients had SCD as confirmed by hemoglobin electrophoresis. We placed patients into 2 cohorts: the treatment group consisted of patients already receiving HU therapy and the control group consisted of patients not taking HU. Among 15 patients, 8 patients were in treatment group and 7 patients were in the control group. In control group, 5 patients were female and 2 patients were male with mean age of 38 years. In treatment group, 7 patients were female and 1 was male with mean age of 35 years. In the treatment group, the mean duration of HU therapy was 4 years. We collected venous blood from all patients and tested for the following blood cell counts: total white blood cell (WBC), total neutrophil, total lymphocyte, CD4, CD8, CD3 cells and CD4/CD8 ratio. We also tested and found that there was no significant difference between the 2 cohorts for the presence of alloantibodies, cytomegalovirus virus and hepatitis C viral status. All patients were found to be HIV- negative. The lymphocyte assay was done using Coulter MAXAM hematology analyzer and using a combination of white blood cell counts and differential count in the same laboratory for all patients. We compared the mean value of total T-lymphocyte counts, T-cell subgroups CD4, CD8, CD3 levels and CD4/CD8 ratios between the 2 groups by performing the t-test (Table 1). Our study showed that the treatment group had a statistically significant increase in total T- lymphocyte count and in levels of the CD4, CD8 and CD3 levels compared to the control group. There was no difference in the CD4/CD8 ratio between the 2 groups. These results provide additional information to our previous observation of a lowered CD4 count in a SCD patient on HU. These results are consistent with findings in HIV positive patients where changes in T- lymphocytes subsets have been observed in patients treated with HU (AIDS2002; 14:619–621 and J Acquir Immune Defic Syndr2000; 25: 329–336). We conclude that in SCD patients HU can affect T-lymphocyte subset counts. The mechanism and clinical significance of the effect, if any, is unknown and requires further investigation.
Table 1: Effects of HU on T-lymphocytes
Blood test Control group treatment group P value * P-value significant below 0.05 Total WBC th/mm3 15.36 12.28 0.23 Neutrophil ct/mm3 7.87 4.92 0.12 Total lymphocyte ct/mm3 2458.83 3739.4 0.01* Absolute CD4, mm3 1621.7 2284.8 0.05* Absolute CD8, mm3 701.42 1340.33 0.01* Absolute CD3, mm3 2520 3723 0.01* CD4/CD8 Ratio 2.321 2.32 0.99