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A growing body of literature points toward the ability of various Panax spp. extracts to influence several immune pathways, including both specific (adaptive) and nonspecific (innate) mechanisms.44,45,46,47,48,49,50,51,52,53,54,55,56,57 Enhanced NK cell activity is perhaps best substantiated, having been reported in several different models from several different laboratories.57,58,59,60,61 In addition to evidence of enhanced innate cellular immunity, there is some indication of adaptive immune activity in the form of vaccine adjuvant effects.62,63,64,65,66,67,68 While most of this work is based on P. ginseng (containing both polysaccharides and ginsenosides), an article by Assinewe et al8 reported that polysaccharide-rich extracts, but not ginsenoside-rich extracts, of P. quinquefolius could stimulate ex vivo rat macrophages to secrete the inflammatory cytokine TNF-α.

Despite these indications of immunological activity from Panax extracts, evidence from randomized controlled trials (RCTs) on human subjects is limited, and clinical utility is controversial.69,70,71,72,73 Prevention of viral respiratory infection (colds and flu) is one potential use of immunomodulation that enjoys some support from controlled trials. The COLD-fX product detailed in this monograph is one good example of a well-defined ginseng extract being subjected to both immunological bioactivity assessment and clinical trials.

CVT-E002/COLD-fX use is supported by both pre-clinical and clinical research. Several laboratory models and methods have indicated immunomodulation. One pilot,14 one phase II study,15 and one confirmatory trial16 have reported evidence suggesting ability to prevent acute respiratory infection. If this is confirmed in future trials, CVT-E002/COLD-fX will become one of the very few—if any—therapies proven to prevent respiratory infection. The benchmark for accepting these results will be high, due to a history of false starts and contradictory evidence with both nutritional and herbal dietary supplements used for both prevention and treatment of ARI. For example, vitamin C, echinacea (Echinacea spp.), and zinc are each supported by roughly equivalent data supporting and refuting preventive efficacy with more than a dozen trials and more than 2,000 participants being studied for each intervention.74,75,76 Also by comparison, 7 trials with at least 896 participants have been published on a proprietary Andrographis and Eleutherococcus extract (containing proprietary extracts of Andrographis paniculata [Burm. F.] Nees (Acanthaceae) [SHA-10] and Eleutherococcus senticosus [Rupr. & Maxim.] Maxim. (Araliaceae), sold as Kang Jang®, SHA-10, Swedish Herbal Institute, Goteborg, Sweden). These trials demonstrate mostly positive results for treating symptoms of ARI and preliminary evidence for a possible preventive effect.77,78 There is longstanding controversy regarding modulation of the non-specific innate immune system in a way that can reduce susceptibility to infectious disease. Epidemiological and prospective cohort data suggest that exercise, nutrition, non-smoking, and positive psychological and social health are associated with greater resistance to respiratory infection, but randomized trials supporting specific interventions are lacking.79,80,81,82 While it is clear that specific adaptive antibody-mediated immunity can be enhanced by immunization, the vast number of antigenic strains of ARI viruses makes immunization impractical.83,84 Influenza is a special case, with a coordinated global effort aimed at detecting emerging strains and producing vaccinations (“flu shots”) in time for each annual epidemic. However, even the highly recommended flu shot is only partially effective, with as many as 30% to 40% of elderly recipients failing to mount a protective antibody response.85,86 If it turns out that specially formulated extract preparations from ginseng such as CVT-E002/COLD-fX are effective for prevention of influenza illness, the next question will be whether these preventive phytomedicines can enhance the effects of flu shots, prevent infection, and reduce morbidity and mortality.

It should be noted that CVT-E002/COLD-fX is not alone in the literature of ginseng-based extracts employed for immune enhancement and ARI prevention. For example, a ginsenoside-containing extract of P. ginseng root marketed as Ginsana® (G115®; Pharmaton, Lugano, Switzerland) has enjoyed a history of both pre-clinical and clinical evaluation. Reported immunomodulatory activities have included lymphocyte proliferation, NK cell stimulation, and enhanced cytokine production in a mouse model.87,88 Activation of human lymphocytes in vitro has also been reported.47 In contrast to CVT-E002, the G115 formulation is standardized to 4% ginsenosides, not polysaccharides, and is clearly a very different formulation.

At least 2 clinical trials have been reported with varieties of the G115 extract in testing for immunological parameters and ARI. In 1990, Scaglione et al published a study in which 60 human subjects ingested either of 2 extracts at 100 mg 2 times daily for 8 weeks.67 Blood samples were drawn at intake, then at 4 and at 8 weeks. A battery of immunoassays were conducted, including cell counts and functional assessments of neutrophil, natural killer cells, and T3, T4, and T8 lymphocytes. Increased chemotaxis, phagocytosis, and cellular proliferation were reported for many, but not all, of the measured outcomes.

In 1996, Scaglione and colleagues reported a double-blinded RCT among 227 adults, and reported fewer colds in the G115 group compared to the placebo group during 12 weeks of preventive treatment and observation (42 vs. 15 cases; p < 0.001).89 Flu shots were given in the fourth week. Anti-influenza antibody titers and NK cell activity were assessed at weeks 4, 8, and 12. Increases in antibody titer (272 vs. 171 units; p < 0.001) and NK activity (46.0 vs. 26.7; p < 0.001) were most prominent at week 8. Limitations include lack of proof of blinding, as well as lack of important detail concerning laboratory procedures and statistical techniques.