Chandy John, MD, MS

 <5 years of age, infections are among the most frequent and serious complications. In the ZIPS-2 randomized clinical trial, daily zinc at a higher dose than previously tested reduced the rate of all-cause infections over 6 months.¹

Chandy C. John, MD, MS, Ryan White Professor of Pediatrics and director of the Ryan White Center for Pediatric Infectious Diseases and Global Health at Indiana University School of Medicine, co-led the trial with collaborators in Jinja, Uganda. In an interview with 

, he discussed how the team arrived at the 20 mg dose and what the trial found.

20 mg Zinc Cuts Infections 38% in Sickle Cell Anemia, With Chandy John, MD

Why ZIPS-2 Raised the Zinc Dose to 20 mg in Sickle Cell Anemia

“20 milligrams has been tried for fairly long term in other populations of children under five with not much in the way of adverse events, whereas when you get into higher doses, there were more reported adverse events,” John said. “So we decided we’ll just try zinc at 20 milligrams daily, because if it doesn’t work, then that’s probably the end of the road for these trials.”

Previous research from the same group found 10 mg of zinc daily for 12 months did not significantly reduce severe or invasive infections in Ugandan children with sickle cell anemia <5 years of age. In the earlier trial, 41% of children receiving zinc remained zinc deficient at 12 months, raising the possibility of an insufficient dose.¹

John said a large dose-finding study was not feasible after those results, so the team selected 20 mg in consultation with zinc experts. Zinc deficiency is common in sickle cell disease, with hemolysis and increased urinary zinc losses among the potential contributing mechanisms. Zinc's role in immune function also provided a rationale for investigating supplementation as an infection prevention strategy.¹

20 mg Zinc Reduces All-Cause Infection Rates in Sickle Cell Anemia

“The goal of it was to at least see a signal that it does to support a larger study, but somewhat to our surprise, it was a highly significant reduction in all-cause infections, so it wasn’t borderline or a trend,” John said.

The double-blind, placebo-controlled pilot trial randomized 100 children aged 12 to 59 months at Jinja Regional Referral Hospital in Uganda to receive 20 mg of zinc sulfate (n = 50) or placebo (n = 50) daily for 6 months. At enrollment, 45% of participants were receiving hydroxyurea, and all participants initiated or continued hydroxyurea during the trial. The primary outcome was the incidence of all-cause infections per 100 person-years.¹

Children receiving zinc experienced 80 infections, compared with 124 among those receiving placebo. Infection rates were 305.7 vs 480.7 per 100 person-years, respectively, corresponding to a 38% lower adjusted infection rate with zinc (adjusted incidence rate ratio [aIRR], 0.62; 95% confidence interval [CI], 0.45-0.86; 

Rates of upper respiratory tract infections (aIRR, 0.61; 95% CI, 0.38-0.96) and suspected severe bacterial infections (aIRR, 0.32; 95% CI, 0.10-0.96) were also lower in the zinc group. Differences in pneumonia and diarrhea were not statistically significant, and no statistically significant difference was observed for malaria (aIRR, 1.04; 95% CI, 0.47-2.31).¹

In the zinc group, the proportion of children with zinc deficiency declined from 46% at baseline to 26% at 6 months. All participants completed follow-up, and no adverse events required discontinuation of the study intervention.¹

Although the primary outcome favored zinc, investigators emphasized the pilot study's single-site design and limited sample size. The trial was powered to detect only large differences in specific infections or infections requiring hospitalization, limiting conclusions about individual infection types and more severe outcomes. Larger, multisite studies are needed to confirm the findings and evaluate effectiveness in older children.¹

Editor’s Note: John reported no relevant disclosures.

Namazzi R, Mellencamp KA, Bagala I, et al. Daily Zinc Supplementation for Infection Prevention in Children With Sickle Cell Anemia: The ZIPS-2 Randomized Clinical Trial. 

Daily 20 mg of zinc reduces infections by nearly 40% in children with sickle cell anemia. News release. Indiana University School of Medicine. Published August 20, 2026. Accessed November 5, 2026. 

https://medicine.iu.edu/news/2026/08/zinc-sickle-cell-infections

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In ZIPS-2, 20 mg daily zinc reduced all-cause infection rates by 38% vs placebo in Ugandan children with sickle cell anemia aged <5 years.

Chandy John, MD, MS

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