From the Department of Medicine,
University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical
School (Dr Monteleone), and the Department of Nutritional Sciences, Cook
College, Rutgers, The State University of New Jersey (Dr Sherman), New
Brunswick.
Outline
Graphics
Abstract^
Asthma is a syndrome that may have many causes resulting in airway inflammation and hyperresponsiveness. The search for the causes of asthma has led to the investigation of genetic, atopic, viral, and nutritional factors. For the last 2 decades, a number of studies have linked particular nutrients to asthma. The studies have examined both the suboptimal status of particular nutrients as causes of asthma and supplements of specific nutrients as therapy for asthma. We reviewed and analyzed data from these studies to determine the role of nutritional therapy in the management of asthma. The studies on food allergies reveal that IgE-mediated reactions to food are a minor cause of respiratory symptoms, affecting more children than adults. Currently, there are no available data to support the use of nutritional supplements in the treatment of chronic asthma.
Arch Intern Med. 1997;157:23-34
Asthma is a chronic lung disease characterized by obstruction, inflammation, and hyperresponsiveness of the airway to a variety of nonspecific stimuli. The obstruction is recurrent, is at least partially reversible, and manifests clinically as dyspnea, wheezing, and/or coughing. For children aged 6 to 11 years, the reported prevalence of asthma obtained from the first National Health and Nutrition Examination Survey conducted from 1971 to 1975 was 4.8%. [1] In the second study conducted from 1976 to 1980, the prevalence of asthma in the same age group increased to 7.6%. [1] For adults, the prevalence of active asthma was estimated to be 2.6%. The follow-up incidence of new cases was estimated at 2.1 cases per 1000 population per year. [2]
Acute episodes of asthma can be triggered by a variety of stimuli, including exercise, cold air, viral infection, emotional factors, and allergens. The allergens are usually inhalant, but can include food and food additives. Approximately 80% of children with asthma and 40% of adults with asthma are allergic [3] and may have an allergic component to their asthma, although some researchers would argue that almost all asthma has an allergic basis. [4]
The role of nutrition in asthma may be 2-fold. First, a food allergy can be a provoking stimulus for acute episodes of asthma. In these cases, avoidance of an allergenic food may lead to amelioration of asthmatic symptoms. In addition, the suboptimal status of specific nutrients may play a role in the cause of asthma in some patients. Supplementation of these nutrients, such as vitamin C and magnesium, may be of use in the treatment of some cases of asthma. This is an active area of research, particularly with the current widespread interest in nonmedicinal, nutritional, or "natural" cures and treatments for diseases. This review summarizes and analyzes the available data on the role of nutrition in the provocation and treatment of asthma.
FOOD ALLERGY^
When an allergen, such as a food protein, enters the
gastrointestinal tract, it encounters a unique mucosal immune system involving
lymphocytes, mast cells, and IgA. [5] The allergen
is first taken up by specializedM cells in the epithelium that process the
protein and transport it from the intestinal lumen to the B and T lymphocytes
in the mucosal Peyer's patches. Once stimulated, the lymphocytes migrate via
the lymphatics into the systemic circulation and then return to the mucosal
lamina propria, where they are primed for interaction with the sensitizing
allergen. B lymphocytes in the intestinal mucosa secrete predominantly IgA,
which acts to limit allergen absorption by the mucosa. Mucosal B cells also
produce IgE against food antigens that penetrate the mucosal barrier. The IgE
mediates the degranulation of mast cells in the gastrointestinal tract, causing
an allergic reaction. [5]
A true food allergy, which involves an immune-mediated response to food, may be difficult to diagnose. [6] Valid diagnostic tests for food allergies include skin prick tests, radioallergosorbent tests (RASTs), and double-blind, placebo-controlled food challenges (DBPCFCs). Overall positive predictive accuracy of food skin prick tests is less than 50%, and therefore a positive result from a skin prick test for a specific food only suggests an allergy. [7] The RAST is an in vitro test for specific IgE antibodies in the individual's serum, which is a slightly less sensitive testing method than skin testing. [7] The DBPCFC is considered the "gold standard" test for the diagnosis of food allergies. [8] Foods to which the individual may be sensitive and placebos are given in lyophilized form in capsules or liquid, beginning with a low dose and doubling the dose every 15 to 60 minutes. False-negative results have been shown to occur in less than 5% of DBPCFCs and false-positive results in less than 1% of DBPCFCs. [7]
