Vitamin C as a Supplementary Therapy in Relieving Symptoms of the Common Cold: A Meta-Analysis of 10 Randomized Controlled Trials
Authors: Hongwu Wang
Wenli Zhao
Li Ran
Ye Zhao
Huaien Bu
Journal: BioMed Research International (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: vitamin C; common cold; supplemental treatment; meta-analysis; antiviral therapy
Affiliations: Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China., Department of Occupational and Environmental Health, School of Health Sciences, Wuhan University, Wuhan 430071, China., Liver Center, Saga University Hospital, Saga University, 849-8501, Japan., School of Health science and Engineering, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China., Qingdao Academy of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Qingdao 266112, China.

Abstract:  Aim: To investigate whether vitamin C performs well as a supplemental treatment for common cold. Method: After systematically searching through the National Library of Medicine (PubMed), Cochrane Library, Elsevier, China National Knowledge Infrastructure (CNKI), VIP databases, and Wanfang databases, 10 randomized controlled trials were selected for our meta-analysis with RevMan 5.3 software. Published in China, all 10 studies evaluated the effect of combined vitamin C and antiviral therapy for the treatment of common cold. Results: The total efficacy (RR = 1.27, 95% CI (1.08, 1.48), P = 0.003), the time for symptom amelioration (MD = -15.84, 95% CI (-17.02, -14.66), P &lt; 0.00001), and the time for healing (I, 95% CI (-14.98, -4.22), P = 0.0005) were better with vitamin C supplementation than with antiviral therapy alone. Conclusions: Vitamin C could be used as a supplementary therapy along with antiviral regimens to relieve patients from the symptoms of common cold. 

