y y (Journal of Nutrition. 2000;130:1512S-1515S.

) 2000 The American Society for Nutritional Sciences

Supplement

Zinc and the Common Cold: A MetaAnalysis Revisited1

Jeffrey L. Jackson*2, Emil Lesho and Cecily Peterson
*

; Department of MedicineEducational Programs, Bethesda, MD 20814,; ; Department of Primary Care, Internal Medicine Service, U.S. Army Medical Activity, Heidelberg, Germany and; ; Department of Medicine, Madigan Army Medical Center, Tacoma, WA 98431
To whom correspondence and reprint request should be addressed.

ABSTRACT
The common cold has been estimated to cost the United States > $3.5 billion per year. Despite several randomized clinical trials, the effect of treating colds with zinc gluconate remains uncertain due to conflicting results. We conducted a meta-analysis of published randomized clinical trials on the use of zinc gluconate lozenges in colds using the random effects model of DerSimonians and Laird. Ten clinical trials of cold treatment with zinc gluconate were identified. After excluding two studies that used nasal inoculum of rhinovirus, eight trials were combined and analyzed. The summary odds ratio for the presence of "any cold symptoms" at 7 d was 0.52 (95% confidence interval, 0.251.2). We conclude that despite numerous randomized trials, the evidence for effectiveness of zinc lozenges in reducing the duration of common colds is still lacking. KEY WORDS: common cold zinc meta-analysis humans

INTRODUCTION
Viral upper respiratory tract infections are one of the most common reasons for physician visits in the United States, with adults experiencing two to four colds per year and children experiencing as many as eight per year (Dingle et al. 1964 , Gwalthey et al. 1966 , Schappert 1992 ). The cost of this common affliction has been calculated to be $3.5 billion in 1984 dollars, with an inestimable price in human misery (Couch 1984 ). Zinc salts have been found

to inhibit rhinovirus replication in vitro at concentrations of 0.1 mmol/L (Korant et al. 1974 ), possibly by interfering with rhinovirus protein cleavage (Korant and Butterworth 1976 ). Alternatively, it has been suggested that zinc salts may protect plasma membranes against lysis by cytotoxic agents, such as microbial toxins and complement (Kelly and Abel, 1983 ). The proposed protective mechanism is either via immunomodulation (Geist et al. 1987 , Novick et al. 1996 ) or via the binding of zinc ions to rhinovirus surface canyons, thus inhibiting viral interaction with intercellular adhesion molecule-1 (ICAM-1)3 , the site of rhinovirus binding to cells (Novick et al. 1996 ). Because ICAM-1 is also the binding site for leukocyte function associated antigen-1 (LFA-1), the block of LFA-1/ICAM-1 binding has been postulated to possibly suppress inflammation (Petrus et al. 1998 ). It has also been suggested that the cold symptoms, sneezing and nasal congestion, might be reduced by elevations in intranasal zinc salts, producing a "chemical clamp" on trigeminal and facial nerve endings (Novick et al. 1996 ). Alternatively, it has been suggested that the effects may be due to correction of a subclinical zinc deficiency (Prasad 1996 ). The biological plausibility for many of these explanations has been questioned because the in vitro inhibitory effect has been found to be weak (Pasternack 1987 ), and zinc salts lozenges dissolved in oral saliva do not reach the area infected by the rhinovirus: the nasal mucosa. As one author pointed out, "The lack of a specific theoretical framework for a zinc effect is troublesome and reminiscent of prior attempts to cure the common cold with other immunologically active micronutrients, such as vitamin C and vitamin A" (Gadomski, 1998 ). We previously published a meta-analysis of eight double-blinded placebo-controlled trials (Jackson et al. 1997 ) in which we found significant heterogeneity and a summary odds ratio (OR) for the presence of "any" cold symptoms at 7 d to be 0.50 with a 95% confidence interval that crossed 1 (0.191.29). We concluded that the overall evidence of benefit for zinc was lacking. However, questions of methodological flaws among the different trials made definitive conclusions difficult. Since this meta-analysis, an additional two double-blinded placebocontrolled randomized clinical trials have been published. Here, we update our previous analysis and include these additional trials.

MATERIALS AND METHODS

A MEDLINE search from 1966 to 1998 was performed using medical subjects heading (MeSH) terms "zinc," "cold" and "randomized clinical trials," which produced nine articles. A separate MEDLINE search using MeSH terms "cold" and "zinc" yielded 274 citations, although only 32 were relevant to this topic. A hand review of the 32 articles as well as the seven identified trials produced three additional trials. A supplementary search to identify studies was performed by a professional librarian. The National Institutes of Health database of funded studies from 1972 through 1998 was searched using the terms "zinc," "common cold," "viruses," "rhinovirus" and "respiratory infection" for possible sources of unpublished data. The Cochrane randomized clinical trial database was also searched. These articles were then stripped of identifying features and reviewed by two investigators for study quality using Chalmers criterion (Chalmers et al. 1981 ). Inter-rater agreement was assessed using the kappa statistic. Data extraction was performed by committee consensus in an unblinded manner. Because of inconsistent reporting between studies, the data point selected for analysis was the presence of "any" cold symptom at 7 d. Additional data that were extracted included country of origin, funding sources, study

