Immunologic effects of hydroxyurea in sickle cell anemia

Abstract

Background and objective: Susceptibility to encapsulated bacteria is well known in sickle cell disease (SCD). Hydroxyurea use is common in adults and children with SCD, but little is known about hydroxyurea's effects on immune function in SCD. Because hydroxyurea inhibits ribonucleotide reductase, causing cell cycle arrest at the G1-S interface, we postulated that hydroxyurea might delay transition from naive to memory T cells, with inhibition of immunologic maturation and vaccine responses.

Methods: T-cell subsets, naive and memory T cells, and antibody responses to pneumococcal and measles, mumps, and rubella vaccines were measured among participants in a multicenter, randomized, double-blind, placebo-controlled trial of hydroxyurea in infants and young children with SCD (BABY HUG).

Results: Compared with placebo, hydroxyurea treatment resulted in significantly lower total lymphocyte, CD4, and memory T-cell counts; however, these numbers were still within the range of historical healthy controls. Antibody responses to pneumococcal vaccination were not affected, but a delay in achieving protective measles antibody levels occurred in the hydroxyurea group. Antibody levels to measles, mumps, and rubella showed no differences between groups at exit, indicating that effective immunization can be achieved despite hydroxyurea use.

Conclusions: Hydroxyurea does not appear to have significant deleterious effects on the immune function of infants and children with SCD. Additional assessments of lymphocyte parameters of hydroxyurea-treated children may be warranted. No changes in current immunization schedules are recommended; however, for endemic disease or epidemics, adherence to accelerated immunization schedules for the measles, mumps, and rubella vaccine should be reinforced.

Keywords: hydroxyurea; immunology; sickle cell disease; vaccines.

FIGURE 1

Samples available for study. A, Patients evaluable for PPV-23 response (vaccinated with PPV-23 with ≥1 preimmunization and 1 postimmunization sample for measurement of pneumococcal antibody levels). B, Vaccinated participants with ≥1 blood sample after immunization for measurement of MMR antibody levels. C, Patients who received randomized treatment before MMR vaccination and evaluable for acute MMR response (with ≥1 blood sample for measurement of MMR antibody levels within the 2- to 10-week acute response window).

FIGURE 2

Effects of hydroxyurea on the absolute number of memory CD4 T cells. Reference line (red dashes) indicates baseline geometric mean (360 cells/mm³, slope = 0). Linear regression lines show slopes (cells/mm³ per month): hydroxyurea, −1.6 and placebo, +1.1.

FIGURE 3

Semilogarithmic plot of IgG antibody concentrations to pneumococcal polysaccharide serotypes 26 (6B) and 51 (7F). Individual patients are represented by scatterplot symbols corresponding to their IgG antibody concentration at pretreatment, age 24 months, age 26 months, and end of study. Plot symbols of patients randomly assigned to hydroxyurea are offset left solid diamonds, with geometric means connected by dashed line. Plot symbols of patients randomly assigned to placebo are offset right open diamonds, with geometric means connected by unbroken line.

FIGURE 4

Log acute antibody levels to MMR. Scatterplot symbols represent log10 (acute response index/1.1) of patients who started randomized treatment before MMR vaccination. Curvilinear lines represent regression of log10 antibody level versus log10 days after MMR vaccination in model that included randomized treatment and treatment by time effects. Horizontal line represents the protective level of antibody. Plot symbols of patients randomly assigned to hydroxyurea are black diamonds with dashed line. Placebo are gray triangles with unbroken lines. Model treatment mean antibody index and rate difference (difference in slope) results were measles, mean P = .010, rate P = .032; mumps, mean P = .516, rate P = .663; rubella, mean P = .008, rate P = .497.