July 24, 2007 — Vitamin C (ascorbic acid) may be effective against the common cold primarily in special populations, according to the results of a systematic Cochrane review published online in the July 18 issue of the Cochrane Database of Systematic Reviews. Most evidence suggests that an oral dose of 0.2 g or more of vitamin C is ineffective in treatment in the general population but may be effective in prevention, especially in special populations.

"In 'ordinary people,' vitamin C does not prevent colds," lead author Harri Hemilä, MD, PhD, an associate professor of Public Health at the University of Helsinki in Finland, told Medscape. "This is an important conclusion because lots of 'ordinary people' are taking vitamin C with the belief that vitamin C prevents colds. But there seem to be some groups of people who seem to get the benefit of vitamin C supplementation for a preventive purpose: people under heavy short-term physical stress are the most explicit group, which we identified in our Cochrane review."

Although vitamin C is widely used to prevent and treat cold symptoms, whether available evidence supports this common wisdom has been a subject of controversy.

"Despite 60 years of research in this area, there still seems to be little evidence to support the use of vitamin C in prevention or treatment of the common cold," Sherif Beniameen Mossad, MD, FACP, FIDSA, from Cleveland Clinic of Case Western Reserve University in Ohio, told Medscape. Dr. Mossad was not involved in the current Cochrane review but was asked by Medscape for independent commentary.

"However, given the significant heterogeneity of studies, and the shown benefit in certain situations, the possibility of benefit in other situations, or using different dosage or frequency should not be discarded," Dr. Mossad said. "Even if the only evidence of benefit for the individual that can be shown is what has been concluded from the current review, translating that to the benefit for the society is significant."

Using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to December 2006), and EMBASE (1990 to December 2006), the authors identified placebo-controlled trials studying the effects of 0.2 g or more per day of vitamin C for cold prevention and treatment.

Two of the authors independently extracted data from these trials and evaluated their quality. Primary outcomes were incidence of colds during prophylaxis, defined as the percentage of participants having at least 1 cold during the trial period, and duration, defined as the mean number of days of illness of cold episodes.

Meta-analysis of the relative risk (RR) of developing a cold while taking prophylactic vitamin C included data from 11,350 study participants enrolled in 30 trials. In this meta-analysis, the pooled RR was 0.96 (95% confidence intervals [CI], 0.92 - 1.00).

However, in a subgroup of 6 trials enrolling a total of 642 marathon runners (4 trials), Swiss schoolchildren in a skiing camp (1 trial), and Canadian soldiers performing subarctic exercises (1 trial), pooled RR was 0.50 (95% CI, 0.38 - 0.66), which was a highly statistically significant effect.

"The 50% average for 6 studies implies benefit for some physically stressed groups of people," Dr. Hemilä said. "Our finding of 50% suggests a clinically important benefit, but I do not believe that this figure is valid for all athletes.... The groups of people who benefit — more accurately defined, how much they benefit and how much vitamin C they should take, are questions requiring further study."

In a meta-analysis of common cold duration that included 30 comparisons involving 9676 respiratory episodes, there was a consistent benefit during prophylaxis with vitamin C, with cold duration decreased by 8% (95% CI, 3% - 13%) in adults and by 13.6% (95% CI, 5% - 22%) in children.

"These findings imply that vitamin C may prevent colds when taken prophylactically in certain situations only, and reduce the duration of colds in those who develop one while taking it prophylactically, but to a small extent; more so in children than adults," Dr. Mossad said. "It has not been shown to decrease the duration or severity of colds when taken therapeutically after the onset of illness."

Interestingly, Dr. Hemilä noted that dosages in most of the adult and child studies of prophylaxis were 1 g of vitamin C per day.

"The regular supplementation studies found strong evidence that vitamin C shortens the duration of colds that occur during supplementation," Dr. Hemilä said. "Regular [supplementation] means administering vitamin C every day over the study.... I think that the adult vs children difference in [these] studies (8% vs 13.6%) is not a real subgroup difference, but is caused by the different dose per weight."

When vitamin C was started after the onset of cold symptoms, there were no significant differences from placebo in cold duration during therapy, based on 7 trial comparisons involving 3294 respiratory episodes. Similarly, in 4 trial comparisons involving 2753 respiratory episodes, vitamin C was no different than placebo in terms of cold severity during therapy.

