Metodología: ensayos Zinc y catarro, Monografías, Ensayos de Derecho

¡Descarga Metodología: ensayos Zinc y catarro y más Monografías, Ensayos en PDF de Derecho solo en Docsity! Zinc for the common cold (Review) Singh M, Das RR This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 6 http://www.thecochranelibrary.com Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. T A B L E O F C O N T E N T S 1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 11RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 19DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Zinc versus placebo, Outcome 1 Duration of cold symptoms. . . . . . . . . . . 50 Analysis 1.2. Comparison 1 Zinc versus placebo, Outcome 2 Subgroup analysis (duration of cold symptoms). . . . 51 Analysis 1.3. Comparison 1 Zinc versus placebo, Outcome 3 Severity of cold symptoms. . . . . . . . . . . 54 Analysis 1.4. Comparison 1 Zinc versus placebo, Outcome 4 Subgroup analysis (severity of cold symptoms). . . . 55 Analysis 1.5. Comparison 1 Zinc versus placebo, Outcome 5 Incidence of common cold. . . . . . . . . . . 56 Analysis 2.1. Comparison 2 Zinc versus placebo, Outcome 1 Number of participants symptomatic after 3 days of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Analysis 2.2. Comparison 2 Zinc versus placebo, Outcome 2 Number of participants symptomatic after 5 days of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Analysis 2.3. Comparison 2 Zinc versus placebo, Outcome 3 Number of participants symptomatic after 7 days of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Analysis 2.4. Comparison 2 Zinc versus placebo, Outcome 4 Time to resolution of cough. . . . . . . . . . 59 Analysis 2.5. Comparison 2 Zinc versus placebo, Outcome 5 Time to resolution of nasal congestion. . . . . . . 60 Analysis 2.6. Comparison 2 Zinc versus placebo, Outcome 6 Time to resolution of nasal drainage. . . . . . . . 61 Analysis 2.7. Comparison 2 Zinc versus placebo, Outcome 7 Time to resolution of sore throat. . . . . . . . . 62 Analysis 2.8. Comparison 2 Zinc versus placebo, Outcome 8 Change in cough symptom score. . . . . . . . . 62 Analysis 2.9. Comparison 2 Zinc versus placebo, Outcome 9 Change in nasal symptom score. . . . . . . . . 63 Analysis 2.10. Comparison 2 Zinc versus placebo, Outcome 10 School absence (days). . . . . . . . . . . . 64 Analysis 2.11. Comparison 2 Zinc versus placebo, Outcome 11 Antibiotic use. . . . . . . . . . . . . . 64 Analysis 2.12. Comparison 2 Zinc versus placebo, Outcome 12 Any adverse event. . . . . . . . . . . . . 65 Analysis 2.13. Comparison 2 Zinc versus placebo, Outcome 13 Bad taste. . . . . . . . . . . . . . . . 66 Analysis 2.14. Comparison 2 Zinc versus placebo, Outcome 14 Nausea. . . . . . . . . . . . . . . . . 67 Analysis 2.15. Comparison 2 Zinc versus placebo, Outcome 15 Constipation. . . . . . . . . . . . . . . 68 Analysis 2.16. Comparison 2 Zinc versus placebo, Outcome 16 Diarrhoea. . . . . . . . . . . . . . . . 69 Analysis 2.17. Comparison 2 Zinc versus placebo, Outcome 17 Abdominal pain. . . . . . . . . . . . . . 70 Analysis 2.18. Comparison 2 Zinc versus placebo, Outcome 18 Dry mouth. . . . . . . . . . . . . . . 71 Analysis 2.19. Comparison 2 Zinc versus placebo, Outcome 19 Mouth irritation. . . . . . . . . . . . . 72 72APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iZinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1.00) (P = 0.05) than those in the control, (I2 statistic = 75%). The incidence rate ratio (IRR) of developing a cold (IRR 0.64, 95% CI 0.47 to 0.88) (P = 0.006) (I2 statistic = 88%), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.58, 95% CI 1.19 to 2.09) (P = 0.002), bad taste (OR 2.31, 95% CI 1.71 to 3.11) (P < 0.00001) and nausea (OR 2.15, 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. The very high heterogeneity means that the averaged estimates must be viewed with caution. Authors’ conclusions Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people but some caution is needed due to the heterogeneity of the data. As the zinc lozenges formulation has been widely studied and there is a significant reduction in the duration of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data. When using zinc lozenges (not as syrup or tablets) the likely benefit has to be balanced against side effects, notably a bad taste and nausea. P L A I N L A N G U A G E S U M M A R Y Zinc for the common cold The common cold is often caused by the rhinovirus. It is one of the most widespread illnesses and is a leading cause of visits to the doctor and absence from school and work. Complications of the common cold include ear infection, sinusitis and exacerbations of reactive airway diseases. There is no proven treatment for the common cold. However, an even partially effective treatment for treating and preventing the common cold could markedly reduce the health problems and economic losses associated with it. Zinc inhibits replication of the virus and has been tested in trials for treatment of the common cold. This review identified 18 randomised controlled trials, enrolling 1781 participants of all age groups, comparing zinc with placebo (no zinc). We found that zinc (lozenges or syrup) reduces the average duration of the common cold in healthy people, when taken within 24 hours of onset of symptoms. In people taking zinc their cold symptoms are also less likely to persist beyond seven days of treatment. Prophylactic zinc supplementation for at least five months reduces incidence, school absences and prescription of antibiotics for children with the common cold, although antibiotics are not required for the common cold. People in whom common cold symptoms might be troublesome (for example, those with underlying chronic illness, immunodeficiency, asthma, etc.) have not been studied, so the use of zinc cannot currently be recommended for them. Given the variability in the dose, formulation and duration of zinc use in the included studies, more research is needed to address these before zinc use can be generally recommended for the common cold. However, as the zinc lozenges formulation has been widely studied, and there is a significant reduction in the duration of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. When using zinc lozenges (not as syrup or tablets) the likely benefit has to be balanced against side effects, notably a bad taste and nausea. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data. 2Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Zinc compared with placebo for the common cold Patient or population: patients with common cold Settings: outpatient Intervention: zinc lozenges or syrup Comparison: usual care Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No. of participants (studies) Quality of the evidence (GRADE) Comments Assumed risk Corresponding risk Placebo Zinc Duration of cold symp- toms (days) The mean duration of cold symptoms ranged across control groups from 5.1 to 9.38 days The mean duration of cold symptoms ranged across control groups from 4 to 12.1 days 1656 (14 studies1) ++O low2,3−5 Severity of symptom score The mean severity of symptom score ranged across control groups from 0.4 to 5.61 The mean severity of symptom score ranged across control groups from 0.2 to 3.45 513 (5 studies6) ++O low3,5,7,8 Incidence of common cold 618 per 1000 382 per 1000 (354 to 431) RR 0.64 (0.47 to 0.88) 394 (2 studies9) +OO very low3,10−12 Number of participants symptomatic after 7 days of treatment 563 per 1000 373 per 1000 (143 to 508) OR 0.45 (0.2 to 1.0) 476 (5 studies13) ++OO very low14−16 School absence (number of days) The mean days of school absence ranged across control groups from 1.3 to 1.35 days The mean days of school absence in the interven- tion groups was 0.37 lower (0.7 to 0.04 lower) 394 (2 studies9) +OO very low10,17,18 3 Z in c fo r th e c o m m o n c o ld (R e v ie w ) C o p y rig h t © 2 0 1 4 T h e C o c h ra n e C o lla b o ra tio n . P u b lish e d b y Jo h n W ile y & S o n s, L td . Antibiotic use 330 per 1000 127 per 1000 (52 to 200) OR 0.27 (0.16 to 0.46) 394 (2 studies9) ++OO low10,19,20 Any adverse event 349 per 1000 424 per 1000 (132 to 898) OR 1.58 (1.19 to 2.09) 1217 (8 studies) +++O moderae21−23 *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1No serious study limitations: all the studies had adequately concealed allocation and blinded both participants and study staff to be considered at low risk of bias. Whether free of other bias was unclear in Macknin 1998; Petrus 1998; Turner 2000a; Turner 2000b; Turner 2000c. Petrus 1998 did not adequately describe the sequence generation. Blinding was inadequate in Turner 2000a; Turner 2000b; Turner 2000c. 2Serious inconsistency: there was high statistical heterogeneity. I2 statistic = 89%. The heterogeneity was due to differences in the nature of the different interventions (zinc gluconate versus acetate lozenges, zinc lozenges versus zinc syrup), wide dose ranges, varied duration of symptoms prior to administration of zinc (varying from 24 to 48 hours) and characteristics of the study population (children versus adults). 3No serious indirectness: studies both from low-income and high-income regions have assessed this comparison. Therefore, the result can be confidently generalised to all situations. 4No serious imprecision: though the 95% CI around the pooled effect is narrow, the lower limit does not suggest a clinically important reduction in the duration of cold (a decrease in duration of ≤ 1 day is not shown to be important to patients). 5Publication bias cannot be ruled out. 6No serious study limitation: all the studies had adequately concealed allocation and blinded both participants and study staff to be considered at low risk of bias. Whether free of other bias was unclear and adequate sequence was not generated in one study (Petrus 1998). 7Serious imprecision: the 95% CI around the pooled effect is wide, the lower limit is crossing the point of no effect. 8Serious inconsistency: there was high statistical heterogeneity. I2 statistic = 84%. The heterogeneity may be due to differences in the nature of the different interventions (zinc gluconate or acetate lozenges, zinc sulphate syrup) and dose range (30 to 160 mg/day) as well as mean duration of symptoms prior to administration of zinc (varying from 24 to 48 hours), as well as the characteristics of the study population (children versus adults). However, subgroup analysis was not possible as there were not enough studies for each variable.4 Z in c fo r th e c o m m o n c o ld (R e v ie w ) C o p y rig h t © 2 0 1 4 T h e C o c h ra n e C o lla b o ra tio n . P u b lish e d b y Jo h n W ile y & S o n s, L td . which appears to explain the rapid therapeutic response to zinc lozenges (Eby 2010). It moves electrons from the nose into the mouth and, in response to the electron flow, it moves positively charged metal ions, such as ionic zinc, from the mouth into the nose. Human rhinoviruses attaching to the nasal epithelium via the intracellular adhesion molecule-1 (ICAM-1) receptor cause most colds. The zinc ion, based on its electrical charge, has an affinity for ICAM-1 receptor sites and may exert an antiviral effect by at- taching to the ICAM-1 receptors in the rhinovirus structure and nasal epithelial cells (Novick 1996). In addition, zinc inhibits viral replication by preventing the formation of viral capsid proteins (Geist 1987; Korant 1976). It has also been suggested that zinc stabilises cell membranes (Pasternak 1987), prevents histamine re- lease (Harisch 1987) and inhibits prostaglandin metabolism (Kelly 1983). Why it is important to do this review There is no proven method of prevention or treatment for the common cold. However, any medication that is only partially ef- fective in the treatment and prevention of the common cold could markedly reduce morbidity and economic losses due to this ill- ness. There have been many clinical trials describing the effect of zinc (lozenges and syrup) on common cold symptoms; there- fore it is important to know the effect of zinc on the common cold. The last review of all available RCTs of zinc for the common cold was published in 1999. Since then, several new studies (Eby 2006; Kartasurya 2012; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; McElroy 2003; Petrus 1998; Prasad 2000; Prasad 2008; Turner 2000a; Turner 2000b; Turner 2000c; Vakili 2009; Veverka 2009) have been published. It is therefore impor- tant to update the information and include all new clinical trials. We undertook the review to assess the overall effectiveness of zinc (lozenges or syrup) in treating the common cold and to provide some guidance with respect to future research. O B J E C T I V E S To assess whether zinc (irrespective of the zinc salt or formulation used) is efficacious in reducing the incidence, severity and duration of common cold symptoms. In addition, we aimed to identify potential sources of heterogeneity in results obtained and to assess their clinical significance. M E T H O D S Criteria for considering studies for this review Types of studies Double-blind, placebo-controlled randomised controlled trials (RCTs). Types of participants Trial participants were of either gender and of any age. Types of interventions Therapeutic trials: interventions commenced within three days of participants developing common cold symptoms and consisted of 1.5 to 2-hourly treatments with a zinc or placebo lozenge during waking hours, for more than six hours a day for a period of five or more consecutive days. Prophylactic trials: intervention commenced and continued throughout the cold season for at least five months. We considered all formulations of zinc (irrespective of the type of salt, formulation and concentration of zinc). Types of outcome measures Outcome measures frequently used to determine the clinical ef- ficacy of any common cold treatment are the incidence, severity and duration of cold symptoms. Accordingly, for inclusion in this review, the incidence and severity of at least throat and nasal symp- toms and cough needed to be assessed. Primary outcomes 1. Duration of symptoms. 2. Severity of symptoms. 3. Incidence of the common cold. Secondary outcomes 1. Proportion of participants symptomatic after three, five or seven days of treatment. 2. Time to resolution of individual symptoms: cough, nasal congestion, nasal drainage and sore throat. 3. Change in individual severity symptom scores: cough, nasal score. 4. School absence (days). 5. Antibiotic use. 6. Adverse events. We defined duration as the number of days to cold resolution from start of treatment. We considered cold resolution to be the resolution of all cold symptoms or resolution of all but one cold symptom, or the participant believed they had recovered from the cold. Severity of cold symptoms needed to be graded: 0 - no symp- toms, 1 - mild symptoms, 2 - moderate symptoms and 3 - severe symptoms. We defined incidence as number of colds per study participant during the study period. Adverse events included any or individual adverse events during or after taking the medications. 7Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Search methods for identification of studies Electronic searches For this 2013 review update we updated the searches in CEN- TRAL, MEDLINE and EMBASE and in addition searched CINAHL, Web of Science and LILACS. We searched the Cochrane Central Register of Controlled Tri- als (CENTRAL) 2012, Issue 12, part of The Cochrane Library, www.thecochranelibrary.com (accessed 18 January 2013), which contains the Acute Respiratory Infections Group’s Specialised Reg- ister, MEDLINE (April 2010 to January week 2, 2013), EMBASE (1974 to January 2013), CINAHL (1981 to January 2013), Web of Science (1985 to January 2013) and LILACS (1982 to January 2013). See details of search strategy in Appendix 1. Details of the previous search strategy are in Appendix 2. Searching other resources We searched the US National Institutes of Health, Department of Health and Human Services trials registry www.clinicaltrials.gov and the WHO ICTRP trials registry http://www.who.int/ictrp/ en/ (18 June 2012). We also searched bibliographies of published papers for unpublished trials. Two review authors (RRD, MS) assessed the studies to ensure appropriate trials were included in the review and to minimise the potential for selection bias. Data collection and analysis More information on the statistical methods used in this review can be found in the relevant section of the Cochrane Acute Respi- ratory Infections Review Group Module. Comparisons were zinc (lozenges or syrup or tablet) with placebo. We compared outcome measures before and after treatment, as well as after day three, five or seven to accommodate trials of different lengths. Selection of studies Two review authors (RRD, MS) independently reviewed the re- sults for inclusion in the analysis. We resolved differences regard- ing study quality through discussion. Data extraction and management We recorded data on a pre-structured data extraction form. The lead review author (MS) entered data directly into Review Man- ager (RevMan) (RevMan 2012). An independent coder verified accuracy of data entry. We made no attempt to contact investiga- tors. Most trials were conducted over 10 years ago and in view of the information required to be provided by the investigators, we thought that they would be unable to comply. Assessment of risk of bias in included studies We assessed risk of bias in all included studies using The Cochrane Collaboration’s ’Risk of bias’ methodology (Higgins 2011). Two review authors (RRD, MS) assessed selection bias (random se- quence generation, allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting) and other biases, if any. Each item was assessed as high, low or unclear risk of bias along with relevant information reported in the RCT. When the method- ological description was unambiguous, one review author entered the methodological description in the ’Risk of bias’ table. When the description of methods was ambiguous, the same review au- thor discussed the issue with the co-author to reach a consensus. The methodological descriptions are summarised in Figure 1 and Figure 2. 8Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality item for each included study. 9Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 50 participants (Prasad 2000; Prasad 2008), four had more than 50 but fewer than 100 participants (Douglas 1987; Farr 1987a; Godfrey 1992; Mossad 1996), eight had more than 100 but fewer than 200 participants (Al-Nakib 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Petrus 1998; Smith 1989; Weismann 1990; Vakili 2009) and four had more than 200 participants (Macknin 1998; Turner 2000a; Turner 2000b; Turner 2000c). Interventions Zinc supplements were provided in the form of either syrup, lozenges or tablets. One trial used zinc sulfate tablet (Vakili 2009) and three trials used zinc sulphate syrup (Kurugol 2006a; Kurugol 2006b; Kurugol 2007). Among the trials using lozenge prepara- tions, two different salts were used: zinc gluconate (Al-Nakib 1987; Farr 1987a; Godfrey 1992; Macknin 1998; Mossad 1996; Smith 1989; Weismann 1990; Turner 2000a) and zinc acetate (Douglas 1987; Petrus 1998; Prasad 2000; Prasad 2008; Turner 2000b; Turner 2000c). The supplements were given for different periods of time in all the trials. In the therapeutic trials the duration of supplement was five days (Farr 1987a), six days (Al-Nakib 1987; Douglas 1987), seven days (Farr 1987a; Godfrey 1992; Smith 1989), 10 days (Kurugol 2006a; Kurugol 2007; Weismann 1990), 14 days (Petrus 1998) and no duration mentioned (i.e. partici- pants were given zinc as long as they were symptomatic) (Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Turner 2000a; Turner 2000b; Turner 2000c). In the three trials also studying the prophylactic role of zinc, the duration of supplement was 4.5 days (Al-Nakib 1987), five months (Vakili 2009) and seven months (Kurugol 2006b). Outcomes Primary Fourteen trials (Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2007; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990; Turner 2000a; Turner 2000b; Turner 2000c) reported the duration of symptoms. Among these, five trials have provided the original data (Kurugol 2006a; Kurugol 2006b; Petrus 1998; Prasad 2000; Prasad 2008). The mean and SD were calculated either from the survival curves (Macknin 1998; Mossad 1996; Prasad 2000; Smith 1989; Turner 2000a; Turner 2000b; Turner 2000c; Weismann 1990) or from t/P value (Douglas 1987; Godfrey 1992) reported in other tri- als. Thirteen trials measured the total severity score of cold symp- toms (Al-Nakib 1987; Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990; Turner 2000a; Turner 2000b; Turner 2000c) but results from only five trials (Kurugol 2006a; Kurugol 2007; Petrus 1998; Prasad 2000; Prasad 2008) could be pooled, as in eight trials (Al-Nakib 1987; Douglas 1987; Godfrey 1992; Smith 1989; Weismann 1990; Turner 2000a; Turner 2000b; Turner 2000c) the results were not reported in a standard for- mat. The incidence of cold symptoms was measured in two trials (Kurugol 2006b; Vakili 2009). Secondary The proportion of participants asymptomatic by day three or day five was reported in three trials (Mossad 1996; Smith 1989; Weismann 1990), whereas the proportion of participants asymp- tomatic by day seven was reported in five trials (Douglas 1987; Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990). In all these trials, ITT analysis was conducted. Time to resolution of individual cold symptoms was reported as follows: time to res- olution of cough in four trials (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008), time to resolution of nasal congestion in five trials (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008), time to resolution of nasal drainage in five trials (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) and time to resolution of sore throat in four tri- als (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008). Change in individual severity symptom score was reported as follows: change in cough symptom score in two trials (Douglas 1987; Petrus 1998), change in nasal symptom score in four tri- als (Douglas 1987; Kurugol 2006a; Kurugol 2007; Petrus 1998), change in throat symptom score in two trials (Douglas 1987; Petrus 1998). Standard error of mean (SEM) was not provided in one trial (Douglas 1987). Effect on school absence and antibiotic use were provided in two trials (Kurugol 2006b; Vakili 2009). Adverse events Fourteen trials (Douglas 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989; Weismann 1990; Vakili 2009; Turner 2000a; Turner 2000b; Turner 2000c) reported adverse events. Common adverse events included bad taste, nausea, constipation, diarrhoea, abdominal pain, dry mouth and oral irritation. We reported the adverse events separately for both lozenges and syrup formulations. Other Six trials using experimentally induced colds with rhinovirus also studied the number of participants shedding the virus, duration of viral shedding, number of virus-positive days, as well as rise in antibody titre. These were not included in the outcome measures as we thought that it would not be of help in drawing conclu- sions. Three trials reported the effect of zinc supplementation on school absence. Among these, two (Kurugol 2006b; Vakili 2009) reported this outcome during a prophylactic trial, though another (Macknin 1998) was a therapeutic trial. 12Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Excluded studies We excluded five trials. 1. Inclusion criteria not defined, disproportionate number of drop-outs from the zinc group (Eby 1984). 2. Two studies were not RCTs (McElroy 2003). 3. Measured upper respiratory tract infection as a whole (including common cold, seasonal influenza) (Veverka 2009). 4. Used both zinc gluconate nasal spray and zinc orotate lozenges simultaneously (Eby 2006). 5. Studies upper respiratory tract infection as a whole, used zinc supplementation for four months (Kartasurya 2012). Risk of bias in included studies Allocation Allocation concealment was adequate in 10 studies (Douglas 1987; Farr 1987a; Godfrey 1992; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008). It was unclear in seven studies (Al-Nakib 1987; Petrus 1998; Smith 1989; Turner 2000a; Turner 2000b; Turner 2000c; Weismann 1990) and not described in one (Vakili 2009). Adequate sequence generation was described in seven studies ( Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996). However, it was not clear in seven studies (Farr 1987a; Prasad 2000; Prasad 2008; Smith 1989; Turner 2000a; Turner 2000b; Turner 2000c) and not generated in four studies (Al-Nakib 1987; Petrus 1998; Vakili 2009; Weismann 1990). Blinding All 18 studies were blinded but placebo blinding was adequately described in 10 trials (Douglas 1987; Godfrey 1992; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989). Zinc-treated par- ticipants also experienced higher incidences of side effects and/or complaints, and in 12 trials, zinc-treated participants complained of altered, bad or unpalatable taste which suggests that the zinc lozenges were distinct from the placebo lozenges and, in this re- spect, blinding may have been compromised. Incomplete outcome data Data were fully detailed in 15 studies and in the remaining three studies (Al-Nakib 1987; Turner 2000a; Turner 2000b; Turner 2000c) details of attrition and exclusions from the analysis were unavailable. Selective reporting Except two studies (Al-Nakib 1987; Weismann 1990), 16 studies scored ’yes’ for being free from selective reporting. Other potential sources of bias Eleven studies were funded by pharmaceutical companies (Al- Nakib 1987; Douglas 1987; Godfrey 1992; Farr 1987a; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Petrus 1998; Smith 1989; Weismann 1990). Five studies were sup- ported Medical Research Foundation (Godfrey 1992; Mossad 1996; Prasad 2000; Prasad 2008; Vakili 2009) and in addition by National Institute of Health (NIH) (Prasad 2008). Information on clearance by Ethics Committees or Institutional Review Boards was available for all except one study (Smith 1989). In three stud- ies, other sources of bias were not clear (Turner 2000a; Turner 2000b; Turner 2000c). Effects of interventions See: Summary of findings for the main comparison 1. Primary outcomes (i) Therapeutic effects of zinc Duration of cold symptoms Fourteen studies (Godfrey 1992; Kurugol 2006a; Kurugol 2007; Macknin 1998; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008; Smith 1989; Turner 2000a; Turner 2000b; Turner 2000c; Weismann 1990) reported this outcome. Results could be pooled from all the studies and there were 1656 participants including both children and adults (Figure 3; Analysis 1.1). The studies were heterogenous in terms of variable formulations (zinc gluconate or acetate lozenges, zinc sulphate syrup) and dose range (30 mg/day to 160 mg/day) as well as MD of symptoms prior to administration of zinc (varying from 24 to 48 hours). Intake of zinc lozenges or syrup was associated with a significant reduction in the duration (days) of common cold (mean difference (MD) -1.03, 95% confidence interval (CI) -1.72 to -0.34) (P = 0.003) when it was administered within 24 hours of the onset of symptoms. However, there was marked heterogeneity among the included trials. We did subgroup analysis for the following: dose (≥ 75 mg/day versus < 75 mg/day), types of lozenges (gluconate versus acetate), formulation (lozenges versus syrup) and age group (children < 16 years versus adults) (Figure 4; Analysis 1.2). 13Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Forest plot of comparison: 1 Zinc versus placebo, outcome: 1.1 Duration of cold symptoms (in days). 14Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (ii) Prophylactic effects of zinc Incidence of common cold This was reported in two studies (Kurugol 2006b; Vakili 2009). The two studies used variable dose, formulation and duration of zinc. The follow-up periods of the two studies were different, therefore we based the calculation of the incidence rates on person- years. The person-time incidence rate is an appropriate measure of incidence when follow-up times are unequal (Rothman 1988). Incidence density is defined as the number of incident cases occur- ring in a susceptible population followed over a given time period; its units are therefore expressed as the number of cases per unit of person-time. The incidence density ratio is defined as the ratio of incidence density of an exposed group to that of an unexposed group. For each study, we calculated the incident rate ratio (IRR) of catching a cold in treated participants compared to the risk in control participants (Analysis 1.5; Figure 6). The IRR of devel- oping a cold in subjects who received the intervention was 0.64 (95% CI 0.47 to 0.88), compared to participants in the control group (P = 0.006). Figure 6. Forest plot of comparison: 1 Zinc versus placebo, outcome: 1.3 Incidence of common cold (IRR). 2. Secondary outcomes (i) Therapeutic effects of zinc Proportion of participants symptomatic after three, five or seven days of treatment Proportion of participants symptomatic after three days of treatment Three studies (Mossad 1996; Smith 1989; Weismann 1990) in- cluded a total of 340 participants. There was no significant dif- ference between the intervention and control group for the pro- portion of participants symptomatic after day three of treatment (odds ratio (OR) 0.81, 95% CI 0.27 to 2.42) (P = 0.7) (Analysis 2.1). Proportion of participants symptomatic after five days of treatment Three studies (Mossad 1996; Smith 1989; Weismann 1990) in- cluded a total of 340 participants. There was no significant differ- ence between the intervention and control group for proportion of participants symptomatic after day five of treatment (OR 0.78, 95% CI 0.32 to 1.95) (P = 0.6) (Analysis 2.2). Proportion of participants symptomatic after seven days of treatment Five studies (Douglas 1987; Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990) included a total of 476 participants. There was a significant difference between the intervention and control group for proportion of participants symptomatic after day seven of treatment (OR 0.45, 95% CI 0.20 to 1.00) (P = 0.05) (Analysis 2.3). Time to resolution of individual cold symptoms This was reported in days in five studies. 17Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Time to resolution of cough Four studies (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008) included a total of 453 participants (intervention = 219, control = 234). The time taken for resolution of cough was sig- nificantly shorter in the intervention group (MD -1.73, 95% CI -3.49 to 0.03) (P = 0.05) (Analysis 2.4). Time to resolution of nasal congestion Five studies (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) included a total of 605 participants (inter- vention = 302, control = 303). The time taken for resolution of nasal congestion was significantly shorter in the intervention group (MD -0.7, 95% CI -1.39 to -0.01) (P = 0.02) (Analysis 2.5). Time to resolution of nasal drainage Five studies (Kurugol 2006a; Macknin 1998; Petrus 1998; Prasad 2000; Prasad 2008) included a total of 599 participants (interven- tion = 298, control = 301). The time taken for resolution of nasal drainage was significantly shorter in the intervention group (MD -1.01, 95% CI -2.01 to -0.01) (P = 0.05) (Analysis 2.6). Time to resolution of sore throat Four studies (Kurugol 2006a; Macknin 1998; Prasad 2000; Prasad 2008) included a total of 430 participants (intervention = 211, control = 219). The time taken for resolution of sore throat was significantly shorter in the intervention group (MD -0.46, 95% CI -0.82 to -0.09) (P = 0.02) (Analysis 2.7). Change in individual severity symptom scores Change in cough symptom score This was reported in two studies (Douglas 1987; Petrus 1998). In the study by Douglas 1987, a total of 63 treatment courses were evaluated (intervention = 33, control = 30) and the mean cough score (standard error of mean (SEM) not provided) was lower in the control group (6.3) than in the intervention group (10.6), which was not statistically significant (P = 0.2). In the study by Petrus 1998, a total of 101 participants were included and there was a significant decrease in the mean cough score in the intervention group (MD -0.23, 95% CI -0.26 to -0.2) (P < 0.00001) (Analysis 2.8). Change in nasal symptom score This was reported in four studies (Douglas 1987; Kurugol 2006a; Kurugol 2007; Petrus 1998). In the study by Douglas 1987, a total of 63 treatment courses were evaluated and the mean nasal score (SEM not provided) was lower in the control group (9.8) than in the intervention group (11.7), which was not statistically significant (P = 0.5). In the study by Petrus 1998, a total of 101 participants were included and there was a decrease in the mean nasal score (not significant) in the intervention group (nasal con- gestion: placebo 1.43 ± 0.05, zinc 1.54 ± 0.08; nasal drainage: placebo 1.61 ± 0.07, zinc 1.45 ± 0.07). In the Kurugol 2006a and Kurugol 2007 studies a total of 314 participants were included and there was no difference between the two groups for the change in nasal symptom score (MD -0.2, 95% CI -1.34 to 0.94) (P = 0.73) (Analysis 2.9). Change in throat symptom score This was reported in two studies (Douglas 1987; Petrus 1998). In one study (Douglas 1987), a total of 63 treatment courses were evaluated and the mean throat score (SEM not provided) was lower in the intervention group (6.1) than in the control group (6.2), which was not statistically significant (P = 0.96). In another study (Petrus 1998), a total of 101 participants were included and there was a decrease in the mean throat score (not significant) in the intervention group (sore throat: placebo 1.34 ± 0.11, zinc 1.26 ± 0.06; scratchy throat: placebo 1.53 ± 0.08, zinc 1.38 ± 0.1). (ii) Prophylactic effects of zinc School absence (days) Three trials reported this outcome. The pooled result from the two preventive trials (Kurugol 2006a; Vakili 2009) showed that zinc- supplemented children were absent for fewer days from school (MD -0.66, 95% CI -0.99 to -0.33) (P < 0.0001) (Analysis 2.10). In one of the therapeutic trials (Macknin 1998), children taking zinc were less likely to be absent than children taking placebo (OR 0.60, 95% CI 0.32 to 1.13) (P = 0.12), but the result was not significant. Antibiotics use Two trials reported this outcome (Kurugol 2006b; Vakili 2009). The antibiotic prescription was more likely in placebo than in zinc-supplemented children (OR 0.27, 95% CI 0.16 to 0.46) (P < 0.00001) (Analysis 2.11). 18Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (iii) Adverse events Thirteen trials (Douglas 1987; Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Macknin 1998; Mossad 1996; Prasad 2000; Prasad 2008; Smith 1989; Turner 2000a; Turner 2000b; Turner 2000c; Weismann 1990) reported any or individual adverse events. The incidence of any adverse event was higher in the zinc group (OR 1.58, 95% CI 1.19 to 2.09) (P = 0.002) than in the placebo group. Among the zinc group, the lozenges formulation (OR 2.00, 95% CI 1.40 to 2.86) (P = 0.0001) was more like to produce any adverse events than the syrup formulation (OR 1.03, 95% CI 0.64 to 1.66) (P = 0.9) (Analysis 2.12). Among individual events, bad taste (OR 2.31, 95% CI 1.71 to 3.11) (P < 0.00001) (Analysis 2.13) and nausea (OR 2.15, 95% CI 1.44 to 3.23) (P = 0.002) (Analysis 2.14) had a higher incidence in the zinc group. Among the zinc group, the lozenges formulation (OR 2.66, 95% CI 1.91 to 3.69) (P < 0.00001) was more like to produce bad taste than the syrup formulation (OR 1.15, 95% CI 0.55 to 2.39) (P = 0.71). There was no significant difference between the two groups in the incidence of constipation (P = 0.17) (Analysis 2.15), diarrhoea (P = 0.08) (Analysis 2.16), abdominal pain (P = 0.25) (Analysis 2.17), dry mouth (P = 0.09) (Analysis 2.18) and oral irritation (P = 0.50) (Analysis 2.19). (iv) Publication bias To assess whether there was a bias in the published literature, we plotted the effect size of each trial versus variance for one of the primary outcome (duration of common cold). The funnel plot generated here shows that most of the precise studies (towards the top of the plots) have effect sizes which are either zero or very close to it (Analysis 1.1). One explanation for such asymmetry might be publication bias. D I S C U S S I O N The discussion is divided into two parts: the first will discuss im- portant methodological issues that have emerged from research in this area, and the second part will discuss the results obtained and their clinical significance. Part 1: methodology Since Eby’s trial in 1984 (Eby 1984), many trials have investigated whether zinc is efficacious in the treatment or prevention of the common cold. Among these 18 trials were included in this 2013 review. We rated the methodological quality of the included trials as good, with two trials excluded because of poor quality. Eby’s trial realised a number of limitations which raised concerns regard- ing the validity of the results. Treatment blinding in the trial has been questioned as zinc lozenges were found to be unpalatable, distorted the taste of participants and caused a higher incidence of side effects. In addition, investigators relied solely on the subjec- tive assessment of cold symptoms; laboratory confirmation of viral infection was not conducted and analyses were only conducted on a subgroup of those originally enrolled in the trial. Eby’s trial was nevertheless instructive and highlighted a number of methodolog- ical issues. Like Eby’s trial, most trials have relied on community-acquired infections. However, five trials recruited participants from volun- teers experimentally inoculated with human rhinovirus (Al-Nakib 1987; Farr 1987a; Turner 2000a; Turner 2000b; Turner 2000c). While high rates of infection with human rhinovirus were at- tained in the later trials and most participants experienced cold symptoms, in trials relying on community-acquired infection, the infecting agent and the infection rates were generally not deter- mined. In trials relying on community-acquired infection, investigators relied on trial participants or family members to assess the inci- dence and severity of cold symptoms. Though in most of the tri- als information was generally provided on how compliance with the recording of symptoms was assessed, objective periodic assess- ments of the clinical severity of respiratory symptoms were not conducted. In the trials conducted by Al-Nakib 1987, Farr 1987a, Macknin 1998, Kurugol 2006a, Kurugol 2006b, Kurugol 2007 and Turner 2000a, Turner 2000b and Turner 2000c, symptoms were assessed by trial personnel thus providing some assurance as to the validity of clinical severity scores and estimates based on such scores. Assessment of response to treatment also depended on objective measurements such as nasal mucus weight or tissue counts, which was measured in one study (Al-Nakib 1987) and the authors found that zinc gluconate reduced both of these pa- rameters. However, as in most studies children were involved, this was not practical. Research by Farr 1987b suggested that in most trials the size of the placebo-blinding study used to determine whether zinc and placebo lozenges were indistinguishable was not sufficiently large to detect a significant difference. In their efforts to find a suitable matching placebo lozenge, Farr showed that a false negative result may occur if a small subject population (i.e. fewer than 20) is used. Given that placebo-blinding studies were only conducted in six of the 18 trials, and with the exception of three trials (Farr 1987a; Prasad 2000; Prasad 2008) the size of the placebo-matching stud- ies in two of the remaining three trials (no information was pro- vided on the size of placebo study conducted by Weismann 1990) ranged from eight to 20, the adequacy of blinding in most trials is questioned. Zinc-treated participants also experienced higher incidences of side effects, complaints or both, and in seven trials zinc-treated participants complained of altered, bad or unpalatable taste, which suggests that zinc lozenges were distinct from placebo lozenges and, in this respect, blinding may have been compro- mised. However, the increased incidence of bad taste and nausea found by Mossad 1996; constipation and mouth dryness found by Prasad 2000; and bad taste, nausea, mouth, tongue or throat 19Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. consequently a combined OR for day five is not appropriate. The combined OR for day three was not significant 0.97 (95% CI 0.62 to 1.5). In three trials (Godfrey 1992; Mossad 1996; Weismann 1990), fewer participants in the zinc group had cold symptoms af- ter seven days. The pooled result (OR 0.53, 95% CI 0.38 to 0.75) obtained from five trials (Douglas 1987; Godfrey 1992; Mossad 1996; Smith 1989; Weismann 1990) indicated fewer participants in the zinc group had cold symptoms after seven days of treatment. However, the test for heterogeneity was statistically significant. In six trials (Godfrey 1992; Kurugol 2006a; Mossad 1996; Petrus 1998; Prasad 2000; Prasad 2008) with similar study designs, methodologies and efficacy assessments, zinc was found to be ef- fective in reducing the duration and severity of common cold symptoms in healthy children and adults, when it was adminis- tered within 24 hours of the onset of symptoms. In another trial (Kurugol 2007) with similar study design, methodology and ef- ficacy assessments, zinc was found to be effective in reducing the severity of common cold symptoms in healthy children (with- out any change in duration), when it was administered within 24 to 48 hours of the onset of symptoms. In the trial by Godfrey 1992, the authors found a significant decrease in the duration and severity of symptoms when treatment was administered within 24 hours, compared to treatment administration within 48 hours. So, if treatment with zinc is to be used for common cold, it should ideally commence within 24 hours of onset of symptoms. There are a number of potential sources of heterogeneity in results obtained from trials included in this review. Most trials relied on community-acquired infections in which the infecting agent was not identified and as such different agents may have been involved which may have differed in their sensitivity to zinc. The amount of zinc taken each day by participants varied largely across the trials, and given that some formulations released less zinc ion than others the effective dose of zinc across trials was variable. Blinding of treatment may not have been adequately controlled in some trials, thereby increasing the potential for performance and detection bias to occur. The time from onset of cold symptoms to commencement of treatment ranged from one to three days. Given the beneficial effects noted in trials commencing treatment with zinc within 24 hours, the results from all the trials may not be comparable. Last but not the least is the fact that the lifestyle of the study population in all the trials was different and the results might have been affected to some degree by this factor. Summary of main results Studies reporting duration and severity of cold symptoms suggest that the intake of zinc is associated with a significant reduction in the overall duration and severity of common cold symptoms. A higher proportion of participants became asymptomatic by day seven of treatment with zinc. Duration of individual cold symp- toms was also significantly reduced in the zinc group, though the individual symptom severity scores were not significantly affected by the intake of zinc. Zinc supplementation led to reduction in the incidence of common cold, decreased school absence and de- creased the risk of antibiotic use when used for at least five months. The incidence of adverse events was significantly higher in the zinc group with the syrup preparation being better tolerated than lozenges. Overall completeness and applicability of evidence The trials included in the analysis involved healthy children and adults of all ages (except infants) and both sexes. All except four trials (Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Vakili 2009) were conducted in upper-middle and high-income coun- tries, where zinc deficiency is uncommon (including in young chil- dren). Out of four trials (Kurugol 2006a; Kurugol 2006b; Kurugol 2007; Vakili 2009), three were conducted in Turkey and one in Iran, which are low-income countries. These later trials found beneficial effects of zinc when used either in syrup or tablet (not lozenges) form. So, any beneficial effect of zinc lozenges might not be directly extrapolated to children and adults of low-income countries. In all the included trials, the main weakness of the data is that most trials, when presenting data, did not differentiate be- tween cold due to rhinovirus and other viruses (as viral studies were not conducted in most of these trials). So it is unclear whether zinc helps those with rhinoviral cold or even cold due to other viruses. However, as rhinovirus is the most common aetiological agent of the common cold all over the world (in both low-income and high-income countries), it may be predicted that zinc lozenges prepared in the above mentioned formulations might also help people living in low-income countries. Quality of the evidence The trial evidence included is generally of good quality, with a low risk of bias. All the studies were blinded, but placebo-blinding was adequately described in only six trials. In 12 trials, zinc-treated participants complained of altered, bad or unpalatable taste which suggests that zinc lozenges were distinct from placebo lozenges and, in this respect, blinding may have been compromised. Allocation concealment was adequate in nine studies and unclear in nine studies. Thirteen trials reported a low rate of loss to follow-up, whereas three trials did not mention any loss to follow-up. This suggests that the studies were of good quality. For all the outcomes, there was more than one study reporting the individual outcome. The majority were carefully conducted community trials, with active mechanisms to promote adherence to the intervention and both active and passive case finding. Last and most importantly, as there was a high degree of heterogeneity among the trials, the result should be interpreted with caution. 22Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Potential biases in the review process All the included trials, as expected, measured the effect of zinc on the common cold. There was therefore the potential to miss trials which may have measured common cold as upper respiratory tract infection in secondary outcomes which were less publicised or less well indexed within the electronic databases. We tried to avoid this by conducting a wide search and assessing the relevance of each paper identified in that search carefully. We extracted data from survival curves or t/P values given in studies that did not provide original data, which might have overestimated or underestimated the effect size. Lastly, publication bias cannot be ruled out as shown by funnel plot asymmetry. Agreements and disagreements with other studies or reviews The important changes in this updated review in comparison to the previous version (Marshall 1999) include the following. 1. Intake of zinc is associated with a significant reduction in the duration and severity of common cold symptoms. 2. Duration of individual cold symptoms was also significantly reduced in the zinc group. 3. The syrup and tablet preparation of zinc is better tolerated than lozenges. 4. Zinc supplementation reduces incidence, school absence and prescription of antibiotics in children with the common cold. In the review conducted by Marshall (Marshall 1999) the included studies had missing information, due to which it was not possible to pool the results across the studies. For example, although most investigators required participants to record the clinical severity of symptoms each day and used similar scales against which to rate symptom severity (symptoms were rated as none, mild, moderate or severe), there was little commonality in the summary estimates used by investigators to describe the duration, incidence and sever- ity of respiratory symptoms. It was therefore only possible to de- termine the proportion of participants who were asymptomatic after three and five days of treatment for three trials and after seven days of treatment for five trials. Except for one study (Godfrey 1992), duration of symptoms was not reported in the rest of the studies. Therefore, again it was not possible to pool the results for this outcome. In the revisit of their previous meta-analysis, Jackson (Jackson 2000) found statistically significant heterogeneity between the zinc trials. They calculated a pooled estimate of the zinc gluconate lozenges in colds using the random-effects model of DerSimonian and Laird from eight trials. The summary OR for the presence of “any cold symptoms” at seven days was 0.52 (95% CI 0.25 to 1.2). They concluded that despite numerous randomised trials, the evidence for the effectiveness of zinc lozenges in reducing the duration of common colds is still lacking. Although, according to them, some of the negative results might be explained by low zinc ion availability, they did not examine the issue. Moreover, they have not looked for the effect of any other formulations, as well as high or low doses of zinc. A review published in 2004 by Hulisz 2004, which was an overview of published articles through MEDLINE (1980 to 2003), con- cluded that zinc effectively reduces the duration and severity of common cold symptoms when administered within 24 hours of the onset of symptoms. The author also had some concerns regard- ing the clinical tests of zinc for the treatment of common colds be- ing inconsistent, primarily because of study design, blinding and lozenge contents; early formulations of lozenges being unpalatable with a higher incidence of side effects. In a systematic review of trials published between 1966 and 2006, Caruso 2007 used 11 features of experimental design affecting signal quality, chance, bias and blinding to evaluate 14 placebo- controlled trials. They gave one point for each of the 11 quality items if it was satisfied, after which only four trials obtained the maximum of 11 points. Based on this, they suggested that the positive results in the zinc trials might be explained by method- ological flaws. However, the use of scales for assessing quality or risk of bias is strongly discouraged in Cochrane systematic reviews. Moreover, such an approach, though simple, is not supported by evidence (Higgins 2011). In another systematic review by Hemilä (Hemilä 2011), the au- thor included 13 placebo-controlled comparisons. Pooling of tri- als using a total daily zinc dose of less than 75 mg found no effect, but those using zinc acetate in daily doses of over 75 mg found a 42% reduction, and those using zinc salts other than acetate in daily doses of over 75 mg found a 20% reduction in the duration of colds. The author concluded that there is strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so that benefit is observed with high doses of zinc but not with low doses. However, there were no descriptions of other formulations of zinc (syrup or tablet). In the latest systematic review (Science 2012), the authors included 17 trials. Compared with patients given placebo, those receiving zinc had a shorter duration of cold symptoms (mean difference (MD) -1.65 days, 95% CI -2.50 to -0.81). However, heterogeneity was high. Zinc shortened the duration of cold symptoms in adults but no significant effect was seen among children. In contrast to this, we found zinc to be effective both in children (< 16 years age) and adults. The reduction in the duration of cold symptoms was greater with high doses of ionic zinc (MD -2.75, 95% CI -3.89 to -1.60) than with lower doses (MD -0.84, 95% CI -1.50 to -0.18). However, we found that