Asthma prevalence has increased dramatically in many countries over recent decades, demonstrating that environmental exposures play a dominant role in the etiology of this disease. Dietary change is one of several causal factors implicated in this trend, and in the past two decades the evidence base on the relation between diet and asthma has increased substantially. In this article we present a perspective on where we believe this literature on asthma is leading, and attempt to identify priorities for further investigation. Our discussion is limited to general effects of diet, and does not address the separate topic of specific food allergy.
Defining and measuring asthma is notoriously difficult, and dietary studies have used many different outcome measures including self-reported diagnosed asthma, symptoms, lung function (particularly FEV1), and airway hyperresponsiveness. In this paper we have concentrated on studies using self-reported diagnosed asthma, wheeze, or airway hyperresponsiveness, because impairment of FEV1 and symptoms of cough and breathlessness, particularly in older individuals, are also strongly associated with chronic obstructive pulmonary disease.
The literature on diet and asthma also covers the full range of levels of evidence, from anecdote and ecological analysis, through cross-sectional and longitudinal observational studies, to randomized controlled clinical trials. As is usually the case, the amount and diversity of evidence decreases with increasing level of study design. Limitations on space in this article preclude a full review of the literature, but thorough and relatively recent reviews are available elsewhere (1–5) and we will cite these in this article where relevant as sources for reference to the older literature. However, we have also provided assessments of the strength and consistency of the available evidence in tables in this article, fully referenced versions of which are available as an online supplement.
The nutrients most strongly implicated in asthma etiology and their putative mechanisms of action are listed in Table 1
Activity and Potential Mechanisms of Effect
|Vitamins A, C, E||Antioxidant; protection against endogenous and exogenous oxidant inflammation|
|Vitamin C||Prostaglandin inhibition|
|Vitamin E||Membrane stabilization, inhibition of IgE production|
|Flavones and flavonoids||Antioxidant; mast cell stabilization|
|Magnesium||Smooth muscle relaxation, mast cell stabilization|
|Selenium||Antioxidant cofactor in glutathione peroxidase|
|Copper, zinc||Antioxidant cofactors in superoxide dismutase|
|n-3 fatty acids||Leukotriene substitution, stabilization of inflammatory cell membranes|
|n-6 polyunsaturated/trans fatty acids||Increased eicosanoid production|
|Sodium||Increased smooth muscle contraction|
|Fruit and vegetable intake||Limited evidence||Evidence||Limited evidence||Limited evidence||N/A|
|No effect||Mixed results||Mixed results||Mixed results|
|Vitamin A or beta-carotene||Limited evidence||Limited evidence||Evidence||Limited evidence||Limited evidence|
|No effect||No effect||Mixed results||No effect||Mixed results|
|Vitamin C||N/A||Evidence||Evidence||Limited evidence||Some evidence|
|Mixed results||Mixed results||No effect||No effect|
|Vitamin E||N/A||Some evidence||Evidence||Limited evidence||Limited evidence|
|No effect||Mixed results||Protective||Mixed results|
|Selenium||N/A||Limited evidence||Evidence||N/A||Limited evidence|
|No effect||Protective||No effect|
|Magnesium||N/A||Some evidence||Evidence||N/A||Limited evidence|
|Copper, zin||N/A||Limited evidence||Evidence||N/A||N/A|
|Mixed results||Mixed results|
|Sodium||Limited evidence||Some evidence||Limited evidence||N/A||Some evidence|
|Mixed results||No effect||Increased risk||Increased risk|
|Fish||Limited evidence||Evidence||Limited evidence||Limited evidence||N/A|
|Mixed results||Mixed results||Mixed results||No effect|
|n-3 fatty acids||N/A||N/A||Limited evidence||Limited evidence||Evidence|
|Mixed results||No effect||Mixed results|
|n-6 polyunsaturated/trans fatty acids||Limited evidence||Limited evidence||Limited evidence||Limited evidence||Some evidence|
|Increased risk||Mixed results||Mixed results||No effect||No effect|
Vitamin C, vitamin E, and vitamin A/β-carotene are the vitamins most extensively investigated for effects on asthma. All are antioxidants, and vitamins C and E may also have other antiinflammatory or antiallergic effects.
