On 2014 Dec 06, Harri Hemila commented:

Errors in the Cochrane review (2011) on zinc for the common cold

The Cochrane review (2011) on zinc for the common cold by Singh M, 2011; DOI; had a number of problems, which were commented on in detail in a separate document. Here the problems in the Cochrane review (2011) are listed and briefly described:

1) Search of the studies was not thorough. Singh M, 2011 did not include Eby GA, 2006 although that study was listed in Pubmed with keywords zinc and the common cold.

2) There were errors in the extraction of data. In Fig. 3 (p.15) Singh M, 2011 claimed that in the Petrus 1998 study (http://dx.doi.org/10.1016/S0011-393X(98)85058-3), the duration of colds in the zinc group was 4.4 days, whereas Petrus reported 3.8 days for the zinc group, see the link.

3) The characteristics of included studies table had errors and was not consistent in describing the included trials.

4) The characteristics of excluded studies table had errors. For example, Singh M, 2011 (p.39) claimed that the study by Turner RB, 2000 was “Not a randomised trial” though the study report clearly describes that the trial was randomised, see pp.1202-3 in DOI.

5) Different methods of administering zinc should be analyzed separately, whereas Singh M, 2011 pooled all together. Some studies administered zinc as syrup or tablets, some as lozenges. It is probable that the benefit of zinc in syrup and tablet trials is caused by biological mechanisms that are different from the mechanisms of the zinc lozenges, which are intended to be dissolved slowly in the mouth, see eg Hemilä H, 2011 and Eby GA, 2004. Combining different methods of zinc administration is the classical apples and oranges problem of meta-analysis.

6) The duration of the common cold should not be arbitrarily dichotomized as was done in Analyses 2.1 to 2.3 (pp.43-5) by Singh M, 2011. Duration is a continuous variable and should be analyzed as a continuous variable. The results of the zinc lozenge studies can be and should be analyzed using cold duration as a continuous variable, see Hemilä H, 2011.

7) Duration of the common cold should have been normalized so that placebo groups have length 100%. There is substantial variation in the duration of colds in the placebo groups of the zinc lozenge trials, from 5.1 days to 9.0 days and 10.8 days, see Hemilä H, 2011. For example, if a 5-day cold is shortened by 4 days, it is not equivalent to a 11-day cold being shortened by 4 days although both differences are equal in absolute units. The former is an 80% decrease in duration, whereas the latter is only a 36% decrease. Although part of the placebo group variation is caused by random variation, it is also caused by differences in viruses and in the severity of disease in different patient groups, and in differences in outcome definitions. Therefore, the relative effect of zinc on the common cold duration should be calculated in percentages, because the relative effect partly adjusts for the variations between patient groups and outcome definitions. In another study, the results of the zinc lozenge studies were analyzed as percentage effects, see Hemilä H, 2011.

8) Subgroup analysis should have been carried out. In the Background section (p.6), Singh M, 2011 wrote that a “significant correlation between total daily dosages of positively charged zinc species and a reduction in the mean duration of common colds” has been reported, however, they did not analyze that question. In the zinc lozenge studies, there is a 6-fold variation in the total zinc dose from 30 to 207 mg per day, see Hemilä H, 2011. Dose-response relation is a basic concept in pharmacology and thus the relation between dose and the effect of zinc lozenges should have been analyzed in the Cochrane review (2011). Hemilä H, 2011 found that none of the low zinc dose studies found effects of zinc lozenges, whereas high zinc dose studies found very strong evidence that colds were shortened by zinc. Such findings are consistent with the dose-response concept.

9) Pooling the adverse effects of all zinc trials is unsound, yet Singh M, 2011 did so in Fig. 6 (p.18). Eby GA, 2004 pointed out that the adverse effects of zinc lozenges, such as bad taste, can be explained largely by the differences in the composition of the lozenges. Furthermore, it is obvious that dissolving a zinc lozenge slowly in the mouth causes different adverse effects compared with ingesting a zinc syrup or tablet straight to the stomach. There is no justification to pool adverse effects of all zinc trials together, ignoring the considerable variations in the zinc products. As to the zinc lozenges, Eby GA, 2004 commented that “although pure zinc gluconate is bland and chalky in taste, it reacts with dextrose and related carbohydrates (excluding fructose) upon aging of lozenge compositions to produce noisome bitterness... On the other hand, zinc acetate allows the production of pleasant tasting, flavor stable lozenges”. In the most recent zinc acetate lozenge trial, Prasad AS, 2008 found no significant differences between the zinc and placebo groups in the occurrence of adverse effects although the daily dose of zinc was 92 mg.

10) Credit should be given to earlier work on the same topic. In the Introduction, Singh M, 2011 (p.7) wrote “The last review of all available RCTs of zinc for the common cold was published in 1999”, which is false. Reviews on zinc and the common cold by Jackson JL, 2000 and Caruso TJ, 2007 were published after 1999 and should have been mentioned as previous reviews on the same topic.

There is much evidence to indicate that high doses of zinc as zinc lozenges have effects on the duration of colds, see Hemilä H, 2011 and Eby GA, 2004. Therefore the topic of Singh M, 2011 is important; however, there were numerous methodological problems which limited the relevance of the conclusions.

Singh M, 2011 concluded that “In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.”

Had Singh M, 2011 separately analyzed the syrup and tablet studies and the lozenge studies, and had they analyzed the relation between the dose and effect, they could have reached much more clear conclusions.

Hemilä H, 2011 limited analysis to the zinc lozenge studies and found that five trials that used the lowest doses of zinc uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, and the pooled result indicated a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). Thus, clear conclusions for patients and for further research could have been drawn from the studies that were available to Singh M, 2011.

