Extra Dose of Vitamin C Based on a Daily Supplementation Shortens the Common Cold: A Meta-Analysis of 9 Randomized Controlled Trials
Authors: Hongwu Wang
Wenli Zhao
Li Ran
Ye Zhao
Huaien Bu
Jingxia Wang
Yiider Tseng
Journal: BioMed Research International (2018)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: vitamin C; common cold; meta-analysis; therapeutic doses; duration
Affiliations: Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China., Department of Neurology, Nankai Hospital, Tianjin Academy of Integrative Medicine, Tianjin 300100, China., Department of Research and Development, Hangzhou DeBuYou Health Technology Co. Ltd., Hangzhou, Zhejiang 310018, China., College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China., Department of Chemical Engineering, University of Florida, Gainesville, Florida 32611, USA.

Abstract:  Aim: To investigate whether vitamin C is effective in the treatment of the common cold. Method: After systematically searching the National Library of Medicine (PubMed), Cochrane Library, Elsevier, China National Knowledge Infrastructure (CNKI), VIP databases, and WANFANG databases, 9 randomized placebo-controlled trials were included in our meta-analysis in RevMan 5.3 software, all of which were in English. Results: In the evaluation of vitamin C, administration of extra therapeutic doses at the onset of cold despite routine supplementation was found to help reduce its duration (mean difference (MD) = -0.56, 95% confidence interval (CI) [-1.03, -0.10], and P = 0.02), shorten the time of confinement indoors (MD = -0.41, 95% CI [-0.62, -0.19], and P = 0.0002), and relieve the symptoms associated with it, including chest pain (MD = -0.40, 95% CI [-0.77, -0.03], and P = 0.03), fever (MD = -0.45, 95% CI [-0.78, -0.11], and P = 0.009), and chills (MD = -0.36, 95% CI [-0.65, -0.07], and P = 0.01). Conclusions: Extra doses of vitamin C could benefit some patients who contract the common cold despite taking daily vitamin C supplements. 