population, disease characteristics, nature and dose of intervention, duration and success of followup. Study directors were contacted for data that were either ambiguous or not directly retrievable from the text. Unweighted data were tested for homogeneity using the methods of (Mantel-Haenszel (Petitti 1994 ) and were found to be inhomogeneous (Q = 47.9, df = 7, P < 0.00001), as reflected visually with the Galbraith plot (Fig. 1 ), so analysis was conducted using the random effects model of DerSimonian and Laird (Fleiss 1993 ). The possibility of publication bias was assessed and rejected (P = 0.09) using the methods of Egger et al. (1997 ).

View larger version (10K): In this window In a new window Figure 1. Galbraith plot, which is a tool to visually assess study heterogeneity. A homogeneous group of studies would all fall within the solid lines.

RESULTS
Eleven randomized clinical trials were identified. One was excluded because it represented a study of zinc gluconate palatability rather than of the effectiveness against colds (Farr and Gwaltney, 1987 ). The remaining 10 trials could be divided into two markedly different study designs (Porter and Hart 1993 ): eight studies investigated the effect of zinc salts on patients in whom colds were developing de novo in the community (Douglas et al. 1987 , Eby et al. 1984 , Godfrey 1992 , Macknin 1998 , Mossad et al. 1996 , Smith et al. 1989 , Weismann et al. 1990 ), and in two studies, volunteers were inoculated with rhinovirus 13 or 39 (Farr et al. 1987 ) or rhinovirus 2 (Al-Nakib et al. 1987 ). Because of concern about combining data from studies with markedly different designs (Potter and Hart 1993 ) and because neither of these studies provided data on the presence of symptoms at d 7, both were excluded. The director of one of these studies (Farr et al. 1987 ) declined to release the data. These two studies reported opposite findings: one found no effect (Farr et al. 1987 ), and one found a small improvement in symptoms among the 12 patients studied (Al-Nakib et al. 1987 ). The comparability of these differing study designs was questioned for several reasons. First, is it possible that experimentally-induced colds do not have the same natural history as those attained de novo (Jackson et al. 1958 )? Second, although rhinovirus is the most common cause of colds, it has > 100 serotypes and as a group is responsible for 3050% of community-acquired colds, raising issues of generalizability (Jackson et al. 1958 , Jennings and Dick 1987 ). The final pool of eight placebo-controlled randomized clinical trials and the excluded trials are shown in Table 1 . The trials had consistent, moderate-quality scores, and there was good inter-

rater agreement on study quality ( = 0.73). Particular problems included a lack of information provided on the method of randomization (Douglas et al. 1987 , Eby et al. 1984 , Macknin 1998 , Weismann et al. 1990 ), lack of testing of blinding effectiveness (Al-Nakib et al. 1987 , Macknin 1998 ), evidence that blinding was ineffective (Douglas et al. 1987 , Eby et al. 1984 , Mossad et al. 1996 ), small sample sizes (Al-Nakib et al. 1987 , Smith et al. 1989 ), failure to use an intention-to-treat analysis (Eby et al. 1984 , Godfrey 1992 , Smith et al. 1989 ), significant losses to followup (Eby et al. 1984 , Godfrey 1992 ), lack of information on losses to follow-up (Weismann et al. 1990 ) and lack of power calculations in negative studies (Douglas et al. 1987 , Smith et al. 1989 , Weismann et al. 1990 ). View this table: In this window In a new window Table 1. Study characteristics The summary OR for the incidence of "any" cold symptom at 1 wk was 0.52, with a 95% confidence limit of 0.251.2. The summary and individual OR as well as confidence limits are given in Figure 2 .

View larger version (13K): In this window In a new window Figure 2. The summary and incidence odds ratios for the incidence of any cold symptom at 1 wk. Error bars indicate 95% confidence intervals. The boxes are proportional to the sample size.

DISCUSSION
In this updated meta-analysis, we failed to find evidence of a statistically significant reduction in cold duration. This negative result occurred despite the fact that the finding of one of the larger trials (Farr et al. 1987 ) of no effect was not included in the analysis. Among studies reporting a benefit from zinc therapy, many have been criticized for poor blinding of study subjects. One used an unflavored placebo with a high dropout rate in the zinc gluconate group due to unpleasant side effects (Eby et al. 1984 ), and another found a higher rate of side effects with the zinc gluconate lozenge than with the calcium lactate pentahydrate placebo (Mossad et al. 1996 ). Lack of adequate blinding was eventually believed to have produced misleading results for benefit in treating colds with ascorbic acid (Chalmers 1973 ).