The number of atopic adults who believe themselves to have at least 1 food sensitivity has been found to be as high as 24%, [9] while as many as 28% of parents believe that their children have had an adverse reaction to a food. [10] However, the confirmed incidence of adverse reactions to food is probably less than 1% in adults, 1% to 2% in young children, and 4% to 6% in infants. [8] Infants have an increased incidence of true food allergies, which is believed to be the result of immaturity both of the gut, allowing the absorption of more antigen, and of the immune system, with less IgA to limit absorption. [11]
The role of food allergies in asthma is controversial. In a questionnaire study conducted by Adler et al, [12] 14.5% of parents of children with asthma stated that food provoked asthmatic symptoms in their children. Subsequently, Oehling et al [13] reviewed 25 000 clinical histories during a 5-year period and diagnosed 400 patients as having food allergy based on history, skin testing, and in vivo tests. Respiratory symptoms after food ingestion were reported by 18.5% and asthma was the main reaction in 15.5%. The foods that are most frequently implicated as causes of respiratory symptoms are eggs and milk. Other offenders include wheat, soy, peanuts, fish, and shellfish. In addition, although the majority of food additives have not been proven to cause respiratory symptoms, antioxidant sulfiting agents are known to exacerbate asthma in sensitive individuals.
Double-blind, placebo-controlled food challenges have been used to establish the true incidence of asthmatic symptoms caused by allergies to food (Table 1). In general, studies have shown that although the overall effect of food allergies in asthma is minor, in a select group of patients food allergies can exacerbate asthma. For example, a 1986 study by Onorato et al [14] found food allergies in 25 of 300 asthmatic adults and children screened using a questionnaire, RASTs, and skin prick tests. During DBPCFCs, 6 (2%) of the screened patients experienced asthma, with 3 of these patients having asthma as their only reaction. Similarly, respiratory symptoms in response to DBPCFCs were demonstrated in 9.2% and asthma in 5.7% of children with asthma studied by Novembre et al. [15] Only 1 child in the study had asthma exclusively, with the remainder having associated cutaneous or gastrointestinal symptoms. The investigators in both studies concluded that IgE-mediated reactions to food are a minor cause of respiratory symptoms.
Table 1. Food Allergies and Asthma*
Bock [16] performed DBPCFCs on 279 children with a history of food-induced asthma and 24% experienced wheezing; 5 children had wheezing as the only symptom. In addition, 10 (5%) of 188 children with a history of an adverse nonrespiratory reaction to food experienced wheezing during DBPCFCs. Similar results were obtained by James et al, [17] who studied children and adults with atopic dermatitis and found expiratory wheezing occurring in 17% of patients with positive DBPCFC results. However, when one fourth of the patients were evaluated with spirometry during food challenges, only 7% experienced greater than a 20% decrease in forced expiratory volume in 1 second (FEV1 ). Both of these studies demonstrate that food can cause wheezing, but it is uncommon even among children with histories of an adverse reaction to food. In addition, when respiratory symptoms do occur after food ingestion, significant objective changes in pulmonary function are not commonly seen.
In contrast to the aforementioned studies, Pelikan and Pelikan-Filipek [18] demonstrated a greater than 20% decrease in FEV1 after open (unblinded) food challenges in 71% of adult patients with histories of food-induced asthma and in 56% of patients with asthma without such histories. The high rate of respiratory reactions to foods demonstrated in this study conflicts with the results of other similar studies. This may be because 80% of the food challenges were open and therefore not as well controlled as DBPCFCs.
The data presented herein suggest that in a small percentage of patients with asthma, food allergies may provoke respiratory symptoms. This effect may be particularly relevant in children. Large, well-controlled studies incorporating objective measures of pulmonary function are needed to identify other types of patients with asthma in whom this clinical effect is important.