"There are not many therapeutic studies, with supplementation starting after the onset of symptoms, and the results are not consistent," Dr. Hemilä said. "Thus, the regular supplementation studies show that vitamin C affects the duration and severity of colds, but they do not help in evaluating its practical relevance."

One study of particular importance, according to Dr. Hemilä, was performed at the National Institutes of Health by Karlowski and colleagues and published in the March 1975 issue of Journal of the American Medical Association. In a 2 × 2 factorial design, subjects received placebo, 3 g/day of prophylactic vitamin C, 3 g/day of therapeutic vitamin C for 5 days, or 3 g/day of prophylactic vitamin C plus 3 g/day of therapeutic vitamin C.

Although the authors concluded that there were no substantial differences in the effect of regular and therapeutic supplementation on the duration of colds, Dr. Hemilä reanalyzed their data and published the findings in the October 1996 issue of the Journal of Clinical Epidemiology. The 3-g/day groups had approximately the same effect and the 6-g/day group had twice this effect (17% reduction in colds), suggesting dose dependency.

"It is noteworthy that the regular supplementation study estimates (8% and 13%) are based on studies mainly using 1 g/day," Dr. Hemilä said. "Thus, these estimates should not be used as a basis to make a decision whether vitamin C is reasonable for therapy or not. Furthermore, it is a subjective issue of values and price of treatment when a person considers whether the minimum effect should be 10% or 20% or something else."

Strengths of the current Cochrane review, according to Dr. Hemilä, are the large number of placebo-controlled studies in different countries enrolling both adults and children. The main limitation is that the therapeutic effect cannot be properly estimated from the published studies because there are few therapeutic studies and they are methodologically diverse. Another limitation is that essentially all the studies were performed in developed countries where the usual dietary intake of vitamin C is high.

Dr. Mossad added that the main strengths of this review are the "extensive personal experience and insight of the authors into this topic" and the "rigorous" methodology. The limitations result from the heterogeneity of studies included with respect to diet, living conditions, climate, dose and duration of therapy.

"There is lots of individual-level experimentation in medicine," Dr. Hemilä explained. "For example, if a antihypertensive drug does not lower blood pressure in 1 person, we try another drug; we do not say that the lack of effect in 1 person is evidence that the first drug is ineffective in general. We say that it does not work for that particular person."

"With similar kind of reasoning I think vitamin C may be tried for treating colds," Dr. Hemilä concluded. "If a person does not feel there is any benefit, he or she need not take it next time. But if vitamin C seems to be helpful, there is a subjective reason to try it again the next time."

In terms of future research, Dr. Hemilä recommended well-planned therapeutic trials of vitamin C dosages well above 1 g/day, because some studies have suggested a dose-response effect with dosages up to 6 g/day. He also recommends a study duration of longer than 5 days, because a few 3-day therapeutic trials found no benefit, and he believes that the negative findings may have been caused by the short study duration.

"More accurate characterization of the 'physical stress' group needs much more research, but I think it is less important from the public health point of view compared with the therapeutic effect mentioned above," Dr. Hemilä said. "Marathon and comparable events are rare, whereas the common cold is ubiquitous among 'ordinary' people."

Dr. Mossad also recommended prophylaxis studies in other populations or under conditions that increase the risk of having colds or of having more severe colds; treatment studies in homogenous populations using a variety of experiments using larger doses, consistent early administration, or more frequent dosing; treatment studies in children; and basic science studies to further elucidate the potential biological effect of vitamin C in preventing or treating the common cold.

"It is somewhat reassuring that serious side effects have not been encountered in any of these studies," Dr. Mossad concluded. "However, as common as the common cold is, even a rare side effect may become more apparent if consistent widespread use is implemented."

Dr. Hemilä has disclosed receiving his salary from the University of Helsinki. He holds no shares and has no other financial relationships with pharmaceutical or other companies that might have interest in vitamin C or in the common cold. He has on a few occasions lectured in meetings organized by drug companies, most recently in 2004. Dr. Mossad has disclosed no relevant financial relationships.

Cochrane Database Syst Rev. Published online July 18, 2007.

Clinical Context

Pearls for Practice

• The effects of oral prophylactic vitamin C on the common cold include decrease in duration, especially in children; slight decrease in severity; and no decrease in incidence, except for a subgroup of persons exposed to extreme cold or physical stress.
• Vitamin C treatment of the common cold has no significant effect on duration or severity of illness.

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