Caveat: Whatever we observe in any of the sectors of the immune response does not necessarily transcribe into anything valuable for the patient. We use a complex network comprised of two major categories: innate or natural immunity, and acquired or more specific immunity. But both are connected, interdependent, and, more importantly, do not exist by themselves or as an entity. They do exist and function because they are also connected to other major systems in our body, such as the central nervous system and the endocrine system.
Whatever influences, modifies, enhances or suppresses the immune response (at any stage or level) does not exist by itself, and is not going to have any effect unless it is harmonised, connected and influenced in two ways. One is by a number of other systems in the body, including first and foremost the central nervous system, which includes the mind. Second is the endocrine system, which creates and influences emotions.
What natural immunity does is essentially give us basic protection against most aggressions. These are primarily infectious agents including parasites, which are in the natural environment without hygiene and cause the most deaths among small children. Then, there are other infectious agents like bacteria, viruses, fungi and yeasts; we are pretty well protected against these by our natural immunity, such as the layers at the interface of the environment and ourselves, meaning the skin and the respiratory and digestive mucosae.
This first line of our natural defences is made of immigration officers—the police that stand at the harbours of countries and screen anything that comes in. These are the macrophages and other derived or similar cells. They use a number of chemical weapons to control and eventually destroy the invaders.
The mucus by itself hosts other cells that can be triggered to release mediators that are highly toxic, not only for invaders but to a certain extent to healthy cells that surround these pro-inflammatory-releasing-agent cells. Mast cells in some tissues are notable for that. They do respond to non-specific stimuli including some from the central nervous system, (for example substance P,) and create tremendous local inflammation due to the release of histamine, among other mediators.
This fairly primitive system is mobile to a certain extent, but not that much. So to get a much better line of defence, the immune system uses a number of other cells and molecules.
However, this more specific, educated system needs inflammation; just as the immigration officer screens people, it will also use the ?computer,? look at memorised data and enter other data into that virtual computer. The computer is shared, meaning all the information is immediately accessible, understandable and usable by many other ?departments,? including the equivalents of the departments of Treasury, Defence, Health and Education, or the bunker of the vice president, etc. The memorised information is critical for the efficacy, specificity and absence of side effects, and the absence of civil war that the immune system is supposed to enjoy.
The feeding of information is important. Obviously, in our genes is the material designed to set up what is good and what is potentially bad for us. We can fairly rapidly build a library. We have a library when we are born, and we can extend the number of volumes in the library that will allow us to identify what is good and bad for us; be more specific in what we ingest and digest to use as bricks and mortar for our bodies; and what we reject. An excellent overview of the immune system, its components, roles and future implications was prepared by the National Cancer Institute.1
Implications and questions:
FF&N: Given the delicious metaphors you?ve been providing, your description of the integration of the immune system and its communication with the other endocrine and organ networks in the body, one question arises. That is, can an ingredient that?s claimed to have an effect on a snapshot of an entire movie of the human immune system influence the host, and is that enough for a company to pursue a product?
An example is the interest focused on NK cells and agents that up-regulate or increase their activity, the assumption being that this will increase immune vigilance against tumours and other external invaders. Yet there is an absence of controlled studies showing that if you give an NK cell-activating agent to a population, the incidence and/or duration of severity of an infection will be changed favourably. The vast majority of the evidence that exists is based on surrogate markers, which are only suggestive; very few studies have been designed and have consumer-relevant outcomes. The consumer doesn?t care and cannot measure NK cell activity, but can tell you over the course of a season whether she has gotten sick fewer times. Given that as the ultimate end point of a product, why are there so few existing products that can actually make such a claim, and what in your mind rises to the top of consumer-relevant outcomes after oral use?
FF&N: It?s a major problem in communication between scientists and the commercial world. Science is uncovering things but doesn?t make a judgement, doesn?t say: ?This is important; this is very important; this is somewhat important; this is it.? Marketing people find an idea seductive and build a story around it.
NK cells are just a tiny part of our immune system. If you stimulate the NK cells, make them very alert, this doesn?t mean that more than 98 per cent of the rest of the immune system will follow. It may; it may not. Therefore, it?s not because you have alert NK cells that you are going to avoid the common cold or not suffer diarrhoea. We don?t know! We need clinical studies; they have to be well conducted; the protocols have to be very good; and people must not cook the books to get nice readings.
