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.

Alteration of lymphocyte phenotype and function in sickle cell anemia: Implications for vaccine responses

“…A notable example is hydroxycarbamide (hydroxyurea), which has been shown to confer beneficial reduction of immune activation in SCA. Specifically, the use of hydroxyurea has been shown to significantly overturn increased lymphocyte count, particularly circulating memory T cells, in individuals with SCA . This is postulated to occur via hydroxyurea‐induced delay in G1 – S phase transition of naïve to memory T cell phenotypes through inhibition of ribonucleaotide reductase .…”

“…Specifically, the use of hydroxyurea has been shown to significantly overturn increased lymphocyte count, particularly circulating memory T cells, in individuals with SCA . This is postulated to occur via hydroxyurea‐induced delay in G1 – S phase transition of naïve to memory T cell phenotypes through inhibition of ribonucleaotide reductase . Hydroxyurea has also been shown to reduce TNF‐α expression by lymphocytes and other immune cells , and is thought to reduce mast cell activation in individuals with SCA .…”

Saccharomyces cerevisiae -derived virus-like particle parvovirus B19 vaccine elicits binding and neutralizing antibodies in a mouse model for sickle cell disease

“…The animal model results are also consistent with our own observations that children with SCD respond well immunologically to parvovirus B19 antigens after a natural infection, and that parvovirus sero-prevalence is similar between children with SCD and their unaffected counterparts [18]. Importantly, we noted that IgG responses against parvovirus B19 persisted at least 13 years (the longest period of time evaluated in the study) in children with SCD; responses were not dampened by hydroxyurea, a common therapy for SCD that is known to cause myleosuppression [19]; and no child who was previously exposed to parvovirus B19 experienced a repeat occurrence of parvovirus-induced disease. All of these factors suggest that parvovirus B19 vaccination has the potential to confer durable protection against infection in patients with SCD [18].…”

Intermittent or uneven daily administration of low‐dose hydroxyurea is effective in treating children with sickle cell anemia in Angola

“…Although mild neutropenia is a frequent adverse effect of hydroxyurea in children treated in HICs, infections due to neutropenia have not been reported, and while hydroxyurea lowers total lymphocyte, CD4, and memory T‐cell counts, the numbers are usually within the normal range of healthy controls, and antibody response to pneumococcal vaccination are unaffected . Regarding malaria, a randomized, double‐blinded, and placebo‐controlled clinical trial in Uganda (Novel Use of Hydroxyurea in an African Region With Malaria—NOHARM) did not show a difference in incidence of malaria or time to malaria infection between children treated with hydroxyurea versus placebo …”