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Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma?
Review article Supported by a grant from AstraZeneca LP
Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma? Sheldon L. Spector, MD* and Marc E. Surette, PhD†‡
Objective: This article discusses the role of diet in the management of asthma. Readers will gain an understanding of how evolution of the western diet has contributed to increased asthma prevalence and how dietary modification that includes management of dietary lipids may reduce symptoms of asthma. Data Sources: Relevant studies published in English were reviewed. Study Selection: Medline search to identify peer-reviewed abstracts and journal articles. Results: Asthma and obesity, which often occur together, have increased in prevalence in recent years. Studies suggest adaption of a western diet has not only contributed to obesity, but that increased intake of specific nutrients can cause changes in the frequency and severity of asthma. Increased asthma prevalence has also been proposed to arise from increased exposure to diesel particles or lack of exposure to infectious agents or endotoxins during childhood, generating a biased Th2 immune response, and increased cytokine and leukotriene production. Antagonists directed against these pro-inflammatory mediators include anticytokines and antileukotrienes. A reduction in the levels of inflammatory mediators associated with asthma has also been seen with dietary interventions, such as the administration of oils containing ␥-linolenic acid and eicosapentaenoic acid. Conclusions: Evidence suggests elevated body mass index and dietary patterns, especially intake of dietary lipids, contribute to symptoms of asthma. Dietary modification may help patients manage their asthma as well as contribute to their overall health. Ann Allergy Asthma Immunol 2003;90:371–377.
INTRODUCTION The past few decades has seen an increase in the prevalence of asthma. One proposed explanation for this increase, ie, the hygiene hypothesis, suggests that lack of exposure to microbial antigens during childhood results in a predominance of the Th2 immune profile, which is associated with pro-inflammatory cytokines, rather than the antiallergic Th1 profile.1 Disease severity may thus be a function of a biased Th2 immune response, in which Th1-mediated immunity is downregulated, leading to increased mediator production, including increased leukotriene production.2,3 An increase in asthma prevalence has also been proposed to arise from increased exposure to diesel particles.4 A concomitant increase in the prevalence of obesity has also been observed. Asthma and obesity often occur together, with weight reduction in obese people with asthma resulting in both immediate and long-term alleviation of asthma symptoms.5 This has led to renewed investigation of the role of diet in asthma, including whether asthma may respond to dietary
* University of California-Los Angeles, Los Angeles, California. † Universite´ Laval, Que´bec, Canada. ‡ Research and Development, Pilot Therapeutics Inc, Winston-Salem, NC. Received for publication April 20, 2002. Accepted for publication in revised form October 14, 2002.
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modification, thereby reducing the need for pharmacologic agents.6 The emphasis on replacing lard and dairy fats rich in saturated fatty acids as the predominant source of fatty acids as being beneficial to cardiovascular health has also led to increased consumption of vegetable oils rich in omega-6 polyunsaturated fatty acids and a simultaneous decrease in consumption of oily fish and leafy vegetables, the major sources of the omega-3 class of polyunsaturated fatty acids. This has resulted in a significant shift in diet, with a fall in consumption of saturated fats and an increase in omega-6 polyunsaturated fatty acids.7 The well documented anti-inflammatory properties of dietary omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and the generally pro-inflammatory properties of dietary omega-6 polyunsaturated fatty acids,6,8,9 such as linoleic acid, suggest these dietary trends may have predisposed some individuals to inflammatory disorders including asthma. Indeed, omega-6 fatty acids are the direct precursors of the leukotrienes, which are derived from the omega-6 fatty acid arachidonic acid. These fatty acids are obligatorily obtained from the diet, as humans do not have the enzymatic capability to synthesize these essential nutrients directly. Considering the important role that leukotrienes play in asthma and the tendency of atopic individuals, including atopic asthmatic patients, to overproduce leukotrienes compared with their healthy coun-
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terparts,10 –19 a possible contributing factor to the increased incidence of asthma in western societies may be the consumption of a pro-inflammatory diet. Despite knowledge that consumption of certain foods encourages production of inflammatory mediators that can cause changes in the frequency and severity of asthma, the National Asthma Education and Prevention Program’s 1997 Guidelines for the Diagnosis and Management of Asthma makes little mention of the role of diet on asthma, apart from suggesting that a detailed medical history of a patient known or thought to have asthma include whether food, food additives, and preservatives such as sulfites may be precipitating and/or aggravating factors and, if so, to recommend avoidance of such products.20 The recent National Asthma Education and Prevention Program Update on Selected Topics 2002 continues to emphasize controlling environmental factors that make asthma worse (eg, allergens and irritants), but diet per se is not mentioned.21 Given the importance of dietary lipids as a component of lifestyle interventions in delaying or modifying symptoms and/or disease progression in a number of other disorders, including type II diabetes,22 effective asthma management should consider dietary factors. METHODS A MEDLINE search was conducted using the terms asthma, borage, linolenic acid(s), fatty acids– essential, leukotrienes, and obesity. Search restrictions included English language and abstract online; no time restrictions were specified. Relevant peer-reviewed abstracts and journal articles published in English were reviewed. The proportion of initially identified studies that met the selection criteria was 68%; eliminated were studies that focused on plant research. RESULTS AND DISCUSSION Pathophysiology of Asthma Asthma is a chronic inflammatory disorder of the airways. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in existing bronchial hyperresponsiveness to a variety of stimuli, as well as possible long-term airway remodeling.20,23,24 Relationship between Asthma, Diet, and Body Weight The role of food intolerance in asthma has been well documented, with food avoidance measures resulting in improvement in asthma symptoms, reduction in the use of pharmacologic agents, and even hospital admissions.25 Recently, suboptimal intake of dietary nutrients such as antioxidants (vitamins A, C, E, and selenium) as well as sodium and magnesium has been recognized as a potential risk factor for
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asthma and may enhance asthmatic inflammation; however, there are insufficient data to establish a causal relationship.25 In developed countries, the increase in prevalence of asthma has been paralleled by an increase in obesity. More than 50% of adults in Europe are overweight (body mass index [BMI] ⱖ25) or obese (BMI ⱖ30.0); the prevalence of obesity is 10 to 20% in men and 15 to 25% in women.26 A component of this weight gain can be attributed to a change in lifestyle, including changes in dietary habits. Camargo et al27 investigated the relation of BMI and weight change to risk of adult-onset asthma in 85,911 women followed prospectively in the Nurses’ Health Study II. From 1991 to 1995, they identified 1,596 incident cases of asthma among women aged 26 to 46 years. Using a multivariate model that controlled for confounding factors such as age, race, smoking, physical activity, and energy intake, among others, multivariate relative risks of asthma for six increasing categories of BMI at baseline were 0.9, 1.0 (reference), 1.1, 1.6, 1.7, and 2.7 (P for trend ⬍ 0.001) for participant-reported physician diagnosis of asthma and use of an asthma medication since diagnosis. Association between BMI and relative risk of asthma among women who reported undergoing a recent health screening examination is shown in Figure 1 (n ⫽ 1,061 cases). Overall risk for asthma was elevated at a BMI of 22.5 to 24.9, which the authors note is below the standard clinical criteria for obesity; women with normal or average BMI were also at a slightly increased risk. In an analysis that controlled for the same variables and BMI at age 18, women who gained weight after age 18 years were found to be at significantly increased risk of developing asthma during the 4-year followup period (P for trend ⬍ 0.001). Depending on case definition, those with a BMI of ⱖ30 in 1991 had a multivariate relative risk of asthma of 2.7 to 3.8 in 1995. BMI was found to have a strong, independent, and positive association with risk of adult-onset asthma and may help explain much of the current epidemic of asthma.
