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Subsequently a series of zinc lozenge trials were carried out but with variable results. The composition of the zinc lozenges differed between trials with some lozenges containing substances that tightly bind to zinc ions, such as citric acid. Therefore, variation in the level of free zinc ions has been proposed as one factor that can explain the significant heterogeneity in the results of the trials [2-10]. Acetate does not chemically bind to zinc ions and therefore zinc acetate may be an ideal zinc salt for composing lozenges that release high levels of free zinc ions [6,9,10].
A recent meta-analysis investigated the role of zinc dosage on the effect of zinc lozenges on cold duration [11]. Five trials with zinc lozenges that contained low doses of zinc, 75 mg/day, as zinc acetate lozenges, consistently found that colds were shortened by a mean of 42% [11]. Five high-dose trials used zinc salts other than acetate and obtained a mean 20% reduction in cold duration [11]. Two other systematic reviews on zinc and the common cold combined zinc lozenge trials with zinc syrup trials [12,13]. Those reviews however overlooked the fact that slowly dissolving zinc lozenges may cause local effects in the pharyngeal region, whereas rapidly swallowed syrup does not. In addition, the two reviews had other severe limitations [14-16].
Nasal administration of zinc shortened the duration of colds in two studies [17,18], which implied that zinc can have a local effect against colds within the nasal region. Similarly, the effects of zinc lozenges may be local within the pharyngeal region instead of being purely systemic. Although the local effects of zinc in the nasal region are of interest for the purposes of researching the mechanisms of the effects of zinc, nasal zinc application might cause anosmia [19,20] and nasal zinc application should be discouraged unless application methods are developed that eliminate such a risk.
When zinc acetate lozenges dissolve in the mouth, zinc ions are released into the saliva of the pharyngeal region where the levels are consequently high. However, zinc lozenges do not seem to increase the level of zinc in the nasal mucosa ([6], p490). If the zinc ion concentration of the mucosa determines the effect of zinc lozenges on the specific symptoms on the particular anatomical region, there might be substantial differences between the effects of zinc on throat symptoms compared with nasal symptoms.
In the original study reports, the duration of each symptom was reported in days. For this meta-analysis, the durations were transformed to a percentage scale so that the duration of each symptom in the corresponding placebo group was 100%. Consequently the pooling of the three studies gives the percentage effect of zinc acetate on the specific symptoms. The transformation to the percentage scale is described in Additional file 2.
We pooled the effect of zinc acetate lozenges on the specific symptoms by using the inverse-variance fixed-effect option in the RevMan program [25] (Additional file 3). Heterogeneity between the three studies was assessed by using the χ2-test and the I2-statistic [26]. The I2-statistic estimates the percentage of total variation across studies that is due to true heterogeneity rather than due to chance. A value of I2 greater than about 75% indicates a high level of heterogeneity. Some of the RevMan forest plots were redrawn with Gnuplot [27] for greater clarity.
The effect of high dose zinc acetate lozenges on the duration of respiratory symptoms of the common cold. In the forest plots on the right side, the vertical line indicates the placebo level. The horizontal lines indicate the 95% CI for the zinc effect and the square in the middle of the horizontal line indicates the point estimate of the effect in the particular trial. Arrows at the end of the horizontal lines indicate that the 95% CI extends out of the forest plot. The sizes of the squares indicate the relative weights of the trials. The diamond shape indicates the pooled effect on the symptoms and its 95% CI. The duration of symptoms was transformed to the relative scale, thus the duration in the respective placebo group was given the value of 100%. The difference between zinc and placebo groups thus directly indicates the effect of zinc lozenges in percentages. See Additional file 2 for the extraction of data and for the calculation of the relative mean and SD values for the duration of symptoms, and Additional file 3 for the raw data and the estimates for individual studies.
