We found that orally administered zinc shortened the duration of cold symptoms. These findings, however, are tempered by significant heterogeneity and quality of evidence. Although there was low-quality evidence that participants receiving zinc were less likely than controls to be symptomatic at one week, there was no difference between groups in symptom severity or presence of symptoms at three days. Our findings question the importance of zinc and suggest that any benefit may be outweighed by adverse events, which were more common among participants given zinc than among controls.
Our demonstration of a reduced duration of cold symptoms (mean difference −1.65 days, 95% CI −2.50 to −0.81) is consistent with the results of the most recent systematic review.11
However, the effect of zinc differed in three subgroup analyses (by age, zinc formulation and ionic zinc dose).
Zinc reduced the duration of cold symptoms in adults; however, the effect was greatly attenuated and not statistically significant among children. Possible explanations include age-related differences in the host inflammatory responses,40
different viruses involved41
with varying abilities of zinc to inhibit these viruses, and consequences of third-party reporting of symptoms in children. Other possible factors include the use of lower doses of ionic zinc in the pediatric studies, as well as the use of syrup formulation (v. lozenge) and less frequent administration (resulting in less local exposure).
With respect to the dose of ionic zinc and the zinc formulation, greater reductions in the duration of symptoms occurred with higher doses than with lower doses, and zinc acetate reduced the duration of symptoms whereas the other formulations showed no effect. These findings suggest a possible dose-dependent effect associated with ionic zinc and is consistent with results of a previous report showing an association between the amount of ionic zinc and the magnitude of clinical response.14
However, these characteristics only partially explain between-study differences.
Our review has several other key differences from the Cochrane review.11
First, we used a different approach to estimating means and standard deviations in trials that reported only medians.32,33
In the Cochrane review, the authors calculated the means and standard deviations by assuming that the 95% CIs presented around the medians also reflected 95% CIs around the means.11
However, this approach resulted in one trial estimate showing a significant difference between the zinc and placebo groups,32
a finding inconsistent with the authors’ conclusion of no difference. In contrast, our approach enabled inclusion of effect estimates in the meta-analysis that were qualitatively consistent with the trial conclusions.
Finally, we included additional trials, obtained additional data from study authors and corrected data that had been incorrectly extracted from one trial.35
For the primary outcome, we were able to obtain data from eight studies, as compared with six studies in the previous review. We also included two additional trials that had previously been excluded because they were not considered to be randomized trials.24
However, the methods described appeared appropriate for inclusion, and we confirmed the methodology with the author. These two trials may have influenced the outcome, because they showed no effect.24
The limitations of our review predominantly relate to the large heterogeneity that remained unexplained despite exploration of several subgroups a priori and the quality of reported summary data. Assumptions were made to calculate the means and standard deviations of several trial estimates, and all studies were industry funded. Although the trials reported double blinding, ineffective blinding related to taste of the placebo may have contributed to bias. Finally, the majority of trials were conducted in developed countries.
We found moderate quality of evidence to suggest that orally administered zinc reduces the duration of symptoms of the common cold. However, the evidence of benefit was limited to adults, and even in this patient group, uncertainty remained about its clinical benefit. Although oral zinc treatment may attenuate the symptoms of the common cold, large high-quality trials enrolling adults and children are needed. Future trials should be designed to maximize the tolerable doses of bioavailable zinc with a balanced consideration toward potential dose-related adverse effects. Until further evidence becomes available, there is only a weak rationale for physicians to recommend zinc for the treatment of the common cold. The questionable benefits must be balanced against the potential adverse effects.