Figure 1. Relative risk of adult-onset asthma by BMI. Reprinted with permission from Archives of Internal Medicine, November 22, 1999, Vol 159, page 2585, copyrighted 1999 by American Medical Association.
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It remains unclear whether patients with poorly controlled asthma gain weight because they limit their activities or if being obese increases asthma risk. To clarify pathophysiologic features of this relationship, Hakala et al28 investigated the effects of weight loss on asthma severity in 14 obese adults (11 women and 3 men aged 25 to 62 years). Peak expiratory flow rate (PEFR) variability and airways obstruction were measured before and after an 8-week, very lowcalorie diet. A decrease in BMI from 37.2 to 32.1 kg/m2 was associated with statistically significant declines in diurnal PEFR variation (P ⫽ 0.01), whereas mean morning PEFR (P ⫽ 0.001), forced expiratory volume in 1 second (FEV1; P ⬍ 0.005), and forced vital capacity (FVC; P ⬍ 0.05) increased. Functional residual capacity (P ⬍ 0.05) and expiratory reserve volume (P ⬍ 0.005) were significantly higher and airways resistance was significantly reduced (P ⬍ 0.01) after weight loss, resulting in improved pulmonary mechanism and better control of airways obstruction. Stenius-Aarniala et al5 also found that weight reduction in obese people with asthma resulted in immediate alleviation of asthma symptoms, as defined by significant improvements in FEV1 (P ⫽ 0.009) and FVC (P ⬍ 0.0001); these effects were still significant at 1 year (FEV1, P ⫽ 0.02 and FVC, P ⫽ 0.001). Number of exacerbations and courses of oral steroids were also reduced.5 This suggests that a treatment program for obese or overweight patients with asthma should include appropriate lifestyle and dietary changes that lead to weight reduction. Role of Leukotrienes in Asthma The leukotrienes, previously identified as slow-reacting substance of anaphylaxis, are important chemical mediators in the pathogenesis of asthma. Leukotrienes are derived from arachidonic acid, an essential omega-6 polyunsaturated fatty acid found in cellular membranes. After release from membrane phospholipids by hydrolysis, arachidonic acid can be metabolized by several pathways, including cyclooxygenase, which produces prostaglandins and thromboxanes, or 5-lipoxygenase, which produces leukotriene B4 and the cysteinyl leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4).23 The final common step in the biosynthesis of leukotrienes is the formation of LTA4; subsequently, one pathway leads to formation of the cysteinyl leukotrienes and the other to formation of LTB4 by the enzyme LTA4 hydrolase. These potent bronchoconstrictors are produced by mast cells and other inflammatory cells, including macrophages, monocytes, eosinophils, and basophils. They bind to specific target receptors and directly induce bronchial smooth muscle contraction, increase vascular permeability, and promote mucus secretion. They also induce infiltration of inflammatory cells into airway tissues.23,24 Discovery of the mechanism of action of leukotrienes has created new and effective opportunities for controlling the symptoms of asthma. Blocking leukotriene synthesis and action for the management of asthma has been a major goal of the pharmaceutical industry. Certain agents such as zileu-
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ton (Zyflo; Abbott, North Chicago, IL) interfere with leukotriene production; other agents, such as zafirlukast (Accolate; AstraZeneca, Wilmington, DE) and montelukast (Singulair; Merck, West Point, PA), block the action of the leukotrienes at the receptor level.24 Several studies have shown that atopic individuals, including atopic asthmatic patients, have an increased capacity to synthesize leukotrienes compared with healthy nonatopic individuals.10 –19 Although it is not clear whether this increased biosynthetic capacity has any consequences on disease severity or progression, considering the central role played by leukotrienes in asthma, strategies to decrease or “normalize” the capacity to synthesize leukotrienes could possibly affect disease severity. Indeed, the mechanism of action of the asthma drug, Zyflo, is through the inhibition of 5-lipoxygenase and thus leukotriene biosynthesis. For example, a 40% decrease in the in vivo biosynthesis of leukotrienes in asthmatic subjects administered Zyflo was associated with a significant improvement in FEV1.29 As leukotrienes are directly derived from dietary omega-6 fatty acids, it has been speculated that the quality of dietary polyunsaturated fatty acids may alter the capacity to synthesize these lipid mediators of inflammation and, hence, affect inflammatory diseases including asthma. Dietary Polyunsaturated Fatty Acids Omega-3 and omega-6 fatty acids are metabolized through a common pathway and compete for acylation sites in cellular phospholipids (Fig 2). An increase in the consumption of dietary omega-3 fatty acids can inhibit arachidonic acid synthesis from dietary linoleic acid, resulting in its reduction in tissues. Omega-3 fatty acids also inhibit the action of cyclooxygenase and 5-lipoxygenase. EPA is both a substrate and an inhibitor, whereas docosahexaenoic acid (DCHA) is only an inhibitor of the cyclooxygenase.7,30 These omega-3 fatty acids, when included in the diet, can competitively inhibit the formation of prostaglandins and leukotrienes derived from arachidonic acid, leading to a suppression of neutrophil function and thus suggesting an antiinflammatory potential.30 Trans fatty acids have been reported to influence desaturation and chain elongation of omega-6 and omega-3 fatty
Figure 2. Metabolism of essential fatty acids.
