Background
Randomized, double-blind, placebo-controlled phase 3 trial (ZIPS-2) of daily zinc supplementation for infection prevention in children with sickle cell anemia at Jinja Regional Referral Hospital, Uganda. N=100 randomized (118 screened) between February and April 2025, with 6 months of follow-up through November 2025. Children aged 1.00 to 4.99 years; mean age 36.0 months, 45% female. At enrollment 45% were already receiving hydroxyurea, and all participants initiated or continued hydroxyurea after enrollment. Rationale: infection remains a leading cause of morbidity and mortality in African children with sickle cell anemia despite penicillin prophylaxis, vaccination, and hydroxyurea, and zinc deficiency is common in this population and impairs innate and adaptive immunity.
Results
Interventions and follow up: Arm A: Zinc sulfate 20 mg orally daily for 6 months (n=50)
Arm B: Matching placebo daily for 6 months (n=50)
Primary endpoint: All-cause infections per 100 person-years, using standardized clinical criteria
mFollow up: 6 months, with complete ascertainment and no loss to follow-up
Results: All-cause infection rate: 305.7 (95% CI, 242.4-380.4) vs 480.7 (95% CI, 399.8-573.1) infections per 100 person-years
Rate difference: -176.0 (95% CI, -300.8 to -51.3) per 100 person-years
Adjusted IRR: 0.62 (95% CI, 0.45-0.86), adjusted for baseline age, sex, and hydroxyurea use
Total infection events: 80 in the zinc group vs 124 in the placebo group
Mortality: NR
Arm B: Matching placebo daily for 6 months (n=50)
Primary endpoint: All-cause infections per 100 person-years, using standardized clinical criteria
mFollow up: 6 months, with complete ascertainment and no loss to follow-up
Results: All-cause infection rate: 305.7 (95% CI, 242.4-380.4) vs 480.7 (95% CI, 399.8-573.1) infections per 100 person-years
Rate difference: -176.0 (95% CI, -300.8 to -51.3) per 100 person-years
Adjusted IRR: 0.62 (95% CI, 0.45-0.86), adjusted for baseline age, sex, and hydroxyurea use
Total infection events: 80 in the zinc group vs 124 in the placebo group
Mortality: NR
Adverse events
Discontinuation for AEs: 0 in both arms — no adverse events required stopping study product
Gastrointestinal: NR in the abstract
Grade ≥3 (any): NR in the abstract
Comment: Zinc sulfate 20 mg daily was well tolerated in children under 5 years with sickle cell anemia.
Gastrointestinal: NR in the abstract
Grade ≥3 (any): NR in the abstract
Comment: Zinc sulfate 20 mg daily was well tolerated in children under 5 years with sickle cell anemia.
Conclusions
Daily zinc sulfate 20 mg reduced all-cause infections by roughly 38% (adjusted IRR 0.62) over 6 months in Ugandan children under 5 years with sickle cell anemia, on a background in which all participants received hydroxyurea. The intervention is inexpensive, oral, widely available, and was well tolerated with complete follow-up. If replicated, zinc supplementation would be a pragmatic addition to infection-prevention bundles in sub-Saharan Africa, where the burden of sickle cell anemia and infectious mortality is highest.
Key Limitations
Single-center trial with only 100 participants and 6 months of follow-up, so the confidence interval around the effect is wide and durability beyond 6 months is unknown. The primary endpoint counted all-cause infections defined by standardized clinical criteria rather than microbiologically confirmed infection, which is pragmatic in this setting but vulnerable to misclassification of febrile illness, including malaria. Hard outcomes such as hospitalization, severe infection, and mortality were not reported in the abstract. Baseline zinc status was not used to select participants, so it is unclear whether the benefit is confined to zinc-deficient children, and generalizability is limited to children under 5 years in a high-malaria, hydroxyurea-treated Ugandan cohort. The authors explicitly call for multisite validation and evaluation in older children.
Clinical Context
Standard infection prevention in young children with sickle cell anemia comprises penicillin prophylaxis, pneumococcal and conjugate vaccination, malaria chemoprophylaxis where endemic, and hydroxyurea, which itself lowers infection and mortality in African cohorts (REACH, NOHARM). Zinc is not currently part of ASH or WHO sickle cell guidance for infection prevention, and no regulatory approval exists for this indication; WHO does endorse zinc for childhood diarrhea, so supply chains and dosing experience already exist in the region. ZIPS-2 is the largest randomized test of this strategy to date and, alongside the earlier ZIPS trial, positions zinc as a candidate low-cost adjunct pending multicenter confirmation and outcome data on hospitalization and mortality.