SODIUM SENSITIVITY^
It has been hypothesized that diets high in salt may
accentuate bronchial reactivity. Animal studies [19] have shown that passive in vitro sensitization of airway
smooth muscle cells leads to increased sodium influx of the cells with the
subsequent stimulation of Na sup +, K sup + -adenosinetriphosphatase, resulting
in the sustained hyperpolarization of the airway smooth muscle cells. The
contractile response of airway smooth muscle cells to specific antigen was
demonstrated to be dependent on the level of hyperpolarization resulting from
the sodium influx.
Several groups of researchers have investigated the relationship between sodium intake and asthma (Table 2). The data have demonstrated a small adverse effect of increased sodium intake on bronchial reactivity, but no significant effect on clinical symptoms has been shown.
Table 2. Sodium Sensitivity and Asthma*
An epidemiological study by Burney [20] examined the relationship between asthma death rates and table salt purchases in regions of Britain. Using accumulated data from more than 37 000 households, Burney demonstrated that a significant proportion (64%) of the variance in asthma mortality among men was explained by table salt purchases. However, no such effect was seen for women. Although it raises some interesting issues, this research cannot prove cause and effect. In addition, the accuracy of using asthma death rates as a measure of asthma prevalence and table salt purchases as a measure of intake is questionable.
To investigate the effect of increasing salt intake on bronchial reactivity, Javaid et al [21] doubled baseline dietary salt intake in patients for 1 month and then performed histamine challenge tests. A significant increase in bronchial reactivity to histamine occurred in 9 of the 10 patients with asthma, but not in the 5 controls. This was a small, open, nonrandomized study in which an unspecified amount of salt was ingested. An observed difference in baseline sodium excretion between the 2 groups was not addressed and individual data were not shown.
Thirty-six adults with asthma were randomized by Burney et al [22] to receive either 80 mmol per day of sodium or a placebo for 2 weeks each in a crossover fashion. The bronchial response to histamine (measured as the dose causing a 10% decrease in FEV1 [PD10 ]) was found to be greater when the men were taking a sodium supplement than when they were taking the placebo. No such change was seen among the women. In addition, no significant change in FEV1 was seen in either group during the study. While the investigators concluded that a high-sodium diet increases bronchial reactivity in men, in fact the statistically significant changes in PD10 are small and may lack clinical significance. Similarly, Medici et al [23] gave patients with asthma a low-salt diet plus an additional 6 g per day of sodium chloride or a placebo for 3 weeks each in a crossover protocol. Finally, all patients received sodium citrate supplementation (equivalent to 154 mmol of sodium) for 3 weeks. Forced expiratory volume in 1 second and peak expiratory flow rate (PEFR) significantly decreased with both sodium chloride and sodium citrate, but there was no effect on the dose causing a 20% decrease in FEV1 (PD20) as a sign of bronchial reactivity. Since the changes in pulmonary function test results were observed with both sodium chloride and sodium citrate loading, the effect appeared to be sodium mediated. This study used a low-salt diet that in fact contained 5 to 6 g per day of sodium chloride and demonstrated only small changes in FEV1 and PEFR. In addition, only a limited number of patients were included and women were not analyzed separately.
Finally, an open trial was conducted by Lieberman and Heimer [24] with adults with asthma who received their normal diet for 2 weeks and were then randomly assigned to either a low- or high-salt diet for another 2 weeks each in a crossover protocol. Peak expiratory flow rates did not change during any of the 3 diet periods and no difference was demonstrated between men and women. From the data presented in this study, it is not known how much sodium the patients actually received. Since neither bronchial reactivity (PD20) nor other pulmonary function tests such as FEV1 were measured, the clinical relevance of these results is unclear.
It is not clear how much salt was actually ingested in all these studies and how this relates to the US average daily intake of 3 to 7 g. While the aforementioned studies lack concordance of results, they do suggest that increased sodium intake adversely affects the bronchopulmonary system. The pathogenesis of this effect is unknown and may or may not involve the airway smooth muscle cells as suggested by studies of animal tissues. Since the studies do not prove that there are clinical implications to these bronchopulmonary changes, there is currently little support for the adoption of low-salt diets by patients with asthma.
