Treatment of Naturally Acquired Common Colds with Zinc: A Structured Review

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1 MAJOR ARTICLE Treatment of Naturally Acquired Common Colds with Zinc: A Structured Review Thomas J. Caruso, 1 Charles G. Prober, 2 and Jack M. Gwaltney, Jr. 3 1 Stanford University School of Medicine and 2 Department of Pediatrics, Stanford University School of Medicine, Stanford, California, and 3 Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville Background. Over the past 20 years, the use of zinc as an over-the-counter alternative therapy for the common cold has vastly grown in popularity. Recent reports of potentially permanent anosmia caused by intranasal zinc therapy warrant careful analysis of the therapeutic effects of zinc. Methods. A search of the Medline database (including articles published during ) for studies of zinc and the common cold produced 105 published reports. Fourteen were randomized, placebo-controlled studies that examined the effect of zinc lozenges, nasal sprays, or nasal gels on naturally acquired common colds. Eleven features of experimental design affecting signal quality, chance, bias, and blinding were used to evaluate the 14 placebo-controlled studies. These criteria were validated case definition, quantifiable hypothesis, sample size calculation, randomized assignment, double blinding, proof of blinding, measurement of compliance, measurement of dropout rate, analysis by intent to treat, description of methods of analysis, and measurements of probability. Equal weight was given to each criterion, because failure to meet any one could potentially invalidate the findings of a clinical trial. Results. Four studies met all 11 criteria. Three of these studies reported no therapeutic effect from zinc lozenge or nasal spray. One study reported positive results from zinc nasal gel. Of the remaining 10 studies, 6 reported a positive effect and 4 reported no effect. Intent-to-treat analysis was the most common criterion not met. Conclusions. This structured review suggests that the therapeutic effectiveness of zinc lozenges has yet to be established. One well-designed study did report a positive effect of zinc nasal gel. Adults experience an average of 3 colds each year, and children may experience as many as 8 10 colds [1]. Colds are caused by a number of viruses, with rhinovirus being the most common causative agent [2]. Cold symptoms include nasal obstruction, rhinorrhea (runny nose), sneezing, sore throat, cough, headache, feverishness, and malaise [3]. The search for a common cold vaccine has proved to be elusive, largely because of the variety of viral types that cause infection. The common cold represents a substantial cost to the workforce as a result of days lost to illness [4]. Inappropriate use of antibiotics to treat cold symptoms Received 19 March 2007; accepted 1 May 2007; electronically published 20 July Reprints or correspondence: Dr. Jack M. Gwaltney, Jr., University of Virginia School of Medicine, Dept. of Internal Medicine, PO Box , Charlottesville, VA (jack_g@earthlink.net). Clinical Infectious Diseases 2007; 45: by the Infectious Diseases Society of America. All rights reserved /2007/ $15.00 DOI: / contributes to the emergence of antibiotic-resistant bacteria [5]. In 1984, Eby et al. [6] reported that zinc gluconate lozenges were effective in reducing the duration of the common cold. Although it has been hypothesized that zinc s mechanism of action may be because of inhibition of rhinovirus binding to the intercellular adhesion molecule-1 located in the nasal mucosa [7], no data have been gathered to support this. Zinc ions have also been hypothesized to inhibit proteolysis during the rhinovirus cell cycle [8] and block facial and trigeminal nerve conduction, thereby reducing nasal congestion and sneezing [7]. An in vitro study showed that zinc ions had minimal inhibitory effects on replication of rhinovirus [9]. These proposed theories of zinc s action rely on the assumption that ions from an orally dissolved lozenge will migrate into the nasal sinuses. The likelihood of ion migration to have a distinguishable therapeutic effect has been challenged [10]. In an effort to provide better bioavailability at the proposed target, intranasal zinc sprays were developed. They alleviated the need Zinc and Colds CID 2007:45 (1 September) 569

