Is nutritional therapy of value in preventing infectious diseases in the developed world? There is a large body of evidence that supports the thesis that insufficient intake of dietary protein adversely affects the immune system and predisposes the malnourished to infectious diseases [
3‐
5]. This inadequate protein intake is usually coupled with reduced intake of calories and is referred to as protein-calorie malnutrition (PCM).
Protein
Since there are no prospective studies in which protein intake is manipulated in order to assess infection risk in non-hospitalized people, indirect studies must be evaluated. The use of serum albumin as an indicator of protein intake is fraught with problems as chronic illnesses in themselves may prevent adequate protein intake and may inhibit the synthesis of albumin [
6].
Preoperative albumin levels have been shown to correlate with the postoperative risk for pneumonia, urinary tract infections and wound infections in a large Veterans Administration study [
7]. This study did not deal directly with nutrition, however. A more relevant study looked at 1,023 acute trauma patients admitted to a Baltimore hospital. Since these patients were acutely ill due to a non-medical condition, their albumin levels were more likely to reflect previous nutritional status rather than previous medical illness. There was a 48% incidence of infection in those admitted with a serum albumin of less than 2.6 gms/dL and a 28% incidence in those with an albumin of 2.6 gms/dL or above (p < 0.001). The infections were predominately respiratory and urinary in nature [
8].
This evidence indirectly supports adequate protein intake as a factor in preventing infections after trauma.
Multivitamins and zinc
Studies have shown that most elderly patients fail to ingest the recommended daily allowance (RDA) of zinc. Supplementation with zinc could improve their immune responses to infection and thus prevent illness. Zinc supplementation for people aged 60–89 (defined as elderly) alone increased their in vitro lymphocytes' response to mitogens [
9]. Their response to skin test antigens however, was not increased. When 15 mg of zinc was added to a multivitamin preparation and compared to a lactose placebo given to people aged 59–85 living in northern New Jersey, there was a significant increase in skin test responses to a panel of seven intradermal antigens [
10]. The incidence of infectious diseases was not studied.
There is a considerable literature concerning the use of zinc as a therapy for the common cold. Marshall has reviewed 8 such studies and concludes that there is no convincing evidence as to zinc's efficacy in reducing the severity or duration of cold symptoms [
11].
There is evidence that zinc supplementation significantly reduces the incidence of infections in people with sickle cell disease. Twenty-one of 32 sickle cell disease patients in the Detroit area were found to have zinc deficiency as determined by lymphocyte or granulocyte zinc levels. Zinc supplementation in those deficient reduced their documented infection rate by as much as 80% [
12]. Their hospitalization rate, however, was unaffected.
Multivitamin and mineral supplementation has not been shown to affect illness or absenteeism rates in 158 adults (age >45 years old) living in North Carolina unless they had type II diabetes [
13]. Diabetics taking a placebo reported a 93% incidence of infection (as opposed to an incidence in non-diabetics of 60%). Strangely, diabetics taking supplementation showed only a 17% incidence of infection-much lower than non-diabetics taking placebo. The infections did not result in hospitalizations. Elderly people (>60 years old) living in central France had no decrease in infection incidence when receiving a multivitamin supplementation as compared to a placebo [
14]. A prospective study relating the intake of carotenoids, vitamins C and E and B-vitamins with the incidence of community acquired pneumonia in over 50,000 U. S. male health professionals aged 40–75 years old failed to show any correlation between pneumonia risk and vitamin intake [
15]. This study looked at both food and supplement sources of vitamins. "Natural" vitamins therefore seemed to be no better than "pharmaceutical" vitamins in preventing pneumonia in this well-educated population of American men. Elderly nursing home residents in the Boston area were given multivitamins with either 4 IU of vitamin E (50% of the RDA) or 200 IU of vitamin E. High intake of vitamin E had no effect on the incidence or duration of lower respiratory tract infection [
16]. There appeared to be a small, but significant effect on the incidence of upper respiratory tract infections (including otitis media), but not on their duration (risk ratio = 0.84 for incidence, but 1.53 for duration).
There are two studies which support the use of vitamin or micronutrient supplementation to prevent community-acquired infections. Chandra [
17] showed that trace elements and multivitamins reduce the number of days with any sort of infection. The study enrolled 96 elderly Newfoundland residents and is apparently the only other study to show such an effect in those not institutionalized.