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acids into precursors of inflammatory mediators. Data from the International Study of Asthma and Allergies in Childhood of 13- to 14-year-old children at 55 centers in 10 European countries found that 12-month prevalence of symptoms of asthma, allergic conjunctivitis, and atopic eczema was significantly associated with intake of trans fatty acids, expressed as a percent of energy intake (P ⬍ 0.001; Fig 3).31 Disparities in consumption of polyunsaturated fatty acids among social classes and regions have been associated with differences in prevalence of allergic disease. Black and Sharpe7 hypothesized that an increase in the dietary omega-6 fatty acid linoleic acid can influence allergic sensitization by increasing prostaglandin E2 (PGE2) formation, leading to a Th2 response and IgE synthesis. An increase in the omega-3 fatty acid EPA, however, inhibits prostaglandin E2 formation. This may explain to some extent how dietary changes have led to an increase in the prevalence of asthma in developed countries. Dietary Omega-3 Polyunsaturated Fatty Acids Historically, results of the effect of dietary supplementation with fish oils rich in omega-3 fatty acids on asthma and leukotriene synthesis have been equivocal. A number of animal studies had indicated that the supplementation of diets with omega-3 fatty acids could have profound effects on the capacity to synthesize leukotrienes both in vivo and in vitro.32,33 However, the effect of these dietary fatty acids on leukotriene synthesis in humans was less consistent. The first study30 in humans investigating the effect on leukotriene synthesis showed that dietary supplementation with EPA and DCHA for 6 weeks led to a reduction in arachidonic acid content of neutrophils and monocytes and a significant reduction in leukotriene biosynthesis. Similarly, supplementation for 10 weeks resulted in a 50% inhibition in leukotriene generation by ionophore-stimulated neutrophils in patients with mild asthma. Neutrophil chemotaxis was also substantially suppressed.34 However, under carefully controlled conditions, dietary omega-3 fatty acids do not seem to have the capacity to inhibit leukotriene formation in humans.35 These inconsistent results are difficult to explain but may be a function of the underlying dietary status of the subjects and the different cell isolation and stimulation protocols used to evaluate biosynthetic capacity. These conflicting results on leukotriene biosynthesis in humans also translated into variable results in clinical trials in which asthma disease endpoints were measured. In a small double-blind study,36 an improvement in FEV1 was measured in subjects supplementing their diet with omega-3 fatty acids over a 9-month period. In patients with mild asthma, fish oil supplementation was found to attenuate allergen-induced late asthmatic response (P ⬍ 0.005)34; however, such supplementation was not shown to have significant clinical effects as measured by changes in airways responsiveness, symptom scores, or bronchodilator use.34,37 Dietary fish oil supplementation also did not prevent seasonal hay fever or asthma in
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Figure 3. Prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema and trans fatty acid intake (1% energy). Reprinted with permission from The Lancet, 1999, Vol 353, page 2041, by Elsevier Science.
pollen season38 and had no effect when added to the diet of patients with asthma for 8 weeks.39 The clinical effects of fish oil supplementation and a diet that increases omega-3 polyunsaturated fatty acids and was compared with those of a diet enriched in omega-6 fatty acids
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in a double-blind, randomized trial in 39 children with asthma. Tumor necrosis factor (TNF)-␣ production fell significantly compared with baseline in the omega-3 group (P ⫽ 0.026) but did not reach significance between the two groups (P ⫽ 0.075). No significant changes in clinical severity of asthma were noted.40 In another randomized, controlled trial,41 29 children with bronchial asthma who were in a longterm treatment hospital received fish oil capsules (84 mg EPA and 36 mg DCHA) or control capsules (300 mg olive oil). Asthma symptom scores were significantly lower than at baseline in the fish oil group after 6 to 10 months of treatment. The authors concluded that fish oil supplementation may be beneficial for children with bronchial asthma in a strictly controlled environment in terms of inhalant allergens and diet.41 Dietary Omega-6 Polyunsaturated Fatty Acids The omega-6 family of fatty acids, which includes arachidonic acid, is generally considered to be pro-inflammatory. However, one dietary omega-6 fatty acid, ␥-linolenic acid (GLA), has been consistently shown to possess anti-inflammatory properties and to inhibit leukotriene synthesis in clinical trials.42 When GLA is presented to inflammatory cells, it is efficiently elongated to dihomogammalinolenic acid, but because these cells lack ␦-5 desaturase activity, it is not converted to arachidonic acid. Dihomogammalinolenic acid is transformed by lipoxygenases and cyclooxygenases to oxygenated compounds which, unlike the arachidonic acid-derived leukotrienes, have anti-inflammatory properties and inhibit the synthesis of leukotrienes.43– 45 Consequently, dietary GLA decreases the potential of inflammatory cells to synthesize leukotrienes. Supplementation of diets with GLA has also been shown to result in a potentially undesirable increase in serum arachidonic acid levels, most likely because of the efficient transformation of dietary GLA to arachidonic acid in the liver.46,47 Because EPA can compete with arachidonic acid for the incorporation into membrane phospholipids and can also inhibit the ␦-5 desaturase step of fatty acid metabolism, a dietary supplementation strategy was developed in which a combination of GLA and EPA resulted in the inhibition of leukotriene synthesis while preventing increases in serum amino acid levels.47 The anti-inflammatory potential of such a dietary strategy has been evaluated in critically ill patients suffering from acute respiratory distress. Results of a prospective, randomized, double-blind, controlled, multicenter trial found that compared with a control diet, enteral nutrition for at least 4 to 7 days with a diet supplemented by EPA, GLA, and antioxidants significantly reduced pulmonary neutrophil recruitment (P ⫽ 0.0081) and inflammation in 146 patients. Further, beneficial effects of the EPA⫹GLA diet on gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggested this dietary strategy would be a useful adjuvant therapy in the clinical management of patients with or at risk of
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developing acute respiratory distress.48 Although the inflammation associated with acute respiratory distress syndrome differs from that associated with asthma, this trial underscores the anti-inflammatory potential of such adjuvant dietary therapy on disease parameters. In a recent randomized, double-blind, parallel-group study in 23 atopic subjects with mild to moderate asthma controlled solely with inhaled -agonists or theophylline, patients received placebo (olive oil) and low-dose and high-dose combinations of GLA and EPA. Stimulated ex vivo LTB4 and TNF-␣ were measured at baseline and after 4 weeks of supplementation. Both combinations significantly suppressed LTB4 and TNF-␣ biosynthesis when compared with placebo.49 It remains to be seen whether the normalization of leukotriene synthesis in asthma patient will be of benefit to ameliorate disease severity. However, given the important role that leukotrienes play in asthma, these results warrant the investigation of such dietary strategies as an adjunct therapy in the management of asthma. CONCLUSION Epidemiologic studies have suggested that dietary patterns, especially intake of dietary lipids, may adversely affect asthmatic symptoms. Given the concomitant rise in obesity and evidence that suggests a decrease in weight can alleviate symptoms of asthma, dietary modification may be beneficial not only for overall health, but also in managing asthma. Additionally, as individuals with asthma produce increased quantities of leukotrienes compared with healthy individuals, dietary interventions that decrease the capacity to synthesize leukotrienes may be warranted; however, studies investigating the impact of such interventions on disease severity, reliance on medication, and quality of life are lacking. With the mounting evidence that diet and elevated BMI contribute to asthma symptoms, it may be beneficial to modify the current treatment guidelines so that diet modification may become one of the initial steps in the management of asthma. REFERENCES 1. Kay AB. Allergy and allergic diseases. N Engl J Med 2001; 344:30 –36. 2. Greene LS. Asthma, oxidant stress, and diet. Nutrition 1999;15: 899 –907. 3. Kuo ML, Huang JL, Yeh KW, et al. Evaluation of Th1/Th2 ratio and cytokine production profile during acute exacerbation and convalescence in asthmatic children. Ann Allergy Asthma Immunol 2001;86:272–276. 4. Diaz-Sanchez D, Penichet-Garcia M, Saxon A. Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity. J Allergy Clin Immunol 2000;106:1140 –1146. 5. Stenius-Aarniala B, Poussa T, Kvarnstro¨m J, et al. Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 2000;320:827– 832. 6. Broughton KS, Johnson CS, Pace BK, et al. Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production. Am J Clin Nutr 1997;65:1011–1017.