MAGNESIUM^
Magnesium plays a role in many enzymatic reactions,
including those involved in the adenylate cyclase system, and acts with calcium
to affect neuromuscular transmission and activity. The mechanism of magnesium's
proposed effect on asthma is unknown, but may involve a direct action on
bronchial smooth muscle, producing airway dilatation. Spivey et al
[25] used an in vitro rabbit model to study this
effect. In a series of experiments, they demonstrated that magnesium relaxes
bronchial smooth muscle, not only when passively stretched, but also when
contracted by different stimuli.
Clinical trials have been conducted to study the effect of magnesium infusion on asthma (Table 3) and have demonstrated a minor role for magnesium in the treatment of acute exacerbations of asthma. One such study by Skobeloff et al [26] involved patients who presented to the emergency department with an acute exacerbation of asthma and who did not respond to initial treatment. Patients were randomly assigned to receive either 1.2 g of magnesium sulfate or saline intravenously and were followed up for 45 minutes after the infusion. The group that received the magnesium infusion showed a significant increase in mean PEFR when compared with the saline group. In addition, only 7 of the 19 patients who received magnesium required admission to the hospital, while 15 of the 19 who received saline were admitted. Unfortunately, this study was short-term and the length of the beneficial effect attributed to magnesium was not reported.
Table 3. Magnesium and Asthma*
The effect of intravenous magnesium in hospitalized patients with acute asthma was studied by Noppen et al. [27] On 2 consecutive days, 6 patients received infusions of 3 g of magnesium sulfate. In 10 of 12 trials, there was a significant improvement in FEV1 immediately after the infusion with a decrease in FEV1 toward baseline after 30 minutes. Inhalation of a beta2 -agonist after magnesium infusion resulted in an increase in FEV1 in 11 of 12 trials, which was greater than the improvement seen after magnesium alone. Overall, the changes in FEV1 after magnesium infusion were small and transient, especially when compared with the changes after beta sub 2 -agonist inhalation.
Conflicting results were obtained by Tiffany et al [28] in a study of 48 patients who presented to the emergency department with asthma. Patients who did not improve after initial therapy were randomized to 1 of 3 treatment groups: an infusion group that received 2 g of intravenous magnesium sulfate followed by a continuous magnesium infusion of 2 g per hour over 4 hours; a bolus group that received 2 g of intravenous magnesium sulfate followed by a placebo infusion; and a placebo group that received a saline placebo both as bolus and infusion. Pulmonary function test results (PEFR and FEV1) showed no difference between the 3 groups at any time during the 260-minute period following infusion.
In 1994, Britton et al [29] tested the hypothesis that magnesium is an independent determinant of lung function in the general population. The average daily intake of magnesium for 2644 subjects was estimated from semiquantitative food-frequency questionnaires. A 100-mg per day higher magnesium intake was found to be independently associated with a 27.7-mL higher FEV1 and reduced airway reactivity to methacholine, even when adjusted for estimated daily intake of calcium or vitamin C, smoking, occupation, or social class. This study did not measure magnesium levels in serum or erythrocytes, and it did not analyze subjects with asthma separately. In addition, the increase in FEV1 was small and may not have been clinically significant, making it difficult to draw any firm conclusions from this study.
Serum and erythrocyte magnesium levels have been measured in patients with asthma. Since magnesium is largely intracellular, it is thought that erythrocyte levels are a more accurate measure of magnesium status than serum levels. In 1992, Falkner et al [30] compared serum magnesium levels in patients during acute exacerbations of asthma with levels in nonasthmatic controls. Serum magnesium levels for both groups were within the normal range. Similary, magnesium levels in serum, erythrocytes, and mononuclear leukocytes were measured by de Valk et al. [31] There were no significant differences found in either extracellular or intracellular magnesium levels in asthmatic vs normal patients.