The biologic plausibility of the effectiveness of zinc salts in treating colds has also been questioned. Both trials that measured viral shedding found no effect on duration or magnitude of viral shedding (Al-Nakib et al. 1987 , Farr et al. 1987 ). Serum zinc concentrations are well below those required for a direct viral effect (Farr et al. 1987 ), and although concentrations in oral saliva reach sufficient levels (Godfrey 1988 ), there is no evidence that this zinc-saliva mixture reaches the nasal mucosa, the site of viral infection. The most scientifically rigorous trials of zinc and its effects on cold symptoms were the two inoculation studies (Al-Nakib et al. 1987 , Farr 1987 ). Under close supervision, patient compliance, cold symptoms and side effects were carefully monitored. Neither trial found a direct effect on viral shedding, in either magnitude or duration. In a trial involving only 12 subjects, Al-Nakib et al. (1987 ) found a small improvement in some cold symptoms on some days, whereas Farr et al. (1987 found no differences in any of the measures. Unfortunately, these were excluded from this meta-analysis, but it is hard to understand how some trials can find such a dramatic reduction (Eby et al. 1984 , Godfrey 1992 , Mossad et al. 1996 , Petrus et al. 1998 ) in all cold symptoms, whereas others found little or no benefit (Douglas et al. 1987 , Farr et al. 1987 , Macknin et al. 1998 , Smith et al. 1990, Weismann et al. 1990 ). Critics of trials finding no benefit from zinc have suggested one of two possibilities for zinc failure in those studies. One has been criticized for using potentially inadequate doses (Weismann et al. 1990 ), whereas three (Douglas et al. 1987 , Weismann et al. 1990 , Farr 1987 ) were criticized for using preparations that could chelate zinc (Eby 1988 , Zarembo et al. 1992 ). The concern about the inactivation of zinc by other substances is controversial, with data from Bristol-Myers chemists suggesting that this does not occur (Lewis 1998 ). Moreover, if zinc does not directly reach the nasopharynx, and it is postulated that serum levels of zinc are responsible for the beneficial effects, the acidity in the stomach would render problems of oral chelation meaningless. This analysis has several important limitations. First, the validity of any meta-analysis is dependent on the validity of the studies analyzed. Some questions of methodology, such as the adequacy of randomization or use of an intention-to-treat analysis, can be used to stratify studies into those of higher and lower quality. However, a meta-analysis has no ability to differentiate truth in the face of conflicting claims of fundamental methodological flaws, as is the case in this analysis. Second, this meta-analysis was limited to a single variable, the presence of "any" cold symptom at 7 d. Other variables, such as the severity of cold symptoms or amount of nasal discharge, which is important in the patient determination of the severity of colds, were not extractable and therefore not analyzable. However, these symptoms paralleled symptom duration, with the studies split on zinc effectiveness on these variables as well. Finally, one of the studies involved pediatric patients, whereas the remaining trials involved adults. If colds or zinc effects are different in children than in adults, then the inclusion of those results is inappropriate. However, there is little evidence to suggest that this is the case, although children have been shown to have more frequent colds than adults. For clinicians advising patients on the use of zinc lozenges, it is difficult to know who is correct. Although one report of an acute zinc overdose found no significant patient harm (Lewis 1998 ), potential adverse effects from excess intake of zinc includes a reduction in serum copper (Prasad

et al. 1978 ) and lymphocyte stimulation as well as a significant reduction in HDL with a slight increase in LDL (Chandra 1984 ). As one author put it, "The ingestion of gram quantities of zinc by many millions of persons as therapy for the common cold would represent a kind of uncontrolled nutritional experiment that is cause for concern. At the very least, therefore, surveillance for potential toxicity will be needed for a good many years if zinc therapy becomes widely adopted for one of mankinds most common and seemingly most intractable maladies" (Prasad 1996 ). Interestingly, a recent review of cold treatment by the author of one of the trials concluded that "a safe effective dose is not yet established" (Chandra 1984 ). Our meta-analysis suggests that the evidence of zinc effectiveness is still lacking.

FOOTNOTES
1

Presented at the international workshop "Zinc and Health: Current Status and Future Directions," held at the National Institutes of Health in Bethesda, MD, on November 45, 1998. This workshop was organized by the Office of Dietary Supplements, NIH and cosponsored with the American Dietetic Association, the American Society for Clinical Nutrition, the Centers for Disease Control and Prevention, Department of Defense, Food and Drug Administration/Center for Food Safety and Applied Nutrition and seven Institutes, Centers and Offices of the NIH (Fogarty International Center, National Institute on Aging, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Drug Abuse, National Institute of General Medical Sciences and the Office of Research on Womens Health). Published as a supplement to The Journal of Nutrition. Guest editors for this publication were Michael Hambidge, University of Colorado Health Sciences Center, Denver; Robert Cousins, University of Florida, Gainesville; Rebecca Costello, Office of Dietary Supplements, NIH, Bethesda, MD; and session chair, Craig McClain, University of Kentucky, Lexington.
3

Abbreviations used: ICAM-1, intercellular adhesion molecule-1; LFA, leukocyte function associated antigen-1; OR, odds ratio.

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