Lower-dose zinc more favourable for managing childhood diarrhoea

Lower doses of zinc (5 or 10 mg) were noninferior to the standard 20-mg dose and were associated with less vomiting in children with acute diarrhoea, the ZTDT* trial has shown.

Despite the declining rates of diarrhoea-related deaths since the 1980s, ~500,000 deaths were reported in 2018. [J Glob Health 2019;9:020801] “Most [could have been] avoided if children received high-quality management recommended by WHO and UNICEF**, [which] includes oral rehydration solutions and supplemental zinc … [As such,] diarrhoeal diseases remain a major public health problem,” said the researchers.

However, zinc supplementation is associated with increased vomiting due to its strong metallic taste and tendency to trigger gastric irritation. [J Health Popul Nutr 2005;23:311-319] “Lower zinc doses … might have the advantage of causing less vomiting than the current recommended dose … [Consequently, the] reduced vomiting may improve food intake and alleviate parents’ concerns about the severity of the illness,” they said.

The study comprised 4,500 children aged 6–59 months from peri-urban outpatient facilities in India and Tanzania who had acute diarrhoea for <72 hours or dysentery. Participants were randomized 1:1:1 to receive 5, 10, or 20 mg of zinc sulphate QD for 14 days. [N Engl J Med 2020;383:1231-1241]

The percentages of children with diarrhoea for >5 days were similar across all arms (7.2, 7.7, and 6.5 percent for 5, 10, and 20 mg, respectively), as were the mean number of diarrhoeal stools (10.8, 10.9, and 10.7, respectively).

These effects may be attributed to improvements in nutrient deficiency and/or immune function, or inhibition of cyclic AMP-mediated chloride secretion. [Am J Clin Nutr 2005;81:495-502; Am J Physiol Gastrointest Liver Physiol 2005;288:G956-G963] “The [lower] doses studied still exceed the recommended daily allowance for young children … [T]herefore, it is plausible that they still work through these suggested mechanisms of action,” noted the researchers.

Less vomiting

The incidence of vomiting within 30 minutes after zinc administration was higher with the 20-mg dose (19 percent) vs the 5-mg (14 percent) and 10-mg doses (16 percent). These translated to significantly lower relative risks (RRs) for comparisons between 20 and 5 mg (RR, 0.71; p<0.001) and 20 and 10 mg (RR, 0.81; p=0.01).

Similar effects were seen for vomiting beyond 30 minutes after zinc dosing (27 percent vs 20 percent; RR, 0.74 [20 vs 5 mg] and 27 percent vs 22 percent; RR, 0.83 [20 vs 10 mg]).

The reduced incidence of vomiting with lower zinc doses seemed greater in Indian vs Tanzanian participants, potentially due to differences in age and nutritional status (Indian children were older and less well-nourished), and rotavirus immunization (very low rate in India). Rotavirus may have been the cause of symptoms in Indian children. [Epidemiol Infect 2013;141:2094-2100]

Addressing the gap

However, the low rates of children with diarrhoea beyond 5 days may have been influenced by the modest rate of severe diarrhoea among participants. Also, the findings were mostly based on caregiver reports. Nonetheless, apart from the large sample and high follow-up rates, participants were from outpatient facilities where most diarrhoea cases are managed, noted the researchers.

“Our trial addresses an important knowledge gap presented by the empirical use of the 20-mg zinc dose, which was recommended for global use without rigorous dose-finding trials,” they said.

“[However,] programmatic uptake of this component of diarrhoea management has been slow to achieve high levels of coverage … [thus] highlighting the supply-side problems of insufficient financial and human capital and a weak global supply chain,” they pointed out. “A renewed public health push will be needed to solve these problems and maximize the benefits of this intervention. Our findings may contribute to these programmatic efforts.”