2 for lozenges, but decreased smell and permanent loss of smell have been reported as potential adverse effects [11, 12]. The original trial of Eby et al. [6] was criticized for lack of blinding and was quickly followed by 3 subsequent trials [13 15], which showed no benefit from zinc. Since then, many studies have examined the efficacy of zinc as a cold treatment, and still no consensus has been reached. The design of these studies has been questioned, prompting several reviews [16 18] that support the use of zinc and 2 meta-analyses [19, 20] that do not. The aim of this report was to provide a structured review of all studies that have examined the efficacy of zinc lozenges, nasal sprays, and nasal gels as treatment for the common cold. Unlike meta-analysis, which assigns varying values to design criteria, this review used a dichotomous scale to state whether criteria necessary for valid experimental design are present or not. This approach alleviates the need to assign arbitrary values to different criteria, as seen in meta-analysis, but provides a systematic, unbiased method to evaluate trials, which previous reviews may have lacked. SEARCH METHODS An initial search of the Medline database (including articles published during January 1966 December 2006), using the keywords zinc and common cold, produced 105 results. Further search refinement with the keywords rhinovirus, common cold treatment, and upper respiratory tract infection, as well as examination of previous zinc meta-analyses and reviews [16 20], yielded 14 placebo-controlled randomized studies. Prophylactic and viral challenge zinc studies were excluded to maintain emphasis on treatment of naturally acquired colds with zinc lozenges, nasal sprays, and nasal gels. This review compared only those studies that used zinc as the exclusive treatment. CRITERIA APPLIED TO EXPERIMENTAL DESIGN The studies were reviewed according to 11 predetermined criteria necessary for valid experimental design [21]. These criteria were chosen on the basis that failure to meet any one could potentially invalidate a study. This method of analysis was previously developed in a review of echinacea, an herbal remedy for the cold [21]. The rationale for the selection of the 11 criteria is as follows. Validated case definition. The validated case definition provides signal quality and reduces noise by ensuring that the cases have the disease of interest based on validated criteria for diagnosis. Signal quality refers to the accurate measurement of an event (signal) of interest in this case, cold symptoms without dilution of the signal by similar events, such as respiratory symptoms due to other causes, such as allergy or respiratory tract irritants that would represent noise. Quantifiable hypothesis. A quantifiable hypothesis provides an end point, which allows for the calculation of sample size relative to defined statistical power. This addresses the problem of chance. Sample size calculation. Given a quantifiable hypothesis, calculations should be performed to assure that a study has a large enough sample size to meet a predetermined statistical power. This also addresses the problem of chance. Randomized assignment. Random assignment of cases to the experimental and control groups is necessary to ensure that study populations are as similar as possible. This reduces known and unknown biases that may affect the validity of the results. Double blinding. Unblinded studies are biased toward finding a treatment effect. Data should be supplied to show that blinding was not only attempted but also was effective. This is especially important for zinc preparations, which characteristically have a medicinal taste and often lead to nausea. Proof of blinding. A separate, controlled experiment to test the adequacy of blinding should ideally be performed before the clinical trial is conducted. When performed after the study, it is acceptable only in a negative study. In a positive study, poststudy proof of blinding is unacceptable, because there is no way to determine whether judgments were made on the basis of a bias or a true therapeutic effect. Measurement of compliance. Signal quality is also dependent on the degree of compliance of subjects. Compliance should be monitored to evaluate the amount of bias that could result from subjects failure to take study preparations as directed. Measurement of dropout rate. Dropout rates should be measured to evaluate whether statistical power was maintained. Intent-to-treat analysis. Results should be analyzed by the intent-to-treat principle to maintain randomization and statistical power. Scores from all cold symptoms included in the research protocol should be reported. Methods of statistical analysis. A description of the methods of statistical analysis should be provided to assess the appropriateness of the tests applied to the data. In this review, only the presence of analysis was verified, not method used. Measurements of probability. This information should be provided to evaluate the precision of the findings. The Cochrane Handbook states, in reference to reviews, failure to meet one or more validity criteria may indicate such a high risk of bias in some reviews that it constitutes grounds Table 1. Placebo-controlled studies that examined the effect of treatment with zinc on the severity of symptoms and duration of the common cold. The table is available in its entirety in the online edition of Clinical Infectious Diseases. 570 CID 2007:45 (1 September) Caruso et al.

3 for exclusion of those studies [22]. Studies that fulfilled all 11 criteria were considered to be the most sound. Studies that did not fulfill all 11 criteria were not assigned quality scores or ranked, because failure to meet just 1 of these predetermined essential criteria may potentially invalidate a study. This review does not recognize value in grading studies that contain varying degrees of invalid design. RESULTS Fourteen placebo-controlled studies were analyzed (table 1). Overall, 7 studies [14, 15, 23 27] reported no effect of zinc as a treatment, and 7 reported a positive effect [6, 28 33] (figure 1). Among the 7 studies reporting no effect, 3 fulfilled all 11 criteria [23 25], 1 met 8 criteria [14], 1 met 7 criteria [15], and 2 met 6 criteria [26, 27]. Among the studies reporting positive effects, 1 met all 11 criteria [28], 2 met 10 criteria [29, 30], 2 met 7 criteria [31, 32], and 2 met 6 criteria [6, 33]. Of the 4 studies that fulfilled all 11 criteria [23 25, 28], 2 studies [23, 25] reported that zinc lozenges have no effect on the symptom severity and duration of common cold, 1 study [24] reported no effect of zinc nasal spray, and 1 study [28] reported a positive effect of zinc nasal gel on the symptoms and duration of the common cold. Intent-to-treat analysis was the most common criterion not met (table 2). Eight of 14 studies [6, 14, 15, 26, 27, 29, 31, 32] did not show an intent-to-treat analysis of all subjects initially enrolled in the study. Seven studies [6, 14, 15, 26, 27, 32, 33] did not have a quantifiable hypothesis or sample size calculation. Proof of blinding was lacking in 7 studies [6, 26, 27, 30 33]. Six studies [6, 15, 26, 27, 31, 33] failed to state the method of randomization or failed to show similarity of groups at trial onset. Two studies did not measure compliance [31, 33]. All studies contained double blinding, valid case definitions, measurement of dropout rates, methods of statistical analysis, and measurements of probability. DISCUSSION The purpose of this review was to provide a critical assessment of studies that have examined the efficacy of zinc lozenges, nasal sprays, and nasal gels as treatment for the common cold. The criteria used to analyze the studies highlight the essential features of valid experimental design. Only 4 of 14 studies had all 11 components of valid design, and 3 of those 4 reported zinc to be an ineffective treatment of the common cold. The results of studies that did not fulfill all 11 criteria were less likely to present scientifically valid results. We chose not to use quality scores for each study; instead, a dichotomous scale was used to state whether a criterion was present or not. Grading scales have been proposed [34, 35], but because there is no reference standard for assessing the true validity of a trial, the possibility of validating any proposed scoring system is limited [36]. Simple scales that qualitatively score trials with or without differential weighting or complex scaling have not been shown to provide reliable assessments of quality [37 39]. The most common criterion not met was intent-to-treat analysis. This type of analysis reduces bias when reporting a treatment effect by including all participants randomized to the trial protocol. When examining a treatment such as zinc, which is known to have adverse effects, such as sore mouth [40], upset stomach [40], and loss of smell [11, 12], subjects may have a greater likelihood of dropping out or not complying with protocol because of such adverse effects. These conditions are countered by intent-to-treat analyses, which provide an unbiased review of the data [41]. The second most common deficiency was proof of blinding, which was lacking in 7 studies. The placebo effect in the treat- Figure 1. Number of criteria met by the study and the reported result of the study. Studies examined the effect of treatment with zinc on the severity of symptoms and duration of the common cold. Zinc and Colds CID 2007:45 (1 September) 571