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925–934. 26. Seidell JC, Flegal KM. Assessing obesity: classification and epidemiology. Br Med Bull 1997;53:238 –252. 27. Camargo CA Jr, Weiss ST, Zhang S, et al. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159:2582–2588. 28. Hakala K, Stenius-Aarniala B, Sovijarvi A. Effects of weight loss on peak flow variability, airways obstruction, and long volumes in obese patients with asthma. Chest 2000;118; 1315–1321. 29. Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;119:1059 –1066. 30. Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 1985;312:1217–1224. 31. Weiland SK, von Mutius E, Husing A, Asher MI. Intake of trans fatty acids and prevalence of childhood asthma and allergies in Europe. ISAAC Steering Committee. Lancet 1999;353: 2040 –2041. 32. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000;71(Suppl):343S–348S. 33. Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr 1990;52:1–28. 34. Arm JP, Horton CE, Mencia-Huerta JM, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988;43:84 –92. 35. Chilton FH, Patel M, Fonteh AN, et al. Dietary n-3 fatty acid effects on neutrophil lipid composition and mediator production. Influence of duration and dosage. J Clin Invest 1993;91: 115–122. 36. Dry J, Vincent D. Effect of a fish oil diet on asthma: results of a 1-year double-blind study. Int Arch Allergy Appl Immunol 1991;95:156 –157. 37. Arm JP, Horton CE, Spur BW, et al. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139:1395–1400. 38. Thien FC, Mencia-Huerta JM, Lee TH. Dietary fish oil effects on seasonal hay fever and asthma in pollen sensitive subjects. Am Rev Respir Dis 1993;147:1138 –1143. 39. Kirsch CM, Payan DG, Wong MY, et al. Effect of eicosapentaenoic acid in asthma. Clin Allergy 1988;18:177–187. 40. Hodge L, Salome CM, Hughes JM, et al. Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children. Eur Respir J 1998;11:361–365. 41. Nagakura T, Matsuda S, Shichijyo K, et al. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J 2000;16: 861– 865. 42. Fan YY, Chapkin RS. Importance of dietary ␥-linolenic acid in human health and nutrition. J Nutr 1998;128:1411–1414. 43. Chilton-Lopez T, Surette ME, Swan DD, et al. Metabolism of gammalinolenic acid in human neutrophils. J Immunol 1996; 156:2941–2947. 44. Chapkin RS, Miller CC, Somers SD, Erickson KL. Utilization of dihomo-␥-linolenic acid (8,11,14-eicosatrienoic acid) by murine peritoneal macrophages. Biochim Biophys Acta 1988;959:
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322–331. 45. Chapkin RS, Miller CC, Somers SD, Erickson KL. Ability of 15-hydroxyeicosatrienoic acid (15-OH-20:3) to modulate macrophage arachidonic acid metabolism. Biochem Biophys Res Commun 1988;153:799 – 804. 46. Johnson MM, Swan DD, Surette ME, et al. Dietary supplementation with ␥-linolenic acid alters fatty acid content and eicosanoid production in healthy humans. J Nutri 1997;127: 1435–1444. 47. Barham JB, Edens MB, Fonteh AN, et al. Addition of eicosapentaenoic acid to ␥-linolenic acid–supplemented diets prevents serum arachidonic acid accumulation in humans. J Nutr 2000; 130:1925–1931. 48. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral
feeding with eicosapentaenoic acid, ␥-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999;27:1409 –1420. 49. Bowton DL, Seeds M, Surette ME, et al. Airozin suppresses leukotriene synthesis in asthmatics. Am J Respir Crit Care Med 2002;165:A95. Requests for reprints should be addressed to: Sheldon L. Spector, MD California Allergy and Asthma Medical Group, Inc 11645 Wilshire Boulevard Los Angeles, CA 90025 E-mail: [email protected]
CME Examination 1–5, Spector SL, Surette ME. 2003;90:371-377. CME Test Questions 1. The increase in prevalence of asthma seen in recent years has been associated with which one of the following? a. Increased exposure to diesel particles. b. Lack of exposure to infectious agents or endotoxins during childhood. c. Increased intake of food that encourage production of pro-inflammatory mediators. d. All of the above. e. None of the above. 2. In the Nurses’ Health Study, BMI was found to have a strong, independent, and positive association with risk of adult-onset asthma. a. True. b. False. 3. The primary dietary sources of the omega-3 class of polyunsaturated fatty acids are: a. Lard and dairy fats. b. Oily fish and leafy vegetables. c. Saturated fats and most vegetable oils.
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d. Red meat and starchy vegetables. e. Nuts and grains. 4. In patients with asthma, administration of oils containing GLA and EPA can: a. Block levels of inflammatory mediators associated with asthma. b. Ameliorate any effect obesity may have on asthma. c. Augment fats found in a typical western diet. d. Balance increased exposure to environmental pollutants. e. Complement lack of exposure to microbial antigens during childhood. 5. Although it remains unclear whether patients with poorly controlled asthma gain weight because they limit their activities or if being obese increases asthma risk, studies suggest weight reduction in obese individuals may alleviate symptoms of asthma. a. True. b. False. Answers found on page 421.