Retracted: No

PubPeer comments:
 # Flaws in the vitamin C and common cold meta-analysis by Ran et al. (2020) There are numerous problems in the meta-analysis by Ran et al. [1]. The authors write in the inclusion criteria (2.2) that they included trials with *u201cvitamin C as a therapeutic technique with antiviral therapiesu201d*. However, there is no description of what Ran et al. mean by u201cantiviral therapiesu201d [1]. There are no known antivirals for the common cold. Furthermore, over decades, vitamin C has been indicated in drug metabolism [2,3], and therefore it is even possible that the undefined u201cantiviralsu201d may cause adverse effects, such that any possible effects of vitamin C might be targeting harms due to the u201cantiviralsu201d, and not the symptoms of the respiratory virus infection. Transparency is a fundamental principle in science. Ran et al. pool 10 Chinese trials, but it is not possible to check the methods of any of those 10 trials (references 21 to 30 in [1]). A Google search does not identify any of them. It is possible to arrange translation of non-English papers to English, so that readers can check what the original publication actually stated in the methods and results. Ideally, Ran et al. could have included the translations in a supplement. In this respect there is a serious problem with transparency. Ran et al. write: *u201cData Availability: Data are all contained within the paperu201d* [1]. This is not correct. It is not possible to trace where the data in the forest plots come from. The diagnosis of the common cold is based on symptoms such as runny nose, cough and or sore throat, etc. Therefore, placebo-control and blinding at all stages of the trial from allocation to outcome assessment is essential in controlled trials on the common cold. However, for every one of the 10 included trials, u201callocation concealmentu201d, u201cblinding of participants and personnelu201d and u201cblinding of outcome assessmentu201d are assessed as u201cunclearu201d (Table 2 in [1]). Thus, it is possible that observations were seriously biased by patients and or researchers knowing who was getting which treatment. In the results section, Ran et al. state that *u201cAll studies were 100% completed and had no bias in selective reporting.u201d* This is based on Table 2, which states u201clow risku201d for all 10 included trials for u201cincomplete outcome datau201d and u201cselective reportingu201d. However, Figures 3 and 4 show only 5 of the 10 included trials. Is there incomplete outcome data and or selective reporting in the 5 trials that are not included in Figures 3 and 4, or why are those trials not shown? The title states u201c10 randomized controlled trialsu201d [1]. However, Table 2 shows that u201crandom sequence generationu201d was u201cunclearu201d in 7 out of the 10 included trials. In the Results section, Ran et al. state that *u201cOnly three articles demonstrated that a random sequence was generated with random number tables, and there was no detailed information in the remaining seven.u201d* All 10 included studies were Chinese trials. There have been serious concerns about the validity of reporting of Chinese controlled trials: *u201cMost reports of randomized controlled trials published in some Chinese journals lacked an adequate description of randomization. Similarly, most so called randomized controlled trials were not real randomized controlled trials owing to a lack of adequate understanding on the part of the authors of rigorous clinical trial designu201d* [4]. Thus, the title appears misleading as there is no guarantee that 7 of the 10 included trials actually were randomized trials. In addition, there is strong evidence of publication bias of Chinese trials [5]. Thus, Ran et al. should have questioned the validity of the 7 trials with no details about the method of allocation, and of all 10 trials because there was no evidence of any level of blinding. Figure 3 shows the effect of vitamin C on u201csymptom alleviationu201d and Figure 4 shows the effect on u201ctime for healingu201d. However, Ran et al. do not describe the difference between these two outcomes. It would seem evident that when symptoms are alleviated, the patient is healed [1]. In the Abstract, Ran et al. summarize the findings as follows: *u201cThe total efficacy (RR = 1.27, 95% CI (1.08, 1.48), P = 0.003), the time for symptom amelioration (MD= u221215.84, 95% CI (-17.02, -14.66), P 0.00001), and the time for healing (I, 95% CI (-14.98, -4.22), P = 0.0005) were better with vitamin Cu201d*. However, nowhere in the paper is there a description of what u201ctotal efficacyu201d measures. The RR is calculated from u201ceventsu201d in Figure 2, but there is no description of what the u201ceventu201d is. The common cold is self-limited [1, p.1] and all patients are cured over time. Therefore, the proportion who are cured is 100% in all common cold patients and this leads to RR (risk ratio) = 1.00 for the comparison of being cured in two groups. Thus, it is not clear what RR = 1.27 means. Furthermore, measurements should show the unit of measurement. However, the Abstract and the main text do not describe whether u201cMD= u221215.84u201d means hours or days or percentages or something else. In the abstract, the effect on the time of healing is reported as u201cIu201d (see paragraph above) which indicates poor reading of the manuscript and proofs by the 5 authors. Usually common cold lasts on average some 7 days [6] and Ran et al. also write in their Introduction that *u201ccommon cold is self-limited and lasts between seven and ten daysu201d* [1, p.1]. However, the distribution of common cold duration is wide, with some colds lasting just 1 day, and some lasting over 3 weeks. In our Cochrane review we calculated from a few dozen trials reporting the SD, that the ratio of SD to mean was on average some 0.7 [7, p.8]. However, in the control groups of Figure 4 [1], the ratio of SD to mean is 0.12 or less for all the 5 trials, which is not believable given the wide distribution in the common cold duration. Reference 22 is puzzling: H. Gao and M. H. Wang, *u201cThe analysis of the clinical efficacy of inhalation of vitamin C injection in the treatment of pediatric upper respiratory tract infection,u201d* World Latest Medicine Information, vol. 14, no. 1, p. 192, 2014. What does inhalation of vitamin C injection mean? The text section [1] does not mention that the method of administration of vitamin C was highly unusual in the Gao and Wang trial. Finally, Ran et al. failed to refer to earlier and more extensive meta-analyses on vitamin C and the common cold [7,8]. Even more strange is the failure to refer to their own earlier meta-analysis on vitamin C and the common cold [9]. In conclusion, there are several issues that challenge the validity of the review by Ran et al. [1]. **References** 1. Li Ran, Wenli Zhao, Hongwu Wang, Ye Zhao, Huaien Bu. Vitamin C as a Supplementary Therapy in Relieving Symptoms of the Common Cold: A Meta-Analysis of 10 Randomized Controlled Trials. 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