Abstract
Response to: Peters JL, Moreno SG, Phillips B, Sutton AJ. Are we sure about the evidence for zinc in prophylaxis of the common cold? Expert Rev. Respir. Med. 6(1), 15–16 (2012).
Peters et al. Citation[1] commented on a recent editorial Citation[2] and a Cochrane review Citation[3] on zinc and the common cold. On the basis of funnel plot analysis, Peters et al. proposed that publication bias might explain the apparent benefit of zinc against colds Citation[1]. However, a series of articles have pointed out that the funnel plot analysis is scientifically unsound Citation[4–7]. A recent recommendation stated that “funnel plot asymmetry is often wrongly equated with publication or other reporting biases” and “as a rule of thumb, tests for funnel plot asymmetry should not be used when there are fewer than ten studies in the meta-analysis … In some situations – for example, when there is substantial heterogeneity – the minimum number of studies may be substantially more than ten” Citation[8]. Nevertheless, ignoring this recommendation, Peters et al. used the funnel plot to analyze only six trials Citation[1]. Furthermore, “heterogeneity will lead to funnel plot asymmetry if it induces a correlation between study sizes and intervention effects” Citation[8], and therefore the level of heterogeneity should be considered.
Heterogeneity between zinc trial findings can be caused by several biological factors. First, it is possible that the effects of zinc lozenges are local (they are slowly dissolved in the mouth), so that they differ from the effects of ordinary tablets, which are dissolved in the stomach. Second, the composition of zinc lozenges has varied and some of them contained substances that form complexes with zinc ions. Therefore, it is possible that some of the negative findings are explained by lozenges that do not release zinc ions Citation[9,10]. Finally, dose dependency is a basic concept of pharmacology, and the negative findings in some studies might be explained by a low total daily zinc dose.
On the basis of these biological considerations, I restricted my meta-analysis of studies on zinc and the common cold to placebo-controlled trials that examined the effect of zinc lozenges on the duration of common cold infections of natural origin Citation[11]. There was a high level of heterogeneity between all of the 13 trials, and therefore I divided the trials into three subgroups. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used high doses of zinc (>75 mg/day) in the form of zinc acetate, and the average duration of colds was 42% shorter in the zinc groups (95% CI: 35–48). The third subgroup consisted of five high-dose trials that used zinc salts other than acetate and in this subgroup the average duration of colds was 20% shorter in the zinc groups (95% CI: 12–28). It does not seem reasonable to assume that publication bias might generate this kind of divergence between the low-dose and high-dose zinc trials. A dose–response relationship is a more sensible explanation for such a divergence. The great effect of zinc acetate is explained by the lack of complex formation between these ions Citation[9,10].
Although several randomized trials indicate that properly composed zinc lozenges can shorten the duration of colds by 20–40%, the topic should be further studied to determine the optimal lozenge compositions and treatment strategies.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
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