FF&N: Is there anything that comes to mind that confidently demonstrates a reduction or prevention of infection, the most prevalent concern and target for marketing products?
FF&N: One that rises to the top is probiotics. We have clinical evidence, among large populations, that eating probiotics, preferably as a food like yoghurt, but also as capsules, does prevent the spread of infectious agents, such as rotavirus, in humans.
FF&N: How about adults? An agent that influences infections in adults, not limited to rotaviruses?
FF&N: Could these results be due to a result of fermentation, effecting a positive outcome with respect to incidence of infection?
FF&N: About this issue—and many more—there?s an excellent review just published in the American Journal of Clinical Nutrition.12 In the early 1990s, I conducted studies in the Davis-Sacramento, California, area; these were conducted on healthy young and senior adults.13,14 We reported a significantly lower incidence of seasonal (summer) diarrhoea, associated with clinical symptoms of ?infection,? only in the group consuming yoghurt with ?live active cultures,? but not in the groups consuming ?killed? yoghurt, or no yoghurt.
FF&N: Recent research found that heat-killed probiotics had an effect, suggesting that the immunoprotective effects are due to the ingestion of nucleic acids. This raises the suggestion: Does it have to be a live organism for all applications, or if a product is losing live count over time, could it still induce a positive effect?
FF&N: A recent article is reporting results with Lactéol Fort (Lactobacillus acidophilus LB) vs placebo in Thai children with severe infectious diarrhoea.15 Seventy-three children (37 L. acidophilus LB, 36 placebo) were enrolled, of whom 40 (17 L. acidophilus LB, 23 placebo) received an antibiotic before inclusion. Rotavirus was identified in approximately 50 per cent of the children in each group. After 24 hours of treatment, the number of rotavirus-positive children with watery stools was significantly lower in the L. acidophilus LB group. Mean duration of diarrhoea was decreased with L. acidophilus LB (43.4 hours) vs placebo (57 hours). This decreased duration was particularly marked in children with no antibiotic therapy before inclusion (31.1 hours): 42.9 hours for the L. acidophilus LB group versus 74.0 hours for the placebo group.
Lactéol Fort sachets is a pharmaceutical preparation containing a lyophilizate of heat-killed L. acidophilus LB (10 billion/ml) and fermented culture medium, which together are responsible for the pharmacological activity. The strain was isolated from a human stool and identified as L. acidophilus (called LB) in accordance with the Bergey?s Manual of Determinative Bacteriology.
In another study, Lactéol Fort proved more effective than live Lactobacilli.16
FF&N: The mechanism of action is not yet established. It may be linked to the bacteria colonising the gut, but this may not always be the case since faecal counts do not always confirm gut colonisation.
FF&N: We are entering poorly chartered waters. I would refer everyone to reference 13. Remember that, as adults, we harbour more than 100 billion live bacteria in our guts (mostly in the colon), of more than 400 different species! Then if every day we take two to four standard yoghurts, with a few million live bacteria, chances for changing a normal—or slightly perturbed—colonic microbial environment are slim. Conversely, live lactic bacteria from yoghurt are potentially very dangerous in immunosuppressed patients.17,18
FF&N: Given the primary creation of products for consumers that boost or up-regulate the immune response, there?s the possibility of an overreaction or overstimulation that could result in an auto-immune phenomenon, or, for those with an auto-immune condition, an undesirable effect. An article was just published describing three people taking echinacea or Spirulina/Aphanizomenon (a different blue-green alga) who experienced actual initiation or flare-up of auto-immune conditions.19 Is that a viable concern from your perspective in terms of how a product should be labelled?
FF&N: We have a problem with statistics. One in 100 looks very nice, but if you?re the one it?s meaningless. Either you consider statistics and take echinacea; there?s a greater than 99 per cent chance you?ll be all right, but if you?re the one who gets worse, you don?t care about the 99 others! The difference between statistics and the practice of medicine is tremendous.
FF&N: Would you recommend a label statement that addresses individuals or patients with certain conditions, says that they should take it only after consultation with their physician? Example: an immune product in the hands of a rheumatoid arthritis or lupus patient.
