Mediterranean Diet and Nutrition for the Primary Prevention of Allergy and Asthma

Chapter 43

Mediterranean Diet and Nutrition for the Primary Prevention of Allergy and Asthma Dean A. Sewell, BA, PhD1 and Aziz Sheikh, BSc, MSc, MD2 1

Heriot-Watt University, Edinburgh, United Kingdom. 2 The University of Edinburgh, Edinburgh, United Kingdom.

ABBREVIATIONS AR DHA EPA GINA IgE IFN-g IL LCPUFA PUFAs RCT SPT Th

allergic rhinitis docosahexaenoic acid eicosapentaenoic acid Global Initiative for Asthma immunoglobulin-E interferon gamma interleukin long-chain polyunsaturated fatty acids polyunsaturated fatty acids randomized controlled trial Skin-prick test T helper cell

INTRODUCTION In recent decades, there has been a marked worldwide increase in allergy and asthma prevalence, especially in children [1,2]. The consequences of allergies range from at worst death—for example, from status asthmaticus or a fatal episode of anaphylaxis triggered by food, drugs, or venom—to at best, minor intermittent morbidity, for example, mild nasal symptoms during the summer grass pollen season, suboptimal educational attainment in children [3], absenteeism (absence from school or work), and presenteeism (reduced working capacity while at school or work). These have concomitant health economic and economic costs, which have major societal impact. The range of allergic disorders is wide and varied and includes, reflecting the typical order of life-course development: atopic eczema/dermatitis, food allergy, allergic rhino-conjunctivitis, asthma, acute urticaria and angioedema (some acute, and most episodes of chronic urticaria/angioedema are nonallergic in origin), and anaphylaxis. Trigger agents include aeroallergens derived from plants and animals, foods, pharmacological and biological agents, insect venom, and occupational allergens. It is unlikely that genetic changes in the profile of populations have been causal in what some have termed the “allergy epidemic.” This is because the rapid changes in prevalence observed cannot be accounted for by changes in genetic makeup. Family studies suggest that immunoglobulin-E (IgE)-mediated allergic disorders result from a complex interplay between genetic and environmental factors; supporting evidence for this comes from the observation that only approximately 50% of atopic individuals actually manifest symptoms of allergy [4]. Hygiene, dietary, socioeconomic, lifestyle, and environmental changes are interrelated with heritable changes in gene expression, that is, epigenetic mechanisms. Tobacco smoking, diet (food allergen, dietary nutrient, and food-processing changes) socioeconomic status, occupational exposures, outdoor pollutants (including coupling with climate change/warming), and aeroallergen and indoor pollution are among the factors that have been identified as potential causes of the increased prevalence of asthma and allergy. Children bear the greatest burden of allergic diseases, principally atopic eczema/dermatitis, food allergy, allergic rhino-conjunctivitis (persistent or intermittent), and asthma [5]. The World Health Organization (WHO) estimates that globally, 235 million

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people currently have asthma and that it is now one of the most common childhood diseases requiring chronic drug therapy [6], while the Global Initiative for Asthma (GINA) program put the burden higher, at 300 million people [7]. This chapter will focus on type I allergic hypersensitivity, that is, classical atopic diseases that underlie allergy mediated by IgE, with a focus on the role that nutrition and the Mediterranean diet might have on the primary prevention (including sensitization) of atopic eczema/dermatitis, food allergy, allergic rhino-conjunctivitis, and asthma. The Mediterranean diet is a cultural, healthy eating model characterized by the abundant intake of fruits and vegetables; other plant foods such as legumes, nuts and seeds, and olive oil; fish; and a low intake of red and processed meats, and of wine consumed with meals [8]. The study of dietary patterns represents a broader picture of food and nutrient consumption compared with single food items and nutrients [9,10]. This potentially provides synergy between the foods, fostering favorable changes in biological mechanisms involved in the primary prevention of allergy and asthma, such as oxidative stress and inflammation.