Although magnesium infusion may cause an immediate improvement in pulmonary function in patients with acute asthma, it does not appear to be as effective as currently available standard therapy. Furthermore, its effectiveness over time, and therefore its clinical usefulness in managing chronic asthma, has not been proven. Finally, patients with asthma have not been shown to have even a marginal deficiency of magnesium. Therefore, all available evidence suggests that intravenous magnesium supplementation may have a minimal role in the treatment of acute asthma, but is of no value in the treatment of chronic asthma.
VITAMIN C^
Vitamin C acts as a reducing agent for hydroxylation
reactions, such as those involved in collagen synthesis, and is important as an
antioxidant. In asthma, vitamin C may act on airways by affecting arachidonic
acid (AA) metabolites, particularly prostaglandins. The major prostaglandins
(PGs) produced in the human lung are PGI2, which causes pulmonary
vasodilation; PGF2alpha and PGD2, which cause
bronchoconstriction; and PGE2, which causes bronchodilation. Work
done by Puglisi et al [32] on guinea pig trachea
showed an antagonistic effect of vitamin C on PGF2alpha -induced
bronchoconstriction. Supporting these results, Ogilvy et al
[33] demonstrated in vivo that ingestion of
indomethacin, an inhibitor of PG synthesis, abolished the protective effect of
vitamin C on methacholine-induced bronchoconstriction.
In search of a possible relationship between vitamin C and asthmatic symptoms, both vitamin C plasma levels and results of vitamin C supplementation have been studied (Table 4). In these studies, supplemental vitamin C has been shown to cause an immediate decrease in airway responsiveness. One of the earlier studies by Olusi et al [34] found significantly higher concentrations of vitamin C in plasma and white blood cells in controls than in either treated or untreated patients with asthma. Similarly, in a study comparing plasma vitamin C levels in children with asthma with levels in healthy controls, Aderele et al [35] found significantly lower levels in children with asthma. However, no relationship was demonstrated between vitamin C levels and atopy or severity or duration of asthma. Unfortunately, this study did not quantify vitamin C intake in the diet or in supplements taken by approximately 50% of the children, making the results difficult to interpret.
Table 4. Vitamin C and Asthma*
In the first National Health and Nutrition Examination Survey, Schwartz and Weiss [36] assessed the relationship between dietary vitamin C intake and pulmonary function in 2526 randomly selected adults, of whom approximately 3% were asthmatic. Lower dietary vitamin C intakes were shown to be directly related to lower values of FEV1. However, the difference in FEV1 was only 40 mL between the highest and lowest tertiles of dietary vitamin C levels and occurred in patients with and without asthma, making the clinical relevance of these results suspect.
Ting et al [37] studied the effect of an intake of 2 g per day of vitamin C on the airways of adults with asthma. No change was demonstrated in any pulmonary function tests performed or in reported asthma symptoms after 4 days of supplementation. This was an unblinded short-term study with obvious limitations. A short-term study of adults with exercise-induced asthma was done by Schachter and Schlesinger. [38] After ingestion of 500 mg of vitamin C, the immediate postexercise PEFR in subjects was significantly improved, while 5 minutes after exercise only forced vital capacity showed significant improvement when compared with the placebo. The authors concluded that the results demonstrate partial protection by vitamin C against exercise-induced airway obstruction with a more prominent effect in the large airways. However, the lack of consistent changes in the pulmonary function test results and the very short follow-up make it difficult to draw any substantial conclusions.
A number of studies have been performed to assess the effect of vitamin C on bronchial challenge testing. Six ragweed-sensitive adults with asthma were studied by Kordansky et al [39] after a 1-week course of 500 mg per day of ingested vitamin C or a placebo. No protective effect of vitamin C against ragweed antigen-induced bronchospasm was demonstrated. In healthy adults studied by Ogilvy et al, [33] ingestion of 1 g of vitamin C caused a 25% reduction in the duration and intensity of methacholine-induced bronchoconstriction. However, responses to methacholine were similar to baseline after the ingestion of indomethacin, indicating that indomethacin abolished the protective effect of vitamin C. In a similar study, Mohsenin et al [40] found that vitamin C decreased airway responses to methacholine and indomethacin significantly reduced this effect in 11 of 14 adults with asthma. The effect of indomethacin in the latter 2 studies supports previous work that shows vitamin C enhancing the production of a bronchodilator PG.