FF&N: If there is any trace of such effects or risks in the published medical/scientific literature, the answer is yes, it would be advisable to have a careful but clear wording that would warn the consumer and could appear as a valid disclaimer.
FF&N: Getting back to the common cold, anything conclusive with echinacea?
FF&N: The latest study was a randomised, double-blind, placebo-controlled trial conducted in New Jersey to evaluate the ability of Echinacea purpurea to prevent infection with rhinovirus RV-39. Forty-eight healthy adults received echinacea or placebo, 2.5ml 3 times/day, for 7 days before and 7 days after intranasal inoculation with RV-39. Symptoms, viral cultures, serologic studies were assessed. 92 per cent of echinacea and 95 per cent of placebo recipients were infected. Colds developed in 58 per cent of echinacea and 82 per cent of placebo recipients. Because of the small sample size, echinacea taken before and after exposure to rhinovirus did not reach statistical significance in its ability to decrease the rate of infection in this small but excellent study.20
The approach to a common respiratory infection is difficult in clinical practice. Many environmental factors are known but uncontrollable; many remain unknown. We don?t know exactly the respective beneficial pro-inflammatory (but very unpleasant) role of ICAM-1, the intercellular adhesion molecule #1 that also serves as the port of entry of rhinoviruses. Some suspect it also has beneficial effects. If you are going to try to suppress ICAM-1 to make people feel better, you may in fact prolong and disseminate the infection and the infectious agent, so that may not be the best thing to do.
Besides, the rhinoviruses by themselves are infectious, true, but they elicit a pretty big inflammatory and painful reaction; therefore, their spread is generally limited. If you don?t allow for the rapid formation of inflammation, these viruses will open the door to much more dangerous microbes, like multi-resistant Streptococcus pneumoniae, and you may end up with lethal meningitis.
It?s also true that spreading infection, such as the common cold, can be efficiently controlled by washing your hands. It works: You don?t transmit colds if you wash your hands immediately after blowing your nose. One should not avoid considering these and other factors while concentrating on a pseudo-panacea like a gel or a lozenge of zinc.
FF&N: Let?s venture into the area of zinc, both orally and intranasally, to prevent or treat upper respiratory tract infections. Given your understanding of the literature and the equivocal literature behind the zinc swab that goes up the nose (Zicam) and the increasing reports linking impairment in sense of smell among users of the Zicam swabs in the nose, what is your take on the use of zinc or zinc lozenges for prophylactic or therapeutic treatment against colds or flu?
FF&N: First, topical zinc. The study on Zicam involved 213 patients with recent-onset cold symptoms, of whom 108 received Zicam and 105 placebo.21 Duration of symptoms was 2.3 (+/-0.9) days in the zinc group, and 9 (+/-2.5) days in the control group. Another study confirmed these results, but was less impressive: 4.3 days (Zn) vs 6 days (placebo).22 However, a nasal spray of 0.12 per cent zinc sulphate had no effect on the duration of the common cold.23
The zinc lozenge is a different story. The most publicised studies, with a positive outcome, were open-label ones, supported by the manufacturer.24 A randomised, double-blind placebo-controlled study using 12.8mg of zinc acetate every 2-3 hours while awake was conducted on 50 ambulatory volunteers recruited within 24 hours of developing symptoms of the common cold. A number of symptoms were recorded daily for 12 days. Plasma zinc and proinflammatory cytokine levels were measured on day 1, and after participants were well.
Compared with the placebo group, the zinc group had shorter mean overall duration of cold symptoms (4.5 vs 8.1 days), cough (3.1 vs 6.3 days), and nasal discharge (4.1 vs 5.8 days). There was no difference in the cytokine levels between the two groups.25 However, in an editorial accompanying the article, Norman A Desbiens points to the poor blinding on the study despite the effort to provide a placebo lozenge ?identical in weight, appearance, flavour and texture?; he also reminds us that ?anything tasting as bad as zinc and with as much aftertaste as zinc must be good medicine.?26,27 I?ll get back to this issue when discussing traditional Chinese medicine. (See sidebar, below.)
