Group 2: Common Cold Prevention with Vitamin C and/or Zinc
Darya Kovtun, Angelina Gambino, Markenzie Jeanbaptiste, Farhana Chowdhury, Genna Giordano

Clinical Scenario: It’s winter and you’re working in a family practice office. Many patients are coming in with runny noses and general malaise. Brenda, a 35 year old working mother comes in for a checkup and says “I’m busy between work and home that I definitely don’t have time to get sick. Can vitamin C or zinc pills I hear about prevent colds?”Clinical Question: In adult patients, does vitamin c and/or zinc decrease the incidence of the common cold?

PICO Question:

P – common cold

I- vitamin C/ ascorbic acid

C- zinc

O- cold prevention

P – common cold, URI, adult
I – vitamin C, ascorbic acid
C – zinc
O – cold prevention, therapeutic use, symptom relief, symptom duration

Search Strategy:

Search terms used:
“common cold and vitamin c” “common cold and zinc”

Database and articles found:
Pubmed: 32 articles (1987-2018)
Cochrane: 5 articles (2011-2016)
Trip database: 229
Filters used:
Adults, humans, english

Articles Chosen
Darya:
Can Fam Physician. 2011 Jan;57(1):31-6.
Complementary and alternative medicine for prevention and treatment of the common cold.
Nahas R1, Balla A.
Author information
Abstract
OBJECTIVE:
To review the evidence supporting complementary and alternative medicine approaches to treatment and prevention of the common cold in adults.
QUALITY OF EVIDENCE:
MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched from January 1966 to September 2009 combining the key words common cold or influenza with echinacea, garlic, ginseng, probiotics, vitamin C, and zinc. Clinical trials and prospective studies were included.
MAIN MESSAGE:
For prevention, vitamin C demonstrated benefit in a large meta-analysis, with possibly increased benefit in patients subjected to cold stress. There is inconsistent evidence for Asian ginseng (Panax ginseng) and North American ginseng (Panax quinquefolius). Allicin was highly effective in 1 small trial. For treatment, Echinacea purpurea is the most consistently useful variety; it was effective in 5 of 6 trials. Zinc lozenges were effective in 5 of 9 trials, likely owing to dose and formulation issues. Overall, the evidence suggests no benefit from probiotics for prevention or treatment of the common cold.
CONCLUSION:
Vitamin C can be recommended to Canadian patients for prevention of the common cold. There is moderate evidence supporting the use of Echinacea purpurea and zinc lozenges for treatment. Ginseng and allicin warrant further research.
PMID: 21322286 PMCID: PMC3024156
[Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024156/

Angelina:
Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials.
Science M, Johnstone J, Roth DE, Guyatt G, Loeb M.
CMAJ. 2012 Jul 10;184(10):E551-61. doi: 10.1503/cmaj.111990. Epub 2012 May 7. Review.
PMID: 22566526
Abstract
BACKGROUND:
Results of randomized controlled trials evaluating zinc for the treatment of the common cold are conflicting. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of zinc for such use.
METHODS:
We searched electronic databases and other sources for studies published through to Sept. 30, 2011. We included all randomized controlled trials comparing orally administered zinc with placebo or no treatment. Assessment for study inclusion, data extraction and risk-of-bias analyses were performed in duplicate. We conducted meta-analyses using a random-effects model.
RESULTS:
We included 17 trials involving a total of 2121 participants. Compared with patients given placebo, those receiving zinc had a shorter duration of cold symptoms (mean difference -1.65 days, 95% confidence interval [CI] -2.50 to -0.81); however, heterogeneity was high (I(2) = 95%). Zinc shortened the duration of cold symptoms in adults (mean difference -2.63, 95% CI -3.69 to -1.58), but no significant effect was seen among children (mean difference -0.26, 95% CI -0.78 to 0.25). Heterogeneity remained high in all subgroup analyses, including by age, dose of ionized zinc and zinc formulation. The occurrence of any adverse event (risk ratio [RR] 1.24, 95% CI 1.05 to 1.46), bad taste (RR 1.65, 95% CI 1.27 to 2.16) and nausea (RR 1.64, 95% CI 1.19 to 2.27) were more common in the zinc group than in the placebo group.
INTERPRETATION:
The results of our meta-analysis showed that oral zinc formulations may shorten the duration of symptoms of the common cold. However, large high-quality trials are needed before definitive recommendations for clinical practice can be made. Adverse effects were common and should be the point of future study, because a good safety and tolerance profile is essential when treating this generally mild illness.
PMID: 22566526 PMCID: PMC3394849 DOI: 10.1503/cmaj.111990
[Indexed for MEDLINE] Free PMC Article
https://www.ncbi.nlm.nih.gov/pubmed/22566526

