Dr. Ron’s Research Review – September 14, 2011

This week’s research review: The Common Cold 2011 – Part 1.

Review Articles

Two recent review articles on the common cold are:

Complementary and alternative medicine for prevention and treatment of the common cold. (Nahas and Balla 2011)

Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. (Roxas and Jurenka 2007)

Zinc

A systematic review found that zinc lozenges may shorten the duration of colds. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). (Hemila 2011)

Eby proposes that the form of zinc is critical. A 7-day reduction in duration of common colds was shown by Eby et al. in 1984 using 23mg zinc gluconate throat lozenges. Positively charged, ionic zinc (iZn), but not bound zinc, is strongly astringent, antirhinoviral, increases interferon-gamma (IFN-gamma) 10-fold, inhibits intercellular adhesion molecule-1 (ICAM-1) and inhibits the release of vasoactive ingredients from mast cell granules. Lozenge iZn fraction varying from 0% to 100% of total lozenge zinc between trials, with zinc acetate (ZA) releasing 100% iZn, zinc gluconate (ZG) releasing 72% iZn and other zinc compounds releasing much less or none at physiologic pH 7.4. (Eby 2010)

A review article on zinc for the common cold was published in the Cochrane Database. Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. Overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06), bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. (Singh and Das 2011)

Vitamin C

A review article published in Canadian Family Physician concluded that Vitamin C can be recommended to Canadian patients for prevention of the common cold. (Nahas and Balla 2011)

An article published in Nutrition proposed that combined inhalational and oral supplementation of ascorbic acid may prevent influenza pandemic emergency. (Banerjee and Kaul 2010)

Vitamin D

Vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Vitamin D deficiency may lead to suboptimal responses toward bacterial and viral infections. (Gombart 2009)

A recent study published in PLoS One found that maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher significantly reduces the incidence of acute viral respiratory tract infections and the burden of illness caused thereby, at least during the fall and winter in temperate zones. (Sabetta, DePetrillo et al. 2010)

A recent randomized controlled trial of school children in Japan taking 1200 IU/d or 200 IU/d of vitamin D3 reported a relative risk of developing influenza A infection of 0.36 (95% confidence interval, 0.17–0.79) for those not taking additional vitamin D.

The groups of people who had the most serious complications from the recent A (H1N1) influenza tended to have low serum 25- hydroxyvitamin D ӿÜ25(OH)DӿÝ levels: pregnant women, Australia Aborigines, Canadian First Nation people, patients with diabetes, obese, and children with neurologic diseases. (Grant 2010)

Thus, during the influenza season, people would be well advised to take steps to increase their serum 25(OH)D concentrations to above 40 ng/mL. In winter, serum 25(OH)D values are generally near 20 ng/ mL. Each 1000 IU/d of vitamin D3 raises serum 25(OH)D values by about 10 ng/mL for the average sized person. People of all ages can safely take 5000 to 10,000 IU/d of vitamin D3 for an extended time unless they have granulomatous diseases, in which case smaller doses are advised. (Grant 2010)

Dr. Ron


Articles

Combined inhalational and oral supplementation of ascorbic acid may prevent influenza pandemic emergency: a hypothesis

(Banerjee and Kaul 2010) Download

Occurrence of influenza pandemics is a worldwide phenomenon and a significant cause of mortality and morbidity throughout the globe. It is due to mutations in the influenza virus genetic material creating antigenic drift of pathogenic viral proteins resulting in emergence of new influenza virus strains. Therefore, the vaccines available for prevention of influenza offer no protection against influenza pandemics caused by new virus strains. Moreover, the existing drugs used to combat influenza may be ineffective to treat influenza pandemics due to the emergence of drug resistance in the pandemic virus strain. Therefore, a working strategy must be developed to combat influenza pandemics. In this review we have addressed this problem and reviewed the published studies on ascorbic acid in the common cold and influenza and laboratory studies on the effect of ascorbic acid on influenza virus. We have also correlated the clinical and laboratory studies and developed a hypothesis to prevent influenza pandemics.