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Diet and asthma: has the role of dietary lipids been overlooked in the management of asthma? Sheldon L. Spector, MD* and Marc E. Surette, PhD†‡
Objective: This article discusses the role of diet in the management of asthma. Readers will gain an understanding of how evolution of the western diet has contributed to increased asthma prevalence and how dietary modification that includes management of dietary lipids may reduce symptoms of asthma. Data Sources: Relevant studies published in English were reviewed. Study Selection: Medline search to identify peer-reviewed abstracts and journal articles. Results: Asthma and obesity, which often occur together, have increased in prevalence in recent years. Studies suggest adaption of a western diet has not only contributed to obesity, but that increased intake of specific nutrients can cause changes in the frequency and severity of asthma. Increased asthma prevalence has also been proposed to arise from increased exposure to diesel particles or lack of exposure to infectious agents or endotoxins during childhood, generating a biased Th2 immune response, and increased cytokine and leukotriene production. Antagonists directed against these pro-inflammatory mediators include anticytokines and antileukotrienes. A reduction in the levels of inflammatory mediators associated with asthma has also been seen with dietary interventions, such as the administration of oils containing ␥-linolenic acid and eicosapentaenoic acid. Conclusions: Evidence suggests elevated body mass index and dietary patterns, especially intake of dietary lipids, contribute to symptoms of asthma. Dietary modification may help patients manage their asthma as well as contribute to their overall health. Ann Allergy Asthma Immunol 2003;90:371–377.
INTRODUCTION The past few decades has seen an increase in the prevalence of asthma. One proposed explanation for this increase, ie, the hygiene hypothesis, suggests that lack of exposure to microbial antigens during childhood results in a predominance of the Th2 immune profile, which is associated with pro-inflammatory cytokines, rather than the antiallergic Th1 profile.1 Disease severity may thus be a function of a biased Th2 immune response, in which Th1-mediated immunity is downregulated, leading to increased mediator production, including increased leukotriene production.2,3 An increase in asthma prevalence has also been proposed to arise from increased exposure to diesel particles.4 A concomitant increase in the prevalence of obesity has also been observed. Asthma and obesity often occur together, with weight reduction in obese people with asthma resulting in both immediate and long-term alleviation of asthma symptoms.5 This has led to renewed investigation of the role of diet in asthma, including whether asthma may respond to dietary
* University of California-Los Angeles, Los Angeles, California. † Universite´ Laval, Que´bec, Canada. ‡ Research and Development, Pilot Therapeutics Inc, Winston-Salem, NC. Received for publication April 20, 2002. Accepted for publication in revised form October 14, 2002.
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modification, thereby reducing the need for pharmacologic agents.6 The emphasis on replacing lard and dairy fats rich in saturated fatty acids as the predominant source of fatty acids as being beneficial to cardiovascular health has also led to increased consumption of vegetable oils rich in omega-6 polyunsaturated fatty acids and a simultaneous decrease in consumption of oily fish and leafy vegetables, the major sources of the omega-3 class of polyunsaturated fatty acids. This has resulted in a significant shift in diet, with a fall in consumption of saturated fats and an increase in omega-6 polyunsaturated fatty acids.7 The well documented anti-inflammatory properties of dietary omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and the generally pro-inflammatory properties of dietary omega-6 polyunsaturated fatty acids,6,8,9 such as linoleic acid, suggest these dietary trends may have predisposed some individuals to inflammatory disorders including asthma. Indeed, omega-6 fatty acids are the direct precursors of the leukotrienes, which are derived from the omega-6 fatty acid arachidonic acid. These fatty acids are obligatorily obtained from the diet, as humans do not have the enzymatic capability to synthesize these essential nutrients directly. Considering the important role that leukotrienes play in asthma and the tendency of atopic individuals, including atopic asthmatic patients, to overproduce leukotrienes compared with their healthy coun-
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terparts,10 –19 a possible contributing factor to the increased incidence of asthma in western societies may be the consumption of a pro-inflammatory diet. Despite knowledge that consumption of certain foods encourages production of inflammatory mediators that can cause changes in the frequency and severity of asthma, the National Asthma Education and Prevention Program’s 1997 Guidelines for the Diagnosis and Management of Asthma makes little mention of the role of diet on asthma, apart from suggesting that a detailed medical history of a patient known or thought to have asthma include whether food, food additives, and preservatives such as sulfites may be precipitating and/or aggravating factors and, if so, to recommend avoidance of such products.20 The recent National Asthma Education and Prevention Program Update on Selected Topics 2002 continues to emphasize controlling environmental factors that make asthma worse (eg, allergens and irritants), but diet per se is not mentioned.21 Given the importance of dietary lipids as a component of lifestyle interventions in delaying or modifying symptoms and/or disease progression in a number of other disorders, including type II diabetes,22 effective asthma management should consider dietary factors. METHODS A MEDLINE search was conducted using the terms asthma, borage, linolenic acid(s), fatty acids– essential, leukotrienes, and obesity. Search restrictions included English language and abstract online; no time restrictions were specified. Relevant peer-reviewed abstracts and journal articles published in English were reviewed. The proportion of initially identified studies that met the selection criteria was 68%; eliminated were studies that focused on plant research. RESULTS AND DISCUSSION Pathophysiology of Asthma Asthma is a chronic inflammatory disorder of the airways. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night and in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in existing bronchial hyperresponsiveness to a variety of stimuli, as well as possible long-term airway remodeling.20,23,24 Relationship between Asthma, Diet, and Body Weight The role of food intolerance in asthma has been well documented, with food avoidance measures resulting in improvement in asthma symptoms, reduction in the use of pharmacologic agents, and even hospital admissions.25 Recently, suboptimal intake of dietary nutrients such as antioxidants (vitamins A, C, E, and selenium) as well as sodium and magnesium has been recognized as a potential risk factor for
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asthma and may enhance asthmatic inflammation; however, there are insufficient data to establish a causal relationship.25 In developed countries, the increase in prevalence of asthma has been paralleled by an increase in obesity. More than 50% of adults in Europe are overweight (body mass index [BMI] ⱖ25) or obese (BMI ⱖ30.0); the prevalence of obesity is 10 to 20% in men and 15 to 25% in women.26 A component of this weight gain can be attributed to a change in lifestyle, including changes in dietary habits. Camargo et al27 investigated the relation of BMI and weight change to risk of adult-onset asthma in 85,911 women followed prospectively in the Nurses’ Health Study II. From 1991 to 1995, they identified 1,596 incident cases of asthma among women aged 26 to 46 years. Using a multivariate model that controlled for confounding factors such as age, race, smoking, physical activity, and energy intake, among others, multivariate relative risks of asthma for six increasing categories of BMI at baseline were 0.9, 1.0 (reference), 1.1, 1.6, 1.7, and 2.7 (P for trend ⬍ 0.001) for participant-reported physician diagnosis of asthma and use of an asthma medication since diagnosis. Association between BMI and relative risk of asthma among women who reported undergoing a recent health screening examination is shown in Figure 1 (n ⫽ 1,061 cases). Overall risk for asthma was elevated at a BMI of 22.5 to 24.9, which the authors note is below the standard clinical criteria for obesity; women with normal or average BMI were also at a slightly increased risk. In an analysis that controlled for the same variables and BMI at age 18, women who gained weight after age 18 years were found to be at significantly increased risk of developing asthma during the 4-year followup period (P for trend ⬍ 0.001). Depending on case definition, those with a BMI of ⱖ30 in 1991 had a multivariate relative risk of asthma of 2.7 to 3.8 in 1995. BMI was found to have a strong, independent, and positive association with risk of adult-onset asthma and may help explain much of the current epidemic of asthma.
