Literature Review and Commentary

by Alan R. Gaby, MD

Since infectious disease is the theme of this issue of the Townsend Letter, I thought it would be useful to review some of my favorite studies on the use of natural remedies for the prevention and treatment of infections. You will note that some of the studies are relatively recent, some date back more than 20 years, and some are more than 40 years old. Many of these “older” studies failed to attract the interest of the mainstream medical community and were never followed up by other researchers. However, they appear to be effective in clinical practice.

Vitamin C for the Common Cold

Eight hundred eighteen volunteers who normally experienced at least one cold per winter were randomly assigned to receive, in double-blind fashion, vitamin C (250 mg 4 times per day, as a mixture of ascorbic acid and sodium ascorbate) or placebo for a mean of 103 days during the winter. At the first sign of any illness, the dosage of vitamin C or placebo was increased to 1 g four times per day. The proportion of subjects who remained free of illness during the study was significantly higher in the vitamin C group than in the placebo group (26% vs. 18%, p < 0.05). The mean number of illnesses was nonsignificantly lower by 7% in the vitamin C group than in the placebo group. The mean total number of days confined to the house because of illness was 30.4% less in the vitamin C group than in the placebo group (p < 0.001). The difference between groups was most marked with respect to constitutional symptoms such as malaise, fever, and chills. Less marked differences were seen for symptoms referable to the nose, throat, and chest. The reduction in days of disability was seen with all types of acute illness, including those that did not involve the upper respiratory tract.

Comment: Vitamin C has demonstrated an antiviral effect in vitro, and it also enhances immune function. Leukocyte vitamin C concentrations have been found to fall precipitously (to the levels seen in people with scurvy) within 24 hours of the onset of a cold.¹ This decline is presumably due to increased vitamin C utilization for implementation of tissue defense mechanisms.² Supplementation with 200 mg per day of vitamin C had no effect on the decline in leukocyte vitamin C levels during colds. However, the decline was largely prevented by prophylactic administration of 1 g per day of vitamin C, increased to 6 g per day for three days at the first sign of a cold.

In the present study, treatment with 1 g of vitamin C four times per day significantly decreased the number of days people had to stay home because of colds or other illnesses. Vitamin C also decreased the number of illnesses by 7%, but that decrease was not statistically significant. Numerous other studies have examined whether vitamin C is an effective treatment for the common cold. Most, though not all, of these studies have reported results similar to those of the present study.

Anderson TW, et al. Vitamin C and the common cold: a double-blind trial. Can Med Assoc J. 1972;107:503-508.

Zinc Lozenges for the Common Cold

One hundred employees of the Cleveland Clinic who developed cold symptoms were randomly assigned to receive, in double-blind fashion, zinc gluconate lozenges (containing 13.3 mg of zinc per lozenge) or placebo. Treatment was begun within 24 hours of the onset of symptoms. The patients dissolved a lozenge in the mouth every two hours while awake, for as long as they had cold symptoms. Median time until symptoms resolved was significantly shorter by 42% in the zinc group than in the placebo group (4.4 vs. 7.6 days; p < 0.001).

Comment: Zinc ions have been reported to inhibit the replication of rhinovirus (a virus that causes colds) in vitro. Ionized zinc may also protect cells from damage by viral toxins. In this study and several other studies, the use of zinc lozenges significantly decreased the duration of cold symptoms.

However, zinc lozenges were not beneficial in several other studies. It has been argued that the negative results in these studies were due to a failure of the lozenges to release zinc ions in the oral cavity. Loosely bound zinc salts such as zinc gluconate and zinc acetate would be expected to release zinc ions more effectively than more tightly bound zinc salts such as zinc picolinate, zinc citrate, zinc orotate, and zinc aspartate. In addition, certain flavoring agents or excipients such as citric acid, mannitol, sorbitol, and tartrate may chelate zinc and prevent it from ionizing in the mouth. Zinc products that have been demonstrated to be effective for adults contain zinc gluconate or zinc acetate, do not contain citric acid, mannitol, sorbitol, or tartrate, and do not contain fatty acids that have been heated to high temperatures. Zinc lozenges do not appear to be beneficial for children or adolescents with colds.

Mossad SB, et al. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med. 1996;125:81-88.

Probiotic Prevents Urinary Tract Infections

Two hundred fifty-two postmenopausal women (mean age, 64 years) with at least three self-reported symptomatic urinary tract infections (UTIs) in the previous year were randomly assigned to receive, in double-blind fashion, antibiotic prophylaxis (480 mg of trimethoprim-sulfamethoxazole once a day) or oral capsules containing 10⁹ colony-forming units of Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 twice a day for 12 months. During the trial, as compared with the year before the trial, the number of UTI episodes fell by 58.5% in the antibiotic group and by 51.4% in the probiotic group (difference not statistically significant). In the antibiotic group, resistance of uropathogenic Escherichia coli to trimethoprim-sulfamethoxazole and to amoxicillin increased from 20-40% at baseline to 80-95% after one month of treatment. In contrast, resistance to these antibiotics did not occur during probiotic treatment.