Mark:
Effect of vitamin C on common cold: randomized controlled trial.
Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S.
Eur J Clin Nutr. 2006 Jan;60(1):9-17.
PMID:
16118650
Abstract
Objective:
To investigate the relationship between the common cold and vitamin C supplementation.
Design:
A double-blind, 5-year randomized controlled trial.
Setting:
A village in Akita prefecture, one of the regions in Japan with the highest mortality from gastric cancer.
Subjects:
Participants in annual screening programs for circulatory diseases conducted under the National Health and Welfare Services Law for the Aged, and diagnosed as having atrophic gastritis. Of the 439 eligible subjects, 144 and 161 were assigned to receive 50 or 500 mg of vitamin C, respectively, after protocol amendment. During the supplementation phase, 61 dropped out, and 244 completed the trial.
Intervention:
Daily vitamin C supplementation of 50 mg (low-dose group) or 500 mg (high-dose group).
Results:
Total number of common colds (per 1000 person-months) was 21.3 and 17.1 for the low- and high-dose groups, respectively. After adjustment for several factors, the relative risks (95% confidence interval (CI)) of suffering from a common cold three or more times during the survey period was 0.34 (0.12–0.97) for the high-dose group. No apparent reduction was seen for the severity and duration of the common cold.
Conclusion:
A randomized, controlled 5-year trial suggests that vitamin C supplementation significantly reduces the frequency of the common cold but had no apparent effect on the duration or severity of the common cold. However, considering several limitations due to protocol amendment, the findings should be interpreted with caution.

https://www.nature.com/articles/1602261

Farhana

Mega-dose vitamin C in treatment of the common cold: a randomised controlled trialhttps://www.mja.com.au/journal/2001/175/7/mega-dose-vitamin-c-treatment-common-cold-randomised-controlled-trial
Carmen Audera, Roger V Patulny, Beate H Sander and Robert M Douglas
Abstract:
Objective: To determine the effect of large doses of vitamin C in the treatment of the common cold.

Study design: Double-blind, randomised clinical trial with four intervention arms: vitamin C at daily doses of 0.03 g (“placebo”), 1 g, 3 g, or 3 g with additives (“Bio-C”) taken at onset of a cold and for the following two days.

Participants and setting: 400 healthy volunteers were recruited from staff and students of the Australian National University, Canberra, ACT, between May 1998 and November 1999. The trial continued for 18 months.

Interventions: Participants were instructed to commence medication when they had experienced early symptoms of a cold for four hours, and to record daily their symptoms, severity, doctor visits and use of other medications.

Main outcome measures: Duration of symptoms and cold episodes; cumulative symptom severity scores after 7, 14 and 28 days; doctor visits; and whether participants guessed which medication they were taking.

Results: 149 participants returned records for 184 cold episodes. No significant differences were observed in any measure of cold duration or severity between the four medication groups. Although differences were not significant, the placebo group had the shortest duration of nasal, systemic and overall symptoms, and the lowest mean severity score at 14 days, and the second lowest at 7 and 28 days.

Conclusions: Doses of vitamin C in excess of 1g daily taken shortly after onset of a cold did not reduce the duration or severity of cold symptoms in healthy adult volunteers when compared with a vitamin C dose less than the minimum recommended daily intake.