Figure 1. Relative risk of adult-onset asthma by BMI. Reprinted with permission from Archives of Internal Medicine, November 22, 1999, Vol 159, page 2585, copyrighted 1999 by American Medical Association.
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It remains unclear whether patients with poorly controlled asthma gain weight because they limit their activities or if being obese increases asthma risk. To clarify pathophysiologic features of this relationship, Hakala et al28 investigated the effects of weight loss on asthma severity in 14 obese adults (11 women and 3 men aged 25 to 62 years). Peak expiratory flow rate (PEFR) variability and airways obstruction were measured before and after an 8-week, very lowcalorie diet. A decrease in BMI from 37.2 to 32.1 kg/m2 was associated with statistically significant declines in diurnal PEFR variation (P ⫽ 0.01), whereas mean morning PEFR (P ⫽ 0.001), forced expiratory volume in 1 second (FEV1; P ⬍ 0.005), and forced vital capacity (FVC; P ⬍ 0.05) increased. Functional residual capacity (P ⬍ 0.05) and expiratory reserve volume (P ⬍ 0.005) were significantly higher and airways resistance was significantly reduced (P ⬍ 0.01) after weight loss, resulting in improved pulmonary mechanism and better control of airways obstruction. Stenius-Aarniala et al5 also found that weight reduction in obese people with asthma resulted in immediate alleviation of asthma symptoms, as defined by significant improvements in FEV1 (P ⫽ 0.009) and FVC (P ⬍ 0.0001); these effects were still significant at 1 year (FEV1, P ⫽ 0.02 and FVC, P ⫽ 0.001). Number of exacerbations and courses of oral steroids were also reduced.5 This suggests that a treatment program for obese or overweight patients with asthma should include appropriate lifestyle and dietary changes that lead to weight reduction. Role of Leukotrienes in Asthma The leukotrienes, previously identified as slow-reacting substance of anaphylaxis, are important chemical mediators in the pathogenesis of asthma. Leukotrienes are derived from arachidonic acid, an essential omega-6 polyunsaturated fatty acid found in cellular membranes. After release from membrane phospholipids by hydrolysis, arachidonic acid can be metabolized by several pathways, including cyclooxygenase, which produces prostaglandins and thromboxanes, or 5-lipoxygenase, which produces leukotriene B4 and the cysteinyl leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4).23 The final common step in the biosynthesis of leukotrienes is the formation of LTA4; subsequently, one pathway leads to formation of the cysteinyl leukotrienes and the other to formation of LTB4 by the enzyme LTA4 hydrolase. These potent bronchoconstrictors are produced by mast cells and other inflammatory cells, including macrophages, monocytes, eosinophils, and basophils. They bind to specific target receptors and directly induce bronchial smooth muscle contraction, increase vascular permeability, and promote mucus secretion. They also induce infiltration of inflammatory cells into airway tissues.23,24 Discovery of the mechanism of action of leukotrienes has created new and effective opportunities for controlling the symptoms of asthma. Blocking leukotriene synthesis and action for the management of asthma has been a major goal of the pharmaceutical industry. Certain agents such as zileu-
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ton (Zyflo; Abbott, North Chicago, IL) interfere with leukotriene production; other agents, such as zafirlukast (Accolate; AstraZeneca, Wilmington, DE) and montelukast (Singulair; Merck, West Point, PA), block the action of the leukotrienes at the receptor level.24 Several studies have shown that atopic individuals, including atopic asthmatic patients, have an increased capacity to synthesize leukotrienes compared with healthy nonatopic individuals.10 –19 Although it is not clear whether this increased biosynthetic capacity has any consequences on disease severity or progression, considering the central role played by leukotrienes in asthma, strategies to decrease or “normalize” the capacity to synthesize leukotrienes could possibly affect disease severity. Indeed, the mechanism of action of the asthma drug, Zyflo, is through the inhibition of 5-lipoxygenase and thus leukotriene biosynthesis. For example, a 40% decrease in the in vivo biosynthesis of leukotrienes in asthmatic subjects administered Zyflo was associated with a significant improvement in FEV1.29 As leukotrienes are directly derived from dietary omega-6 fatty acids, it has been speculated that the quality of dietary polyunsaturated fatty acids may alter the capacity to synthesize these lipid mediators of inflammation and, hence, affect inflammatory diseases including asthma. Dietary Polyunsaturated Fatty Acids Omega-3 and omega-6 fatty acids are metabolized through a common pathway and compete for acylation sites in cellular phospholipids (Fig 2). An increase in the consumption of dietary omega-3 fatty acids can inhibit arachidonic acid synthesis from dietary linoleic acid, resulting in its reduction in tissues. Omega-3 fatty acids also inhibit the action of cyclooxygenase and 5-lipoxygenase. EPA is both a substrate and an inhibitor, whereas docosahexaenoic acid (DCHA) is only an inhibitor of the cyclooxygenase.7,30 These omega-3 fatty acids, when included in the diet, can competitively inhibit the formation of prostaglandins and leukotrienes derived from arachidonic acid, leading to a suppression of neutrophil function and thus suggesting an antiinflammatory potential.30 Trans fatty acids have been reported to influence desaturation and chain elongation of omega-6 and omega-3 fatty
Figure 2. Metabolism of essential fatty acids.