Comment: Lactobacilli and other probiotics are normal inhabitants of the vagina. Probiotics may help prevent the development of UTIs by competitively excluding pathogenic organisms and by producing compounds that inhibit the growth of these pathogens. In the present study, two specific probiotic strains were nearly as effective as antibiotics for preventing UTI recurrences in postmenopausal women. These strains may be preferable to other probiotic organisms for preventing and treating UTIs since they appear to be more effective at colonizing the vaginal mucosa and inhibiting bacteria that cause UTIs. L. rhamnosus GR-1/L. reuteri RC-14 is available in the US under the names Pro-Flora Women’s Probiotic (Integrative Therapeutics), Fem-Dophilus (Jarrow), and UltraFlora Women’s (Metagenics).³

Beerepoot MA, et al. Lactobacilli vs antibiotics to prevent urinary tract infection. A randomized, double-blind, noninferiority trial in postmenopausal women. Arch Intern Med. 2012;172:704-712.

D-Mannose Prevents Urinary Tract Infections

Three hundred eight women (aged 29-58 years) with an acute urinary tract infection (UTI) and a history of recurrent UTIs were treated with ciprofloxacin (500 mg twice a day for 1 week) and were then randomly assigned to receive 2 g of D-mannose in 200 ml of water once a day in the evening, 50 mg of nitrofurantoin once a day in the evening, or no prophylaxis (control group) for six months. Women with urinary tract anomalies, interstitial cystitis, or diabetes, and those who were pregnant or taking hormone therapy or contraceptives were excluded. During the study, 98 women (31.8%) had a recurrent UTI. The recurrence rate was significantly lower in the groups that received D-mannose (14.6%) and nitrofurantoin (20.4%) than in the control group (60.8%) (p < 0.001). The recurrence rate did not differ significantly between the D-mannose and nitrofurantoin groups. The incidence of side effects was significantly lower in the D-mannose group than in the nitrofurantoin group (8% vs. 27%; p < 0.0001). The only side effect of D-mannose was diarrhea, which occurred in 8% of patients and did not require discontinuation of treatment.

Comment: About 25 years ago, Dr. Jonathan Wright began using D-mannose (a sugar structurally similar to glucose) to prevent and treat UTIs. This treatment was based on in vitro evidence that D-mannose prevents uropathogenic Escherichia coli from adhering to the epithelial cells of the genitourinary tract. Since then Dr. Wright has administered D-mannose to hundreds of patients. In his experience, it is effective in 85-90% of patients, although it is not effective for UTIs caused by organisms other than E. coli.

For treatment of UTIs, Dr. Wright recommends a dosage of 1 teaspoonful (about 2 g) for adults and 1/2 to 1 teaspoonful for children, dissolved in a glass of water or juice and repeated every two to three hours. Treatment should be continued for two to three days after symptoms have disappeared.⁴

Many practitioners are now using D-mannose because of the writings and teachings of Dr. Wright. Informal surveys that I conducted at medical conferences revealed that these practitioners generally concur with Wright’s observations. The results of this randomized controlled trial from 2014 confirm the anecdotal evidence regarding the efficacy of D-mannose.

Kranjcec B, Papes D, Altarac S. D-Mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014;32:79-84.

Green Tea Extract Prevents Influenza

One hundred twenty-four elderly residents of a nursing home in Japan (mean age, 83 years) gargled three times per day with an aqueous solution of green tea catechins (polyphenon E; 200 µg/ml) or with a control solution for three months during the winter. The concentration of catechins in the gargles of the active-treatment group was half that of commercial green tea beverages. It was not stated whether the study was randomized or blinded. All participants received an influenza vaccine. The incidence of influenza during the study was significantly lower in the active-treatment group than in the control group (1.3% vs. 10.4%; p < 0.03). No adverse effects were observed.

Comment: In this study, gargling with an aqueous solution that contained a green tea extract decreased the incidence of influenza in elderly nursing home residents. In another randomized controlled trial, administration of a proprietary green tea extract (1 capsule twice a day for 3 months) to young healthy volunteers decreased the number of days with cold or flu symptoms by 35.6%, compared with placebo (p < 0.002).⁵ Green tea extracts may work in part by inhibiting the growth of influenza virus, an effect that has been demonstrated in vitro.⁶ Green tea extracts also enhance the function of a subset of T cells that play a role in the immune response.⁵ Based on this research, it would seem reasonable to expect that regularly drinking green tea could also help prevent influenza.