only zinc lozenges containing high dose (≥ 75 mg/day) reduced the cold duration significantly. A U T H O R S ’ C O N C L U S I O N S 23Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Implications for practice Evidence shows that zinc is beneficial for the common cold in healthy children and adults living in high-income countries. Pooled results from the trials showed that zinc reduced the dura- tion (not the severity) of common cold symptoms when used ther- apeutically. However, the effect of zinc lozenges on common cold duration is heterogeneous so that benefit is observed with high doses but not with low doses of zinc. The effects of zinc lozenges should be further studied to determine the optimal lozenge com- positions and treatment strategies. Zinc also reduced the incidence of the common cold, school absence and antibiotic use in healthy children when used prophylactically, although antibiotics are not required for the common cold. All the studies included healthy participants; we could not find any evidence regarding use of zinc in participants at increased risk of developing the common cold. As the zinc lozenges formulation has been widely studied, and there is a significant reduction in the duration (days) of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data. When using zinc lozenges one should be aware of the side effects. Implications for research Morbidity associated with the common cold is not trivial. The median duration of a cold episode is 7.4 days, with 25% of cases continuing for two weeks. The burden of the common cold is even more pronounced in individuals with chronic co-morbidities or clinical risk factors, including those with asthma and chronic obstructive pulmonary disease, the elderly, those with a history of otitis media or sinusitis, and those who are immunocompromised. Asthmatic children experience more cold episodes than non-asth- matic children, which is a common risk factor for acute asthma exacerbations. Future studies should therefore focus on the role of zinc in these populations rather than healthy people, as the results would be more meaningful for them. Investigators also need to recognise the difficulties that have been encountered, particularly with respect to blinding and bioavail- ability (with various formulations). More research is needed in this area. Given the potential for zinc lozenges to induce adverse effects, the zinc lozenges preparation which produces minimal ad- verse effects should be formulated. We also need more trials on syrup and tablet preparations of zinc as well as more preventive trials in order to support or refute the above mentioned beneficial findings with these preparations. Although laboratory confirmation of infection is desirable, in large community-based trials the costs associated with such investiga- tions limit the extent to which serology can be undertaken. How- ever, unlike trials relying on experimentally induced rhinoviral colds, findings from large community-based trials will address is- sues relating to the diversity of and generalisability to the common cold. A C K N O W L E D G E M E N T S We wish to thank Ian IR Marshall, the previous author of this review. We acknowledge all the help and infrastructure provided by the Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh and All India Institute of Medical Sci- ences (AIIMS), New Delhi. We acknowledge the help provided by Elizabeth Dooley, Managing Editor and Sarah Thorning, Tri- als Search Co-ordinator of the Cochrane Acute Respiratory Infec- tions Group, for the EMBASE search and obtaining full-text arti- cles of studies. We are very grateful to the following referees who commented on drafts of this review: Durhane Wong-Rieger, Ann Fonfa, Anna Joseph, Craig Mellis, Robert Black, Conor Teljeur, Mark Jones and Paul Little. R E F E R E N C E S References to studies included in this review Al-Nakib 1987 {published data only} Al-Nakib W, Higgins PG, Barrow I, Batstone G, Tyrell DAJ. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. Journal of Antimicrobial Chemotherapy 1987;20:893–901. Douglas 1987 {published data only} Douglas R, Miles H, Moore B, Ryan P, Pinnock C. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrobial Agents and Chemotherapy 1987;31(8):1263–5. Farr 1987a {published data only} Farr B, Conner E, Betts R, Oleski J, Minnefor A, Gwaltney J. Two randomised controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrobial Agents and Chemotherapy 1987;31(8):1183–7. Godfrey 1992 {published data only} Godfrey JC, Sloanne BB, Smith D, Turco JH, Mercer N, Godfrey NJ. Zinc gluconate and the common cold: a controlled clinical study. Journal of International Medical Research 1992;20(3):234–46. Kurugol 2006a {published data only} Kurugol Z, Akilli M, Bayram N, Koturoglu G. The prophylactic and therapeutic effectiveness of zinc sulphate 24Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Novick 1996 Novick SG, Godfrey JC, Godfrey NJ, Wilder HR. How does zinc modify the common cold? Clinical observations and implications regarding mechanisms of action. Medical Hypotheses 1996;46:295–302. Pasternak 1987 Pasternak CA. Virus, toxin, complement: common actions and their prevention by Ca2+ or Zn2+. Bioassays 1987;6: 14–9. Pfeiffer 1980 Pfeiffer CC, Papaioannou R, Sohler A. Effect of chronic zinc intoxication on copper levels, blood formation and polyamines. Journal of Orthomolecular Psychiatry 1980;9: 79–89. RevMan 2012 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012. Rothman 1988 Rothman KJ. Causal inference. Epidemiology Resources, Boston: Chestnut Hill 1988. Science 2012 Science M, Johnstone J, Roth DE, Guyatt G, Loeb M. Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. Canadian Medical Association Journal 2012;184(10):E551–61. Simasek 2007 Simasek M, Blandino DA. Treatment of the common cold. American Family Physician 2007;75(4):515–20. Turner 2001 Turner RB. The treatment of rhinovirus infections: progress and potential. Antiviral Research 2001;49:1–4. Zarembo 1992 Zarembo JE, Godfrey JC, Godfrey NJ. Zinc(II) in saliva: determination of concentrations produced by different formulations of zinc gluconate lozenges containing common excipients. Journal of Pharmaceutical Sciences 1992;81(2): 128–30. References to other published versions of this review Marshall 1999 Marshall IIR. Zinc for the common cold. Cochrane Database of Systematic Reviews 1999, Issue 2. [DOI: 10.1002/14651858.CD001364.pub3] Singh 2011 Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews 2011, Issue 2. [DOI: 10.1002/14651858.CD001364.pub3] ∗ Indicates the major publication for the study 27Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Al-Nakib 1987 Methods Double-blind, placebo-controlled randomised trial Participants Healthy adults 18 to 50 years Interventions Therapeutic trial: participants took 1 lozenge 2-hourly for 6 days Intervention group: zinc gluconate lozenges containing 23 mg zinc Placebo group: not stated Prophylactic trial: participants took 1 lozenge/2 waking hours for a total of 12 lozenges/ day for 4.5 days. On the second day they were challenged with HRV-2 Intervention group: zinc gluconate lozenges containing 23 mg zinc Placebo group: not stated Outcomes Severity of symptoms Mean daily nasal secretions Total tissue counts Viral shedding Biochemical and haematological parameters Trial 1: urinary zinc levels Notes Although adults were stated to be healthy, no exclusion criteria were stated Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) High risk Not described. Participants divided into groups balanced by age and sex Allocation concealment (selection bias) Unclear risk The method of concealment was not de- scribed in detail to allow a definite judge- ment Blinding (performance bias and detection bias) All outcomes Unclear risk Insufficient information to permit judge- ment of ‘low risk’ or ‘high risk’ of bias Incomplete outcome data (attrition bias) All outcomes Low risk There were no drop-outs or withdrawals Selective reporting (reporting bias) High risk 1 or more outcomes of interest in the re- view were insufficiently reported so that they could not be entered in a meta-analy- sis 28Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Al-Nakib 1987 (Continued) Other bias Unclear risk The zinc and placebo lozenges were gifted by RBS Pharma, Milan Douglas 1987 Methods Double-blind, placebo-controlled randomised trial Participants Participants in the trial were healthy adults who had in the previous year participated in a study of interferon prophylaxis against rhinovirus infection Interventions Participants took 6 to 8 lozenges/day at 2nd-hourly intervals for a minimum of 3 days and maximum of 6 days if symptoms persisted. New course commenced after 2 weeks if symptoms persisted but type of treatment may differ. Consequently 33 zinc courses and 30 placebo courses Treatment group: zinc acetate lozenges containing 10 mg zinc Placebo group: lozenges contained sodium acetate Outcomes Duration and severity of symptoms (nasal, throat or cough) Viral cultures Notes The duration of the common cold was ≤ 2 days before starting treatment for 56 of the 58 participants. 2 zinc and 5 placebo treatment courses were excluded because lozenges had not been used for ≥ 3 days and at the rate of ≥ 4 per day. The SD value was not reported and was calculated from P value. The zinc lozenges contained high amount of tartrate; as a result zinc dissociates from acetate and binds instantly to tartrate Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Used sequentially numbered bottles Allocation concealment (selection bias) Low risk Used blocked randomisation in blocks of 4. The code was broken twice (once in middle of study and then at the end of study) Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants and key study per- sonnel ensured. It was unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Plausible effect size (difference in means) amongst missing outcomes was insufficient to have a clinically relevant impact on ob- served effect size 29Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Godfrey 1992 (Continued) number and subject identification number Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants and key study per- sonnel ensured, and unlikely that the blind- ing could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Plausible effect size (difference in means) amongst missing outcomes was insufficient to have a clinically relevant impact on ob- served effect size Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified Other bias Unclear risk The study was sponsored by Godfrey Sci- ence and Design, PA and by a grant from the Rorer Pharmaceutical corporation, PA, USA Kurugol 2006a Methods Double-blind, placebo-controlled trial Participants The study was conducted at Ege University Nursery and Primary School including children aged 2 to 10 years. Children with chronic disease, immunodeficiency disorder, asthma and history of hypersensitivity were excluded Interventions Therapeutic trial: children received syrup preparation of zinc twice daily for 10 days Intervention group: zinc syrup consisted of 1.32 g zinc sulphate in 100 cm3 (15 mg of zinc in a 5 cm3 spoonful) and glycerin, glucose, sunset yellow, orange essence, nipajin Placebo group: similar to above, but lacking the zinc component Outcomes Duration and severity of cold symptoms Notes Used zinc sulfate syrup. A total of 6 (3%) subjects discontinued, 4 for non-compliance and 2 for adverse effects due to medication Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Computer random numbers generator 32Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Kurugol 2006a (Continued) Allocation concealment (selection bias) Low risk A statistical consultant programmed a com- puter-generated randomisation code and pre- pared the packages of medication Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Missing outcome data balanced in numbers across intervention groups, with similar rea- sons for missing data across groups Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified Other bias Low risk Berko Ilac Company, Turkey, supplied the ac- tive and placebo medications and digital ther- mometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report Kurugol 2006b Methods Double-blind, placebo-controlled trial Participants The study was conducted at Ege University Nursery and Primary School including children aged 2 to 10 years. Children with chronic disease, immunodeficiency disorder, asthma and history of hypersensitivity were excluded Interventions Prophylactic trial: children received syrup preparation of zinc once daily for 7 months. Intervention group: zinc syrup consisted of 1.32 g zinc sulphate in 100 cm3 (15 mg of zinc in a 5 cm3 spoonful) and glycerin, glucose, sunset yellow, orange essence, nipajin Placebo group: similar to above, but lacking the zinc component Outcomes Number of colds per study child Cold-related school absence Concomitant antibiotic use Notes Used zinc sulfate syrup. A total of 6 (3%) participants discontinued, 4 for non-compliance and 2 for adverse effects due to medication Risk of bias Bias Authors’ judgement Support for judgement 33Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Kurugol 2006b (Continued) Random sequence generation (selection bias) Low risk Computer random numbers generator Allocation concealment (selection bias) Low risk A statistical consultant programmed a com- puter-generated randomisation code and pre- pared the packages of medication Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Missing outcome data balanced in numbers across intervention groups, with similar rea- sons for missing data across groups Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified Other bias Low risk Berko Ilac Company, Turkey, supplied the ac- tive and placebo medications and digital ther- mometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report Kurugol 2007 Methods Double-blind, placebo-controlled trial Participants The study was conducted at Ege University Nursery and Primary School including children aged 1 to 10 years. The children who developed symptoms of common cold within the first 24 to 48 hours were registered in the study. Exclusion criteria were common cold symptoms for > 48 hours, immunodeficiency disorder, chronic disease, recent acute respiratory disease (diagnosed by a physician in the previous 2 weeks), zinc allergy, allergic disease or non-allergic rhinitis, positive culture for group A Streptococcus and a positive cell culture for influenza A or B viruses Interventions Participants were asked to take 1 spoonful of syrup twice a day for 10 days Treatment group: zinc syrup consisted of 1.32 g of zinc sulfate in 100 ml (15 mg of zinc in 5 ml spoonful) and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative Placebo group: identical to above, but lacking the zinc component Outcomes Duration and severity of cold symptoms 34Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Mossad 1996 Methods Double-blind, placebo-controlled trial Participants Participants were recruited from among the Cleveland Clinic staff through announce- ments in internal clinic publications and by word of mouth. They were older than 18 years of age. Inclusion required that the cold had lasted for ≤ 24 hours. Exclusion criteria were pregnancy, immune deficiency or symptoms of the common cold for > 24 hours prior to interview Interventions Participants took 1 lozenge 2-hourly for every waking hour Treatment group: zinc gluconate lozenges containing 13.3 mg zinc Placebo group: lozenges contained 5% calcium lactate Outcomes Duration and severity of cold symptoms Notes Participants were assessed for non-adherence to treatment; reasons for non-adherence were: participants had taken antibiotics, condition diagnosed by physician to be other than the common cold, participants filled in diaries from memory, or insufficient lozenges were taken (i.e. fewer than 4 per day for the first 4 days). One participant in the zinc group withdrew from the study on the first day because she could not tolerate the lozenges. Mean and SD were not reported and were estimated from the figure. The zinc lozenge contained glycine, which binds zinc tightly and therefore the free zinc ion level probably was lower than suggested by the total zinc dose Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Computer random numbers generator Allocation concealment (selection bias) Low risk A statistical consultant prepared a computer- generated randomisation code and the pack- ages of medication Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk The effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified 37Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Mossad 1996 (Continued) Other bias Low risk The study was supported by grants from the General Pediatrics Research Fund and the De- partments of Infectious Diseases and General Pediatrics of the Cleveland Clinic Foundation Petrus 1998 Methods Double-blind, placebo-controlled trial Participants Participants were recruited from the campus of the University of Texas through posted announcements. They were 18 to 54 years of age. Participants were excluded if they had a serious illnesses, organ transplants or disability (including HIV infection) Interventions Participants were instructed to use a lozenge every 1.5 hours while awake during day 0, then 1 lozenge every 2 hours while awake on following days while