Genna

Intake of vitamin C and zinc and risk of common cold: a cohort study.
Takkouche B, Regueira-Méndez C, García-Closas R, Figueiras A, Gestal-Otero JJ.
Epidemiology. 2002 Jan;13(1):38-44.
PMID:
11805584
https://www.ncbi.nlm.nih.gov/pubmed/11805584

Abstract:
To examine whether intake of vitamin C and zinc is associated with a decrease in the risk of a common cold, we analyzed data from a cohort study carried out in a population of 4,272 faculty and staff from five Spanish universities. Participants were 21-65 years of age, were full-time workers at those universities, and did not have antecedents of asthma or chronic obstructive pulmonary disease. Daily intake of vitamin C and zinc was assessed at baseline by means of a food frequency questionnaire of which the validity and reproducibility were determined in a sample of the population. Subjects were traced for 1 year to detect episodes of common cold, the diagnosis of which was based on symptoms and was validated by additional clinical signs. We detected 1,667 cases of common cold in 79,240 person-weeks of follow-up. Intake of vitamin C and zinc was not related to the occurrence of common cold. Compared with the first quartile of intake, women in the fourth quartile of vitamin C intake showed an adjusted incidence rate ratio of 1.0 (95% CI = 0.7-1.3), and for zinc intake this figure was 1.1 (95% CI = 0.8-1.5). The incidence rate ratios for men in the fourth quartile were 1.1 (95% CI = 0.8-1.4) for vitamin C and 1.3 (95% CI = 0.9-1.8) for zinc.

Summary of the Evidence:
Author (Date):Nahas, (Jan 2011)
Level of Evidence: systematic review, review of the clinical trials(# of subjects/ studies, cohort definition etc. )
Sample/Setting: EMBASE, Cochrane Database of Systematic review that reviewed articles (RCT, double blind placebo studies and clinical trials)from January 1966 to August 2009 with key words “common cold or influenza with echinacea, garlic, ginseng, probiotics, vitamin C and zinc.” The studies were done in United States, Australia, and in Canada.

Outcome(s) studied:

Vitamin C:
Cochrane systematic review used to evaluate treatment and prevention of common cold. To evaluate treatment, meta-analysis of 11 RCT used to evaluate 3294 cold episodes (8g of vitamin C). To evaluate prevention, meta-analysis of 30 RCT in children and adults (11,350 participants).

Zinc Lozenges: 4 RCT trials studied zinc nasal spray compared with placebo, and 13 clinical trials evaluated the effectiveness of zinc in treating common cold. Studied the dose (high: 13 to 23 mg every 2 hours compared to a low dose). Another outcome studied was bioavailability of Zinc when used with other formulations such as citric, tartaric acid, sorbitol, mannitol.

Key Findings
Vitamin C: common cold treatment dose (8 g vs. 4g) of vitamin C in treating. For prevention, 1g of vitamin C per day was used to evaluate the number of episodes of common cold and duration of symptoms.

Zinc lozenges: Treatment of common cold duration and severity of symptoms.
Vitamin C
Treatment: one trial found 8g had “more ‘short colds’” compared to 4g (46% to 39% P= 0.046) other studies found no benefit.

Prevention: number of colds had slight decrease
(OR=0.96, 95% CI= 0.92-1.0). One gram of vitamin C per day has shown to reduce the symptoms by 1 to 2 days, a 8% moderate reduction of symptoms.

Zinc Lozenges
13 mg every 2 hours (no more than 6 to 8 weeks) in the beginning of cold symptoms is effective for treating colds in reducing “symptom duration and severity.” However, the dose and bioavailability was inconclusive. Also, there is no evidence in effectiveness of zinc in preventing common cold.

Limitations and Biases:

Limitations: The article excluded some of the “other potentially useful intervention,” in treating common cold. The review was not comprehensive.

Bias: failed to include the conclusion of the zinc nasal spray compared to placebo. According to Eby & Halcomb (2006) zinc nasal spray is not recommended.

Source: https://www.ncbi.nlm.nih.gov/pubmed/16454145 (ineffectiveness of zinc nasal spray in cold treatment (Eby Ga, Halcomb WW, 2006). (note: this article was included).

 

Author: Audera, C., Patulny, R. V., Sander, B. H., & Douglas, R. M. (Sep 25, 2001).
Level of evidence: Double-blind, Randomized control clinical trial
Sample/Setting: 400 healthy subject-
Eligibility criteria: 18 years of age, not pregnant or planning to become pregnant, in good health, and do not take vitamin supplements regularly or take vitamin C, echinacea, zinc or Chinese herbal preparations
Four intervention groups: .03g,1g,3g, bio C
Participants were instructed to start medication if they experience at least two of the following symptoms for a minimum of four hours: sore or scratchy throat,nasal congestion or discharge headache or stinging eyes, muscle aches, fever.

