Higher Doses of Zinc May Be Needed to Prevent Infection in Pediatric Sickle Cell Anemia

Twelve months of daily zinc supplementation does not prevent severe or invasive infection or remediate all cases of zinc deficiency in children with sickle cell anemia (SCA). These study results were published in Blood Advances.

This randomized, double-blinded, placebo-controlled trial was conducted from March 2019 to December 2020 at the Nalufenya Sickle Cell Clinic in Uganda. Participants (n=252) included those with SCA who were between 1 and 4.99 years old and weighed at least 5.0 kg. Children with clinically significant medical conditions or severe malnutrition were excluded. Researchers randomly assigned participants to receive either daily treatment with zinc sulfate 10 mg (n=124) or placebo (n=126) for 12 months. All participants received standard care for SCA, and follow-up visits occurred at 1, 3, 6, 9, and 12 months. Of note, treatment with hydroxyurea was encouraged among all participants during the study period.

The primary outcome was the incidence of severe or invasive infection. The incidence of infection, severe adverse events (AEs), and SCA-related AEs was compared between the groups using negative binomial regression or Poisson mixed-effects regression models, with adjustment for duration of hydroxyurea treatment. Cox proportional hazards regression was used to measure binary outcome measures, with hydroxyurea as a time-varying covariate.

There were no significantly different demographic or clinical characteristics observed between participants in the zinc and control groups, and treatment adherence was high in both groups (97.2% and 97.0%, respectively). The most common severe or invasive infections included sepsis, malaria, gastroenteritis, and pharyngitis/tonsillitis.

The incidence of severe or invasive infection did not significantly differ between participants in the zinc and control groups (282.2 vs 270.5 per 100 person-years [py], respectively), with a time on hydroxyurea-adjusted incidence rate ratio (aIRR) of 1.04 (95% CI, 0.81, 1.32; P =.78). There were also no significant between-group differences in the incidence of culture-confirmed bacterial infections.

Further analysis of participants in the zinc vs control groups showed that the incidence of severe AEs per 100 py was 6.8 vs 13.7 (aIRR, 0.45; 95% CI, 0.06-3.43; P =.44). Mortality occurred among 2 participants in the zinc group and 7 in the control group (adjusted hazard ratio [aHR], 0.28; 95% CI, 0.06-1.35; P =.11). Of the 9 participants who died, mortality was attributed to pneumonia (n=5), sepsis (n=1), severe malaria (n=1), and an unspecified cause (n=2).

Although an increase in zinc levels and a decrease in zinc deficiency rates was observed among participants in the zinc group at 12 months, 41.3% had deficient zinc levels at the conclusion of the study.

The composite endpoint of stroke or death was observed among 2 participants in the zinc group and 9 in the control group (aHR, 0.22; 95% CI, 0.05-1.00; P =.05). However, the study was not powered to evaluate this endpoint.

Limitations include that only 1 dose of zinc was evaluated, the lack of data on zinc levels at infection onset, and the lack of data on urinary zinc losses. Moreover, serum zinc may not be an accurate measure of zinc levels.

“A substantial proportion of children remained zinc-deficient despite a year of zinc supplementation,” the researchers noted. “This unexpected finding suggests that higher doses of zinc may be required to resolve zinc deficiency, and potentially to decrease infection,” they concluded.