Omega-3 fatty acid intake is not an effective prevention or treatment for asthma prevalence and severity in school-aged children

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1 Oregon Health & Science University Omega-3 fatty acid intake is not an effective prevention or treatment for asthma prevalence and severity in school-aged children Michaela Zucker-Kimberly Kelsey-Melissa Misley

2 Overview According to the American Lung Association, asthma is the most common chronic disorder in childhood, and affects approximately 7.1 million children under the age of 18 years. Asthma accounts for roughly 3,300 preventable deaths and costs our nation $56 billion annually (1). Omega-3 fatty acid consumption [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] has been reported to ease asthma symptoms by such popular media outlets as LiveStrong and the Daily Mail in their medical advice for the general public. However, controlled studies investigating the relationship between omega-3 fatty acid intakes and asthma symptoms show mixed results, often with small sample sizes (2). To treat asthma in children under 18 years old, 84 mg of EPA and 36 mg of DHA have been taken by mouth, or 120 mg omega-3 fatty acids total (3). We have used this value (120 mg/day) to define high ( 120 mg/day) and low (<120 mg/day) intakes of omega-3 fatty acids among children aged 5-17 years. Analyzing a large sample of cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) will allow additional scientific insight to support or disclaim this popular advice. Results of this study will provide support for further research, and the inclusion and analysis of the confounding variables "BMI percentile" and "income ratio to poverty" may help identify sources of variability in previous study designs. Further research into dietary intake of omega-3 fatty acids and asthma benefit members of the general public by presenting an accurate, evidence-based response to popular health tips. Research question Is higher consumption of omega-3 fatty acids (EPA + DHA) associated with decreased prevalence and severity of asthma in school-aged (5 17 years) children? 1

3 Research aims 1) To determine whether there is an association between asthma diagnosis and/or asthma severity (low: 0-1, high: 2-3, based on 0-3 severity score) and omega-3 fatty acid consumption in school-aged children. 2) To determine the difference in omega-3 fatty acid consumption between groups of children with a BMI percentile (%ile) 85 to those <85 %ile, and between groups of children >1.0 income poverty ratio to those 1.0 Hypotheses 1) Higher ( 120 mg/day) omega-3 fatty acid consumption is associated with fewer cases of asthma and lower asthma severity (0-1) in school-aged children. 2) Children who consume few omega-3 fatty acids per day (<120 mg) are more likely to have a BMI 85 th %ile and live in a household with an income to poverty ratio <1.0. Background Inflammation is an important and necessary part of a host s defense against foreign bodies and pathogens. Inflammation functions by killing pathogens, creating unfavorable pathogenic environments, and changing the host s metabolism. Asthma is the most common chronic disorder in childhood. Those with asthma experience localized inflammation and swelling, and elevated concentrations of inflammatory mediators in their respiratory tracts (2). Inflammatory mediators include lipid-derived mediators (prostaglandins, leukotrienes, 2

4 endocannabinoids, platelet activating factor), peptide mediators (cytokines, chemokines), reactive oxygen species (superoxide anion, hydrogen peroxide), amino acid derivatives (histamine, nitric oxide), and enzymes (matrix processes). Omega-3 (n-3) fatty acids are polyunsaturated fatty acids with a double bond between carbons 3 and 4. The long chain n-3 fatty acids of interest are eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). EPA and DHA are often referred to as marine n-3 fatty acids because they are found primarily in fish and seafood, and possess anti-inflammatory properties that could possibly be helpful in alleviating asthmatic symptoms. Consumption of n-3 fatty acids changes the composition of cell membrane phospholipids to include a higher concentration of EPA and DHA. The incorporation of n-3 fatty acids into the cell membrane may reduce production of inflammatory mediators and infiltration of pro-inflammatory factors into the airways and lungs (2). Changes in fatty acid composition of cell membranes can modify lipid raft formation, altered gene expression, and production of lipid mediators. A 10-month double-blind, randomized, controlled trial investigated the effects of fish oil supplementation, a source of the EPA and DHA (or n-3 fatty acids), on prevalence and severity of asthma symptoms in children with bronchial asthma (4). The authors proposed that the positive effects of n-3 fatty acids on asthma may be mediated by EPA reduced formation of inflammatory cytokines, and inhibition of the development of broncho-constricting leukotrienes and prostaglandins (from arachidonic acid; alpha-linolenic acid (ALA), and omega-6 fatty acids). Experimental subjects received daily fish oil capsules containing 84 mg EPA and 36 mg DHA (EPA: mg kg body weight, DHA: mg kg body weight), while control subjects received capsules containing 300 mg olive oil. The mean plasma concentration of EPA (ug ml - 1 ) in the experimental group at 0, 2, 4, and 7 months were 24.19±3.30, 45.81±3.84, 45.80±3.06, 49.06±4.59, and 55.76±8.34). By the end of the study, mean plasma EPA was two times higher compared to baseline values (at 0 months) in the experimental group, and remained unchanged in the control group. However, while EPA blocked the late asthmatic response to inhaled 3