Outcomes studied: The research aim to explore the effect of large dose of vitamin C on duration and severity of cold symptoms.
Duration of symptoms and cold episodes
Cumulative symptom severity
scores after 7, 14 and 28 days
Doctor visits
Whether participants guessed
which medication they were taking.

Key findings: There were no significant difference between groups who took low dose of vitamin C and high dose of vitamin C in reducing duration or severity of cold symptoms at days 7,14, 28

No significant difference between the groups in either mean duration or mean severity score
Placebo group had the shortest duration of nasal, systemic and overall symptoms and the lowest mean severity at 14 days
Only 14 people guessed correctly that they were taking a high dose of vit C
“Mean cold duration was 9.8 days, SD 6.6 days 80% power to detect a 40% difference in cold duration with a 95% Cl”
“Mean severity score at Day 28 was 32 with a standard deviation of 32.3, 80% power to detect a 50% difference in severity at the 95% Cl”

Limitations and biases:

Relatively small sample size

A potential bias in socioeconomic and educational status of participants

Participant rate was low

participants to decide when the criteria for commencing medication were met
The search was conducted on Australia
The research is older than 10 years

Angelina:
Author: Science, M., Johnstone, J., Roth, D. E., Guyatt, G., & Loeb, M. (2012)
Level of evidence: Systematic Review and Meta-Analysis
Sample/setting: 17 trials, 2,121 subjects

Outcomes studied: The efficacy and safety of zinc for the treatment of the common cold.
Colds were naturally acquired. Treatment regimens included zinc gluconate lozenges (8 trials) or tablets (1), zinc acetate lozenges (4), zinc sulfate syrup (2), and either zinc gluconate or zinc acetate (2) compared with placebo. The duration of treatment was different in all trials (range 3–14 days or until symptom resolution).

Findings: Treatment with zinc compared with placebo reduced the duration of cold symptoms in adults. The reduction in the duration of cold symptoms was greater with high doses of ionic zinc than with lower doses. Trials using zinc acetate had a better effect on cold duration than using zinc gluconate or zinc sulfate.

Limitations/ Biases: Heterogeneity was high. Assumptions were made to calculate the means and standard deviations of several trial estimates and all studies were industry funded. The trials reported double blinding, however infective blinding may have contributed to bias. Many of the trials were conducted in developed countries.

Markenzie
Author: Sasazuki S,
Level of evidence: Double- Blind , Randomized Control Trial
Sample/setting: 244 subjects, men and women aged 40–69 years. Participants had a h/o of chronic atrophic gastritis. They also had no history of gastric cancer, gastric surgery, liver cancer, cirrhosis, or other cancers within the previous 5 years; no abnormal liver function, no use of diet supplements containing β-carotene or vitamin C; and no expectation of moving outside the study area within 1 year.

Outcomes studied: Daily vitamin C supplementation of 50 mg (low-dose group, n=120) or 500 mg (high-dose group, n=124) x 5 years to study vitamin C supplementation on common cold incidence, duration and severity.
Findings: Total number of common colds (per 1000 person-months) was 21.3 and 17.1 for the low- and high-dose groups, respectively. Vitamin C supplementation was inversely related with common cold incidence, defined as a common cold episode occurring three or more times, while it had no effect on common cold duration or severity.
Limitations/ Biases: Relatively small sample size, large drop out at protocol amendment, and lack of placebo arm. There was also no clear definition of the common cold and the response of the participants were based off their interpretation of the common cold.