Vitamin C is the most extensively investigated and has been shown in several case-control and cross-sectional studies to be associated with a reduced risk of asthma (1–4, 6, 7), but in the only available substantive longitudinal study, vitamin C intake had no effect on asthma incidence (8). In randomized trials, vitamin C given in combination with other antioxidants protects against ozone-induced bronchoconstriction in asthma (1, 9, 10), but the evidence on the effect of vitamin C given alone is much less conclusive (11, 12). We have recently reported the largest randomized placebo-controlled clinical trial of vitamin C to date, involving 201 patients randomized to vitamin C or placebo for 16 weeks, and found no effect on clinical asthma control (13).
Vitamin E effects have been less widely studied and there is relatively little cross-sectional evidence linking vitamin E with asthma (1–4). There is, however, evidence of an inverse association between vitamin E intake and both allergen skin sensitization and total serum IgE levels in adults (14), and longitudinal evidence that a high vitamin E intake is associated with reduced asthma incidence (8). As cited above, vitamin E is effective when given with other antioxidant vitamins in protecting against ozone effects in asthma (1, 9, 10), but in a recently completed randomized placebo-controlled study of vitamin E supplements for 6 weeks in 72 patients with asthma, we found no evidence of clinical benefit (15).
The evidence on vitamin A and/or β-carotene effects is also limited, with some recent cross-sectional studies suggesting a protective effect (1–4, 6, 16), but no association with asthma incidence in longitudinal study (8). Aside from the ozone studies (1, 9, 10), we are aware of two randomized clinical trials, both from the same research group, reporting evidence of protection against exercise-induced bronchoconstriction after 1 week of supplementation by either a natural source of vitamin A (17), or a food extract rich in the carotenoid lycopene (18).
Several cross-sectional studies have demonstrated a reduced risk of asthma in relation to a high fruit intake (1–4, 19–24), possibly with modification by smoking (25). However, the available longitudinal evidence relates to COPD rather than to asthma (1–4), and we are not aware of any clinical trials in asthma.
The flavones and flavonoids are naturally occurring antioxidants found particularly in fruits and red wine, which may account for some of the protective effect associated with these foods (1–4). To date, however, there is only one report suggesting protection by flavones against markers of COPD (26), and no direct epidemiologic or clinical trial evidence relating to asthma.
Selenium is also involved in antioxidant defenses as a coenzyme in glutathione peroxidase. Early case-control studies demonstrated decreased selenium intake and serum levels in patients with asthma in New Zealand (1–4), and this finding has been confirmed more recently in the United Kingdom (27) but not in Spain (28). We also found no evidence of association between serum selenium levels and airway hyperresponsiveness in adults in the United Kingdom (work published in abstract ). The only available randomized placebo-controlled trial involved 14 weeks of supplementation in 24 patients with asthma, and found evidence of improvement in clinical assessments of asthma control in the selenium group but no effect on objective markers of disease (30).
Magnesium has several biological effects of potential relevance to asthma, including bronchodilatation when given intravenously in acute severe asthma (31). There is also strong cross-sectional epidemiologic evidence of protection by dietary magnesium against asthma (1–4), but our recent randomized placebo-controlled trial of magnesium supplementation showed no evidence of benefit after 4 months of supplementation (13). At least one other substantive clinical trial, to our knowledge published only in abstract, is also negative (32).
Early epidemiologic evidence suggesting that a high sodium intake may be associated with increased airway responsiveness (1–4) has led to several intervention studies of sodium supplementation and/or restriction. The research suggests that the effects of sodium are limited to individuals with asthma; however, current research has not provided conclusive evidence that sodium restriction improves asthma (33, 34), though at least one study suggests that sodium loading exacerbates hyperresponsiveness (35).