A French study gave a placebo, zinc and selenium supplements, or multivitamins with zinc and selenium to institutionalized people over the age of 65 [
18]. The sample size was a total of 81 and over a two year follow-up period, they found that the number of pneumonias and UTIs decreased by about 50% in those who received the zinc and selenium with or without multivitamins. The multivitamins had no statistically significant effect alone.
If there is little or no effect of micronutrient and multivitamin supplementation on infection rates on apparently uninfected members of the community, how about those chronically infected with viruses? A small study from the era prior to the availability of effective anti-HIV therapy studied nutrient and vitamin intake in 56 HIV infected New Yorkers. Vitamin intake varied from 2% to 50,000% of the RDA. No correlation could be found between nutrient intake and CD4 lymphocyte count or absolute lymphocyte count [
19].
A more intriguing study of HIV-infected people in Baltimore correlated their micronutrient intake as estimated by data from a questionnaire and the subsequent progression of HIV disease [
20]. This study did not take any changing dietary habits into account. The study correlated any intake of zinc supplements with decreased survival. High intake of vitamins B
1, B
2 and B
6 were correlated with increased survival. Studies of this nature always raise the question of whether the increased intake reflected a healthier life style or produced a healthier life. A review of fifteen studies utilizing vitamin and micronutrient supplementation in HIV-infected people concluded that such supplementation effected no reduction in mortality or morbidity in HIV-infected adults. HIV-infected children in under-developed countries could benefit from vitamin A supplementation, however [
21].
Hepatitis C has a prevalence between 1% and 2% in the U. S. population. Could nutritional therapy affect the progression to cirrhosis or hepatoma? The only vitamin supplementation studies done with hepatitis C involve the use of vitamin E as an anti-oxidant to limit hepatic fibrosis [
22]. Two studies which show decreased transaminase levels when patients with hepatitis C are given supplemental vitamin E [
23,
24] although there is no data on vitamin E's effect on the viral load.
Vitamin C
The RDA for vitamin C is between 45 and 60 mg per day. The writings of Linus Pauling have popularized the use of vitamin C as a prophylactic and therapeutic agent for the common cold [
25]. The nutritional value of a vitamin ingested at more than 10 times its RDA begs the question of whether the vitamin is nutritional or pharmacologic. A comprehensive meta-analysis has been published [
26] which finds that huge doses of vitamin C have a minimal effect on reducing cold symptoms. No effect on cold prevention could be found unless groups undergoing hypothermic stress were studied.
There is a published study which supplemented British patients over the age of 65 with a placebo or 200 mg of vitamin C if they were admitted to hospital with bronchitis or pneumonia [
27]. The patients were followed for 4 weeks. If patients who died were excluded from the analysis, the study showed that vitamin C administration lessened the symptom score of surviving patients. Only one of the six deaths in the study occurred in a vitamin C recipient, but the sample size was too small (n = 57) to show significance.
Cranberry juice
Many people believe that drinking cranberry juice will treat or prevent urinary tract infections. There is evidence that cranberry juice contains anti-adhesive molecules which could interfere with bacterial virulence mechanisms [
28]. Cranberry juice (300 ml/day) or a colored drink containing no cranberry products were provided to female residents of a long-term care facility in Boston [
29]. Monthly urine samples were analyzed. At one month, the percentage of urine samples with more than 100,000 CFU/ml of urine was identical whether or not cranberry juice was ingested. After one month, there was a consistent decrease in high-grade bacteriuria in the cranberry juice drinkers. The calculated relative risk for bacteriuria with pyuria for cranberry drinkers was 0.42 (p = 0.0004). Antibiotic use for UTI was almost halved in those drinking cranberry juice. In this study, the distinction between UTI prevention and treatment is unclear, but its ability to obviate the use of antibiotics is significant.
A Canadian study randomized 150 sexually active women who had ≥ 2 UTIs in the previous year into three groups: 1) 250 ml of diluted pineapple juice (colored red) thrice daily and a placebo tablet twice daily; 2) A concentrated cranberry extract tablet twice daily and placebo juice; 3) 250 ml of cranberry juice thrice daily and a placebo tablet [
30]. The study continued for a year. Symptomatic infections were treated with antibiotics for 3 days and the prophylaxis restarted. The placebo group showed 32% of entrants with at least one UTI during the year of study. The tablet group had 18% with at least one infection and the cranberry juice group had 20%. The difference between the tablet or juice groups and placebo was significant (p < 0.05). The mean number of UTIs per year was approximately halved by the use of a cranberry product.