symptoms were present for 14 days or 6 hours after disappearance of last symptoms Treatment group: zinc acetate lozenges containing 9 mg zinc in a 2.7 g dextrose base Placebo group: lozenges contained sucrose octaacetate (0.169 mg) Outcomes Duration and severity of symptoms Notes One subject was lost to follow-up Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) High risk Not described Allocation concealment (selection bias) Unclear risk The method of concealment is not described or not described in sufficient detail to allow a definite judgement Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants and key study per- sonnel ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk The effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified 38Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Petrus 1998 (Continued) Other bias Unclear risk Funded by Weider Nutrition International, Salt Lake City, Utah Prasad 2000 Methods Double-blind, placebo-controlled trial Participants Participants were students, staff and employees at Wayne State University, Michigan, who were ≥ 18 years. Inclusion required that the cold had lasted for ≤ 24 hours. Exclusion criteria were pregnancy, underlying immunodeficiency, chronic illness, symptoms of common cold for more than 24 hours, or had previously used zinc lozenges to treat common cold Interventions Participants were asked to use 1 lozenge every 2 to 3 hours while awake for as long as they had symptoms Treatment group: zinc acetate lozenges containing 12.8 mg zinc Placebo group: lozenges contained 0.25 mg of sucrose octaacetate, 6 mg of peppermint oil, 16 mg silica gel, 3877.75 mg dextrose DC and 100 mg glycerol monostearate Outcomes Duration of symptoms Plasma levels of zinc and pro inflammatory cytokines Notes Two participants in the placebo group dropped out on day 2 Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Used randomisation code Allocation concealment (selection bias) Low risk A research consultant prepared the randomi- sation code and the packages of medication Blinding (performance bias and detection bias) All outcomes Low risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk The effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified 39Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Smith 1989 (Continued) Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified Other bias Unclear risk The study was supported by a grant from Mc- Neil Consumer Products Company Turner 2000a Methods Double-blind, placebo-controlled trial Participants Participants were recruited at 4 different study sites: IMTCI (Lenexa, KS), GFI Phar- maceutical Services (Evansville, IN), TKL Research (Paramus, NJ) and Research Across America (RAA; Dallas). They were 18 to 65 years of age Inclusion required that the cold had lasted for ≤ 1 calendar day (effectively < 36 hrs). Exclusions not described Interventions Participants took the lozenges every 2 to 3 hours (a total of 6 per day) while awake until cold symptoms resolved Treatment group: zinc gluconate lozenges containing 13.3 mg zinc Placebo group: lozenges contained tannic acid, sucrose octaacetate, quinine Outcomes Duration and severity of symptoms Notes Loss to follow-up not described. Analysis was based on intention-to-treat principle. Mean and SD were not reported and were estimated from the figure. The zinc gluconate lozenge contained glycine, which effectively binds to zinc and therefore the free zinc ion level probably was lower than suggested by the total zinc dose Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Used drug randomisation code Allocation concealment (selection bias) Unclear risk The method of concealment is not described in sufficient detail to allow a definite judgement Blinding (performance bias and detection bias) All outcomes High risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Loss to follow-up not described 42Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Turner 2000a (Continued) Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists Turner 2000b Methods Double-blind, placebo-controlled trial Participants Participants were recruited from 4 different study sites: IMTCI (Lenexa, KS), GFI Phar- maceutical Services (Evansville, IN), TKL Research (Paramus, NJ) and Research Across America (RAA; Dallas). They were 18 to 65 years of age Inclusion required that the cold had lasted for ≤ 1 calendar day (effectively < 36 hrs). Exclusions not described Interventions Participants took the lozenges every 2 to 3 hours (a total of 6 per day) while awake until cold symptoms resolved Treatment group: zinc gluconate lozenges containing 11.5 mg zinc Placebo group: lozenges contained tannic acid, sucrose octaacetate, quinine Outcomes Duration and severity of symptoms Notes Loss to follow-up not described. Analysis was based on intention-to-treat principle. Mean and SD were not reported and were estimated from the figure. The zinc gluconate lozenge contained glycine, which effectively binds to zinc and therefore the free zinc ion level probably was lower than suggested by the total zinc dose Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Used drug randomisation code Allocation concealment (selection bias) Unclear risk The method of concealment is not described in sufficient detail to allow a definite judgement Blinding (performance bias and detection bias) All outcomes High risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Loss to follow-up not described 43Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Turner 2000b (Continued) Selective reporting (reporting bias) Low risk The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-spec- ified Other bias Unclear risk Insufficient information to assess whether an important risk of bias exists Turner 2000c Methods Double-blind, placebo-controlled trial Participants Participants were recruited from 4 different study sites: IMTCI (Lenexa, KS), GFI Phar- maceutical Services (Evansville, IN), TKL Research (Paramus, NJ) and Research Across America (RAA; Dallas). They were 18 to 65 years of age Inclusion required that the cold had lasted for ≤ 1 calendar day (effectively < 36 hrs). Exclusions not described Interventions Participants took the lozenges every 2 to 3 hours (a total of 6 per day) while awake until cold symptoms resolved Treatment group: zinc gluconate lozenges containing 5 mg zinc Placebo group: lozenges contained tannic acid, sucrose octaacetate, quinine Outcomes Duration and severity of symptoms Notes Loss to follow-up not described. Analysis was based on intention-to-treat principle. Mean and SD were not reported and were estimated from the figure. The zinc gluconate lozenge contained glycine, which effectively binds to zinc and therefore the free zinc ion level probably was lower than suggested by the total zinc dose Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Used drug randomisation code Allocation concealment (selection bias) Unclear risk The method of concealment is not described in sufficient detail to allow a definite judgement Blinding (performance bias and detection bias) All outcomes High risk Blinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken Incomplete outcome data (attrition bias) All outcomes Low risk Loss to follow-up not described 44Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Weismann 1990 (Continued) Other bias Unclear risk The lozenges were manufactured and sup- plied by a firm SD: standard deviation Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Eby 1984 The trial was rated of poor methodological quality. A higher incidence of side effects and complaints in the zinc group may have reduced compliance with treatment (no information was provided on whether compliance with treatment was assessed). Intention-to-treat analyses were not conducted; analyses were only conducted on a subset of those originally enrolled in the trial. Inclusion criteria were not adequately addressed and therefore there may have been potential for selection bias to occur. In addition, no information was provided on how allocation to treatment groups was concealed, and the power of the study was not stated Eby 2006 Used both zinc gluconate nasal spray and zinc orotate lozenges simultaneously Kartasurya 2012 Studied upper respiratory tract infection as a whole, used zinc supplementation for 4 months McElroy 2003 Poor methodological quality. Not a randomised trial Potter 1993 Poor methodological quality. Not a randomised trial Veverka 2009 Poor methodological quality. Measured upper respiratory tract infection as a whole (common cold and seasonal flu) 47Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. D A T A A N D A N A L Y S E S Comparison 1. Zinc versus placebo Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Duration of cold symptoms 14 1656 Mean Difference (IV, Random, 95% CI) -1.03 [-1.72, -0.34] 2 Subgroup analysis (duration of cold symptoms) 14 5996 Mean Difference (IV, Random, 95% CI) -1.07 [-1.43, -0.71] 2.1 Dose of zinc ≥ 75 mg/day 7 620 Mean Difference (IV, Random, 95% CI) -1.97 [-3.09, -0.85] 2.2 Dose of zinc < 75 mg/day 5 722 Mean Difference (IV, Random, 95% CI) 0.13 [-0.54, 0.79] 2.3 Zinc gluconate lozenges 6 798 Mean Difference (IV, Random, 95% CI) -0.81 [-1.86, 0.25] 2.4 Zinc acetate lozenges 6 544 Mean Difference (IV, Random, 95% CI) -1.21 [-2.69, 0.28] 2.5 Zinc lozenges 12 1342 Mean Difference (IV, Random, 95% CI) -1.04 [-2.02, -0.05] 2.6 Zinc syrup 2 314 Mean Difference (IV, Random, 95% CI) -0.65 [-0.92, -0.39] 2.7 Children < 16 years age 3 561 Mean Difference (IV, Random, 95% CI) -0.62 [-0.82, -0.42] 2.8 Adults 11 1095 Mean Difference (IV, Random, 95% CI) -1.12 [-2.17, -0.06] 3 Severity of cold symptoms 5 513 Mean Difference (IV, Random, 95% CI) -1.06 [-2.36, 0.23] 4 Subgroup analysis (severity of cold symptoms) 5 513 Mean Difference (IV, Random, 95% CI) -1.06 [-2.36, 0.23] 4.1 Zinc lozenges 3 199 Mean Difference (IV, Random, 95% CI) -1.55 [-3.62, 0.52] 4.2 Zinc syrup 2 314 Mean Difference (IV, Random, 95% CI) -0.27 [-1.51, 0.97] 5 Incidence of common cold 2 1522 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.47, 0.88] Comparison 2. Zinc versus placebo Outcome or subgroup title No. of studies No. of participants Statistical method Effect size 1 Number of participants symptomatic after 3 days of treatment 3 340 Odds Ratio (M-H, Random, 95% CI) 0.81 [0.27, 2.42] 2 Number of participants symptomatic after 5 days of treatment 3 340 Odds Ratio (M-H, Random, 95% CI) 0.78 [0.32, 1.95] 3 Number of participants symptomatic after 7 days of treatment 5 476 Odds Ratio (M-H, Random, 95% CI) 0.45 [0.20, 1.00] 4 Time to resolution of cough 4 453 Mean Difference (IV, Random, 95% CI) -1.73 [-3.49, 0.03] 5 Time to resolution of nasal congestion 5 605 Mean Difference (IV, Random, 95% CI) -0.70 [-1.39, -0.01] 6 Time to resolution of nasal drainage 5 599 Mean Difference (IV, Random, 95% CI) -1.01 [-2.01, -0.01] 7 Time to resolution of sore throat 4 430 Mean Difference (IV, Fixed, 95% CI) -0.46 [-0.82, -0.09] 8 Change in cough symptom score 1 101 Mean Difference (IV, Fixed, 95% CI) -0.23 [-0.26, -0.20] 9 Change in nasal symptom score 2 314 Mean Difference (IV, Fixed, 95% CI) -0.20 [-1.34, 0.94] 48Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 School absence (days) 2 394 Mean Difference (IV, Fixed, 95% CI) -0.66 [-0.99, -0.33] 11 Antibiotic use 2 394 Odds Ratio (M-H, Fixed, 95% CI) 0.27 [0.16, 0.46] 12 Any adverse event 8 1217 Odds Ratio (M-H, Fixed, 95% CI) 1.58 [1.19, 2.09] 12.1 Lozenge formulation 6 897 Odds Ratio (M-H, Fixed, 95% CI) 2.00 [1.40, 2.86] 12.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.03 [0.64, 1.66] 13 Bad taste 12 1483 Odds Ratio (M-H, Fixed, 95% CI) 2.31 [1.71, 3.11] 13.1 Lozenges formulation 10 1163 Odds Ratio (M-H, Fixed, 95% CI) 2.66 [1.91, 3.69] 13.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.15 [0.55, 2.39] 14 Nausea 8 932 Odds Ratio (M-H, Fixed, 95% CI) 2.15 [1.44, 3.23] 14.1 Lozenges formulation 6 612 Odds Ratio (M-H, Fixed, 95% CI) 2.46 [1.56, 3.89] 14.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.24 [0.50, 3.08] 15 Constipation 7 874 Odds Ratio (M-H, Fixed, 95% CI) 1.60 [0.82, 3.10] 15.1 Lozenges formulation 5 554 Odds Ratio (M-H, Fixed, 95% CI) 2.00 [0.88, 4.55] 15.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.0 [0.31, 3.21] 16 Diarrhoea 6 764 Odds Ratio (M-H, Fixed, 95% CI) 1.89 [0.92, 3.89] 16.1 Lozenges formulation 4 444 Odds Ratio (M-H, Fixed, 95% CI) 2.09 [0.92, 4.75] 16.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.34 [0.30, 6.09] 17 Abdominal pain 6 824 Odds Ratio (M-H, Fixed, 95% CI) 1.31 [0.83, 2.07] 17.1 Lozenges formulation 4 504 Odds Ratio (M-H, Fixed, 95% CI) 1.27 [0.76, 2.11] 17.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.52 [0.53, 4.33] 18 Dry mouth 7 874 Odds Ratio (M-H, Fixed, 95% CI) 1.37 [0.95, 1.99] 18.1 Lozenges formulation 5 554 Odds Ratio (M-H, Fixed, 95% CI) 1.42 [0.95, 2.11] 18.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.13 [0.43, 3.01] 19 Mouth irritation 7 822 Odds Ratio (M-H, Fixed, 95% CI) 1.15 [0.77, 1.73] 19.1 Lozenges formulation 5 502 Odds Ratio (M-H, Fixed, 95% CI) 1.08 [0.67, 1.73] 19.2 Syrup formulation 2 320 Odds Ratio (M-H, Fixed, 95% CI) 1.40 [0.62, 3.15] 49Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (. . . Continued) Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Heterogeneity: Tau2 = 1.36; Chi2 = 24.69, df = 5 (P = 0.00016); I2 =80% Test for overall effect: Z = 1.49 (P = 0.14) 4 Zinc acetate lozenges Douglas 1987 33 12.1 (9.8) 30 7.7 (9.8) 0.5 % 4.40 [ -0.45, 9.25 ] Petrus 1998 52 4.4 (1.4) 49 5.1 (2.8) 2.2 % -0.70 [ -1.57, 0.17 ] Prasad 2000 25 4.5 (1.6) 23 8.1 (1.8) 2.1 % -3.60 [ -4.57, -2.63 ] Prasad 2008 25 4 (1.04) 25 7.12 (1.26) 2.3 % -3.12 [ -3.76, -2.48 ] Turner 2000b 68 6.89 (3.35) 71 7.55 (3.96) 2.0 % -0.66 [ -1.88, 0.56 ] Turner 2000c 72 7.9 (4.25) 71 7.55 (3.96) 1.9 % 0.35 [ -1.00, 1.70 ] Subtotal (95% CI) 275 269 10.9 % -1.21 [ -2.69, 0.28 ] Heterogeneity: Tau2 = 2.81; Chi2 = 53.84, df = 5 (P<0.00001); I2 =91% Test for overall effect: Z = 1.59 (P = 0.11) 5 Zinc lozenges Douglas 1987 33 12.1 (9.8) 30 7.7 (9.8) 0.5 % 4.40 [ -0.45, 9.25 ] Godfrey 1992 35 4.86 (2.7) 38 6.13 (2.7) 1.9 % -1.27 [ -2.51, -0.03 ] Macknin 1998 123 9.37 (4.81) 124 9.5 (4.53) 2.0 % -0.13 [ -1.30, 1.04 ] Mossad 1996 49 5.2 (2.83) 50 9.38 (5.47) 1.6 % -4.18 [ -5.89, -2.47 ] Petrus 1998 52 4.4 (1.4) 49 5.1 (2.8) 2.2 % -0.70 [ -1.57, 0.17 ] Prasad 2000 25 4.5 (1.6) 23 8.1 (1.8) 2.1 % -3.60 [ -4.57, -2.63 ] Prasad 2008 25 4 (1.04) 25 7.12 (1.26) 2.3 % -3.12 [ -3.76, -2.48 ] Smith 1989 57 7.23 (2.29) 53 7.57 (3.01) 2.1 % -0.34 [ -1.35, 0.67 ] Turner 2000a 68 7.41 (3.88) 71 7.55 (3.96) 1.9 % -0.14 [ -1.44, 1.16 ] Turner 2000b 68 6.89 (3.35) 71 7.55 (3.96) 2.0 % -0.66 [ -1.88, 0.56 ] Turner 2000c 72 7.9 (4.25) 71 7.55 (3.96) 1.9 % 0.35 [ -1.00, 1.70 ] Weismann 1990 61 7.16 (2.62) 69 6.72 (2.29) 2.2 % 0.44 [ -0.41, 1.29 ] Subtotal (95% CI) 668 674 22.6 % -1.04 [ -2.02, -0.05 ] Heterogeneity: Tau2 = 2.55; Chi2 = 103.98, df = 11 (P<0.00001); I2 =89% Test for overall effect: Z = 2.05 (P = 0.040) 6 Zinc syrup Kurugol 2006a 97 4.7 (0.8) 97 5.3 (0.7) 2.5 % -0.60 [ -0.81, -0.39 ] Kurugol 2007 60 5.5 (1.97) 60 6.5 (1.97) 2.3 % -1.00 [ -1.70, -0.30 ] Subtotal (95% CI) 157 157 4.8 % -0.65 [ -0.92, -0.39 ] Heterogeneity: Tau2 = 0.01; Chi2 = 1.13, df = 1 (P = 0.29); I2 =12% Test for overall effect: Z = 4.82 (P < 0.00001) 7 Children < 16 years age -4 -2 0 2 4 Favours zinc Favours placebo (Continued . . . ) 52Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (. . . Continued) Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Kurugol 2006a 97 4.7 (0.8) 97 5.3 (0.7) 2.5 % -0.60 [ -0.81, -0.39 ] Kurugol 2007 60 5.5 (1.97) 60 6.5 (1.97) 2.3 % -1.00 [ -1.70, -0.30 ] Macknin 1998 123 9.37 (4.81) 124 9.5 (4.53) 2.0 % -0.13 [ -1.30, 1.04 ] Subtotal (95% CI) 280 281 6.8 % -0.62 [ -0.82, -0.42 ] Heterogeneity: Tau2 = 0.0; Chi2 = 1.83, df = 2 (P = 0.40); I2 =0.0% Test for overall effect: Z = 6.07 (P < 0.00001) 8 Adults Douglas 1987 33 12.1 (9.8) 30 7.7 (9.8) 0.5 % 4.40 [ -0.45, 9.25 ] Godfrey 1992 35 4.86 (2.7) 38 6.13 (2.7) 1.9 % -1.27 [ -2.51, -0.03 ] Mossad 1996 49 5.2 (2.83) 50 9.38 (5.47) 1.6 % -4.18 [ -5.89, -2.47 ] Petrus 1998 52 4.4 (1.4) 49 5.1 (2.8) 2.2 % -0.70 [ -1.57, 0.17 ] Prasad 2000 25 4.5 (1.6) 23 8.1 (1.8) 2.1 % -3.60 [ -4.57, -2.63 ] Prasad 2008 25 4 (1.04) 25 7.12 (1.26) 2.3 % -3.12 [ -3.76, -2.48 ] Smith 1989 57 7.23 (2.29) 53 7.57 (3.01) 2.1 % -0.34 [ -1.35, 0.67 ] Turner 2000a 68 7.41 (3.88) 71 7.55 (3.96) 1.9 % -0.14 [ -1.44, 1.16 ] Turner 2000b 68 6.89 (3.35) 71 7.55 (3.96) 2.0 % -0.66 [ -1.88, 0.56 ] Turner 2000c 72 7.9 (4.25) 71 7.55 (3.96) 1.9 % 0.35 [ -1.00, 1.70 ] Weismann 1990 61 7.16 (2.62) 69 6.72 (2.29) 2.2 % 0.44 [ -0.41, 1.29 ] Subtotal (95% CI) 545 550 20.6 % -1.12 [ -2.17, -0.06 ] Heterogeneity: Tau2 = 2.67; Chi2 = 99.43, df = 10 (P<0.00001); I2 =90% Test for overall effect: Z = 2.07 (P = 0.038) Total (95% CI) 2986 3010 100.0 % -1.07 [ -1.43, -0.71 ] Heterogeneity: Tau2 = 1.34; Chi2 = 464.05, df = 51 (P<0.00001); I2 =89% Test for overall effect: Z = 5.82 (P < 0.00001) Test for subgroup differences: Chi2 = 12.55, df = 7 (P = 0.08), I2 =44% -4 -2 0 2 4 Favours zinc Favours placebo 53Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.3. Comparison 1 Zinc versus placebo, Outcome 3 Severity of cold symptoms. Review: Zinc for the common cold Comparison: 1 Zinc versus placebo Outcome: 3 Severity of cold symptoms Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Kurugol 2006a 97 0.2 (4.92) 97 0.4 (5.9) 19.6 % -0.20 [ -1.73, 1.33 ] Kurugol 2007 60 0.3 (4.64) 60 0.7 (6.97) 15.7 % -0.40 [ -2.52, 1.72 ] Petrus 1998 52 1.41 (0.29) 49 1.5 (0.28) 26.9 % -0.09 [ -0.20, 0.02 ] Prasad 2000 25 2.7 (2) 23 5.4 (1.9) 22.6 % -2.70 [ -3.80, -1.60 ] Prasad 2008 25 3.45 (5) 25 5.61 (2.5) 15.2 % -2.16 [ -4.35, 0.03 ] Total (95% CI) 259 254 100.0 % -1.06 [ -2.36, 0.23 ] Heterogeneity: Tau2 = 1.62; Chi2 = 24.69, df = 4 (P = 0.00006); I2 =84% Test for overall effect: Z = 1.61 (P = 0.11) Test for subgroup differences: Not applicable -20 -10 0 10 20 Favours zinc Favours placebo 54Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.2. Comparison 2 Zinc versus placebo, Outcome 2 Number of participants symptomatic after 5 days of treatment. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 2 Number of participants symptomatic after 5 days of treatment Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Mossad 1996 23/50 36/50 32.9 % 0.33 [ 0.14, 0.76 ] Smith 1989 45/57 36/53 32.2 % 1.77 [ 0.75, 4.18 ] Weismann 1990 40/61 48/69 34.9 % 0.83 [ 0.40, 1.74 ] Total (95% CI) 168 172 100.0 % 0.78 [ 0.32, 1.95 ] Total events: 108 (Zinc), 120 (Placebo) Heterogeneity: Tau2 = 0.48; Chi2 = 7.61, df = 2 (P = 0.02); I2 =74% Test for overall effect: Z = 0.52 (P = 0.60) Test for subgroup differences: Not applicable 0.002 0.1 1 10 500 Favours zinc Favours placebo 57Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.3. Comparison 2 Zinc versus placebo, Outcome 3 Number of participants symptomatic after 7 days of treatment. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 3 Number of participants symptomatic after 7 days of treatment Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M- H,Random,95% CI M- H,Random,95% CI Douglas 1987 19/33 12/30 18.9 % 2.04 [ 0.75, 5.56 ] Godfrey 1992 5/35 17/38 17.3 % 0.21 [ 0.07, 0.65 ] Mossad 1996 9/50 29/50 19.9 % 0.16 [ 0.06, 0.40 ] Smith 1989 24/57 29/53 21.7 % 0.60 [ 0.28, 1.28 ] Weismann 1990 31/61 48/69 22.2 % 0.45 [ 0.22, 0.93 ] Total (95% CI) 236 240 100.0 % 0.45 [ 0.20, 1.00 ] Total events: 88 (Zinc), 135 (Placebo) Heterogeneity: Tau2 = 0.60; Chi2 = 15.99, df = 4 (P = 0.003); I2 =75% Test for overall effect: Z = 1.96 (P = 0.050) Test for subgroup differences: Not applicable 0.005 0.1 1 10 200 Favours zinc Favours placebo 58Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.4. Comparison 2 Zinc versus placebo, Outcome 4 Time to resolution of cough. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 4 Time to resolution of cough Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI Kurugol 2006a 97 2.9 (1.6) 97 3.2 (2) 30.4 % -0.30 [ -0.81, 0.21 ] Macknin 1998 72 7 (8.65) 89 7.5 (7.21) 19.2 % -0.50 [ -3.00, 2.00 ] Prasad 2000 25 3.1 (2.55) 23 6.3 (3.43) 24.0 % -3.20 [ -4.92, -1.48 ] Prasad 2008 25 2.16 (1.7) 25 5.08 (2.97) 26.4 % -2.92 [ -4.26, -1.58 ] Total (95% CI) 219 234 100.0 % -1.73 [ -3.49, 0.03 ] Heterogeneity: Tau2 = 2.59; Chi2 = 20.81, df = 3 (P = 0.00012); I2 =86% Test for overall effect: Z = 1.92 (P = 0.055) Test for subgroup differences: Not applicable -50 -25 0 25 50 Favours zinc Favours placebo 59Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.7. Comparison 2 Zinc versus placebo, Outcome 7 Time to resolution of sore throat. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 7 Time to resolution of sore throat Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Kurugol 2006a 97 1.8 (1.4) 97 2.4 (1.8) 65.6 % -0.60 [ -1.05, -0.15 ] Macknin 1998 64 4.5 (2) 74 4.5 (2.15) 28.2 % 0.0 [ -0.69, 0.69 ] Prasad 2000 25 2 (1.78) 23 3 (3.18) 6.2 % -1.00 [ -2.48, 0.48 ] Prasad 2008 25 1.96 (1.83) 25 3.24 (0) Not estimable Total (95% CI) 211 219 100.0 % -0.46 [ -0.82, -0.09 ] Heterogeneity: Chi2 = 2.57, df = 2 (P = 0.28); I2 =22% Test for overall effect: Z = 2.43 (P = 0.015) Test for subgroup differences: Not applicable -4 -2 0 2 4 Favours zinc Favours placebo Analysis 2.8. Comparison 2 Zinc versus placebo, Outcome 8 Change in cough symptom score. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 8 Change in cough symptom score Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Petrus 1998 52 1.28 (0.07) 49 1.51 (0.09) 100.0 % -0.23 [ -0.26, -0.20 ] Total (95% CI) 52 49 100.0 % -0.23 [ -0.26, -0.20 ] Heterogeneity: not applicable Test for overall effect: Z = 14.28 (P < 0.00001) Test for subgroup differences: Not applicable -1 -0.5 0 0.5 1 Favours zinc Favours placebo 62Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.9. Comparison 2 Zinc versus placebo, Outcome 9 Change in nasal symptom score. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 9 Change in nasal symptom score Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Kurugol 2006a 97 0 (0) 97 0.3 (4.92) Not estimable Kurugol 2007 60 0.1 (2.32) 60 0.3 (3.87) 100.0 % -0.20 [ -1.34, 0.94 ] Total (95% CI) 157 157 100.0 % -0.20 [ -1.34, 0.94 ] Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.73) Test for subgroup differences: Not applicable -20 -10 0 10 20 Favours zinc Favours placebo 63Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.10. Comparison 2 Zinc versus placebo, Outcome 10 School absence (days). Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 10 School absence (days) Study or subgroup Zinc Placebo Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Kurugol 2006b 97 0.9 (2.1) 97 1.3 (1.9) 34.7 % -0.40 [ -0.96, 0.16 ] Vakili 2009 100 0.55 (1.09) 100 1.35 (1.79) 65.3 % -0.80 [ -1.21, -0.39 ] Total (95% CI) 197 197 100.0 % -0.66 [ -0.99, -0.33 ] Heterogeneity: Chi2 = 1.26, df = 1 (P = 0.26); I2 =21% Test for overall effect: Z = 3.90 (P = 0.000095) Test for subgroup differences: Not applicable -10 -5 0 5 10 Favours zinc Favours placebo Analysis 2.11. Comparison 2 Zinc versus placebo, Outcome 11 Antibiotic use. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 11 Antibiotic use Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Kurugol 2006b 5/97 18/97 31.2 % 0.24 [ 0.08, 0.67 ] Vakili 2009 20/100 47/100 68.8 % 0.28 [ 0.15, 0.53 ] Total (95% CI) 197 197 100.0 % 0.27 [ 0.16, 0.46 ] Total events: 25 (Zinc), 65 (Placebo) Heterogeneity: Chi2 = 0.07, df = 1 (P = 0.79); I2 =0.0% Test for overall effect: Z = 4.80 (P < 0.00001) Test for subgroup differences: Not applicable 0.002 0.1 1 10 500 Favours zinc Favours placebo 64Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.14. Comparison 2 Zinc versus placebo, Outcome 14 Nausea. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 14 Nausea Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 1 Lozenges formulation Douglas 1987 6/30 0/28 1.2 % 15.12 [ 0.81, 282.27 ] Macknin 1998 36/123 20/124 42.6 % 2.15 [ 1.16, 3.99 ] Mossad 1996 10/49 2/50 4.8 % 6.15 [ 1.27, 29.75 ] Prasad 2000 0/25 1/23 4.6 % 0.29 [ 0.01, 7.59 ] Prasad 2008 3/25 1/25 2.7 % 3.27 [ 0.32, 33.84 ] Smith 1989 14/57 8/53 18.9 % 1.83 [ 0.70, 4.80 ] Subtotal (95% CI) 309 303 74.7 % 2.46 [ 1.56, 3.89 ] Total events: 69 (Zinc), 32 (Placebo) Heterogeneity: Chi2 = 5.02, df = 5 (P = 0.41); I2 =0% Test for overall effect: Z = 3.88 (P = 0.00010) 2 Syrup formulation Kurugol 2006a 6/100 5/100 14.2 % 1.21 [ 0.36, 4.11 ] Kurugol 2007 5/60 4/60 11.1 % 1.27 [ 0.32, 4.99 ] Subtotal (95% CI) 160 160 25.3 % 1.24 [ 0.50, 3.08 ] Total events: 11 (Zinc), 9 (Placebo) Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.96); I2 =0.0% Test for overall effect: Z = 0.46 (P = 0.64) Total (95% CI) 469 463 100.0 % 2.15 [ 1.44, 3.23 ] Total events: 80 (Zinc), 41 (Placebo) Heterogeneity: Chi2 = 6.50, df = 7 (P = 0.48); I2 =0.0% Test for overall effect: Z = 3.72 (P = 0.00020) Test for subgroup differences: Chi2 = 1.75, df = 1 (P = 0.19), I2 =43% 0.002 0.1 1 10 500 Favours zinc Favours placebo 67Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.15. Comparison 2 Zinc versus placebo, Outcome 15 Constipation. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 15 Constipation Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 1 Lozenges formulation Macknin 1998 2/123 2/124 14.0 % 1.01 [ 0.14, 7.27 ] Mossad 1996 1/49 0/50 3.4 % 3.12 [ 0.12, 78.55 ] Prasad 2000 6/25 0/23 2.8 % 15.67 [ 0.83, 295.88 ] Prasad 2008 2/25 1/25 6.6 % 2.09 [ 0.18, 24.61 ] Smith 1989 6/57 5/53 33.0 % 1.13 [ 0.32, 3.94 ] Subtotal (95% CI) 279 275 59.8 % 2.00 [ 0.88, 4.55 ] Total events: 17 (Zinc), 8 (Placebo) Heterogeneity: Chi2 = 3.22, df = 4 (P = 0.52); I2 =0.0% Test for overall effect: Z = 1.65 (P = 0.10) 2 Syrup formulation Kurugol 2006a 1/100 2/100 14.1 % 0.49 [ 0.04, 5.55 ] Kurugol 2007 5/60 4/60 26.1 % 1.27 [ 0.32, 4.99 ] Subtotal (95% CI) 160 160 40.2 % 1.00 [ 0.31, 3.21 ] Total events: 6 (Zinc), 6 (Placebo) Heterogeneity: Chi2 = 0.45, df = 1 (P = 0.50); I2 =0.0% Test for overall effect: Z = 0.0 (P = 1.0) Total (95% CI) 439 435 100.0 % 1.60 [ 0.82, 3.10 ] Total events: 23 (Zinc), 14 (Placebo) Heterogeneity: Chi2 = 4.04, df = 6 (P = 0.67); I2 =0.0% Test for overall effect: Z = 1.38 (P = 0.17) Test for subgroup differences: Chi2 = 0.90, df = 1 (P = 0.34), I2 =0.0% 0.002 0.1 1 10 500 Favours zinc Favours placebo 68Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.16. Comparison 2 Zinc versus placebo, Outcome 16 Diarrhoea. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 16 Diarrhoea Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 1 Lozenges formulation Macknin 1998 13/123 5/124 39.8 % 2.81 [ 0.97, 8.15 ] Mossad 1996 2/49 2/50 17.0 % 1.02 [ 0.14, 7.55 ] Prasad 2000 2/25 1/23 8.6 % 1.91 [ 0.16, 22.63 ] Prasad 2008 1/25 1/25 8.6 % 1.00 [ 0.06, 16.93 ] Subtotal (95% CI) 222 222 73.9 % 2.09 [ 0.92, 4.75 ] Total events: 18 (Zinc), 9 (Placebo) Heterogeneity: Chi2 = 1.06, df = 3 (P = 0.79); I2 =0.0% Test for overall effect: Z = 1.75 (P = 0.080) 2 Syrup formulation Kurugol 2006a 2/100 2/100 17.5 % 1.00 [ 0.14, 7.24 ] Kurugol 2007 2/60 1/60 8.6 % 2.03 [ 0.18, 23.06 ] Subtotal (95% CI) 160 160 26.1 % 1.34 [ 0.30, 6.09 ] Total events: 4 (Zinc), 3 (Placebo) Heterogeneity: Chi2 = 0.20, df = 1 (P = 0.66); I2 =0.0% Test for overall effect: Z = 0.38 (P = 0.70) Total (95% CI) 382 382 100.0 % 1.89 [ 0.92, 3.89 ] Total events: 22 (Zinc), 12 (Placebo) Heterogeneity: Chi2 = 1.50, df = 5 (P = 0.91); I2 =0.0% Test for overall effect: Z = 1.74 (P = 0.083) Test for subgroup differences: Chi2 = 0.25, df = 1 (P = 0.62), I2 =0.0% 0.002 0.1 1 10 500 Favours zinc Favours placebo 69Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.19. Comparison 2 Zinc versus placebo, Outcome 19 Mouth irritation. Review: Zinc for the common cold Comparison: 2 Zinc versus placebo Outcome: 19 Mouth irritation Study or subgroup Zinc Placebo Odds Ratio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 1 Lozenges formulation Douglas 1987 4/30 4/28 8.4 % 0.92 [ 0.21, 4.11 ] Macknin 1998 16/123 20/124 40.5 % 0.78 [ 0.38, 1.58 ] Mossad 1996 12/49 10/50 17.5 % 1.30 [ 0.50, 3.36 ] Prasad 2000 10/25 4/23 5.8 % 3.17 [ 0.83, 12.13 ] Prasad 2008 1/25 2/25 4.5 % 0.48 [ 0.04, 5.65 ] Subtotal (95% CI) 252 250 76.7 % 1.08 [ 0.67, 1.73 ] Total events: 43 (Zinc), 40 (Placebo) Heterogeneity: Chi2 = 3.89, df = 4 (P = 0.42); I2 =0.0% Test for overall effect: Z = 0.30 (P = 0.76) 2 Syrup formulation Kurugol 2006a 8/100 7/100 15.1 % 1.16 [ 0.40, 3.32 ] Kurugol 2007 7/60 4/60 8.3 % 1.85 [ 0.51, 6.68 ] Subtotal (95% CI) 160 160 23.3 % 1.40 [ 0.62, 3.15 ] Total events: 15 (Zinc), 11 (Placebo) Heterogeneity: Chi2 = 0.31, df = 1 (P = 0.58); I2 =0.0% Test for overall effect: Z = 0.82 (P = 0.41) Total (95% CI) 412 410 100.0 % 1.15 [ 0.77, 1.73 ] Total events: 58 (Zinc), 51 (Placebo) Heterogeneity: Chi2 = 4.51, df = 6 (P = 0.61); I2 =0.0% Test for overall effect: Z = 0.68 (P = 0.50) Test for subgroup differences: Chi2 = 0.30, df = 1 (P = 0.58), I2 =0.0% 0.002 0.1 1 10 500 Favours zinc Favours placebo 72Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. A P P E N D I C E S Appendix 1. Details of June 2012 search update We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 6, part of The Cochrane Library, www.thecochranelibrary.com (accessed 18 June 2012), which contains the Acute Respiratory Infections Group’s Specialised Register, MEDLINE (April 2010 to June week 1, 2012), EMBASE (1974 to June 2012), CINAHL (1981 to June 2012), Web of Science (1985 to June 2012) and LILACS (1982 to June 2012). We used the following search strategy to search CENTRAL and MEDLINE. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). We adapted the search strategy to search EMBASE, CINAHL, Web of Science and LILACS (see search strategies below). MEDLINE (OVID) 1 Common Cold/ (3280) 2 common cold*.tw. (2476) 3 Rhinovirus/ (2615) 4 rhinovir*.tw. (3057) 5 Rhinitis/ (7817) 6 rhinit*.tw. (17002) 7 coryza.tw. (355) 8 (respiratory infection* adj3 upper).tw. (1799) 9 (infection* adj3 upper respiratory).tw. (5524) 10 (urti or uri).tw. (890) 11 or/1-10 (33957) 12 Zinc/ (45397) 13 (zinc or zn).tw. (87052) 14 exp Zinc Compounds/ (6713) 15 Micronutrients/ (2677) 16 micronutrient*.tw. (6384) 17 Trace Elements/ (11474) 18 (trace adj2 (mineral* or element*)).tw. (10816) 19 or/12-18 (114540) 20 11 and 19 (237) EMBASE.com 24. #20 AND #23 23. #21 OR #22 22. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR ’cross-over’:ab,ti OR volunteer*: ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((doubl* OR singl*) NEAR/2 (blind* OR mask)):ab,ti 21. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp 20. #13 AND #19 19. #14 OR #15 OR #16 OR #17 18. ’trace element’:ab,ti OR ’trace elements’:ab,ti OR ’trace mineral’:ab,ti OR ’trace minerals’:ab,ti 17. micronutrient*:ab,ti 16. ’trace element’/de 15. zinc:ab,ti OR zn:ab,ti 14. ’zinc’/exp 13. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 12. urti:ab,ti OR uri:ab,ti 11. ’upper respiratory tract infection’:ab,ti OR ’upper respiratory tract infections’:ab,ti OR ’upper respiratory infection’:ab,ti OR ’upper respiratory infections’:ab,ti 73Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10. ’upper respiratory tract infection’/de 9. rhinit*:ab,ti 8. ’rhinitis’/de 7. coryza:ab,ti 6. rhinovir*:ab,ti 5. ’rhinovirus infection’/de 4. ’rhinovirus’/exp 3. ’common cold symptom’/exp 2. ’common cold’:ab,ti OR ’common colds’:ab,ti 1. ’common cold’/exp CINAHL (EBSCO) S29 S19 and S28 S28 S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 S27 (MH “Quantitative Studies”) S26 TI placebo* OR AB placebo* S25 (MH “Placebos”) S24 TI random* OR AB random* S23 TI ((singl* or doubl* or tripl* or trebl*) W1 (mask* or blind*)) OR AB ((singl* or doubl* or tripl* or trebl*) W1 (mask* or blind*)) S22 TI clinic* trial* OR AB clinic* trial* S21 PT clinical trial S20 (MH “Clinical Trials+”) S19 S10 and S18 S18 S11 or S12 or S13 or S14 or S15 or S16 or S17 S17 TI (trace W2 (mineral* or element*)) OR AB (trace W2 (mineral* or element*)) S16 (MH “Trace Elements”) S15 TI micronutrient* OR AB micronutrient* S14 (MH “Micronutrients”) S13 TI (zinc or zn) OR AB (zinc or zn) S12 (MH “Zinc Compounds+”) S11 (MH “Zinc”) S10 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 S9 TI (urti or uri) OR AB (urti or uri) S8 TI infection* N3 upper respiratory OR AB infection* N3 upper respiratory S7 TI respiratory infection* N3 upper OR AB respiratory infection* N3 upper S6 TI coryza OR AB coryza S5 TI rhinit* OR AB rhinit* S4 (MH “Rhinitis”) S3 TI rhinovir* OR AB rhinovir* S2 TI common cold* OR AB common cold* S1 (MH “Common Cold”) Web of Science (Thomson Reuters) 74Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. F E E D B A C K Zinc for the common cold feedback: the Eby 1984 report, flavor and flavor masking issues, and what is next, 23 February 2011 Summary My congratulations are extended to Meenu Singh and Rashmi R Das for a very comprehensive review of the zinc for common cold literature. However, some comments are needed concerning the Eby et al. 1984 report, flavor issues and where we need to go next. Concerning the original 1984 Eby, Davis and Halcomb article Our original 1984 article[1] started this line of inquiry by showing that it was possible to shorten common colds by 7 days (P = 0.0005) with 23 mg zinc (zinc gluconate) lozenges when taken each two wakeful hours. These lozenges (unflavored and unsweetened dietary supplement tablets) lasted about 30 minutes in the mouth which provided sufficient time for local absorption into oral tissues. This protocol was developed after observing that 50 mg zinc (zinc gluconate) tablets slowly dissolved in the mouth of a 3-year old child with acute lymphocytic leukemia (T-cell) resulted in her severe common colds disappearing within 2 hours without further treatment and many similar informal observations in the general community. Our report has drawn some criticism, mainly since the taste of the zinc gluconate lozenges was modestly objectionable resulting in more dropouts in the zinc-treated group than in the placebo-treated group. Bias would occur if zinc-treated subjects who received little or no benefit selectively dropped out or failed to return reports. We were concerned about this potential for bias, and to protect our results we estimated the maximum effect of such bias by assuming that all dropouts and all non-reporters in both zinc and placebo treatment groups received no benefit and responded as if they were on placebo. The effect of zinc in that analysis remained substantial and statistically strong (P = 0.007), and this potential bias was shown to be irrelevant. These modifications to our main results were published in our Discussion section on page 23 right-hand column, but they have been ignored in reviews by others, thus adversely biasing results of several critical reviews. Therefore, I am disappointed that this error was also committed by Singh and Das. Flavor and flavor-masking issues Concern about blinding evolved from concern over “bad taste” of zinc lozenges. There is much difference in the taste of zinc lozenges, which should be considered in evaluating bias. Zinc gluconate in tablets with no other soluble ingredients1 are moderately objectionable tasting, but tolerable, to most people. Zinc gluconate releases 72% of its zinc as ionic zinc at physiologic pH 7.4.