5 allergens, it did not block the immediate response, likely due to EPA s inability to inhibit the release of histamine from mast cells. After 10-months of intervention, asthma symptoms decreased, participants overall asthma scores decreased, and their acetylcholine threshold increased in the cohort receiving n-3 fatty acid supplementation. Studies have found that supplementation with EPA and DHA reduces tumor necrosis factor (TNF)-α and interleukin (IL)-1b mrna expression (5) and the production of leukotrienes (LT), prostaglandins (PG), and TNF-α and IL-1b from primary human asthmatic alveolar macrophages (6, 7, 8). Several studies reported anti-inflammatory effects of fish oil on the human monocytic THP-1 cell line (5, 8), human peripheral blood neutrophils (9), and ovalbuminsensitized mice (10). Anti-inflammatory effects included, decreased production of 4-series LTs, improved leukocyte chemotaxis (5, 9), down-regulation of nuclear translocation of nuclear factor-κb (NF-κB) (10, 8), and protective effects on bronchial hyper-responsiveness and asthma in children (11). Mickleborough et al, showed that in cell cultures, EPA was a more potent inhibitor of inflammatory responses in human asthmatic AMφ cells compared to DHA (6), while Weldon et al, suggests that DHA might actually be more effective than EPA in alleviating LPS-induced proinflammatory cytokine production in macrophages (8). Human asthmatic AMφ cells and inflammatory cytokines are typical components of the body s inflammatory response and are highly active during an inflammatory response, such as those occurring in an individual with asthma. A 3-week, double-blind, randomized, control trial aimed to determine whether n-3 fatty acid supplementation inhibits airway sensitivity to inhaled mannitol, a bronchial irritant (12). Control subjects were given a placebo while experimental subjects were given a daily dose of 4.0 g EPA and 2.0 g DHA. This study concluded that n-3 fatty acid supplementation is not useful in short-term treatment of asthma. 4

6 Hodge et al, found that while n-3 fatty acid supplementation may have reduced inflammatory factors, there was no effect on the clinical severity of asthma in children (7). In a mouse study comparing supplementation with fish oil to lyprinol (a complex mixture of various marine lipids plus vitamin E and olive oil), mice in the lyprinol group experienced suppressed development of allergic inflammation and airway hyper-responsiveness in allergic airway disease, while the fish oil group did not (13). Additionally, Broadfield et al, found that increased self-reported [in mg, mean (SD)] dietary EPA [0.13 (0.13)] and DHA [0.17 (0.15)] intake among people with asthma, was associated with a greater risk of the disease (14). There are several gaps in the current literature regarding childhood asthma and n-3 fatty acid intake. These gaps include few studies conducted on childhood asthma, asthma severity, duration of intervention needed to elicit a physiological response, concentration of n-3 fatty acids (EPA & DHA) appropriate for use in interventions, and effectiveness of EPA compared to DHA. Results have not been consistent when assessing high doses of dietary n-3 fatty acids on bronchial hyper-responsiveness (BHR). Many of the reviewed studies agreed that many aspects of the potential anti-inflammatory effects of EPA and DHA metabolism that remain unclear and warrant further research. Through our data analysis, we will attempt to determine if there is an association between asthma diagnosis and/or asthma severity and n-3 fatty acid consumption in school-aged children, specifically. Methods Subjects and setting: Subjects will be selected from NHANES data to include children between five and seventeen years of age. Health interview and physical examination data are collected among a nationally representative sample of 5,000 participants each year. Dietary information was collected through 2 24-hour recalls, one completed in person at the initial appointment and 5