Research into fatty acid effects has focused on two main areas: intake of omega-3 polyunsaturated fatty acids from fish oils, which is potentially beneficial, and of omega-6 and trans-fatty acids, which may be detrimental to asthma (1–4). The observational evidence on fish oil effects has been relatively consistent in demonstrating protection against asthma and/or allergy in relation to a high intake (1–4), though the clinical trial evidence is less strongly conclusive (36, 37). Similarly, ecological and other cross-sectional data support the hypothesis that omega-6 acids may increase asthma risk (38–40), and other studies indicate that full fat cream and butter (rich in saturated fats) is associated with a reduced risk of asthma in young children (21, 41). However, there are no relevant intervention studies.
In this article we have passed over the considerable literature, predominantly cross-sectional, linking reduced lung function to a low intake of antioxidant vitamins, fruits, flavones, and magnesium (1–4). There are also longitudinal studies providing evidence that a high intake of fruits and vitamin C is associated with a reduced rate of decline in FEV1 over time (42–44), though with no evidence of an effect of magnesium intake (44). These studies thus provide support for the hypothesis that fruits and/or their constituents may protect against COPD, but are not specific to asthma.
There have been three major nutrient intervention trials in which the supplement has consisted of multinutrients, all of which were designed to address other primary hypotheses, but have also provide data on relevant respiratory outcomes. The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study randomized over 29,000 adults to receive either d1-α-tocopherol, β-carotene, both, or placebo for 5 to 8 years and found that supplementation did not decrease the incidence or recurrence of symptoms of cough, sputum production, or dyspnea (45). In the Carotene and Retinol Efficacy Trial, there was no difference in rate of lung function decline over 11 years in over 18,000 subjects randomized to β-carotene and retinyl palmitate, or placebo (study reported, to our knowledge, only in abstract ). Most definitive is the Heart Protection Study, a trial of the effect of 5 years' supplementation with antioxidant vitamins (vitamin E, vitamin C, and β-carotene, or a matching placebo) on major coronary events in over 20,000 adults (47). FEV1 and FVC, and hospitalizations for asthma or COPD during the 5-year study period, were assessed as secondary outcomes at the end of the study, and no differences were found (47). These three intervention trials are thus conclusive in demonstrating no appreciable effect of antioxidant vitamin supplements on markers of COPD and/or asthma, and therefore question the likelihood that further supplementation studies with these nutrients are likely to demonstrate any benefit.
Although far from complete in relation to all of the above nutrients, there is a consistent theme in the evidence cited above, which is that although a wide range of nutrients appear to have an effect on asthma outcomes in cross-sectional study, evidence from longitudinal studies and randomized clinical trials is far less consistent or conclusive. Indeed, in longitudinal study only vitamin E has been shown to have a protective effect on asthma (8), whereas in clinical trials no effect has been demonstrated for vitamin E on asthma control (15, 47). The clinical trial evidence on vitamin C and magnesium also implies no effect on asthma (13), and for other nutrients is based on small numbers and/or relatively weak outcomes (17, 18, 30). Although shown to protect the airway against ozone effects therefore (1, 9, 10), it appears that the hypothesis that individual nutrients alone or in combination have a major impact on clinical asthma severity or incidence is far from proved. It is therefore important to consider the possible explanations for the inconsistencies in the evidence, and there are several.
For many of the diet–asthma associations, understanding is limited by a current lack of evidence. This is particularly true for determining the longitudinal effect of diet on asthma, especially as diet may potentially have different roles in the incidence of asthma and severity of disease.
Much of the cross-sectional work on diet and asthma has been performed by secondary analysis of existing datasets. Particularly in older publications, it is often unclear whether the dietary associations reported arose as a result of testing a genuine a priori hypothesis, or from a hypothesis-generating analysis of the available data. It is likely that many of the single nutrient associations with disease reported to date are indeed false positives arising from multiple hypothesis testing by different, if not the same, investigators.
Diet is complex and measurement is difficult. Food-frequency questionnaires, 24-house diet recall, examination of individual food items, food patterns, serum nutrients, and other methods all have their relative strengths and weaknesses, all can introduce substantial misclassification, and the close correlation of many nutrients presents problems when trying to identify independent nutrient effects. Part of the difficulty of interpreting dietary studies is likely to arise from measurement errors and biases inherent in the methods used.
