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To the editor and authors,
We have several concerns about the zinc results in this systematic review
1. Weismann et al. 1990 RCT evaluates zinc for treating, not preventing infections, yet is included in the prevention meta-analyses (Figure-6).
2. Farr et al. 1987 reports post-exposure prophylactic and treatment results for two RCTs. Which RCT was used? Why was the other ignored? Supp-Table-5 reports an incorrect sample size and MD rather than RR. The validity of combining pre- and postexposure prophylactic trials is questionable and at the very least, should be discussed.
3. Turner et al. 2000 reports two RCTs, both had 4 arms. Why was one RCT and two of the three zinc arms ignored? If these arms were included, an explanation for how the means (SDs) were combined is missing.
4. Table 3 lacks transparency as the studies used in each subgroup are not cited and often it is unclear what data was used. For example, none of the five RCTs included in the zinc prevention meta-analysis reported infection rates for males and females, yet this is reported.
5. The authors claim there was no evidence of a dose response for zinc used for treatment. Only two RCTs evaluated a dose ≤13.3mg/day. Both used intranasal sprays/gels. All other treatment studies evaluated lozenges. Comparing doses for different administration routes is clinically meaningless. All this analysis tells us is there is no difference between intranasal and sublingual adminis...
5. The authors claim there was no evidence of a dose response for zinc used for treatment. Only two RCTs evaluated a dose ≤13.3mg/day. Both used intranasal sprays/gels. All other treatment studies evaluated lozenges. Comparing doses for different administration routes is clinically meaningless. All this analysis tells us is there is no difference between intranasal and sublingual administration routes.
6. The control lozenge used by Turner et al. 2000 should probably be classified as an active control as it contained quinine hydrochloride. At the very least it should be discussed, and a sensitivity analysis conducted.
7. The authors fail to acknowledge that language bias is a limitation of their review. Only English language databases were searched, and articles excluded “for which there was no standard translation” are not reported. We are aware of three RCTs indexed only in Chinese language databases and published in Chinese. Two are large RCTs that evaluated a zinc gluconate nasal spray for prevention of upper respiratory infections [1, 2] and the other evaluated zinc gluconate nasal spray for treatment .
8. Other concerns with the comprehensiveness of the literature search include only searching two databases. This is the bare minimum for a systematic review and is not recommended when the intervention is used as a complementary medicine/natural product as some relevant journals are not indexed in PubMed or Embase.
9. Despite searching “published systematic reviews by hand” one zinc RCT identified by two other systematic reviews was missed [4-6].
10. A key RCT that is very relevant to the current pandemic was also missed. In 2007, Prasad et al.  reported an RCT involving 50 participants age 55-87 years who were given 45mg/day of oral zinc or placebo for 12 months. The effects of zinc for prevention of upper respiratory infections, tonsillitis, common cold, and flu were each reported separately.
11. The lack of a protocol and no discussion of the review’s limitations add to our concerns about the reliability of the review findings.
1. Wei J, Chen HW, You LH: [Zinc gluconate nasal spray for the prevention of upper respiratory tract infection: A randomised, double-blinded, placebo-controlled trial]. Medical Journal of Chinese People's Liberation Army 2009, 34(7):838-840.
2. Zhang LJ, Liu GX, Zhang YX, Xing XY, Cai HX, Zeng G: [Zinc gluconate nasal spray for the prevention of acute upper respiratory tract infection]. Journal of Preventive Medicine Information 2009, 25(7):508-510.
3. Yao WZ, Yang W, Shen N, Liu YN, Wang PL, Lin JT: [Zinc gluconate nasal spray versus common cold nasal spray in treating common cold: A randomised, multi-center, controlled trial]. Chinese Journal of Clinical Pharmacology 2005, 21(2):87-90.
4. Belongia EA, Berg R, Liu K: A randomized trial of zinc nasal spray for the treatment of upper respiratory illness in adults. The American journal of medicine 2001, 111(2):103-108.
5. D'Cruze H, Arroll B, Kenealy T: Is intranasal zinc effective and safe for the common cold? A systematic review and meta-analysis. Journal of primary health care 2009, 1(2):134-139.
6. Hulisz D: Efficacy of zinc against common cold viruses: an overview. Journal of the American Pharmacists Association 2004, 44(5):594-603.
7. Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, Cardozo LJ: Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr 2007, 85(3):837-844.