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acids into precursors of inflammatory mediators. Data from the International Study of Asthma and Allergies in Childhood of 13- to 14-year-old children at 55 centers in 10 European countries found that 12-month prevalence of symptoms of asthma, allergic conjunctivitis, and atopic eczema was significantly associated with intake of trans fatty acids, expressed as a percent of energy intake (P ⬍ 0.001; Fig 3).31 Disparities in consumption of polyunsaturated fatty acids among social classes and regions have been associated with differences in prevalence of allergic disease. Black and Sharpe7 hypothesized that an increase in the dietary omega-6 fatty acid linoleic acid can influence allergic sensitization by increasing prostaglandin E2 (PGE2) formation, leading to a Th2 response and IgE synthesis. An increase in the omega-3 fatty acid EPA, however, inhibits prostaglandin E2 formation. This may explain to some extent how dietary changes have led to an increase in the prevalence of asthma in developed countries. Dietary Omega-3 Polyunsaturated Fatty Acids Historically, results of the effect of dietary supplementation with fish oils rich in omega-3 fatty acids on asthma and leukotriene synthesis have been equivocal. A number of animal studies had indicated that the supplementation of diets with omega-3 fatty acids could have profound effects on the capacity to synthesize leukotrienes both in vivo and in vitro.32,33 However, the effect of these dietary fatty acids on leukotriene synthesis in humans was less consistent. The first study30 in humans investigating the effect on leukotriene synthesis showed that dietary supplementation with EPA and DCHA for 6 weeks led to a reduction in arachidonic acid content of neutrophils and monocytes and a significant reduction in leukotriene biosynthesis. Similarly, supplementation for 10 weeks resulted in a 50% inhibition in leukotriene generation by ionophore-stimulated neutrophils in patients with mild asthma. Neutrophil chemotaxis was also substantially suppressed.34 However, under carefully controlled conditions, dietary omega-3 fatty acids do not seem to have the capacity to inhibit leukotriene formation in humans.35 These inconsistent results are difficult to explain but may be a function of the underlying dietary status of the subjects and the different cell isolation and stimulation protocols used to evaluate biosynthetic capacity. These conflicting results on leukotriene biosynthesis in humans also translated into variable results in clinical trials in which asthma disease endpoints were measured. In a small double-blind study,36 an improvement in FEV1 was measured in subjects supplementing their diet with omega-3 fatty acids over a 9-month period. In patients with mild asthma, fish oil supplementation was found to attenuate allergen-induced late asthmatic response (P ⬍ 0.005)34; however, such supplementation was not shown to have significant clinical effects as measured by changes in airways responsiveness, symptom scores, or bronchodilator use.34,37 Dietary fish oil supplementation also did not prevent seasonal hay fever or asthma in
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Figure 3. Prevalence of asthma, allergic rhinoconjunctivitis, and atopic eczema and trans fatty acid intake (1% energy). Reprinted with permission from The Lancet, 1999, Vol 353, page 2041, by Elsevier Science.
pollen season38 and had no effect when added to the diet of patients with asthma for 8 weeks.39 The clinical effects of fish oil supplementation and a diet that increases omega-3 polyunsaturated fatty acids and was compared with those of a diet enriched in omega-6 fatty acids
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in a double-blind, randomized trial in 39 children with asthma. Tumor necrosis factor (TNF)-␣ production fell significantly compared with baseline in the omega-3 group (P ⫽ 0.026) but did not reach significance between the two groups (P ⫽ 0.075). No significant changes in clinical severity of asthma were noted.40 In another randomized, controlled trial,41 29 children with bronchial asthma who were in a longterm treatment hospital received fish oil capsules (84 mg EPA and 36 mg DCHA) or control capsules (300 mg olive oil). Asthma symptom scores were significantly lower than at baseline in the fish oil group after 6 to 10 months of treatment. The authors concluded that fish oil supplementation may be beneficial for children with bronchial asthma in a strictly controlled environment in terms of inhalant allergens and diet.41 Dietary Omega-6 Polyunsaturated Fatty Acids The omega-6 family of fatty acids, which includes arachidonic acid, is generally considered to be pro-inflammatory. However, one dietary omega-6 fatty acid, ␥-linolenic acid (GLA), has been consistently shown to possess anti-inflammatory properties and to inhibit leukotriene synthesis in clinical trials.42 When GLA is presented to inflammatory cells, it is efficiently elongated to dihomogammalinolenic acid, but because these cells lack ␦-5 desaturase activity, it is not converted to arachidonic acid. Dihomogammalinolenic acid is transformed by lipoxygenases and cyclooxygenases to oxygenated compounds which, unlike the arachidonic acid-derived leukotrienes, have anti-inflammatory properties and inhibit the synthesis of leukotrienes.43– 45 Consequently, dietary GLA decreases the potential of inflammatory cells to synthesize leukotrienes. Supplementation of diets with GLA has also been shown to result in a potentially undesirable increase in serum arachidonic acid levels, most likely because of the efficient transformation of dietary GLA to arachidonic acid in the liver.46,47 Because EPA can compete with arachidonic acid for the incorporation into membrane phospholipids and can also inhibit the ␦-5 desaturase step of fatty acid metabolism, a dietary supplementation strategy was developed in which a combination of GLA and EPA resulted in the inhibition of leukotriene synthesis while preventing increases in serum amino acid levels.47 The anti-inflammatory potential of such a dietary strategy has been evaluated in critically ill patients suffering from acute respiratory distress. Results of a prospective, randomized, double-blind, controlled, multicenter trial found that compared with a control diet, enteral nutrition for at least 4 to 7 days with a diet supplemented by EPA, GLA, and antioxidants significantly reduced pulmonary neutrophil recruitment (P ⫽ 0.0081) and inflammation in 146 patients. Further, beneficial effects of the EPA⫹GLA diet on gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and the reduction of new organ failures suggested this dietary strategy would be a useful adjuvant therapy in the clinical management of patients with or at risk of
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developing acute respiratory distress.48 Although the inflammation associated with acute respiratory distress syndrome differs from that associated with asthma, this trial underscores the anti-inflammatory potential of such adjuvant dietary therapy on disease parameters. In a recent randomized, double-blind, parallel-group study in 23 atopic subjects with mild to moderate asthma controlled solely with inhaled -agonists or theophylline, patients received placebo (olive oil) and low-dose and high-dose combinations of GLA and EPA. Stimulated ex vivo LTB4 and TNF-␣ were measured at baseline and after 4 weeks of supplementation. Both combinations significantly suppressed LTB4 and TNF-␣ biosynthesis when compared with placebo.49 It remains to be seen whether the normalization of leukotriene synthesis in asthma patient will be of benefit to ameliorate disease severity. However, given the important role that leukotrienes play in asthma, these results warrant the investigation of such dietary strategies as an adjunct therapy in the management of asthma. CONCLUSION Epidemiologic studies have suggested that dietary patterns, especially intake of dietary lipids, may adversely affect asthmatic symptoms. Given the concomitant rise in obesity and evidence that suggests a decrease in weight can alleviate symptoms of asthma, dietary modification may be beneficial not only for overall health, but also in managing asthma. Additionally, as individuals with asthma produce increased quantities of leukotrienes compared with healthy individuals, dietary interventions that decrease the capacity to synthesize leukotrienes may be warranted; however, studies investigating the impact of such interventions on disease severity, reliance on medication, and quality of life are lacking. With the mounting evidence that diet and elevated BMI contribute to asthma symptoms, it may be beneficial to modify the current treatment guidelines so that diet modification may become one of the initial steps in the management of asthma. REFERENCES 1. Kay AB. Allergy and allergic diseases. N Engl J Med 2001; 344:30 –36. 2. Greene LS. Asthma, oxidant stress, and diet. Nutrition 1999;15: 899 –907. 3. Kuo ML, Huang JL, Yeh KW, et al. Evaluation of Th1/Th2 ratio and cytokine production profile during acute exacerbation and convalescence in asthmatic children. Ann Allergy Asthma Immunol 2001;86:272–276. 4. Diaz-Sanchez D, Penichet-Garcia M, Saxon A. Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity. J Allergy Clin Immunol 2000;106:1140 –1146. 5. Stenius-Aarniala B, Poussa T, Kvarnstro¨m J, et al. Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 2000;320:827– 832. 6. Broughton KS, Johnson CS, Pace BK, et al. Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production. Am J Clin Nutr 1997;65:1011–1017.
