Daily zinc substantially reduced infections in young children with sickle cell anaemia, but a separate phase 3 trial found no benefit from intravenous arginine for acute pain episodes.
Daily zinc supplementation cut infections by almost 40% in young children with sickle cell anaemia in a randomised controlled trial, raising the prospect of a simple addition to existing preventive care.
The ZIPS-2 randomised controlled trial found children given 20mg of zinc each day had significantly fewer infections over six months than those receiving placebo, despite both groups receiving hydroxyurea and other standard preventive treatments.
The findings, published in JAMA, come as a separate phase 3 trial reported disappointing results for intravenous arginine in sickle cell disease, with the treatment failing to shorten acute pain episodes and the study stopped early for futility.
In ZIPS-2, researchers randomised 100 Ugandan children aged 12 to 59 months with confirmed HbSS sickle cell anaemia to 20mg daily zinc sulfate or placebo for six months.
Forty-five children were already taking hydroxyurea at enrolment, and all participants subsequently received or continued hydroxyurea.
The children also received standard sickle cell care, including pneumococcal vaccination, twice-daily penicillin prophylaxis, folic acid, and malaria prophylaxis, while insecticide-treated bed nets were provided at enrolment.
Researchers recorded 80 all-cause infections in the zinc group compared with 124 in the placebo group, corresponding to rates of 305.7 and 480.7 infections per 100 person-years respectively.
After adjustment for baseline age, sex, and hydroxyurea use, zinc was associated with a 38% lower infection rate (adjusted incidence rate ratio 0.62, 95% CI 0.45-0.86; P=0.005). All 100 children completed follow-up.
The most common infections were upper respiratory tract infections, with 88 events, followed by malaria with 45 and suspected severe bacterial infections with 22.
Rates of upper respiratory tract infections were significantly lower with zinc (aIRR 0.61, 95% CI 0.38-0.96), as were suspected severe bacterial infections (aIRR 0.32, 95% CI 0.10-0.96).
Pneumonia and diarrhoea were also less frequent in the zinc group, although those differences did not reach statistical significance. Zinc had no apparent effect on malaria, with an aIRR of 1.04.
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When malaria was excluded in a post-hoc analysis, zinc was associated with a 47% reduction in infection incidence (aIRR 0.53, 95% CI 0.36-0.76). Severe or invasive infections were also less frequent in the zinc group (aIRR 0.55, 95% CI 0.30-0.99).
There was no significant difference in vaso-occlusive crises between the groups, while one child in the placebo group experienced a stroke.
Zinc appeared well tolerated. No adverse events required discontinuation, serious adverse events were rare, and there were no deaths. Overall adverse events were less frequent among children receiving zinc, largely reflecting the reduction in infections.
Serum zinc levels also increased in the treatment group. At baseline, 46% of children allocated to zinc and 38% receiving placebo were zinc deficient. After six months, the prevalence of zinc deficiency had fallen to 26% in the zinc group but remained at 38% in the placebo group.
The researchers said zinc deficiency was common in sickle cell disease because of factors including ongoing haemolysis, urinary zinc loss, and increased release of zinc during bone degradation in vaso-occlusive crises.
Zinc is important to both innate and adaptive immune function, and deficiency has been associated with increased susceptibility to infection.
“Zinc deficiency is common in children, adolescents, and adults with SCA, with studies of children in North America with SCA showing zinc deficiency rates ranging from approximately 44% to 57%, rates similar to children in Uganda,” the researchers wrote.
“Given reported high rates of zinc deficiency in North American studies of children with sickle cell disease, evaluation of zinc supplementation for prevention of infection in children with SCD living in high-income countries may be warranted.”
An earlier Ugandan randomised trial of 10mg zinc daily had failed to reduce infections in children under five, but 41% of those receiving supplementation remained zinc deficient after 12 months.
That finding raised the possibility that the dose was inadequate and provided the rationale for testing 20mg daily in ZIPS-2.
The researchers cautioned that the new study was small, conducted at a single centre, and followed children for only six months. They called for multisite trials to validate the result and determine whether supplementation was also effective in older children.
The positive zinc findings contrasted with results from the STArT trial, also published in JAMA, which tested intravenous arginine for acute sickle cell pain.
Acute pain episodes were a major driver of emergency department visits and hospital admissions in sickle cell disease, but disease-targeted treatments for acute episodes remained limited, the researchers wrote.
Arginine had attracted interest because haemolysis disrupts the arginine-nitric oxide pathway, contributing to endothelial dysfunction and vasoconstriction. Low arginine bioavailability has also been associated with longer crises, longer hospital stays, and greater intravenous opioid requirements.
Previous smaller randomised trials had suggested arginine could reduce opioid use and improve pain and cardiopulmonary function, leading investigators to test the treatment in the larger phase 3 STArT trial.
The multicentre, double-blind US study enrolled patients aged three to 21 years who presented to emergency departments with sickle cell acute pain requiring parenteral opioids. Participants were randomised to intravenous arginine or saline placebo at 10 children’s hospitals.
Of 274 participants randomised, 271 received treatment, with 129 receiving arginine and 142 placebo.
The median age was about 15 years, around three-quarters were prescribed hydroxyurea, and about 41% reported chronic sickle cell pain on at least 15 days a month.
The primary endpoint was time to crisis resolution, defined as the period from the first study drug dose until the final dose of parenteral opioids.
Median time to crisis resolution was 60.8 hours with arginine compared with 65.8 hours with placebo, with no significant difference between the groups.
There were also no significant differences in total parenteral opioid requirements, pain scores, patient-reported outcomes, or safety events.
The trial had planned to randomise 360 patients but was stopped after enrolling about 76% of its target.
At the second formal interim analysis, conditional power for the primary endpoint was less than 6%, even assuming the treatment effect originally hypothesised, prompting the data and safety monitoring board to recommend stopping for futility.
The researchers said that intravenous arginine did not shorten crisis resolution in children and young adults with acute sickle cell pain, despite the encouraging results from earlier, smaller studies.
“Emerging evidence suggests that new SCD acute pain trials are also likely to yield null or inconclusive results if they continue relying on traditional designs that focus on this same outcome measure,” they concluded.
“To advance the field, novel clinical trial approaches are needed, as well as coordinated stakeholder efforts to identify new end points or surrogate biomarkers that can more accurately capture meaningful clinical benefit.”