[2] Zinc gluconate can be sweetened without bitterness using a fructose tablet base as was done in the Al-Nakib trial at the Great Britain Common Cold Unit.[3] However, mixing zinc gluconate with any other sweetener, especially sucrose and/or dextrose, results in products that age within 30 days to be as bitter as the bitterest substance known, sucrose octaacetate. This unexpected and adverse effect caused researchers to search for alternatives to zinc gluconate and for ways to flavor-mask zinc gluconate. Extreme bitterness likely affected only the results of Weisman et al., although they compensated by using very small amounts of zinc.[4] Although pure zinc acetate, which releases 100% ionic zinc at physiologic pH 7.4,2 tastes vastly more vile than pure zinc gluconate, it is easily flavor-masked by a variety of sweeteners in either hard-candy compositions such as the lozenges tested by Prasad et al.[5] or compressed tablets as tested by Prasad et al.[6] and Petrus et al.[7] These zinc acetate lozenges did not contain flavor-masking additives. Zinc acetate tastes and works best when present in a 1:100 ratio with dextrose in very highly compressed tablets which last about 30 minutes when being dissolved in the mouth. One failure occurred in effervescent lozenges containing zinc acetate which were flavor- masked with tartaric acid and sodium bicarbonate, resulting in elimination of ionic zinc.[8],[9] Citric acid was used to flavor-mask the objectionable taste of zinc gluconate in a corn syrup and sucrose hard candy lozenge.[10] Citric acid has a high affinity for ionic zinc and no zinc ions were available for absorption into oral tissues, resulting in clinical failure.2 Due to its pleasant taste, this formula is commonly used in commercial zinc lozenges in the United States resulting in no effect against common colds other than nutritional support. Glycine was used to flavor-mask zinc gluconate in several clinical trials, with two[11],[12] showing efficacy and one[13] showing lack of efficacy. Variability in results may have been caused by glycine since it eliminates about one half (or more) of the ionic zinc from lozenges.2 NOTE: This formula does not release “over 90% ionic zinc” at physiologic pH 7.4 as portrayed by Sing and Das, but it does release that amount at pH 5.0, a nonsense pH. Availability of ionic zinc is dependent upon a number of variables including pH, concentration, temperature and compound being tested, and such is a subject of extensive research by solution equilibrium inorganic chemists .2 Consequently, to say that effective zinc lozenges have an objectionable taste that can bias clinical trials is not necessarily factual. The worst possible taste and most bias in effective zinc lozenges results from zinc gluconate in a non-fructose carbohydrate hard candy or 77Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. tablet base, which was found only in the Weisman trial.4 Zinc gluconate in a non-soluble tablet base is about 1/10th as objectionable,1 while zinc gluconate in a fructose tablet base,3 zinc gluconate-glycine11,12,13 and zinc acetate5,6,7 in a 1:100 dextrose tablet base are each commercially acceptable in taste. However, zinc acetate lozenges are potentially the most effective, use the least zinc, and are the best tasting. Zinc acetate lozenges also had the least potential for bias due to their pleasant taste, although they had an astringent mouth- feel demonstrating release of zinc ions. A perfect placebo would have been astringent in mouth-feel, perhaps like tannin. Pursuit of a pleasant tasting and effective zinc lozenge has led to both clinical successes and failures, and the large variety of formulations has greatly complicated the analytical picture. What is next? As the researcher that originally discovered the effect of ionic zinc from throat lozenges on the duration of common colds, I am very concerned that the statement “zinc is good for colds” released on nearly every U.S. national TV news program, radio station and newspaper (and perhaps also in Europe, Australia and elsewhere) due to loose journalistic interpretation of the Singh and Das report. It is far too broad and too simplistic to be accurate, and it will likely lead to OTC products that will not have the features necessary to shorten colds more than a day, thus 26 years of zinc lozenge research could be lost and perhaps not regained for decades or a century. These features were previously described in my 2009 review.2 That review showed dose-response linearity of lozenges by their ionic zinc content on the duration of colds. It showed that reductions in the mean (P=0.001) and median (P=0.004) durations of common colds were statistically significant and meaningful. It also showed that the effects of a compressed dextrose tablet containing 18 mg of zinc (zinc acetate dyhydrate - 60 mg), glycerol monostearate as a tablet lubricant and peppermint oil on silica gel, which happens to be a 2X homeopathicZincum aceticum formula, is expected to shorten common colds by 7 days. These lozenges released the same amount of ionic zinc as did our 23 mg zinc gluconate lozenges tested in 1984.1 They are 1.9 cm (¾ inch) diameter and 1.27 cm (1/2 inch) thick tablets which are best produced on heavy production machines like a Stokes 328-2 tablet press. Magnesium stearate was not used as a lubricant due to concerns about concentrated magnesium greatly stimulating rhinovirus replication.[14] These zinc acetate lozenges are pleasant tasting and taste like peppermint candy. If these tablets are compressed to a sufficient hardness, they will dissolve in the mouth in about 30 minutes. Fick’s laws of membrane permeability show that the amount of a solute absorbed across a membrane is time and concentration dependent. Thirty minutes is a reasonable time for oral dissolution. Also, the dextrose- based formula does not excessively promote saliva production. I suggest that it is now time to focus on this basic formulation and go forward with research on it. I see no necessity to focus on zinc compounds that do not release 100% of their zinc as ionic zinc, or on products that dissolve too fast for significant oral absorption, or on products that contain too little ionic zinc to be effective. From the time of contact with the oral mucosa aspects of Fick’s laws, the use of syrups or orally ingested tablets to treat common colds are not advised if large reductions in their duration are desired. Perhaps there is also a requirement to consider how ionic zinc works in shortening colds and the work of Merluzzi et al. in showing that ionic zinc, but not bound zinc, inhibits the replication of rhinoviruses should be considered vital,[15] along with the extensive pioneering work of Korant and Butterworth in showing the inhibitor effects of ionic zinc on rhinoviral replication.[16],[17],[18],[19],[20],[21],[22],[23] These articles should give support to the notion that the main effect of ionic zinc in treating common colds is by rhinovirus replication inhibition. Although I cannot see into the future, I have proposed here what I believe to be the most likely route to successful treatment of common colds, and I hope that new zinc lozenge researchers will follow my advice. If they do follow my advice, they should be able to demonstrate in a coordinated manner the massive benefits of zinc in treating colds in just a few years, rather than in the decades or centuries that I expect from future distortions of the literature if researchers continue to test faulty products and publish those results. Provided with good results, manufactures can follow through with products that will shorten colds by a week in the general public. Then, and only then, can we say that there is a cure for the common cold! [1] Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother. 1984;25:20-4. [2] Eby GA. Zinc lozenges as cure for the common cold--a review and hypothesis. Med Hypotheses. 2010;74:482-92. [3] Al-Nakib W, Higgins PG, Barrow I, Batstone G, Tyrrell DA. Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges. J Antimicrob Chemother. 1987;20:893-901. [4] Weismann K, Jakobsen JP, Weismann JE, Hammer UM, Nyholm SM, Hansen B, Lomholt KE, Schmidt K. Zinc gluconate lozenges for common cold. A double-blind clinical trial. Dan Med Bull. 1990;37:279-81. [5] Prasad AS, Beck FW, Bao B, Snell D, Fitzgerald JT. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate. J Infect Dis. 2008;197:795-802. [6] Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2000;133:245-52. 78Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [7] Petrus, EJ, Lawson KA, Bucci LR, Blum K. Randomized, Double-Masked, Placebo-Controlled, Clinical Study of the Effectiveness of Zinc Acetate Lozenges on Common Cold Symptoms in Allergy-Tested Subjects. Current Therapeutic Research. 1998;59:595 - 607. [8] Douglas RM, Miles HB, Moore BW. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrobial Agents and Chemotherapy. 1987;31:1263-1265.| [9] Eby GA. Chapter 4.C.2. Handbook for Curing the Common Cold: The Zinc Lozenge Story. George Eby Research. Austin. 1994. Accessed February 22, 2011. http://web.archive.org/web/20080622211606/http://george-eby-research.com/html/handbook- for-curing-the-common-cold.html [10] Farr BM, Conner EM, Betts RF, Oleske J, Minnefor A, Gwaltney JM Jr. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrob Agents Chemother. 1987;31:1183-7. [11] Godfrey JC, Conant Sloane B, Smith DS, Turco JH, Mercer N, Godfrey NJ. Zinc gluconate and the common cold: a controlled clinical study. J Int Med Res. 1992;20:234-46. [12] Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. 1996;125:81-8. [13] Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E. Zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial. JAMA. 1998;279:1962-7. [14] Fiala M, Kenny GE. Effect of magnesium on replication of rhinovirus HGP. J Virol 1967;1:489-93. [15] Merluzzi VJ, Cipriano D, McNeil D, Fuchs V, Supeau C, Rosenthal AS, Skiles JW. Evaluation of zinc complexes on the replication of rhinovirus 2 in vitro. Res Commun Chem Pathol Pharmacol. 1989;66:425-40. [16] Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage: interaction of zinc with capsid polypeptides. J Virol 1976;18:298-306. [17] Korant BD, Kaurer JC, Butterworth BE. Zinc ions inhibit replication of rhinoviruses. Nature 1974;248:588-90. [18] Butterworth BE, Grunert RR, Korant BD, et al. Replication of rhinoviruses. Arch Virol 1976;51:169-89. [19] Korant BD, Butterworth BE. Inhibition by zinc of rhinovirus protein cleavage. Interaction of zinc with capsid polypeptides. Chem Abstr 1976;85:76. Abs. 85:814y. [20] Korant BD. Role of cellular and viral proteases in the processing of picornavirus proteins. In: Perez-Bercoff R, editor. The molecular biology of picornaviruses. New York: Plenum Publishing; 1979. [21] Korant BD. Inhibition of viral protein cleavage. In: Gauri KK, editor. Design of inhibitors of viral functions. New York: Academic Press; 1979. [22] Butterworth BE, Korant BD. Characterization of the large picornaviral polypeptides produced in the presence of zinc ion. J Virol 1974;14:282-91. [23] Korant BD, Kauer JC, Butterworth BE. Molecular basis of zinc as a viral inhibitor. In: Risby TH, editor. Ultratrace metal analysis in biological sciences and environment. Washington, DC: American Chemical Society; 1979. Reply We thank Dr Eby for his comment on the review as well as giving his expert opinion on the future direction of zinc cold research. Addressing the issue of bias that has occurred in their trial (which has also been highlighted in many other reviews), we want to point out that, though the author (Eby et al) have discussed about the bias resulting from increase drop out in their study in the designated paragraph described above, it should be noted that there are many drawbacks in their trial that make the quality score of a trial poor (please refer to the Cochrane handbook on bias before giving good score to a randomized clinical trial and thus qualifying them for inclusion in a review). Regarding Dr Eby’s description of how zinc acts in the treatment of common cold, it is very true that it is the ionic zinc that plays major role and we hope that authors of future trials will take these issues into account before any meaningful conclusion can be drawn from a particular trial (we have also highlighted these facts in the present review). However, this mechanism might not play important role in the preventive act of zinc for the common cold. But, as zinc has been found in clinical trials to have preventive role for the common cold (zinc also has role in prevention of lower respiratory tract infection/pneumonia, found in a recent Cochrane review), other mechanisms might play role, including enhancement of innate as well as acquired immunity and correction of underlying zinc deficiency. Only future research in this area can answer these questions. Contributors George Eby 79Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. problems in the zinc common cold research. But in the next updated version, we will add the funnel plot. Regarding the application of random and/or fixed model effect in the meta-analysis, they have their inherent problems. Last concern regarding inclusion of MD instead of SMD, we have replied it below [actually, the MD for the duration of cold is -1.48 (around 2 days)]. Contributors Yours sincerely, Jaime L Peters, Santiago G Moreno, Bob Phillips, Alex J Sutton. Comment from Christopher Cates, 7 March 2011 Summary Dear Sir, I have not personally started taking zinc tablets for the common cold, as I do not think the average answer tells me enough to justify a change in practice (too much heterogeneity and a very wide predictive interval [-4.2 to 1.2 days when analyzed as mean difference]. See method in: Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ. 2011;342:d549). Prasad seems to me to be measuring something different to the other studies, as the mean difference of 3 days in these studies is incompatible with all the other study results? It would be easier for readers to understand these results if they were presented as a mean difference in days (rather than SMD). Surely the overall average result is of limited usefulness when there is such diversity between the study results? Yours faithfully. Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback. Reply The mean difference (in days) for the duration of cold is -1.48 (around 2 days). We agree with the authors regarding the heterogeneity of results, as a result of which no recommendation was possible about zinc for the common cold (already described in conclusion). Contributors Chris Cates MA FRCGP Comment from Catherine McIlwain, 14 March 2011 Summary I’d like to request that one line of text (“Zinc inhibits rhinoviral replication”) in the plain language summary be restated in simpler terms. That phrasing resulted in quite a few comments from consumers who don’t understand virus replication. If you are amenable to a change, I would recommend using the word ‘virus’ instead of ‘rhinoviral’ throughout the plain language summary. In addition, would it be acceptable to change ‘rhinoviral replication’ to ‘the spread of the virus’ only in the plain language summary, of course. Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback. 82Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Reply No. replication and spread of virus does not mean necessarily the same thing. But we can say it as follows: zinc inhibits replication of common cold virus. Contributors Catherine McIlwain The zinc for the common cold review by Singh and Das has a number of problems which should be considered when the review is next time updated, 5 September 2011 Summary 1) Search of the studies: Eby and Halcomb (2006) reported a randomized double-blind placebo-controlled trial on zinc for the common cold [1], which is missing from the review. The trial is included in MEDLINE (PMID: 16454145) and Singh and Das should have found it and listed among the trials requiring an assessment. 2) Extraction of data: Singh and Das describe that “The lead review author (MS) entered data directly into Review Manager. An independent coder verified accuracy of data entry”. However, looking at their Analysis 1.1 led me to wonder how can they claim that the findings of the Petrus (1998) trial were non-significant (the 95% CI covering the “no effect”), given that Petrus (1998 p. 600) wrote that “t-test showed that the mean duration of all symptoms was significantly lower in the zinc group (3.8±0.2 days) than in the placebo group (5.1±0.4 days)(P=0.008)”. In their Analysis 1.1, Singh and Das give the mean duration of colds in the zinc group as 4.4 days, and not as the 3.8 days reported by Petrus (above). The value of 4.4 days is given in the Petrus (1998) Table II as the overall mean duration of colds, i.e. the mean for all zinc and placebo participants combined, but Table II also gives the 3.8 days for the duration of colds in the zinc group. In their paper, Petrus (1998) gives the accuracy of the mean as the SE (standard error), whereas the Review Manager needs the SD (standard deviation). The SE values reported by Petrus (1998) are highly inaccurate (above), yet Singh and Das calculated the corresponding SD estimates from them. To get the accurate Petrus (1998) trial results, I contacted the statistician of the group and got their results: 3.797 (SD 1.630) days in the zinc group and 5.106 (SD 2.955) in the placebo group (Ken Lawson, email 4 Mar 2009). The Petrus (1998) values in Analysis 1.1 should be replaced with these correct and accurate values. 