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Taken together, published trial data support a role for zinc supplements in preventing and treating upper respiratory infections caused by viruses other than SARS-CoV-2 in adults, a meta-analysis found.

Pooled data from eight randomized controlled trials involving a total of some 3,500 people indicated that five infections were prevented for every 100 person-months of oral or intranasal zinc treatment, reported Jennifer Hunter, PhD, MScPH, of Western Sydney University in Penrith, Australia, and colleagues.

Moreover, in about 1,000 people contracting respiratory virus infections, treatment with sublingual or intranasal zinc preparations reduced symptom duration by an average of 2 days relative to placebo, the group reported in .

But these apparent benefits came with numerous cautions: the strength of evidence (particularly for zinc as a treatment for ongoing infection) was low. The analysis was marred by substantial bias in the included studies, low participant numbers, and significant heterogeneity, the researchers conceded.

And the benefits were modest, they noted, as zinc didn't appear to reduce symptom severity nor prevent infection after deliberate viral challenge.

Notably, the analysis didn't address whether zinc could prevent or treat COVID-19, as it only included studies published through May 2020 -- by which point it would have been too soon to have designed, conducted, and published a randomized trial regarding SARS-CoV-2. (At least seven COVID trials of zinc were still ongoing when Hunter and colleagues were finalizing their manuscript, they noted.)

The researchers identified 28 randomized controlled trials with available results for zinc in preventing or treating respiratory viral infections in adults. Formulations used in these studies were most commonly lozenges; others included nasal sprays and gels.

Oral doses for prevention ranged from 15 to 45 mg/day, given for up to 12 months. In treating active infections, sublingual lozenge doses of 45 to 300 mg/day were used; nasally administered doses were in the range of 0.9 to 2.6 mg/day. All but three of the 28 trials had placebo control; two used a quinine lozenge as control (their authors called it placebo, but Hunter and colleagues deemed it active), and one had active control with naphazoline.

Four studies examined zinc lozenges for preventing rhinovirus infection in volunteers who agreed to be inoculated with live virus. Two of these began treatment prior to virus challenge and two examined post-exposure prophylaxis, and all used placebo control. None of these studies showed a preventive effect for the zinc treatment (relative risk 0.96, 95% CI 0.77-1.21), and the evidence strength was considered moderate.

But for infections acquired in ordinary community settings, daily zinc supplements (at least for oral and intranasal formulations) did seem to help for prevention. Besides the number needed to treat (NNT) of 20 for all infection, the meta-analysis found an 87% reduced risk of developing "moderately severe symptoms" of flu-like illness, as well as 28% less risk of mild symptoms resembling common colds. The NNT for preventing moderately severe illness per 100 person-months was 100.

In treatment of ongoing infection, the meta-analysis showed that zinc helped reduce symptom severity at day 3 of clinical illness, but not when averaged across the entire duration of illness. Hunter and colleagues indicated, however, that the quality of the underlying studies was low.

Generally, adverse effects attributed to the zinc treatment were minor and infrequent; they were numerically more common versus placebo (incidence rate ratio 1.63) when used for prophylaxis, but not to the point of statistical significance (95% CI 0.81-3.31). The higher doses used for treatment of active infection, however, did lead to gastrointestinal discomfort in some participants, and the sublingual lozenges were associated with irritation in the mouth. Nasal sprays and gels seemed to be better tolerated.

Any meta-analysis is vulnerable to publication bias, and this one was no exception. "While publication bias was not strongly suspected, visual inspection of funnel plots are necessarily subjective and a statistical test for hazard ratios was not performed," the group wrote.

Additionally, they acknowledged that "the number of studies and sample sizes were small," and the researchers issued the standard call for more research -- not only for efficacy and safety of particular formulations, but also to clarify the mechanisms by which zinc may combat viral infections.

But, overall, Hunter and colleagues felt that zinc would be worth a try for many individuals. "The marginal benefits, strain specificity, drug resistance and potential risks of other over-the-counter and prescription medications makes zinc a viable 'natural' alternative for the self-management of non-specific [respiratory tract infections]," they wrote.

Physicians could benefit too, they suggested: "It also provides clinicians with a management option for patients who are desperate for faster recovery times and might be seeking an unnecessary antibiotic prescription."

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