4 Table 2. Number of criteria evaluating how experimental design affected signal quality, chance, bias, and blinding that were missed in studies that examined the effect of treatment with zinc on the severity of symptoms and duration of the common cold. Criterion No. of studies lacking criterion References Intent-to-treat analysis 8 [6, 14, 15, 26, 27, 29, 31, 32] Quantifiable hypothesis and end point 7 [6, 14, 15, 26, 27, 32, 33] Sample size calculation 7 [6, 14, 15, 26, 27, 32, 33] Proof of blinding 7 [6, 26, 27, 30 33] Specified method of randomization and similarity of groups 6 [6, 15, 26, 27, 31, 33] Measurement of compliance 2 [31, 33] Double blinding 0 Validated case definition 0 Measurement of dropout rate 0 Method of statistical analysis 0 Measurements of probability 0 ment of colds was first shown 170 years ago [42] and has since been demonstrated in subsequent studies [43 45]. With regard to zinc lozenges, Farr and Gwaltney [40] showed statistically significant differences with respect to recognition of zinc lozenges versus placebo on the basis of aftertaste, nausea, and mouth soreness. Although recent studies have attempted to mask the taste of zinc and its potential adverse effects, separate controlled studies should be completed to address the effectiveness of blinding. Quantifiable hypothesis and sample size calculation were also deficient in 7 studies. These criteria provide a predetermined end point and effect size. Although a sample size calculation based on described statistical power should be included in every randomized controlled trial, it is likely that some of the studies in this review contained enough participants for statistical relevance (table 1). The findings of this review support the meta-analyses of Jackson et al. [19, 20] and contradict those of previous reviews [16 18] that have supported the use of zinc for the common cold. Only 4 studies fulfilled all 11 predetermined criteria that are necessary for valid experimental design. The results of these 4 studies provide the greatest likelihood of valid results. Two of these studies examined zinc lozenges, and neither reported a therapeutic effect. Two examined zinc nasal applications, 1 of which reported a positive effect with zinc nasal gel, and 1 of which reported no effect with spray. Two other studies involving nasal zinc application, each of which fulfilled 6 criteria, reported no therapeutic effect. Further work is necessary to clarify zinc s effectiveness with intranasal application. In addition to the treatment studies reviewed here concerning naturally acquired colds, well-designed viral challenge studies also have tested zinc as a cold remedy. Farr et al. [13] infected healthy volunteers with rhinovirus and used viral cultures and increases in antibody titer to confirm virus infection. Volunteers were subsequently treated with zinc gluconate lozenges or placebo. To ensure compliance and demonstrate bioavailability, serum zinc levels were measured and shown to be significantly increased in subjects. Zinc therapy did not reduce the severity or duration of cold symptoms or the frequency or duration of viral shedding [13]. With respect to intranasal zinc, Turner [46] challenged healthy volunteers with rhinovirus and confirmed infection by virus isolation in cell culture. Volunteers received intranasal zinc gluconate or placebo both before and after inoculation with virus. Zinc treatment had no effect on the severity or duration of cold symptoms, nor did it have an effect on the proportion of infected volunteers who developed clinical colds [46]. Non influenza-related viral respiratory tract infections in the United States represent a total economic impact of $40 billion annually, spread over the 500 million colds contracted annually [47]. The seemingly benign common cold represents an economic cost far greater than that of many other clinical conditions [47] and warrants continued research designed to reduce incidence and morbidity. After 20 years of research on 572 CID 2007:45 (1 September) Caruso et al.

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