But zinc has proven life-saving in children with pneumonia.28,29 A zinc compound (zinc-carnosine, polaprezinc) enhances the response to interferon therapy in patients with chronic hepatitis C,30 controls growth and proliferation of Helicobacter pylori in the stomach,31,32 improves the efficacy of the combination antibiotics/proton-pump-inhibitor in the healing of gastric ulcers,33,34 and can be considered an ?ulcer healer.?35
There are two other ingredients that warrant mention. An immunoregulator is any substance that can quiet or activate the immune system, depending on circumstances. Medicinal mushrooms can help the immune system stay awake and strike the perfect balance between overactivity and sluggishness. Weakening of the immune system is constant as we age after puberty and is associated with a rise in disease rates.
Beta-glucans are polysaccharides found in mushrooms that give them some medicinal properties. They bind to certain receptors on the surface of macrophages and other white blood cells, and have been shown to stimulate the production of some cytokines.36
Medicinal mushrooms also contain terpenoids with anti-infectious properties. Bioxanthracenes from Cordyceps pseudomilitaris BCC 1620 demonstrated anti-malarial activity.37Lentinula edodes (shiitake) fights oral bacteria vs caries; mycelium-free culture fluid was bacteriostatic vs Streptococcus pyogenes, Staphylococcus aureus and Bacillus megaterium; and the active substance is heat-stable with MW ~1000, probably Lenthionine (S).38
Xylitol is a sugar alcohol initially isolated in Finland from the sap of the birch tree. It reduces caries by inhibiting Streptococcus mutans, prevents adhesion of some pathogens to mucosal cells (in the mouth), and has significant effect on the intestinal flora. A quantity of 1-5 per cent xylitol reduced growth of hemolytic Streptococci. Xylitol chewing gum significantly reduced the incidence of acute otitis media in children.39
FF&N: Any parting thoughts?
FF&N: You can add some prayer, pilgrimages, meditation, yoga; lots of things work. People who can control their emotions and eventually make their central nervous system work so that it does influence their immune response are generally much better off. We do know that people who have a positive attitude toward life generally enjoy a much better immune response.
Georges M Halpern, MD, PhD, is distinguished professor of pharmaceutical sciences, Hong Kong Polytechnic University. Anthony L. Almada, MSc, is founder & CSO of IMAGINutrition Inc, in California. Todd Runestad is FF&N science editor.
Respond: [email protected]
All correspondence will be forwarded to the authors.
1. Understanding the Immune System. http://press2.nci.nih.gov/sciencebehind/immune/immune00.htm
2. Henderson R. Simple steps to minimize chance of traveler?s diarrhea. J Occup Med 1982; 24:184.
3. Gorbach SL. Lactic acid bacteria and human health. Ann Med 1990; 22:37-41.
4. Marteau PR, et al. Protection from gastrointestinal diseases with the use of probiotics. Am J Clin Nutr 2001; 73:430S-436S.
5. Lewis SJ, Freedman AR. The use of biotherapeutic agents in the prevention and treatment of gastrointestinal disease. Aliment Pharmacol Ther 1998; 12:807-22.
6. Erickson KL, Hubbard NE. Probiotic immunomodulation in health and disease. J Nutr 2000; 130:S403-9.
7. Gismondo MR, Drago L, Lombardi A. Review of probiotic available to modify gastrointestinal flora. Int J Antimicrob Agents 1999; 12:287-92.
8. D?Souza AL, et al. Probiotics in prevention of antibiotic associated diarrhoea: meta?analysis. BMJ 2002; 324:1361?6.
9. Sakamoto I, et al. Suppressive effect of Lactobacillus gasseri OLL 2716 (LG21) on Helicobacter pylori infection in humans. J Antimicrob Chemother 2001; 47:709-10.
10. Oh Y, et al. Folk yoghurt kills Helicobacter pylori. J Appl Microbiol 2002; 93:1083-8.
11. Sheu BS, et al. Impact of supplement with Lactobacillus- and Bifidobacterium-containing yogurt on triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther 2002; 16:1669-75.
12. Bourlioux P, et al. The intestine and its microflora are partners for the protection of the host: report on the Danone Symposium ?The Intelligent Intestine? held in Paris, June 14, 2002. Am J Clin Nutr 2003; 78:675-8.