Placebo-controlled studies involving histamine bronchial challenges have been performed with vitamin C. Zuskin et al [41] measured changes in airway response to histamine in healthy adults after ingestion of 500 mg of vitamin C or a placebo. Less histamine-induced reduction in flow rates occurred following the ingestion of vitamin C than after the placebo. Similar results were obtained by Bucca et al [42] using 2 g of vitamin C or a placebo. Vitamin C was shown in this study to acutely decrease airway responsiveness to inhaled histamine. In contrast, Malo et al [43] demonstrated that ingestion of 2 g per day of vitamin C for 4 days had no effect on histamine-induced bronchoconstriction in adults with asthma. In all 3 studies, observed changes in bronchial challenge test results secondary to vitamin C use were small. In none of them did vitamin C prevent histamine-induced bronchoconstriction.
Two long-term studies on the effects of vitamin C on pulmonary function test results and immunity have been done by Anderson et al. [44,45] During a 6-month period, Anderson et al [44] supplemented 10 children with asthma with histories of recurrent respiratory tract infections with 1 g per day of vitamin C and performed pulmonary function tests and immunologic studies. Six children demonstrated improved pulmonary function test results with return of peak flow and maximum midexpiratory flow to greater than 85% of normal; 9 children remained free of infection after 6 months. In addition, 2 patients with reduced neutrophil chemotaxis and 4 patients with decreased lymphocyte transformation had values increase to normal; 7 patients with increased antistreptolysin O levels had the levels decrease significantly. In 1983, Anderson et al [45] studied children with asthma, randomly assigning 7 patients to receive 1 g per day of vitamin C plus standard asthma therapy and 9 patients to receive standard asthma therapy alone for 6 months. Vitamin C supplementation was demonstrated to improve neutrophil motility and decrease antistreptolysin O levels. The acute effect of 1 g of intravenous vitamin C on exercise-induced bronchoconstriction was studied in the first 10 patients and no protective effect of vitamin C was seen. The clinical benefit of the demonstrated immunologic changes is not clear. In the first study by Anderson et al [44] the improvement in pulmonary function test results may have been related to the decreased rate of infections, rather than to a direct effect of vitamin C. In the second study by Anderson et al, [45] vitamin C had no effect on pulmonary function.
The majority of these studies suggest at least a short-term protective effect of vitamin C on airway responsiveness. It remains to be proven whether consistent use of vitamin C would have a positive effect on objective measures of pulmonary function. More long-term, controlled studies need to be done to clarify the possible role of vitamin C in the treatment of chronic asthma.
SELENIUM^
Selenium acts as an antioxidant and thus interacts with
other nutrients, such as vitamin E, that protect cells against oxidative
stress. Selenium is an essential component of the enzyme glutathione peroxidase
(GSH-Px), which reduces hydrogen peroxide and other organic peroxides to
harmless substances. By detoxifying peroxides, GSH-Px prevents peroxidation and
subsequent instability of cell membranes.
Inflammatory cells in asthmatic airways oxidize nicotinamide-adenine dinucleotide phosphate, producing oxygen-derived free radicals and peroxides. [46] It has been proposed that selenium, as a component of GSH-Px, can protect membranes in asthmatic airways from damage caused by peroxides and can protect antiproteases in the lung from inactivation by toxic antioxidants. [47]
Studies performed to examine a possible relationship between low selenium levels and asthma (Table 5) have yielded inconsistent results. In New Zealand, Shaw et al [48] surveyed 708 children and found a prevalence of current wheezing of 21.3%. For 26 of the children with current wheezing and for 61 healthy control children, stored serum samples drawn 8 years prior were tested for IgE and selenium levels. It was found that current wheezing was more common in those with high levels of IgE or low levels of selenium. This type of study cannot assume cause and effect. It is possible that the high IgE level has more to do with current wheezing than the low selenium level, and it is unfortunate that current serum levels were not measured.