The effect of high dose zinc acetate lozenges on the duration of systemic symptoms of the common cold. In the forest plots on the right side, the vertical line indicates the placebo level. The horizontal lines indicate the 95% CI for the zinc effect and the square in the middle of the horizontal line indicates the point estimate of the effect in the particular trial. Arrows at the end of the horizontal lines indicate that the 95% CI extends out of the forest plot. The sizes of the squares indicate the relative weights of the trials. The diamond shape indicates the pooled effect on the symptoms and its 95% CI. The duration of symptoms was transformed to the relative scale, thus the duration in the respective placebo group was given the value of 100%. The difference between zinc and placebo groups thus directly indicates the effect of zinc lozenges in percentages. See Additional file 2 for the extraction of data and for the calculation of the relative mean and SD values for the duration of symptoms, and Additional file 3 for the raw data and the estimates for individual studies.
The effect of high dose zinc acetate lozenges on the duration of common cold symptoms. The pooled estimates and their 95% CIs are shown in this figure. The horizontal lines indicate the 95% CI for the effect and the squares in the middle of the horizontal lines indicate the point estimates of the effect on the particular respiratory and systemic symptoms. See Additional files 2 and 3 for the calculations.
There is substantial variation between the mean durations of individual symptoms. For example, in the placebo group of the Prasad et al. (2008) trial, muscle ache lasted for a mean of 2.0 days, but cough lasted for 5.1 days; whereas the total duration of colds was 7.1 days (Table 3). Therefore the percentage effect of zinc on the specific symptoms should be considered together with the duration of untreated symptoms. Figure 5 shows the duration of symptoms so that they are normalized by the total duration of the colds in the three trials. For example, in the three trials, mean nasal discharge lasted for 73% (95% CI 60% to 85%) of the total common cold duration.
The common cold is usually caused by respiratory viruses that have over 100 serotypes [30]. The distribution of viruses varies over time and geography and therefore the common cold episodes in different controlled trials have different aetiologies. In addition, variations in outcome definitions also generate variation between trials and the interventions are also not identical. For these reasons, variation between trials investigating the effects of common cold treatments is to be expected. Nevertheless, only for sore throat and cough was there substantial heterogeneity in the effect of zinc acetate lozenges over the three included studies with I2 above 60% (Figure 2).
In the three trials analyzed, the systemic symptoms of colds were much shorter than the respiratory symptoms. Muscle ache and headache lasted for a quarter and fever lasted for less than a tenth of the total common cold duration (Figure 5). Only muscle ache was shortened significantly by zinc. Nevertheless, it seems probable that the three studies did not have sufficient statistical power to estimate the effect of zinc acetate lozenges on headache and fever since the pooled 95% CIs were wide for both symptoms.
In the USA, the recommended dietary zinc intake is 11 mg/day for men and 8 mg/day for women [32]. Thus, the 80 to 92 mg/day doses used in the zinc acetate lozenge trials are substantially higher than the recommended daily intakes. However, in several clinical trials zinc has been administered to patients at a dose of 150 mg/day for months [33-37]. A decrease in copper levels and haematological changes have been reported as adverse effects of long-term high dose zinc administration, but those changes were completely reversed with the cessation of zinc intake [38-42]. Thus, given that 150 mg/day of zinc administration for months does not cause permanent harm, it seems plausible that the use of about 80 mg/day of zinc for up to two weeks in the form of zinc acetate lozenges is unlikely to cause serious adverse effects.
In some zinc lozenge trials the lozenges caused short-term adverse effects, such as bad taste, but the bad taste can be explained by the specific lozenge composition and does not necessarily reflect the effects of zinc ions themselves [9,10]. None of the high dose zinc acetate lozenge trials reported bad taste to be a problem and there was no substantial difference between the zinc and placebo groups in the recorded adverse effects, and only a few drop-outs occurred. Furthermore, if a common cold patient suffers from acute adverse effects such as bad taste, the patient can simply stop taking the zinc acetate lozenges.
Evidence-based medicine focuses primarily on the effect of interventions on clinically relevant outcomes in controlled trials, which is also the approach of this meta-analysis. Nevertheless, the potential biological mechanisms are also of interest. Although the mechanism of zinc in the alleviation of colds is not known, possible mechanisms have been proposed. In laboratory studies zinc inhibited the replication of respiratory viruses and enhanced the effect of interferons [10,43,44]. Non-immune mechanisms have also been proposed to explain the effect of zinc lozenges on the common cold [10,45,46]. However, the lack of well-formulated mechanistic explanations should not hamper the implications of these three randomized trials with clinically relevant outcomes. 59ce067264