3) The characteristics of included studies table: In the Characteristics of included studies table, Singh and Das write about the Al-Nakib (1987) trial that there was “unclear risk” for the item “incomplete outcome data addressed?”. However, Singh and Das write that “there were no drop-outs or withdrawals”. Lack of drop-outs does not justify their judgment (“unclear risk”). Furthermore, Singh and Das state that in the Al-Nakib trial there is “high risk” for the item “free of selective reporting?”. The statement that there is “high risk” calls for justification, whereas none is given. Furthermore, Singh and Das list six outcomes for the Al-Nakib (1987) trial, yet only one of them is relevant to the review: “the severity of symptoms”. However, I cannot see this outcome in any of their Analysis tables. The outcome section of the included studies table should list only those outcomes that are used in the review. Furthermore, it would help the reader if the included studies table describes in which Analysis the values of the outcomes are presented. Singh and Das state that in the Smith (1987) trial there is “low risk” for the item “incomplete outcome data addressed?”. Smith started with 176 participants and reported the results for only 110 participants, which means that they reported data for only 62% of the initial participants. In their Methods section, Singh and Das write that “we considered that incomplete outcome data had been adequately addressed if 85% or more of the participants were included in the analysis, or if less than 85% were included but adequate steps were taken to ensure or demonstrate that this did not bias the results.” In their included studies table, Singh and Das do not describe why the analysis of 62% of initial participants is acceptable for the Smith (1987) trial although they give the limit of 85% in their Methods. Stating that the Smith (1987) trial has “low risk” with the 38% drop-out rate, and the Al-Nakib (1987) trial has “unclear risk” with no drop-outs (above) is puzzling. Singh and Das use an inclusion criterion “randomized controlled trials”. Weismann (1990) did not report the method of allocation in their trial report. Nevertheless, Singh and Das describe in their included studies table the Weismann (1990) trial: “Methods: randomized trial”. Since their report did not describe the method of allocation, I contacted Kaare Weismann, who wrote to me “It was a consequetive allocated study with the same number of patient in the two groups” (email 2 Jul 2010). Thus, the Weismann (1990) trial was not randomized. 83Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Given their inclusion criteria, Singh and Das should exclude the Weismann trial or they should re-write the inclusion criteria so that they also include pseudo-randomized trials which have used, for example, alternative allocation. Furthermore, Singh and Das state that there is “unclear risk” for the item “allocation concealment?” in the Weismann (1990) trial, even though the trial was double blind. The term double-blind means that both the patients and researchers are unaware of the type of treatment until the trial is concluded. Consequently, neither of them can know to which group a patient had been allocated. Thus, double-blind means that there must have been allocation concealment. Otherwise the patients and researchers could not remain blind after randomization. This same error is seen in the description of the Al-Nakib (1987) and Petrus (1998) trials, which also were double-blind trials. As a consequence of this error, Figure 1 gives an impression that several studies were methodologically less satisfactory than they actually were. More details of the trials should be given in the included studies table. For example, in their “implications for practice”, Singh and Das state that “We could not find any trials conducted in low-income countries, so our results cannot be applied to people living in low-income countries.” However, three trials by Kurugol (2006a, 2006b, 2007) were carried out in Turkey, and one trial by Vakili (2009) was carried out in Iran. These are low-income countries. According to World Bank statistics, the GDP per capita in Turkey and Iran is 80% and 90% lower than in Germany, as an example. Thus, the above statement is false although there are countries which are much poorer than Turkey and Iran. To help the reader to understand the contexts of the trials, it would be useful to describe the country and the settings of the trials. Such information affects the generalization of the findings. Studies in Turkey and Iran cannot be directly extrapolated, for example, to the western countries. 4) The characteristics of excluded studies table: In the Characteristics of excluded studies table, Singh and Das comment on the Eby (1984) trial: “Intention-to-treat analyses were not conducted; analyses were only conducted on a subset of those originally enrolled in the trial.” However, this is also true for the Smith (1987) trial, which included only 62% of the initial participants in the analysis (above). Eby (1984 p. 20-21) described: “Of 146 original volunteers, 120 subjects returned reports. Initially, to use as much of the data as possible, we analyzed the 80 complete reports from 108 subjects who had been ill for 10 days or less at the start of treatment. ... this report is restricted to those 65 subjects who reported being ill for 3 days or less before starting the experiment.” Singh and Das use an inclusion criterion “interventions commenced within three days of participants developing common cold symptoms”. Given such a criterion, Eby’s post-randomization restriction to 65 subjects who were ill for 3 days or less before the treatment started is relevant data. In any case, Singh and Das should treat Eby (1984) and Smith (1987) trials consistently, so that both are included or excluded on the basis of the high rate of participants not included in the analysis. Singh and Das further criticise the Eby (1984) trial: “The trial relied on subjective assessment of symptoms by subjects.” However, this applies to essentially all zinc and common cold studies. In evidence-based medicine, the subjective symptoms are most essential outcomes. Subjective symptoms determine whether a patient goes to work or school, stays at home, or visits a physician. Double-blinding prevents systematic bias in the subjective assessment of symptoms, and therefore “subjective” per se cannot cause bias in a double-blind trial. Furthermore, if Singh and Das consider that “subjective assessment” is a basis to exclude the Eby (1984) trial, they should apply the same criterion to the other trials. Singh and Das also comment on the Eby (1984) trial: “Inclusion criteria were not adequately addressed and therefore there may have been potential for selection bias to occur.” In randomized trials, the primary concern is the comparability of trial arms, so that there are no systematic differences that could lead to bias. All randomized trials use inclusion criteria of some kind, but that has nothing to do with the question whether the trial arms are comparable. Inclusion criteria are relevant when we consider the possibility to generalize the results, but not when considering the internal validity of a trial. Finally, Singh and Das conclude their criticism of the Eby (1984) trial: “In addition, no information was provided on how allocation to treatment groups was concealed, the power of the study was not stated and viral studies were not conducted”. First, in most other zinc and common cold studies there is no information about how allocation was concealed (i.e. how blinding was maintained). Second, statistical power is relevant when planning a trial, but not after the trial is concluded, since the confidence interval gives the same information. Third, given that the primary goal in evidence-based medicine is to find out whether a treatment has clinically important effects, viral studies are not relevant. All these issues are missing in most of the zinc and common cold studies. Thus, if Singh and Das consider that these arguments give a sound basis to exclude the Eby trial, they should apply the same criteria also to the other trials. In the Characteristics of excluded studies table, Singh and Das comment on the Turner (2000) trial: “Poor methodological quality. Not a randomised trial”. However, Turner writes “Subjects who met the criteria for randomization to treatment were randomly assigned to 1 of the 4 treatments in accordance with the drug-randomization code” (p. 1202), [for induced colds:] “Subjects were randomized to receive study medication 24 h after challenge if they had a total daily symptom score ≥ 3” (p. 1203), [for natural colds:] “Subjects who presented to the study sites with a common-cold illness of ≤ 1 calendar day’s duration (effectively 36 h), reported ≥ 2 different symptoms, and had a total symptom score of ≥ 2 were randomized to receive 1 of the 3 treatments” (p. 1203).Thus, the statement by Singh and Das is false, unless they have information that disproves the text of the Turner (2000) report. In such a case, they should present their evidence. The Turner (2000) trial was reported as a randomized placebo-controlled double-blind study, and there is no basis to claim that it was of “poor methodological quality”. 5) Different methods of administering zinc should be analyzed separately: 84Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [12] Simkin PA. Oral zinc sulphate in rheumatoid arthritis. Lancet 1976;2:539-42. http://dx.doi.org/10.1016/S0140-6736(76)91793- 1 [13] Jackson JL et al. Zinc and the common cold: a meta-analysis revisited. J Nutr 2000;130(5S Suppl):1512S-5S. http:// jn.nutrition.org/cgi/reprint/130/5/1512S [14] Caruso TJ et al. Treatment of naturally acquired common colds with zinc: a structured review. Clin Infect Dis 2007;45:569-74. http://dx.doi.org/10.1086/520031 Submitter agrees with default conflict of interest statement:I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback. Reply 1) The Eby and Halcomb (2006) trial has been mentioned under “excluded studies” in the updated review. 2) The Petrus (1998) values in Analysis 1.1 has been replaced with these correct and accurate values in this updated review. 3) About the Al-Nakib (1987) trial, for the item “incomplete outcome data addressed?”, the assessment has been changed into “low risk” in the characterstics of study table. Again, for the Al-Nakib trial, “high risk” for “free of selective reporting?” has been justified in the updated review. Furthermore, regarding the “the severity of symptoms” outcome reported in Al-Nakib (1987) trial, it was not possible to analyse the data, as the same was not avialble and also the trial was conducted almost 26 years back. This might be the reason that, no meta-analysis till date has been able to pool this trial result. Regarding the the Smith (1987) trial, in the updated review it has been changed to “high risk” for the item “incomplete outcome data addressed?”. Regarding the inclusion of Smith (1987) trial in the meta-analysis, please go through the paragraph “dealing with the missing data”. Regarding the inclusion of Weismann (1990) trial, it is a randomized trial, and previous meta-analyses (Jackson et al 2000, Hemilä 2011) has handled this as a randomized trial in their analyses. So, there is no point in excluding this trial or lebeling this as a “pseudo-randomized trial”. Regarding, contacting the authors, we have already mentioned that we did not try to contact authors of the trials conducted 10 years back. Infact, this trial was conducted almost 20 years back. More details of the Weismann (1990) trial, Al-Nakib (1987) and Petrus (1998) trial have been given in the included studies table in the updated review. The “implications for practice” section has been modified and the sentence “We could not find any trials conducted in low-income countries, so our results cannot be applied to people living in low-income countries” has been removed. 4) Regarding the exclusion of Eby trial (1984), please go through the inclusion criteria and dealing with the missing data section in the updated review. We have remoed the points like “subjective assessment” and ”viral studies were not conducted”, as they are not stronger criterion to exclude the Eby (1984) trial. The other points made to exclude the trial are valid and >50% loss to follow up in any trial is not at all acceptable, even if the authors have tried to maintain the integrity of the data. So, we stand on our decision to exclude the Eby trial. Regarding the Turner (2000) trial, it has been included in the updated review. 5) Different methods of administering zinc have been analyzed separately in the updated review. 6) Regarding the duration of the common cold should not be dichotomized, we did not make any change. They are actually not visible, if somone does not really want to visualise them. 7) The duration of the common cold has been normalized so that the placebo group has length 100%. The changes have been made in the updated review. 8) Subgroup analysis has been carried out in the updated review. 9) Though pooling the adverse effects of all zinc trials is unsound, we still reported it as we thought it would be useful and is part of any systematic review. There is no clear cut mechanism postulated and all are assumptions how adverse events occur with zinc lozenges. 10) In the updated version, we have discussed about the earlier reviews by Jackson et al [2000] and Caruso [2007] under the subtitle “Agreements and disagreements with other studies or reviews”. Please go through them. Contributors Harri Hemilä 87Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Zinc for the common cold feedback, 8 April 2014 Summary Were the Hirt and Mossad study that tested intranasal administration excluded from the analysis because of the route of administration? Or were there other reasons as well? I agree with the conflict of interest statement below: I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback. Reply We thank David Riley for the feedback on our paper. The Hirt and Mossad study that tested intranasal administration was excluded from the analysis because of the route of administration. Regards, Dr Rashmi Ranjan and Dr Meenu Singh. Contributors David Riley W H A T ’ S N E W Last assessed as up-to-date: 18 January 2013. Date Event Description 29 July 2014 Feedback has been incorporated Feedback comment added to the review (number 7) H I S T O R Y Protocol first published: Issue 1, 1999 Review first published: Issue 2, 1999 Date Event Description 11 December 2013 Amended Authors have readdressed their reply to the Feedback comment (number 6) 18 October 2013 Amended Changes made in response to comments received from the Cochrane Editorial Unit 18 January 2013 New citation required but conclusions have not changed Conclusion regarding the recommendation of zinc for the common cold remains unchanged 88Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. (Continued) 18 January 2013 New search has been performed Searches updated. Three new trials were in- cluded in this updated review (Turner 2000a;Turner 2000b;Turner 2000c) and two new trials were excluded (Eby 2006;Kartasurya 2012) 23 March 2012 Amended Typographical errors to feedback comment amended. 9 January 2012 Feedback has been incorporated Feedback incorporated. 7 September 2011 Amended Authors’ replies to Feedback comments added to re- view. 8 August 2011 Feedback has been incorporated Feedback comments added to review. 17 February 2011 Amended ’Summary of findings’ table amended. 29 June 2010 New citation required and conclusions have changed A new team of review authors have updated this pre- viously withdrawn review. In the previous review, the role of zinc for the common cold was inconclusive, as the results could not be pooled due to the paucity of trials measuring clinically relevant outcomes. In this updated review we were able to undertake pooling of results due to the addition of new trials and we found that zinc is beneficial for the common cold 1 June 2010 New search has been performed Searches conducted. We included eight new trials (Kurugol 2006a;Kurugol 2006b;Kurugol 2007;Mack- nin 1998;Petrus 1998;Prasad 2000;Prasad 2008;Vak- ili 2009) and excluded three new trials (McElroy 2003;Turner 2000a;Veverka 2009) in this update 17 June 2008 Amended Converted to new review format. 4 May 2006 Amended Review withdrawn. 24 February 1999 New search has been performed Review first published Issue 2, 1999. C O N T R I B U T I O N S O F A U T H O R S Dr Meenu Singh (MS) and Dr Rashmi Ranjan Das (RRD) jointly prepared and edited the review. 89Zinc for the common cold (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.