The potential for confounding in cross-sectional and longitudinal studies of diet and asthma is substantial, particularly because the sources of many of the above nutrients are the perceived “healthy” foods—such as fruits and green vegetables—are also relatively rich in other antioxidant vitamins, flavones and flavonoids, magnesium, and other potentially beneficial nutrients. To deal with this, it is necessary to control for other nutrient effects in analysis, but because of the strong correlation between nutrient intakes this demands sample sizes that are typically far in excess of most of those reported to date. Few if any of the available studies has attempted to control for the full range of nutrients potentially involved, and in our view none has succeeded. Diet is also strongly related to other recognized determinants of asthma risk, such as smoking and socioeconomic status, and depending on the quality of the available measures, controlling for these confounders can also be difficult. Confounding is therefore likely to be a major problem in much of the observational work.
It is also possible that any beneficial effect of diet is mediated through the combined effect of several nutrients, rather than any one or small group alone. The implication of this is that any further studies of nutrient supplementation should pursue an extensive “polypill” approach, delivering a cocktail of potentially beneficial nutrients, rather than the single or limited combinations tested to date. The ozone studies (1, 9, 10) provide some evidence that this may indeed be the case, though the lack of any impact of an antioxidant vitamin cocktail on asthma admissions in the Heart Protection Study suggests that the protective effect on acute airway responses does not translate into clinical benefit (47).
It is also possible that dietary antioxidants also have prooxidant activity (48). If so, any net benefit of supplementation might be restricted to patients and populations that are relatively depleted in antioxidants, whereas in less depleted individuals this benefit may be counterbalanced by prooxidant actions. To date there is no strong evidence that this is the case in relation to asthma.
Another implication of the confounding argument above is that if diet has an effect on asthma, the nutrients responsible may not those that have been widely studied to date. Increased understanding of the role of different nutrients in maintaining antioxidant defense, such as the phenolic lipids, may open up new areas of nutrient research that prove more productive.
The benefit of diet for asthma may be from combined nutritional value in particular foods of the combined interaction of foods or combined effect of foods in a healthy diet. The clear and obvious extension to the above is that the best way to deliver a suitably comprehensive and synergistic range of nutrients is to supplement the diet with foods that provide the best combination of nutrients, such as fresh fruits and vegetables. We are currently assessing the effect of fruit supplementation on the prevalence of asthma in young children, capitalizing on a natural experiment arising from the phased introduction by the UK government of a scheme providing all 4- to 6-year-old children with a free portion of fruit every day at schools. Data comparing asthma incidence and prevalence between children who commenced the scheme in 2004 and those who did not will be available during 2005. We are not aware of any other fruit supplementation trials with respiratory outcomes in progress.
It is also likely that genetic factors, as for example polymorphisms in the glutathione S-transferase gene (49), determine susceptibility to oxidant damage and to benefit from antioxidant supplementation. Further work is necessary to elucidate this and other potential genetic influences.
It is possible that the effects of diet on lung disease outcomes arise from effects occurring in prenatal or very early life, and are apparent in cross-sectional studies later in life because broad dietary habits tend to track through life. If so, dietary effects would be expected to be evident in cross-sectional and longitudinal studies, but not in intervention trials in adults, as the period of intervention would need to be in early life. There is to date relatively little evidence regarding dietary intervention during pregnancy and/or infancy, though some recent clinical trials indicate promise with omega-3 fatty acid supplementation (5, 50, 51).
Our interpretation of the evidence and the above arguments is that if diet plays an important role in asthma, the most likely and most efficient method of exploiting that effect to individual and population benefit is probably dietary manipulation to increase intake of natural foods, and particularly fresh fruits and vegetables, in a balanced diet throughout life. This is not only the most logical and pragmatic interpretation, it is also the strategy most likely to yield benefits in other disease areas. The way forward, we believe, is therefore in dietary manipulation rather than a continued search for, and attempts to intervene in, individual nutrient effects. However, general advice on diet for patients with asthma needs to be based on evidence rather than supposition, and it is therefore important that the effects of dietary change on lung health are properly tested in appropriate trial designs.
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