7 one by telephone 3-10 days later. To collect dietary data for children under the age of 6 a proxy is used, for 6-11 years old a proxy assist with the 24-hour recall and data was self reported for children 12 years of age and older. BMI was established during the physical examination. Body Mass Index (BMI) was determined for each participant through a standing height measurement and weight was collected in kilograms (kg) on a digital scale. BMI category was calculated for children between ages 2-19 years using growth chart percentiles for the age at the time of examination. Ratio of family income to poverty was calculated using Health and Human Services (HHS) poverty guidelines by dividing family income to poverty guidelines for household size. The sample will include all participants with complete data. Subjects with and without asthma will be separated based on answering "yes" or "no" to the medical condition question "Do you still have asthma (MCQ035)". Any subjects who responded yes to the questions Does anyone smoke inside home? (SMD410), or Do you now smoke cigarettes? (SMQ040) will be excluded from the study due to known effects of cigarette smoking on asthma. Institutional review board: This study was deemed exempt by the OHSU Institutional Review Board. Data collection tools and procedures: NHANES data (15) will be sorted using Microsoft Excel. Average total, 2-day EPA consumption will be determined by calculating the mean± standard deviation (SD) of values from the following NHANES data questions: PFA 20:5 (Eicosapentaenoic) (gm) [Total Nutrient Intakes -- First Day] (DR1TP205), and PFA 20:5 (Eicosapentaenoic) (gm) [Total Nutrient Intakes -Second Day] (DR2TP205). Average total 2-day DHA consumption will be determined by calculating the mean± SD of values from the following NHANES data questions: PFA 22:6 (Docosahexaenoic) (gm) [Total Nutrient Intakes -- First Day] (DR1TP226), and PFA 22:6 6

8 (Docosahexaenoic) (gm) [Total Nutrient Intakes -Second Day] (DR2TP226) Average total EPA and DHA intake will be calculated by summing the total mean EPA and total mean DHA of each individual, and will then be calculated into a total mean±sd for the group. Participants with total n-3 consumption of at least 120 mg/day will be separated from those with n-3 consumption of less than 120 mg/day. Those with an income to poverty ratio below 1.0 will be separated within the n-3 groups for comparison to participants with a ratio of at least 1.0. Participants with a BMI at or above the 85%ile will be compared to those with a BMI below the 85%ile within the n-3 groups. An asthma severity score of 0-3 will be constructed for participants with asthma based on 1 point each for affirmative answers to the questions: "Have you had an asthma attack in the last year?", "Have you had an emergency care visit for asthma in the past year?", "Has a Dr. prescribed medication for your asthma?" Participants with asthma will then be grouped by their responses into the 0, 1, 2, and 3 severity levels. Statistical analysis: Using Microsoft Excel, odds ratios will be performed to determine whether there is a relationship between consumption of at least 120 mg n-3 fatty acids per day with asthma diagnosis and severity of asthma. To complete the odds ratio regarding severity and n-3 consumption, children with a low severity score (0-1) and a high severity score (2-3) will be grouped together and then compared among those consuming 120 mg n-3 and <120 mg n-3 per day. This will explore whether there is a relationship between increasing levels of asthma severity and consumption of at least 120 mg n-3 fatty acids per day. As increased BMI percentile, as well as family poverty could both be confounding variables in our study, odds ratios will be completed to examine this potential influence. We will compare children consuming 120 mg n-3 and <120 mg n-3 per day with children who have a BMI of 85%ile and <85%ile, as well as 1.0 and <1.0 of family income to poverty ratio. 7

9 Summary: Asthma is the most prevalent chronic disorder in childhood and accounts for roughly 3,300 preventable deaths per year and costs our nation $56 billion (1). Treatment has been attempted by administering 120 mg/day n-3 fatty acids in the form of an oral supplement (3). We will be examining the relationship in children 5-17 years of age between asthma prevalence and severity and n-3 consumption of at least the 120mg/day using NHANES crosssectional data. While we are able to account for certain confounding variables such as BMI %ile and family ratio of income to poverty, one limitation of this study is the inability to account for additional confounding variables such as urban or rural location, or personal smoking of study subjects.. We are also unable to include any n-3 intake through supplements and our data is based on dietary intake solely. There will also be variance based on self-reporting of food intake. Results of this study could be used to provide evidence-based clarity on the use of increased n-3 consumption for the prevention and treatment of asthma in children. Results could potentially provide direction for further research examining asthma treatments. 8