The daily ingestion of cranberry juice concentrate or a placebo did not affect bacteriuria rates in children requiring intermittent catheterization [
31].
There is sufficient reason based on these two positive studies and others reviewed by Raz et al [
29] to recommend a cranberry product to women with recurrent UTIs.
Yogurt
Yogurt is cow's milk usually fermented using two synergistic bacterial species
Lactobacillus delbrueckii subspecies
bulgaricus and
Streptococcus thermophilus. The amount of fat and even the bacteria used to ferment the milk may vary from study to study. The presence or absence of living bacteria must be kept in mind when evaluating studies which employ yogurt. There are few randomized studies in which yogurt (as opposed to lactobacilli or yeast in pure form) is administered in the developed world. Beniwal
et al gave 109 American patients 227 grams of vanilla flavored yogurt twice daily for 8 days if they were receiving intravenous or oral antibiotics [
32]. The yogurt contained
L. acidophilus as well as
L. bulgaricus and
S. thermophilus. The control group of 97 patients received no yogurt. The mean number of days of yogurt intake was 6.6 days. Diarrhea as defined by 3 or more loose bowel movements per day was reported in 13% of yogurt ingesters and 23% of those not eating yogurt. The duration of diarrhea was not significantly decreased. Israeli soldiers eating yogurt with living
L. casei did not have fewer diarrheal episodes than those soldiers eating yogurt containing no living bacteria [
33]. The study had approximately 250 soldiers in each arm and the mean incidence of diarrhea was 14%. If there were an undetected effect, it would have had to be a small one.
While not a nutritional therapy
per se lactobacilli are used by those who do not tolerate yogurt or find it unfeasible.
Lactobacillus casei strain GG was administered in capsules (not yogurt) to American children receiving concurrent antibiotics. The living bacteria reduced the percentage of children with diarrhea (defined as more than one liquid stool/day) from 26 to 8% when compared to an inulin placebo [
34]. A Finnish study using
Lactobacillus strain GG found that recovery from diarrhea was one day quicker on average in those children that received living bacteria in capsular form as opposed to children who received a placebo [
35]. The same
Lactobacillus casei strain reduced the incidence of antibiotic-associated diarrhea in Finnish children from 16% to 5% [
36].
When the effect of the same GG strain was used to prevent antibiotic associated diarrhea in American adults, the results were disappointing. A study analyzed 268 hospitalized patients and found almost identical diarrhea rates and frequencies in those receiving the live bacteria and in those receiving a placebo [
37].
The "non pathogenic" yeast
Saccharomyces boulardii has been shown to reduce antibiotic-related diarrhea in hospitalized Americans when administered in capsule form [
38]. Enthusiasm for this therapy has waned due to reports such as that of 7 French patients who developed fungemia after ingesting this yeast in the setting of an intensive care unit [
39].
The ability of yogurt or lactobacilli to prevent diarrhea is still in question. Should yogurt contain living bacteria? Do the species of bacteria matter? Can yogurt be made with skim milk? Does the flavoring matter? How much yogurt should be ingested? These questions probably will never be answered. At present, yogurt cannot be recommended as a proven method of diarrhea prevention.
Table
1 summarizes the effects of various nutritional interventions on infections in the general population and in institutionalized people.
Table 1
Summary of randomized, controlled trials of the impact of nutritional interventions on infections in the non-hospitalized population
Zinc supplementation | No effect on common colds | 11 |
Zinc supplementation | reduced infection incidence in sickle cell patients | 12 |
Zinc and selenium supplementation | Reduced infection incidence | 18 |
Vitamin and mineral supplementation | Reduced infection incidence in type II diabetics only | 13 |
Vitamin and mineral supplementation | Reduced infection incidence | 17 |
Multivitamin supplements | No effect on infection incidence | 14 |
Multivitamin supplements | No effect on pneumonia incidence | 15 |
Vitamin E supplements | Reduced URI rate, no effect on lower respiratory tract rate | 16 |
Vitamin C therapy or supplements | No effect on common cold unless used in hypothermic conditions | 26 |
Cranberry juice | Reduced incidence of bacteriuria | 29, 30 |
Yogurt | Reduced diarrhea incidence in adults taking antibiotics | 32 |
Yogurt | No effect on diarrhea incidence | 33 |
Lactobacilli | Reduced incidence of diarrhea in children | 34–36 |
Lactobacilli | No effect on diarrhea incidence in adults | 37 |