On 2014 Dec 06, Harri Hemila commented:

Errors in the Cochrane review (2011) on zinc for the common cold

The Cochrane review (2011) on zinc for the common cold by Singh M, 2011; DOI; had a number of problems, which were commented on in detail in a separate document. Here the problems in the Cochrane review (2011) are listed and briefly described:

1) Search of the studies was not thorough. Singh M, 2011 did not include Eby GA, 2006 although that study was listed in Pubmed with keywords zinc and the common cold.

2) There were errors in the extraction of data. In Fig. 3 (p.15) Singh M, 2011 claimed that in the Petrus 1998 study (http://dx.doi.org/10.1016/S0011-393X(98)85058-3), the duration of colds in the zinc group was 4.4 days, whereas Petrus reported 3.8 days for the zinc group, see the link.

3) The characteristics of included studies table had errors and was not consistent in describing the included trials.

4) The characteristics of excluded studies table had errors. For example, Singh M, 2011 (p.39) claimed that the study by Turner RB, 2000 was “Not a randomised trial” though the study report clearly describes that the trial was randomised, see pp.1202-3 in DOI.

5) Different methods of administering zinc should be analyzed separately, whereas Singh M, 2011 pooled all together. Some studies administered zinc as syrup or tablets, some as lozenges. It is probable that the benefit of zinc in syrup and tablet trials is caused by biological mechanisms that are different from the mechanisms of the zinc lozenges, which are intended to be dissolved slowly in the mouth, see eg Hemilä H, 2011 and Eby GA, 2004. Combining different methods of zinc administration is the classical apples and oranges problem of meta-analysis.

6) The duration of the common cold should not be arbitrarily dichotomized as was done in Analyses 2.1 to 2.3 (pp.43-5) by Singh M, 2011. Duration is a continuous variable and should be analyzed as a continuous variable. The results of the zinc lozenge studies can be and should be analyzed using cold duration as a continuous variable, see Hemilä H, 2011.

7) Duration of the common cold should have been normalized so that placebo groups have length 100%. There is substantial variation in the duration of colds in the placebo groups of the zinc lozenge trials, from 5.1 days to 9.0 days and 10.8 days, see Hemilä H, 2011. For example, if a 5-day cold is shortened by 4 days, it is not equivalent to a 11-day cold being shortened by 4 days although both differences are equal in absolute units. The former is an 80% decrease in duration, whereas the latter is only a 36% decrease. Although part of the placebo group variation is caused by random variation, it is also caused by differences in viruses and in the severity of disease in different patient groups, and in differences in outcome definitions. Therefore, the relative effect of zinc on the common cold duration should be calculated in percentages, because the relative effect partly adjusts for the variations between patient groups and outcome definitions. In another study, the results of the zinc lozenge studies were analyzed as percentage effects, see Hemilä H, 2011.

8) Subgroup analysis should have been carried out. In the Background section (p.6), Singh M, 2011 wrote that a “significant correlation between total daily dosages of positively charged zinc species and a reduction in the mean duration of common colds” has been reported, however, they did not analyze that question. In the zinc lozenge studies, there is a 6-fold variation in the total zinc dose from 30 to 207 mg per day, see Hemilä H, 2011. Dose-response relation is a basic concept in pharmacology and thus the relation between dose and the effect of zinc lozenges should have been analyzed in the Cochrane review (2011). Hemilä H, 2011 found that none of the low zinc dose studies found effects of zinc lozenges, whereas high zinc dose studies found very strong evidence that colds were shortened by zinc. Such findings are consistent with the dose-response concept.

9) Pooling the adverse effects of all zinc trials is unsound, yet Singh M, 2011 did so in Fig. 6 (p.18). Eby GA, 2004 pointed out that the adverse effects of zinc lozenges, such as bad taste, can be explained largely by the differences in the composition of the lozenges. Furthermore, it is obvious that dissolving a zinc lozenge slowly in the mouth causes different adverse effects compared with ingesting a zinc syrup or tablet straight to the stomach. There is no justification to pool adverse effects of all zinc trials together, ignoring the considerable variations in the zinc products. As to the zinc lozenges, Eby GA, 2004 commented that “although pure zinc gluconate is bland and chalky in taste, it reacts with dextrose and related carbohydrates (excluding fructose) upon aging of lozenge compositions to produce noisome bitterness... On the other hand, zinc acetate allows the production of pleasant tasting, flavor stable lozenges”. In the most recent zinc acetate lozenge trial, Prasad AS, 2008 found no significant differences between the zinc and placebo groups in the occurrence of adverse effects although the daily dose of zinc was 92 mg.

10) Credit should be given to earlier work on the same topic. In the Introduction, Singh M, 2011 (p.7) wrote “The last review of all available RCTs of zinc for the common cold was published in 1999”, which is false. Reviews on zinc and the common cold by Jackson JL, 2000 and Caruso TJ, 2007 were published after 1999 and should have been mentioned as previous reviews on the same topic.

There is much evidence to indicate that high doses of zinc as zinc lozenges have effects on the duration of colds, see Hemilä H, 2011 and Eby GA, 2004. Therefore the topic of Singh M, 2011 is important; however, there were numerous methodological problems which limited the relevance of the conclusions.

Singh M, 2011 concluded that “In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.”

Had Singh M, 2011 separately analyzed the syrup and tablet studies and the lozenge studies, and had they analyzed the relation between the dose and effect, they could have reached much more clear conclusions.

Hemilä H, 2011 limited analysis to the zinc lozenge studies and found that five trials that used the lowest doses of zinc uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, and the pooled result indicated a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). Thus, clear conclusions for patients and for further research could have been drawn from the studies that were available to Singh M, 2011.