10 References 1. Center for Disease Control (CDC). Asthma - Kids. Version current 2 September Internet: (accessed 22 November 2014). 2. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta In Press. 3. Mayo Clinic. Omega-3 fatty acids, fish oil, alpha-linolenic acid. Version current 1 November Internet: (accessed 2 November 2014). 4. Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J. 2000;16(5): Mullen A, Loscher CE, Roche HM. Anti-inflammatory effects of EPA and DHA are dependent upon time and dose-response elements associated with LPS stimulation in THP-1-derived macrophages. J Nutr Biochem ;21(5): Mickleborough TD, Tecklenburg SL, Montgomery GS, Lindley MR. Eicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells. Clin Nutr. 2009;28: Hodge L, Salome C, Hughes J, Liu-Brennan D, Rimmer J, Allman M, 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(2): Weldon SM, Mullen AC, Loscher CE, Hurley LA, Roche HM. Docosahexaenoic acid induces an anti-inflammatory profile in lipopolysaccharide-stimulated human THP-1 macrophages more effectively than eicosapentaenoic acid. J Nutr Biochem ;18(4): Arm JP, Horton CE, Mencia-Huerta JM, House F, Eiser NM, Clark TJ, et al. Effect of dietary supplementation with fish oil lipids on mild asthma. Thorax. 1988;43(2): Flesher RP, Herbert C, Kumar RK. Resolvin E1 promotes resolution of inflammation in a mouse model of an acute exacerbation of allergic asthma. Clin Sci. 2014;126(11): Tabak C, Wijga AH, de Meer G, Janssen NAH, Brunekreef B, Smit HA. Diet and asthma in Dutch school children (ISAAC-2). Thorax. 2006;61(12): Brannan JD, Bood J, Alkhabaz A, et al. The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia and mast cell mediators in asthma. Chest Wood LG, Hazlewood LC, Foster PS, Hansbro PM. Lyprinol reduces inflammation and improves lung function in a mouse model of allergic airways disease. Clin Exp Allergy. 2010;40(12): Broadfield EC, McKeever TM, Whitehurst A, Lewis SA, Lawson N, Britton J, et al. A case control study of dietary and erythrocyte membrane fatty acids in asthma. Clin Exp Allergy. 2004;34(8): Survey methods and analytic guidelines. Centers for Disease Control and Prevention. Accessed October, Saadeh D, Salameh P, Baldi I, Raherison C. Diet and allergic diseases among population aged 0 to 18 years: Myth or reality? Nutrients. 2013;5(9):

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12 Evidence Table Study Citation Study Design Study Duration Subject Characteristics Arm JP, Horton CE, Mencia- Double-blind randomized 2-4 week baseline n=20 Huerta JM, et al. Effect of control trial period Mild asthma dietary supplementation with fish oil lipids on mild asthma. Experimental group 10 week trial years, mean Thorax. 1988;43(2): received 3.2 g EPA and years g DHA, control group received olive oil capsules Regular diet was consumed Brannan JD, Bood J, Alkhabaz A, et al. The effect of omega-3 fatty acids on bronchial hyperresponsiveness, sputum eosinophilia and mast cell mediators in asthma. Chest Broadfield EC, McKeever TM, Whitehurst A, Lewis SA, Lawson N, Britton J, et al. A case control study of dietary and erythrocyte membrane fatty acids in asthma. Clin Exp Allergy. 2004;34(8): Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, Double-blind randomized control trial. Determining if omega-3 supplementation inhibits airway sensitivity to inhaled mannitol. Case-control study design. If higher omega-6 consumption or lower omega-3 consumption increased risk of asthma FFQ questionnaire and erythrocyte membrane fatty acid as a biomarker of intake Average daily intake of [0.13g (0.13)] EPA and [0.17g (0.15)] DHA Describes mechanism behind inflammatory 3 week study n=23 Average age = 28 years Snapshot from FFQ biomarker to estimate intake. Study in press. Submitted May Asthma population (n=89) Control population (n=89) No study participants Outcomes Fish oil enriched diet attenuates neutrophil function w/o changing asthma severity. Omega-3 supplementation is not useful in short-term treatment of asthma Odds of asthma were reduced in omega-6 membrane levels. Omega-3 fatty acids don't play a major role in protecting against asthma. More research needs to be completed for 11

13 mechanisms and clinical relevance. Biochim Biophys Acta Survey methods and analytic guidelines. Centers for Disease Control and Prevention. nes/survey_methods.htm.acce ssed October, 2014 Flesher RP, Herbert C, Kumar RK. Resolvin E1 promotes resolution of inflammation in a mouse model of an acute exacerbation of allergic asthma. Clin Sci (Lond). 2014;126(11): 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(2): Mayo Clinic. Omega-3 fatty acids, fish oil, alpha-linolenic acid. Version current 1 November Internet: process and omega-3 interactions and completed literature review NAHANES methods of survey. Investigation of the effects of RvE1 in a model of an acute exacerbation of chronic allergic asthma in mice Double-blind randomized control trial Omega-3 and omega-6 group g omega-3/day. General public summary of current research and recommendations recommendations Conflicting interest from peerreviewed articles on omega-3 intake and its association with asthma Some effects of omega-3 fatty acids on inflammatory cells mediated and/or associated with changes in fatty acid composition of cell membranes Study published in Low level challenged with aerosol antigen for 4 weeks before moderate level challenge to induce asthmatic response. 6 month intervention Last updated November No study participants. Pathogen free female mice. n= years No study participants Protocols for how data was collected with NHANES data. RvE1 can facilitate resolution of airway inflammation in asthma. RvE1 is endogenous lipid derived mediator. Omega-3 supplementation increased plasma levels, but had no effect on the asthma severity in cohort 84 milligrams of EPA and 36 milligrams of DHA to treat asthma in populations under 18 years of age. 12