Zinc lozenges as cure for the common cold--a review and hypothesis

            (Eby 2010) Download

A 7-day reduction in duration of common colds was shown by Eby et al. in 1984 using 23mg zinc gluconate throat lozenges. Over the following 25years, 14 double-blind, placebo-controlled, randomized clinical trials produced widely differing results with about one-half showing success and the remainder showing failure. Positively charged, ionic zinc (iZn), but not bound zinc, is strongly astringent, antirhinoviral, increases interferon-gamma (IFN-gamma) 10-fold, inhibits intercellular adhesion molecule-1 (ICAM-1) and inhibits the release of vasoactive ingredients from mast cell granules. Solution equilibrium chemistry analytical techniques showed lozenge iZn fraction varying from 0% to 100% of total lozenge zinc between trials, with zinc acetate (ZA) releasing 100% iZn, zinc gluconate (ZG) releasing 72% iZn and other zinc compounds releasing much less or none at physiologic pH 7.4. Since only iZn has in vitro benefits, iZn variations are hypothesized to have produced the widely varying clinical results. In support of the iZn hypothesis, lozenge iZn and total daily iZn in trials were found highly correlated with reductions in common cold durations with statistical significance for mean duration (P<0.001) and median duration (P<0.004), while total zinc (iZn plus bound) showed no correlation with changes in duration. Duration reductions (mean 0 days, median 0.43 days) for multi-ligand ZG and ZA lozenges differed significantly from duration reductions (mean 3.37 days, median 2.9 days) for single ligand ZA and ZG lozenges (P<0.001) showing that additive ligands as flavor-masks damaged or eliminated efficacy. Five of 6 trials with lozenges whose zinc compositions had a first stability constant of 1.7 or less succeeded, while only 2 of 9 trials of lozenges with higher stability succeeded (P<0.02). From the strong, multiple statistical relationships found, it is inferred that iZn is the active ingredient in zinc lozenges for colds, as it is in vitro against rhinoviruses, and that solution chemistry analytical techniques used at physiological pH are correct means for lozenge iZn analysis. Zinc lozenges slowly dissolving in the mouth over a 20-30 min period releasing adequate iZn (18 mg) used each 2h are hypothesized to shorten common colds by 6-7 days, which is a cure for the common cold. Due to inadequate lozenge iZn very few of more than 40 different brands of zinc lozenges on the US market are expected to have any effect on the duration or severity of common colds.

The vitamin D-antimicrobial peptide pathway and its role in protection against infection

         (Gombart 2009) Download

Vitamin D deficiency has been correlated with increased rates of infection. Since the early 19th century, both environmental (i.e., sunlight) and dietary sources (cod liver) of vitamin D have been identified as treatments for TB. The recent discovery that vitamin D induces antimicrobial peptide gene expression explains, in part, the 'antibiotic' effect of vitamin D and has greatly renewed interest in the ability of vitamin D to improve immune function. Subsequent work indicates that this regulation is biologically important for the response of the innate immune system to wounds and infection and that deficiency may lead to suboptimal responses toward bacterial and viral infections. The regulation of the cathelicidin antimicrobial peptide gene is a human/primate-specific adaptation and is not conserved in other mammals. The capacity of the vitamin D receptor to act as a high-affinity receptor for vitamin D and a low-affinity receptor for secondary bile acids and potentially other novel nutritional compounds suggests that the evolutionary selection to place the cathelicidin gene under control of the vitamin D receptor allows for its regulation under both endocrine and xenobiotic response systems. Future studies in both humans and humanized mouse models will elucidate the importance of this regulation and lead to the development of potential therapeutic applications.

Vitamin D supplementation could reduce the risk of type A influenza infection and subsequent pneumonia

            (Grant 2010) Download


Zinc lozenges may shorten the duration of colds: a systematic review

            (Hemila 2011) Download

BACKGROUND: A number of controlled trials have examined the effect of zinc lozenges on the common cold but the findings have diverged. The purpose of this study was to examine whether the total daily dose of zinc might explain part of the variation in the results. METHODS: The Medline, Scopus and Cochrane Central Register of Controlled Trials data bases were searched for placebocontrolled trials examining the effect of zinc lozenges on common cold duration. Two methods were used for analysis: the P-values of the trials were combined by using the Fisher method and the results of the trials were pooled by using the inverse-variance method. Both approaches were used for all the identified trials and separately for the low zinc dose and the high zinc dose trials. RESULTS: Thirteen placebo-controlled comparisons have examined the therapeutic effect of zinc lozenges on common cold episodes of natural origin. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect. Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%). CONCLUSIONS: This study shows 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. The effects of zinc lozenges should be further studied to determine the optimal lozenge compositions and treatment strategies.

Complementary and alternative medicine for prevention and treatment of the common cold

            (Nahas and Balla 2011) Download

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.

Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations

            (Roxas and Jurenka 2007) Download

The common cold is the leading cause of doctor visits in the United States and annually results in 189 million lost school days. In the course of one year the U.S. population contracts approximately 1 billion colds. Influenza infection is still a leading cause of morbidity and mortality, accounting for 20-25 million doctor visits and 36,000 deaths per year in the United States. Conventional therapies for colds and flu focus primarily on temporary symptom relief and include over-the-counter antipyretics, anti-inflammatories, and decongestants. Treatment for influenza also includes prescription antiviral agents and vaccines for prevention. This article reviews the common cold and influenza viruses, presents the conventional treatment options, and highlights select botanicals (Echinacea spp., Sambucus nigra, larch arabinogalactan, Astragalus membranaceous, Baptisia tinctoria, Allium sativa, Panax quinquefolium, Eleutherococcus senticosus, Andrographis paniculata, olive leaf extract, and Isatis tinctoria) and nutritional considerations (vitamins A and C, zinc, high lactoferrin whey protein, N-acetylcysteine, and DHEA) that may help in the prevention and treatment of these conditions.

Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults

         (Sabetta, DePetrillo et al. 2010) Download

BACKGROUND: Declining serum concentrations of 25-hydroxyvitamin D seen in the fall and winter as distance increases from the equator may be a factor in the seasonal increased prevalence of influenza and other viral infections. This study was done to determine if serum 25-hydroxyvitamin D concentrations correlated with the incidence of acute viral respiratory tract infections. METHODOLOGY/FINDINGS: In this prospective cohort study serial monthly concentrations of 25-hydroxyvitamin D were measured over the fall and winter 2009-2010 in 198 healthy adults, blinded to the nature of the substance being measured. The participants were evaluated for the development of any acute respiratory tract infections by investigators blinded to the 25-hydroxyvitamin D concentrations. The incidence of infection in participants with different concentrations of vitamin D was determined. One hundred ninety-five (98.5%) of the enrolled participants completed the study. Light skin pigmentation, lean body mass, and supplementation with vitamin D were found to correlate with higher concentrations of 25-hydroxyvitamin D. Concentrations of 38 ng/ml or more were associated with a significant (p<0.0001) two-fold reduction in the risk of developing acute respiratory tract infections and with a marked reduction in the percentages of days ill. CONCLUSIONS/SIGNIFICANCE: Maintenance of a 25-hydroxyvitamin D serum concentration of 38 ng/ml or higher should significantly reduce the incidence of acute viral respiratory tract infections and the burden of illness caused thereby, at least during the fall and winter in temperate zones. The findings of the present study provide direction for and call for future interventional studies examining the efficacy of vitamin D supplementation in reducing the incidence and severity of specific viral infections, including influenza, in the general population and in subpopulations with lower 25-hydroxyvitamin D concentrations, such as pregnant women, dark skinned individuals, and the obese.

Zinc for the common cold

            (Singh and Das 2011) Download

BACKGROUND: The common cold is one of the most widespread illnesses and is a leading cause of visits to the doctor and absenteeism from school and work. Trials conducted since 1984 investigating the role of zinc for the common cold symptoms have had mixed results. Inadequate treatment masking and reduced bioavailability of zinc from some formulations have been cited as influencing results. OBJECTIVES: To assess the effect of zinc on common cold symptoms. SEARCH STRATEGY: We searched CENTRAL (2010, Issue 2) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to May week 3, 2010) and EMBASE (1974 to June 2010). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials using zinc for at least five consecutive days to treat, or for at least five months to prevent the common cold. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: We included 13 therapeutic trials (966 participants) and two preventive trials (394 participants). Intake of zinc is associated with a significant reduction in the duration (standardized mean difference (SMD) -0.97; 95% confidence interval (CI) -1.56 to -0.38) (P = 0.001), and severity of common cold symptoms (SMD -0.39; 95% CI -0.77 to -0.02) (P = 0.04). There was a significant difference between the zinc and control group for the proportion of participants symptomatic after seven days of treatment (OR 0.45; 95% CI 0.2 to 1.00) (P = 0.05). The incidence rate ratio (IRR) of developing a cold (IRR 0.64; 95% CI 0.47 to 0.88) (P = 0.006), school absence (P = 0.0003) and prescription of antibiotics (P < 0.00001) was lower in the zinc group. Overall adverse events (OR 1.59; 95% CI 0.97 to 2.58) (P = 0.06), bad taste (OR 2.64; 95% CI 1.91 to 3.64) (P < 0.00001) and nausea (OR 2.15; 95% CI 1.44 to 3.23) (P = 0.002) were higher in the zinc group. AUTHORS' CONCLUSIONS: Zinc administered within 24 hours of onset of symptoms reduces the duration and severity of the common cold in healthy people. When supplemented for at least five months, it reduces cold incidence, school absenteeism and prescription of antibiotics in children. There is potential for zinc lozenges to produce side effects. In view of this and the differences in study populations, dosages, formulations and duration of treatment, it is difficult to make firm recommendations about the dose, formulation and duration that should be used.


References

Banerjee, D. and D. Kaul (2010). "Combined inhalational and oral supplementation of ascorbic acid may prevent influenza pandemic emergency: a hypothesis." Nutrition 26(1): 128-32.

Eby, G. A., 3rd (2010). "Zinc lozenges as cure for the common cold--a review and hypothesis." Med Hypotheses 74(3): 482-92.

Gombart, A. F. (2009). "The vitamin D-antimicrobial peptide pathway and its role in protection against infection." Future Microbiol 4(9): 1151-65.

Grant, W. B. (2010). "Vitamin D supplementation could reduce the risk of type A influenza infection and subsequent pneumonia." Pediatr Infect Dis J 29(10): 987.

Hemila, H. (2011). "Zinc lozenges may shorten the duration of colds: a systematic review." Open Respir Med J 5: 51-8.

Nahas, R. and A. Balla (2011). "Complementary and alternative medicine for prevention and treatment of the common cold." Can Fam Physician 57(1): 31-6.

Roxas, M. and J. Jurenka (2007). "Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations." Altern Med Rev 12(1): 25-48.

Sabetta, J. R., P. DePetrillo, et al. (2010). "Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults." PLoS One 5(6): e11088.

Singh, M. and R. R. Das (2011). "Zinc for the common cold." Cochrane Database Syst Rev(2): CD001364.