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925–934. 26. Seidell JC, Flegal KM. Assessing obesity: classification and epidemiology. Br Med Bull 1997;53:238 –252. 27. Camargo CA Jr, Weiss ST, Zhang S, et al. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med 1999;159:2582–2588. 28. Hakala K, Stenius-Aarniala B, Sovijarvi A. Effects of weight loss on peak flow variability, airways obstruction, and long volumes in obese patients with asthma. Chest 2000;118; 1315–1321. 29. Israel E, Rubin P, Kemp JP, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med 1993;119:1059 –1066. 30. Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 1985;312:1217–1224. 31. Weiland SK, von Mutius E, Husing A, Asher MI. Intake of trans fatty acids and prevalence of childhood asthma and allergies in Europe. ISAAC Steering Committee. Lancet 1999;353: 2040 –2041. 32. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000;71(Suppl):343S–348S. 33. Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr 1990;52:1–28. 34. Arm JP, Horton CE, Mencia-Huerta JM, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax 1988;43:84 –92. 35. Chilton FH, Patel M, Fonteh AN, et al. Dietary n-3 fatty acid effects on neutrophil lipid composition and mediator production. Influence of duration and dosage. J Clin Invest 1993;91: 115–122. 36. Dry J, Vincent D. Effect of a fish oil diet on asthma: results of a 1-year double-blind study. Int Arch Allergy Appl Immunol 1991;95:156 –157. 37. Arm JP, Horton CE, Spur BW, et al. The effects of dietary supplementation with fish oil lipids on the airways response to inhaled allergen in bronchial asthma. Am Rev Respir Dis 1989; 139:1395–1400. 38. Thien FC, Mencia-Huerta JM, Lee TH. Dietary fish oil effects on seasonal hay fever and asthma in pollen sensitive subjects. Am Rev Respir Dis 1993;147:1138 –1143. 39. Kirsch CM, Payan DG, Wong MY, et al. Effect of eicosapentaenoic acid in asthma. Clin Allergy 1988;18:177–187. 40. Hodge L, Salome CM, Hughes JM, et al. Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children. Eur Respir J 1998;11:361–365. 41. Nagakura T, Matsuda S, Shichijyo K, et al. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J 2000;16: 861– 865. 42. Fan YY, Chapkin RS. Importance of dietary ␥-linolenic acid in human health and nutrition. J Nutr 1998;128:1411–1414. 43. Chilton-Lopez T, Surette ME, Swan DD, et al. Metabolism of gammalinolenic acid in human neutrophils. J Immunol 1996; 156:2941–2947. 44. Chapkin RS, Miller CC, Somers SD, Erickson KL. Utilization of dihomo-␥-linolenic acid (8,11,14-eicosatrienoic acid) by murine peritoneal macrophages. Biochim Biophys Acta 1988;959:
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322–331. 45. Chapkin RS, Miller CC, Somers SD, Erickson KL. Ability of 15-hydroxyeicosatrienoic acid (15-OH-20:3) to modulate macrophage arachidonic acid metabolism. Biochem Biophys Res Commun 1988;153:799 – 804. 46. Johnson MM, Swan DD, Surette ME, et al. Dietary supplementation with ␥-linolenic acid alters fatty acid content and eicosanoid production in healthy humans. J Nutri 1997;127: 1435–1444. 47. Barham JB, Edens MB, Fonteh AN, et al. Addition of eicosapentaenoic acid to ␥-linolenic acid–supplemented diets prevents serum arachidonic acid accumulation in humans. J Nutr 2000; 130:1925–1931. 48. Gadek JE, DeMichele SJ, Karlstad MD, et al. Effect of enteral
feeding with eicosapentaenoic acid, ␥-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999;27:1409 –1420. 49. Bowton DL, Seeds M, Surette ME, et al. Airozin suppresses leukotriene synthesis in asthmatics. Am J Respir Crit Care Med 2002;165:A95. Requests for reprints should be addressed to: Sheldon L. Spector, MD California Allergy and Asthma Medical Group, Inc 11645 Wilshire Boulevard Los Angeles, CA 90025 E-mail: [email protected]
CME Examination 1–5, Spector SL, Surette ME. 2003;90:371-377. CME Test Questions 1. The increase in prevalence of asthma seen in recent years has been associated with which one of the following? a. Increased exposure to diesel particles. b. Lack of exposure to infectious agents or endotoxins during childhood. c. Increased intake of food that encourage production of pro-inflammatory mediators. d. All of the above. e. None of the above. 2. In the Nurses’ Health Study, BMI was found to have a strong, independent, and positive association with risk of adult-onset asthma. a. True. b. False. 3. The primary dietary sources of the omega-3 class of polyunsaturated fatty acids are: a. Lard and dairy fats. b. Oily fish and leafy vegetables. c. Saturated fats and most vegetable oils.
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d. Red meat and starchy vegetables. e. Nuts and grains. 4. In patients with asthma, administration of oils containing GLA and EPA can: a. Block levels of inflammatory mediators associated with asthma. b. Ameliorate any effect obesity may have on asthma. c. Augment fats found in a typical western diet. d. Balance increased exposure to environmental pollutants. e. Complement lack of exposure to microbial antigens during childhood. 5. Although it remains unclear whether patients with poorly controlled asthma gain weight because they limit their activities or if being obese increases asthma risk, studies suggest weight reduction in obese individuals may alleviate symptoms of asthma. a. True. b. False. Answers found on page 421.
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