Retracted: No

PubPeer comments:
 # Shortcomings in the vitamin C and common cold meta-analysis by Ran et al. (2018) Ran et al. (2018)[1] write in their Abstract that the aim of their study was *u201cto investigate whether vitamin C is effective in the treatment of the common cold.u201d* However there are numerous methodological problems with the study. Treatment of a disease is initiated after a person becomes sick. However, two of the trials included in the Ran study administered 1 g day vitamin C regularly each day for a few months [2,3] and one trial administered 3 g day vitamin C regularly for nine months [4]. In these three trials, the dosage was increased when a common cold episode occurred. These three trials are not treatment trials as participants took vitamin C continuously, even when they were in good health. Thus, it is possible that there was a beneficial effect from the continuous supplementary high dosage of 1 to 3 g day of vitamin C rather than from the short increased dosage when the participant fell sick. Ran et al. write in the Results section (3.1) that they included 9 trial reports *u201c... after removing duplicatesu201d* [1]. However, the Lewis (1975) and the Karlowski (1975) reports are about one single trial. Karlowski (1975) was the primary trial report published in JAMA [4], whereas Lewis (1975) was a meeting report (duplicate) published in the Annals of the NY Academy of Sciences [5]. Furthermore, because this is one single trial, the divergence in the assessment of risk of bias of the two reports is erroneous in Table 2 [1]. A single controlled trial cannot simultaneously have u201cunclearu201d and u201clow risku201d for random sequence generation and blinding of outcome assessment. Ran et al. write in the Results section (3.3) that *u201cAll the studies were 100% completedu201d* [1]. This is not the case. In the Karlowski (1975) trial, only 61% (190 311) of the randomized participants completed the trial [4]. In the Anderson (1972) trial, only 82% (818 1000) of the included participants completed the trial [2; p.504]. In the Elwood (1977) trial, only 75% (688 923) of the included participants completed the trial [6, p.194]. In the Cowan (1950) trial, only 85% of the enrolled participants completed the Cowan (1950) trial [7]. Evidently, the statement by Ran et al. that *u201cAll the studies were 100% completedu201d* [1, sect. 3.3] is not true. The title states *u201c9 randomized controlled trialsu201d* [1]. However, Table 2 shows that u201crandom sequence generationu201d was u201cunclearu201d in 4 out of the 8 trials shown in that table. It is not clear why those 4 trials were included if the authors were not convinced that they were randomized. For some reason, Ran et al. did not assess the validity of the Anderson (1974) trial [3] in Table 2. As to the effects of regular vitamin C administration, there is strong evidence that colds occuring during the supplementation period are shorter [8]. However, so far there is no evidence that vitamin C treatment, started after the onset of symptoms, is effective for reducing the duration of the common cold [8]. That said, there have been several methodological issues in the treatment trials to date which have been previously discussed: *u201cTechnically the therapeutic trials are in several ways much more complicated than regular supplementation trials. If the timing of supplementation initiation, the duration of supplementation, or the dosage, influence the size of the benefit, false negative findings might result from inappropriate study protocolsu201d* [8, p.18]. This comment is followed by a lengthy discussion of the methodological issues in the published treatment trials [8]. These methodological issues were not considered by Ran et al in their study [1], nor did they refer to the earlier discussions about the methodological problems in other treatment trials on vitamin C. In the Abstract, Ran et al. write: *u201cIn the evaluation of vitamin C, administration of extra therapeutic doses at the onset of cold despite routine supplementation was found to help reduce its duration (mean difference (MD) = -0.56, ... P = 0.02)u201d* [1]. However, there is great variation in the duration of colds from 1 day to longer than 3 weeks. Therefore, a single estimate on the absolute scale such as a 0.56-day reduction in common cold duration is uninformative. The relative scale has been shown to be superior in the analysis of common cold duration [9] and was used in our earlier major meta-analysis on vitamin C for the common cold [8]. From regular supplementation trials it was estimated that vitamin C reduced the duration of colds by 8% in adults [8]. Another significant statistical problem in the Ran et al. meta-analysis was that participants in the placebo group were double counted [1]. Further discussion of this problem can be found by Senn [10]. In the Abstract, Ran et al. write: [vitamin C] *u201crelieve the symptoms associated with it, including chest pain ... P = 0.03u201d.* The calculation for chest pain is shown in Figure 7 [1]. The single placebo group of 146 participants of the Anderson (1975) trial [11] is used for two vitamin C arms of the trial and thereby the number of placebo participants is doubled to 292. This leads to a deceptively small P-value. An appropriate approach would have been to split the single placebo group in half and use the two halves as separate placebo groups for both the trial intervention arms. This way, the total number of placebo participants in the analysis would have been correct. However, doing this increases the P-value from 0.03 to 0.10. See the Figure below which reproduces the incorrect analysis by Ran et al. [1] and shows the correct analysis without the double-counting of participants in the placebo group. This same problem also occurs in Ranu2019s Figures 2-6 and 8-10 [1]. Therefore, all the estimates of effect and corresponding P-values in those figures are invalid. All the P-values in the Abstract are invalid for the same reason. In conclusion, there are several issues that challenge the validity of the meta-analysis by Ran et al. (2018) [1]. **References** 1. Ran L, Zhao W, Wang J, Wang H, Zhao Y, Tseng Y, Bu H. Extra Dose of Vitamin C Based on a Daily Supplementation Shortens the Common Cold: A Meta-Analysis of 9 Randomized Controlled Trials. Biomed Res Int. 2018 Jul 5;2018:1837634. https: doi.org 10.1155 2018 1837634 https: www.ncbi.nlm.nih.gov pmc articles PMC6057395 2. Anderson (1972) https: www.ncbi.nlm.nih.gov pmc articles PMC1940935 3. Anderson (1974) https: www.ncbi.nlm.nih.gov pmc articles PMC1947567 4. Karlowski (1975) https: doi.org 10.1001 jama.1975.03240220018013 5. Lewis (1975) https: doi.org 10.1111 j.1749-6632.1975.tb29309.x 6. Elwood (1977) https: dx.doi.org 10.1136 jech.30.3.193 https: www.ncbi.nlm.nih.gov pmc articles PMC478963 7. Cowan (1950) https: doi.org 10.1001 jama.1942.02830510006002 8. Hemilu00e4 Chalker (2013) https: doi.org 10.1002 14651858.CD000980.pub4 https: helda.helsinki.fi handle 10138 225864 9. Hemilu00e4 (2017) https: doi.org 10.1186 s12874-017-0356-y https: www.ncbi.nlm.nih.gov pmc articles PMC5427521 10. Senn (2009) Overstating the evidence: double counting in meta-analysis and related problems. https: doi.org 10.1186 1471-2288-9-10 https: www.ncbi.nlm.nih.gov pmc articles PMC2653069 11. Anderson (1975) https: www.ncbi.nlm.nih.gov pmc articles PMC1958969 ![file] , 
 We appreciated seeing Dr. Hemilu00e4u2019s concerns about double counting. We submitted these same concerns to the publisher on August 13, 2020 (our submitted text below). A publishing editor indicated that the authors were contacted on October 7, 2020. We first became aware of this meta-analysis as it was referenced by [Calder et al.] who wrote about nutrition and viral infections in the context of COVID-19. We critiqued the interpretation by Calder et al. of the strength of the evidence for several nutrients in a [letter] (and expanded our description on [PubPeer] ) and noted there that Ran et al. u201crepeatedly commit a unit-of-analysis error by pooling two arms of the same study, which invalidates the effect estimates.u201d Indeed, [many other citations] to Ran et al. have accumulated in the context of COVID-19. Given its public health interest, we hope Ran et al. will make the necessary corrections expeditiously so additional authors do not mis-calculate the strength of the evidence for vitamin C (as Dr. Hemilu00e4u2019s calculation suggests, at least some statistical conclusions will change). *Our submitted text to the publishing editor:* **Error: Double counting placebo groups** We noticed that the meta-analysis has instances of an error where the placebo group is u2018double countedu2019 in trials with more than two intervention arms. This occurs when the authors used data from the studies included in the table below, throughout the analyses sub-group analyses (Figure # used for simplicity). Double counting placebo groups is an error that invalidates the error estimates. The error is described in the Cochrane handbook, which provides recommendations on how to include such trials in a meta-analysis: https: handbook-5-1.cochrane.org chapter_16 16_5_4_how_to_include_multiple_groups_from_one_study.htm u201cThere are several possible approaches to including a study with multiple intervention groups in a particular meta-analysis. One approach that must be avoided is simply to enter several comparisons into the meta-analysis when these have one or more intervention groups in common. This u2018double-countsu2019 the participants in the u2018sharedu2019 intervention group(s), and creates a unit-of-analysis error due to the unaddressed correlation between the estimated intervention effects from multiple comparisons (see Chapter 9, Section 9.3). u2026u201d | Error observed in:| Study from which data was u2018double countedu2019 | | ------------- |-------------| | Figure 2 | Anderson 1975, Anderson 1974, Audera 2001| | Figure 3 | Anderson 1975, Audera 2001| t | Figure 4 | Anderson 1975, Audera 2001| t | Figure 5 | Anderson 1975| | Figure 6 | Anderson 1975| | Figure 7 | Anderson 1975| | Figure 8 | Anderson 1975| | Figure 9 | Anderson 1975| | Figure 10 | Anderson 1975, Anderson 1974| Sincerely, Colby J. Vorland, Andrew W. Brown ,