13. Halpern GM, et al. Influence of long-term yogurt consumption in young adults. Int J Immunother 1991; 7:205-210.
14. Trapp CL, et al. The influence of chronic yogurt consumption on populations of young and elderly adults. Int J Immunother 1993; 9:53-64.
15. Simakachorn N, et al. Clinical evaluation of the addition of lyophilized, heat-killed Lactobacillus acidophilus LB to oral rehydration therapy in the treatment of acute diarrhea in children. J Ped Gastroenter Nutr 2000; 30:60-72.
16. Xiao SD, et al. Multicenter, randomized, controlled trial of heat-killed Lactobacillus acidophilus LB in patients with chronic diarrhea. Adv Therapy 2003; 20:253-260.
17. MacGregor G, et al. Yoghurt biotherapy: contraindicated in immunosuppressed patients? Postgrad Med J 2002; 78:366-7.
18. Presterl E, et al. Endocarditis by Lactobacillus rhamnosus due to yogurt ingestion. Scand J Infect Dis 2001; 33:710-4.
19. Lee AN, Werth VP. Activation of autoimmunity following use of immunostimulatory herbal supplements. Arch Dermatol 2004; 140:723-7.
20. Sperber SJ, et al. Echinacea purpurea for prevention of experimental rhinovirus colds. Clin Infect Dis 2004; 38:1367-71
21. Hirt M, et al. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J 2000; 79:778-80,782.
22. Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM 2003; 96:35-43.
23. Belongia EA, et al. A randomized trial of zinc nasal spray for the treatment of upper respiratory illness in adults. Am J Med 2001; 111:103-8.
24. McElroy BH, Miller SP. An open-label, single-center, phase IV clinical study on the effectiveness of zinc gluconate glycine lozenges (Cold-EEze) in reducing the duration and symptoms of the common cold in school-aged subjects. Am J Ther 2003; 10:324-9.
25. Prasad AS, et al. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. Ann Intern Med 2000; 133:245-52.
26. Desbiens NA. Lessons learned from attempts to establish the blind in placebo-controlled trials of zinc for the common cold. Ann Intern Med 2000; 133:302-3.
27. Farr BM, Gwaltney JM Jr. The problems of taste in placebo matching: an evaluation of zinc gluconate for the common cold. J Chronic Dis 1987; 40:875-9.
28. Brooks WA, et al. Zinc for severe pneumonia in very young children: double-blind placebo controlled trial. Lancet 2004; 363:1683-8.
29. Bhandari N, et al. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ 2002; 324:1358.
30. Takagi H, et al. Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat 2001; 8:367-71.
31. Sunairi M. Effect of Z-103, a new anti-ulcer agent on Helicobacter pylori. Jpn Pharmacol Ther 1994; 23:3771-5.
32. Wollschlaeger B. Zinc-carnosine for the management of gastric ulcers: clinical application and literature review. JANA 2003; 6(2):32-9.
33. Hojo M, et al. Do mucosal defensive agents improve the cure rate when used with dual or triple therapy regimens for eradicating Helicobacter pylori infection? Aliment Pharmacol Ther 2000; 14:193-201.
34. Kashimura H, et al. Polaprezinc, a mucosal protective agent, in combination with lansoprazole, amoxicillin and clarithromycin increases the cure rate of Helicobacter pylori infection. Aliment Phamacol Ther 1999; 13:483-7.
35. Halpern GM. Ulcer Free! Nature?s safe and effective remedy for ulcers. SquareOne Publ, Garden City Park, NY, 2004. 1 vol, 196p.
36. Halpern GM, Miller AH. Medicinal mushrooms: ancient remedies for modern ailments. M Evans & Co, New York. 2002; 172p.
37. Jaturapat A, et al. Bioxanthracenes from the insect pathogenic fungus. Cordyceps pseudomilitaris BCC 1620. I. Taxonomy, fermentation, isolation and antimalarial activity. J Antibiot (Tok) 2001; 54:29-35.
38. Hatvani N. Antibacterial effect of the culture fluid of Lentinus edodes mycelium grown in submerged liquid culture. Int J Antimicrob Agents 2001; 17:71-4.
39. Uhari M, et al. Xylitol in preventing acute otitis media. Vaccine 2000 Dec 8; 19 Suppl1:S144-7.