Table 5. Selenium and Asthma*
Selenium concentrations and GSH-Px activity were measured in both adults with asthma and healthy controls for a study by Stone et al. [49] Patients with asthma had lower concentrations of selenium in plasma and whole blood but not in platelets when compared with controls. There was no accompanying reduction in GSH-Px activity found in whole blood or platelets. The authors concluded that the reduced selenium status of the patients with asthma did not contribute to decreased antioxidant defenses. Somewhat different results were obtained by Flatt et al [50] who found that whole blood, but not plasma, selenium concentrations and GSH-Px activity were lower in adults with asthma than in controls. The authors conclude that whole blood levels reflect a longer term index of selenium status than plasma and that the study results are consistent with a role for lowered selenium concentrations in the pathogenesis of asthma. Similarly, reduced GSH-Px activity in whole blood was found by Powell et al [51] in 37 children with asthma when compared with controls. Although these studies showed some measurements of selenium levels to be lower in patients with asthma, the effect on GSH-Px activity was inconsistent. In addition, the mechanism for low selenium levels in the pathogenesis of asthma has not been shown.
Pearson et al [52] studied aspirin-sensitive patients with asthma who were thought to have an acetylsalicylic acid-induced release of oxygen radicals. They found aspirin-tolerant patients with asthma to have higher mean serum selenium concentrations than either aspirin-sensitive patients with asthma or normal patients. However, only aspirin-sensitive patients with asthma were found to have reduced platelet GSH-Px activity. The authors conclude that reduced GSH-Px activity in aspirin-sensitive patients with asthma must be dependent on another unknown factor in addition to lowered serum selenium levels. They could not explain, however, the higher selenium concentration seen in the aspirin-tolerant asthmatic population.
A therapeutic role for selenium in the management of asthma was suggested in a case report by Ahlrot-Westerlund and Norrby. [53] They treated a 35-year-old man with a posterior subcapsular cataract, keratoconus, atopic eczema, and asthma with daily supplements of selenium and vitamin E for 2 months. After treatment, the patient had no signs of atopic eczema or asthma. In 1993, Hasselmark et al [54] conducted a study of 24 adults with asthma in which half of the patients were randomized to receive 100 micrograms of selenium per day for 14 weeks, while the other half received a placebo. Six patients from the selenium-supplemented group and 1 from the placebo group noted significant subjective clinical improvement, although neither group showed improvement in pulmonary function test results or a histamine inhalation challenge. The authors are cautious in their interpretation of these inconsistent results.
There are no current data demonstrating a beneficial effect of selenium supplementation on objective tests of pulmonary function in patients with asthma. In addition, the data on whole blood selenium levels and GSH-Px activity are inconsistent. A possible correlation between low serum levels of selenium and wheezing is not sufficient to support the use of selenium supplements in the treatment of asthma.
FISH OILS^
There are 2 classes of polyunsaturated fatty acids
obtained from our diets: [omega ]-6 fatty acids are represented by linoleic
acid, which is metabolized in humans and animals to AA, and [omega ]-3 fatty
acids are represented by alpha-linolenic acid, which is metabolized in humans
and animals to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Arachidonic acid is obtained in our diet mainly from grain-fed animals, while
EPA and DHA are obtained from fatty fish. Humans consume more [omega ]-6 fatty
acids than [omega ]-3 fatty acids.
Arachidonic acid is incorporated into cell membranes from which it is released to act as the precursor for the 2 series of PGs and thromboxanes and the 4 series of leukotrienes (LTs). These metabolites promote such responses as smooth muscle contraction, bronchoconstriction, increased vascular permeability, and leukocyte chemotaxis. When humans ingest fish or fish oil, EPA and DHA replace AA in cell membranes. When EPA is released from cell membranes, it is the precursor for the 3 series of PGs and thromboxanes and the 5 series of LTs. Therefore, EPA leads to decreased production of the inflammatory metabolites of AA and replaces them with metabolites that have less inflammatory potential. It is this change in the pattern of metabolites and the potential effect on airway inflammation that have led to an interest in fish oil supplementation in the management of asthma (Table 6). However, clinical studies have not shown the expected benefits on airway functioning.