14 gs-supplements/omega-3- fatty-acids-fish-oil-alpha- linolenic-acid/dosing/hrb (accessed 2 November 2014). Mickleborough TD, Tecklenburg SL, Montgomery GS, Lindley MR. Eicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells. Clin Nutr. 2009;28(1): Mullen A, Loscher CE, Roche HM. Anti-inflammatory effects of EPA and DHA are dependent upon time and dose-response elements associated with LPS stimulation in THP-1-derived macrophages. J Nutr Biochem. 2010;21(5): Compare effects of EPA and DHA as antiinflammatories BALF samples taken from each subject to obtain AMphi cells. Cells divided into 6 treatment groups with different amounts of omega-6 fatty acids. Monocytic THP-1 cell lines purchased from animal cell cultures. Inhaled corticosteroids, 5- lipoxygenase inhibitors and leukotriene receptor antagonists withheld for 4 weeks prior to harvesting cells n/a n=21 Adults with mild to moderate persistent asthma No study participants EPA is a more effective inhibitor rather than DHA in the inflammatory responses in asthmatic AMphi cells. DHA is more potent antiinflammatory omega-3 PUFA. EPA and DHA down-regulate production of cytokines. Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J. 2000;16(5): Double-blind randomized controlled trial. Conducted in controlled environment (hospital in Japan) to reduce variation from diet and inhalant allergens. Given multiple fish-oil capsules for a daily total of mg*kg body weight/day for EPA and 10 month study 01/ / month observation period, 10 month intervention n=29, all with bronchial asthma 15 in experimental group (11 finished) 14 in control group (12 finished) Asthma symptoms decreased with omega-3 supplementation. asthma score, acetylcholine threshold 13

15 Saadeh D, Salameh P, Baldi I, Raherison C. Diet and allergic diseases among population aged 0 to 18 years: Myth or reality? Nutrients. 2013;5(9): Tabak C, Wijga AH, de Meer G, Janssen NA, Brunekreef B, Smit HA. Diet and asthma in dutch school children (ISAAC- 2). Thorax. 2006;61(12): Weldon SM, Mullen AC, Loscher CE, Hurley LA, Roche HM. Docosahexaenoic acid mg*kg body weight per day PubMed Search on allergic diseases. Papers in English or French 101 articles reviewed - 11 specific to fat/fish consumption Included asthma, allergic rhinitis and atopic dermatitis as health outcomes related to diet. ISAAC questionnaire (International Study on Allergy and Asthma in Childhood) completed in Netherlands. BHR tests completed as well as common allergen sensations. Dietary questionnaire sent to all parents of children who completed BHR testing FFQ used to estimate dietary intake Considering pure EPA and DHA on cytokine expression and nuclear Articles from The most recent search was March years of age for all articles reviewed n=598 Ages were 8-13 years n/a no study participants Mixed results 11 articles specific to fat/fish intake in association with allergic disease 4 found positive benefits on asthma related to consumption 2 found negative outcomes of asthma related to consumption 4 weren't specific to asthma 1 was looking at SFA (negative correlation between SFA intake and allergic diseases Whole grain and fish intake was inversely associated with asthma. Intake of fruits, vegetables and dairy products showed no conclusive associations with asthma. The effects of DHA were significantly more potent than EPA. 14

16 induces an anti-inflammatory profile in lipopolysaccharidestimulated human THP-1 macrophages more effectively than eicosapentaenoic acid. J Nutr Biochem. 2007;18(4): Wood LG, Hazlewood LC, Foster PS, Hansbro PM. Lyprinol reduces inflammation and improves lung function in a mouse model of allergic airways disease. Clin Exp Allergy. 2010;40(12): factor kappab activation in humans. Experiments on cell cultures Animal subjects (mice). One group received omega-3 supplementation, the other olive oil. 14 day study duration. Mice population. Supplementation with lyprinol was have beneficial effects in asthma. It is likely the mechanism of lyprionol may involve omega-3 PUFA content. Intervention using a whole food approach offer most promise as opposed to supplementation. 15