Genna:

Author: Bahi Takkouche, Carlos Reguiera-Mendez, Reina Garcia-Closas, Adolfo Figueiras, and Juan J. Gestal-Otero (1998-1999)
Level of evidence: Prospective cohort
Sample/ setting: 4,272 full-time faculty & staff from 5 Spanish universities, participants 21-65 y/o, 46% females, 54% males. Excluded those w/ h/o asthma, COPD or lung disease, allergic rhinitis, upper respiratory tract disease, or recent/current common cold
Outcomes studied: Does vitamin C and zinc in the regular diet have a protective effect on the risk of developing a common cold? Daily intake of zinc and vitamin C assessed by means of self-reported food frequency questionnaire. Participants self-reported on incidence/symptoms of common cold over 1 year using standardized questionnaire: presence of 8 symptoms (runny nose, sneezing, nasal congestion, headache, chills, sore throat, cough, and malaise) with each rated on severity scale of 0-4. 3 criteria to indicate common cold episode: Presence of rhinorrhea for at least 3 consecutive days, subjective sensation of having experienced common cold symptoms, and 12/24 combined score on the severity scale.
Findings: Findings of study did not provide evidence to support a protective effect of vitamin C and zinc obtained in a regular diet against the risk of common cold. Detected 1,667 cases of common cold in 79,240 person-weeks of follow-up. Women in 4th quartile of vitamin C intake showed adjusted incidence rate ratio of 1.0 (95% CI=0.7-1.3) and for zinc intake was 1.1 (95% CI=0.8-1.5). Incidence rate ratios for men in 4th quartile were 1.1 (95% CI=0.8-1.4) for vitamin C and 1.3 (95% CI=0.9-1.8) for zinc.
Limitations/ biases: For zinc, only 22% of women and 4% of men consumed the recommended daily intake of zinc (8mg and 11mg/day, respectively). In contract, vitamin C intake was normal to high. Possible explanation for lack of protective effects shown in study is the fact that intake of both vitamin C and zinc for participants was below the recommended daily intake. Less than 8% consumed supplements of vitamin C or zinc.
22% of participants dropped out before end of study, presumed to have developed a cold, may present bias because researchers did not include this data.
Patients self-reported both food items and cold symptoms/severity.
Nasal congestion, although those w/ h/o allergic rhinitis were excluded, could still be related to allergies.
Correlation coefficient for validity of food frequency questionnaire results was 0.67 for vitamin C and 0.40 for zinc, indicating that the intake of both were measured with error.
Plasma levels of ascorbic acid and zinc were not measured.
Serologic/virulogic testing for definitive diagnosis of viral infections was not used.

Conclusion:
After appraising our individual articles we came to the conclusion that there is no significant evidence to support the fact that vitamin C and/or zinc are clinically effective at preventing the incidence of the common cold. While some studies show that vitamin C and/or zinc taken in higher doses may decrease symptom severity or duration, the results vary between studies and are inconclusive in regards to common cold prevention.

Clinical Bottom Line:
In practice we would recommend to Brenda that she can try an OTC zinc and/or vitamin C supplement if she wanted to (especially with the popularity of OTC zicam, cold eeze, emergenC, airborne, etc.), but that studies have not proven for it to be effective in decreasing the incidence of the common cold. We would inform her however that it may help to shorten the severity and duration of her illness if taken early on.

References:
Nahas, R., & Balla, A. (2011). Complementary and alternative medicine for prevention and treatment of the common cold. Canadian family physician Medecin de famille canadien, 57(1), 31–36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024156/

Science, M., Johnstone, J., Roth, D. E., Guyatt, G., & Loeb, M. (2012). Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, 184(10), E551–E561. doi:10.1503/cmaj.111990 https://www.ncbi.nlm.nih.gov/pubmed/22566526

Sasazuki S., Sasaki S., Tsubono Y., Okubo S., Hayashi M., Tsugane S. Effect of vitamin C on common cold: randomized controlled trial, European Journal Of Clinical Nutrition, 2005/08/24/online 609 Nature Publishing Group, https://doi.org/10.1038/sj.ejcn.1602261, doi10.1038/sj.ejcn.1602261

Audera, C., Patulny, R. V., Sander, B. H., & Douglas, R. M. (2001). Mega‐dose vitamin C in treatment of the common cold: a randomised controlled trial. Medical Journal of Australia, 175(7), 359-362.

Takkouche, B., Regueira-Méndez, C., García-Closas, R., Figueiras, A., & Gestal-Otero, J. J. (2002). Intake of vitamin C and zinc and risk of common cold: a cohort study. Epidemiology, 13(1), 38-44.