Yamada H, et al. Gargling with tea catechin extracts for the prevention of influenza infection in elderly nursing home residents: a prospective clinical study. J Altern Complement Med. 2006;12:669-672.

Vitamin A for Chickenpox

Ninety-three children with chickenpox who had no clinical evidence of vitamin A deficiency were randomly assigned to receive a single dose of vitamin A (200,000 IU) or placebo. In addition, eight exposed siblings who had not yet shown signs of illness were given the same dose of vitamin A during the incubation period. Crusting of the lesions (a sign of recovery) occurred significantly earlier in the vitamin A group than in the placebo group (mean, 5.34 vs. 6.37 days; 16.2% reduction; p < 0.01). Fewer children developed complications (viral pneumonia, conjunctivitis, or gastroenteritis) in the vitamin A group than in the placebo group (0 vs. 5). Among vitamin A-treated siblings, mean time to healing was only 5.1 days, even though secondary cases in the same household are normally expected to be more severe than initial cases.

Comment: Vitamin A plays a role in immune function. In addition, vitamin A has been shown to inactivate a number of different viruses in vitro. Most infections provoke an acute-phase response that reduces the synthesis of retinol-binding protein in the liver, and thereby decreases circulating vitamin A levels. Moreover, urinary excretion of vitamin A increases during infections, particularly infections associated with fever. Therefore, infections may lead to low vitamin A status or to a decreased capacity to mobilize vitamin A to areas in the body where it is needed. These changes could, in turn, reduce a person’s ability to combat the infection. In numerous studies, treatment with vitamin A significantly decreased morbidity and mortality in patients with measles. The present study demonstrated that vitamin A is also beneficial in the treatment of chickenpox.

Ozsoylu S, Cemeroglu AP, Gunay M. Vitamin A for varicella. J Pediatr. 1994;125:1017-1018.

Bromelain for Sinusitis

Fifty-nine patients with acute or chronic sinusitis, most of whom had an allergic background with superimposed bacterial infection, were randomly assigned to receive, in double-blind fashion, an enteric-coated bromelain preparation (Ananase; 40 mg 4 times per day) or placebo for six days. Conventional treatments, including antibiotics, decongestants, or both, were also given. The proportion of patients who had an excellent response was significantly higher in the bromelain group than in the placebo group (69% vs. 23%; p < 0.01).

Comment: Bromelain is an extract of pineapple stem that has anti-inflammatory and fibrinolytic activity. Through its de-polymerizing action on fibrin and other inflammatory products, bromelain appears to increase the permeability and reduce the viscosity of inflammatory exudates, thereby promoting drainage and enhancing access of antibacterial agents (i.e., antibodies, other components of the immune system, and antibiotics) to the site of an infection.

The enteric-coated product used in this study was a prescription medication that is no longer commercially available. Non-enteric-coated bromelain would presumably be partially inactivated by gastric enzymes after ingestion. While clinical experience suggests that currently available bromelain products have beneficial effects, dosage comparisons with Ananase are difficult. For non-enteric-coated bromelain, a dosage of 250-500 mg 4 times per day would be reasonable for the short-term treatment of sinusitis.

Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye Ear Nose Throat Mon. 1967;46:361-365.

Probiotic Prevents Clostridium difficile Infections

One hundred twenty-four patients with Clostridium difficile infection were treated with vancomycin or metronidazole and were randomly assigned to receive, in double-blind fashion, Saccharomyces boulardii (500 mg twice a day) or placebo for four weeks. The patients were then followed for an additional four weeks. The probability of a recurrence during the follow-up period was 57% lower in the S. boulardii group than in the placebo group (p < 0.05).

Comment: C. difficile is a Gram-positive bacterium that is a common cause of antibiotic-associated diarrhea and pseudomembranous colitis. It occurs most often in frail, elderly hospitalized patients but has also been seen in previously healthy individuals. C. difficile infection usually manifests as mild-to-moderate diarrhea, but severe colitis culminating in colectomy or death may also occur. Since around the year 2000, there has been a marked increase in the incidence of C. difficile infection. Increases in disease severity and mortality rates have also been observed, apparently because of the emergence of a more virulent strain of the organism. C. difficile infection is usually treated with vancomycin or metronidazole. The infection recurs in approximately 20% of patients after treatment with these antibiotics; and in patients who have a recurrence, subsequent recurrences are even more frequent.

The present study demonstrates that treatment with Saccharomyces boulardii, which is a fungal probiotic organism, can decrease the recurrence rate of C. difficile infections.

McFarland LV, et al. A randomized placebo-controlled trial of Saccharomyces boulardii in combination with standard antibiotics for Clostridium difficile disease. JAMA. 1994;271:1913-1918.