Effect of Hydroxyurea Therapy on the Incidence of Infections in Ugandan Children with Sickle Cell Anaemia

Hydroxyurea is efficacious against sickle cell anaemia (SCA)-related complications in African children. Prior studies demonstrated conflicting results on the effect of hydroxyurea on risk of infection, the most common cause of morbidity and mortality in African children with SCA.

We evaluated the incidence of infections before and after starting hydroxyurea in 117 children aged 1-5 years with SCA enrolled in the Zinc for Infection Prevention in Sickle cell anaemia (ZIPS) clinical trial that received zinc or placebo treatment for one year (Clinicaltrials.gov, NCT03528434). Children were enrolled between March 2018 and November 2019 and initiated on hydroxyurea (20 mg/kg/day) if they met Uganda SCA guideline criteria for hydroxyurea treatment at any time during the study. We compared the incidence of infections before and after hydroxyurea therapy, adjusting for zinc treatment.

Overall, the mean duration on hydroxyurea was 223.8 (85.2) person days. The mean(SD) incidence of any severe/invasive infections (infections meeting strict clinical and laboratory or radiological diagnostic criteria) was 6.2(9.0) vs. 1.9(2.3) infections per child per year before and after hydroxyurea (incidence rate ratio [IRR]: 0.40, 95%CI: 0.29-0.54, p<0.001), including a decrease in the incidence of bacteremia [IRR: 0.05] malaria, [IRR 0.28], cellulitis [IRR: 0.24], gastroenteritis [IRR: 0.41], pharyngitis [IRR: 0.59] and sinusitis [IRR: 0.38] (all p<0.05). Similarly, the incidence of clinically defined infections (infections meeting clinical but not laboratory/radiological criteria) decreased after hydroxyurea, (IRR: 0.49, 0.41-0.59), influenced primarily by large reductions in the incidence of lower and upper respiratory tract infections (p<0.001 for both). As expected, hydroxyurea treatment was also associated with a decrease in complications of SCA, including vaso-occlusive crises, hospitalizations and transfusions (all p<0.001). There was no interaction between zinc and hydroxyurea therapy on risk of infection and SCA-related complications.

In Ugandan children with SCA, hydroxyurea therapy not only decreases the incidence of SCA-related complications, but also substantially reduces the incidence of infections. Research to understand the underlying mechanisms of protection from hydroxyurea against infection and exploration of its potential use for infection prevention is warranted.