Table 6. Fish Oil and Asthma*
Payan et al [55] and Kirsch et al [56] studied the effect of fish oil in adults with asthma who were randomized into 2 groups receiving either 0.1 g per day of EPA or 4 g per day of EPA for 8 weeks. Only the high-dose supplement decreased LTB4 generation from AA by leukocytes and suppressed neutrophil but not mononuclear leukocyte chemotaxis to multiple stimuli. Neither dose led to any change in clinical status or pulmonary function test results in the 8-week testing period. In a study by Arm et al, [57] patients with asthma received either 3.2 g per day of EPA and 2.2 g per day of DHA or a placebo for a 10-week period. The neutrophils of the patients receiving EPA and DHA showed decreased LTB4 generation and decreased chemotaxis in response to stimuli. There was, however, no change in reported symptoms, pulmonary function test results, or bronchial responsiveness to either histamine or exercise in either group. The authors suggest that since neutrophil function was suppressed without a concomitant change in severity of asthma, either neutrophils do not play a major role in the pathogenesis of asthma or the suppression of function was not adequate to see a clinical effect. Since neutrophils are believed to have a role in late-phase reactions in asthma, the second explanation seems more likely than the first.
Twelve adults with asthma were randomized into 2 groups receiving either 1 g per day of EPA and DHA or a placebo for 1 year in a study by Dry and Vincent. [58] Pulmonary function test results showed an increased FEV1 only at 9 months of supplementation. In this study, the baseline FEV1 varied substantially between the 2 groups, making any claim of a significant effect of fish oil supplementation questionable. In another long-term study, Thien et al [59] supplemented adults with asthma with 3.2 g per day of EPA and 2.2 g per day of DHA or a placebo for 6 months and demonstrated no change in peak flow, bronchial responsiveness to histamine, symptom score, or medication use for either group.
The effect of fish oil supplementation on the early and late asthmatic responses to antigen has been studied by Arm et al. [60] Bronchial responses to allergen (measured as the dose causing a 35% decrease in FEV1 [PD35 ]) were measured in adults with asthma, 9 of whom received 3.2 g per day of EPA and 2.2 g per day of DHA and 8 of whom received a placebo for 10 weeks. In contrast to those receiving the placebo, the group taking the EPA and DHA demonstrated a smaller late asthmatic response to allergen when compared with baseline. They did not, however, show any change in clinical parameters, such as peak flows or symptom scores. In addition, the effect on the late-phase response of the EPA and DHA supplements could not be compared with that of the placebo since the baseline late-phase response was much greater in the EPA/DHA-supplemented group than in the placebo group.
It has been demonstrated by Picado et al [61] that fish oil supplementation might be detrimental to patients with asthma who are aspirin intolerant. Ten aspirin-intolerant adults with asthma received 6 weeks of a control diet containing placebo supplementation followed by 6 weeks of a diet enriched with 3 g per day of [omega ]-3 fatty acids. While neither diet caused a change in symptom scores, peak expiratory flow values were significantly lower and bronchodilator use was greater during the last 2 weeks of the fish oil-supplemented diet.
These studies do not show clinical improvement in patients with asthma using fish oil supplementation, despite some changes seen in inflammatory cell functions. There is, at this time, no data to support the recommendation of using fish oil in the treatment of asthma.
SUMMARY^
It is clear from a review of the existing data that
there is no proven role for nutritional therapy in the management of asthma.
Food allergies may occasionally be involved in the exacerbation of asthma,
particularly in children. Magnesium infusion may have a place in the acute
treatment of asthma, but does not seem to have long-term benefits. The studies
of sodium, selenium, and fish oils do not show convincing evidence of clinical
benefits. Vitamin C, however, did demonstrate a possible effect on bronchial
responsiveness and pulmonary function. Whether these changes have clinical
importance can only be determined by further studies. Until more definitive
studies are completed, the use of nutritional supplements for the treatment of
asthma cannot be recommended.
Accepted for publication August 9, 1996.
Reprints: Catherine A. Monteleone, MD; University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School; 1 Robert Wood Johnson Pl, CN19; New Brunswick; NJ 08901.
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