BASIC ALLERGY CONCEPTS Clemens von Pirquet [11] is credited with the first use of the term allergy and described the general concept of “changed reactivity” following exposure to an “antigen.” The word allergy became corrupted with the passage of time, and is commonly used to describe hypersensitivity mechanisms that operate transiently, or persistently, in a limited group of conditions, particularly the IgE-mediated allergic diseases [12]. This changed reactivity, according to von Pirquet could be immune (protective) or hypersensitive (harmful), and the antigen could be either an infectious agent or an allergen. Common allergenic agents include house dust mites, pollens, pet dander, food proteins, and venom of stinging insects. The term allergy has, more recently therefore, been limited by some to refer solely to IgE-mediated hypersensitivity reactions; others, however, remain truer to von Pirquet’s original definition and use the terms allergy and hypersensitivity interchangeably, describing any exaggerated response of the immune system to allergenic agents. The practice of allergology (clinical allergy) in the UK is concerned mainly with IgE-mediated (type I) hypersensitivity reactions to allergenic antigens, whereas other, non IgE-mediated hypersensitivity disorders tend to be treated by organ-based specialists (e.g., respiratory physicians, dermatologists, and gastroenterologists) or immunologists. The main conditions in which type I hypersensitivity (Gell and Coombs Classification [13]) is important in the pathophysiology are atopic eczema/dermatitis, food allergy, allergic rhino-conjunctivitis, asthma, acute urticaria and angioedema, and anaphylaxis. Type II, III, and IV hypersensitivity involves other immunoglobulin mediators (IgG and IgM) and T lymphocyte-dependant delayed hypersensitivity, resulting in conditions such as autoimmune haemolytic anaemia (type II), systemic lupus erythematosis (type III), and contact dermatitis (type IV). The formation of specific-IgE antibodies is provoked by an allergen (foreign protein or hapten), which may result in an allergic response. Hypersensitivity resulting from being affected with one or more IgE-mediated allergic conditions should be used to describe “objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal persons” [14]. Atopy is the form of immunological activity of the individual in which IgE antibody is readily produced in response to ordinary exposure to common allergens in that individual’s environment [15]. This may, or may not, result in manifestation of allergy symptoms. The revised nomenclature of the World Allergy Organisation (WAO) suggests that the term atopy should be reserved to describe the predisposition to become IgE-sensitised to allergens commonly occurring in the environment and to which everyone is exposed, but to which the majority do not produce a response [14]. Atopy is thus mainly used in the context of aeroallergens and is a clinical definition of an IgE-antibody high-responder. Those affected can develop typical symptoms of atopic eczema/dermatitis, rhino-conjunctivitis, or asthma. In clinical practice in the UK, the term atopy is used to refer to those individuals who develop a positive weal and flare response to skin prick tests (SPT) with common allergens, or demonstrate IgE antibodies in serum (i.e., exhibit sensitisation), irrespective of whether or not the person displays symptoms on exposure to those allergens. The key principles of management of allergic disorders are firstly, to diagnose the condition (e.g., atopic eczema/dermatitis and/or asthma); secondly, to identify the allergic trigger (e.g., the house dust mite); thirdly, to provide treatment; and fourthly, to monitor response to treatment and modify management accordingly. The definition and diagnosis of an allergic condition is not always straightforward. Selected, common type I allergies occurring in early life will be defined here.

COMMON TYPE I ALLERGIES Atopic Eczema/Dermatitis Atopic eczema/dermatitis is characterized by an itchy skin rash plus three or more of the following: a history of flexural involvement; a history of asthma/hay fever; a history of generalized dry skin; onset of rash under two years of age; or visible flexural dermatitis [16]. The UK Working Party diagnostic criteria for atopic dermatitis [17], a refinement of the Hanifin– Rajka criteria, are widely accepted in epidemiological and clinical research. While there is broad acceptance for defining

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and diagnosing established atopic dermatitis, Simpson et al. [16] have proposed the need for better defining incident cases of atopic dermatitis within the accepted diagnostic criteria, which they propose is needed for longitudinal birth cohort or interventional prevention studies. The use of the UK Working Party criteria with the addition of a specified time requirement of 4 weeks has therefore been proposed, allowing for early treatment intervention during the course of a prospective study that does not require the atopic dermatitis to be untreated for four weeks if anti-inflammatory therapy is needed. One of the barriers to the use of the criteria in large epidemiological studies is the need for visual confirmation of flexural dermatitis by a trained investigator, though it has been shown that the criteria are a practical, reliable, epidemiological tool that can be used by mothers to obtain results comparable with a trained investigator [18].

Food Allergy Food allergies most commonly result from IgE-mediated responses to a food protein and are distinct from other adverse, generally more chronic responses to food, such as food intolerances. There are also non IgE-mediated food allergic reactions, typically more delayed in onset compared with IgE-mediated responses. The eight most common allergenic foods on a worldwide basis, accounting for more than 90% of all IgE-mediated food allergies [19] are cow’s milk, hen’s eggs, soybean, wheat, peanuts, tree nuts, fish, and crustacea (Table 1). This list was adopted by the Codex Alimentarus Commission. Food allergy responses include rash, urticaria and angioedema, gastrointestinal symptoms (e.g., nausea, abdominal pain, vomiting, and diarrhea), and cardiovascular and respiratory distress (i.e., anaphylaxis). Food allergy testing is based on SPT, prick-prick testing, blood immunoCAP to measure allergen specific IgE (which has replaced the radioallergosorbent test to detect IgE antibodies to particular allergens), or, as a gold standard, oral food challenge (preferably double-blind) under clinical supervision. Diagnosis is based on the acute onset of illness (typically within minutes but up to 1–2 h) with involvement of the skin, mucosal tissue, or both (e.g., generalized urticaria, itching or flushing, swollen lips–tongue–uvula). The diagnosis of anaphylaxis is based on these symptoms and other clinical criteria, such as a) respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxaemia; or b) reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence) [20].

Allergic Rhino-Conjunctivitis A reasonable consensus has been reached on a definition for allergic rhinitis (AR), which is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation. Symptoms of AR include rhinorrhea, nasal obstruction, and nasal itching and sneezing, which are reversible spontaneously or with treatment [21,22]. AR is conventionally subdivided into “intermittent” or “persistent” disease [21], although other classification schemes also exist, e.g., seasonal AR (hayfever) and perennial (year-round) forms [22]. The severity of AR is also classified as “mild” or “moderate/severe,” depending on symptoms and quality of life. Conjunctival symptoms such as itch, redness, tearing, and pain can also occur, and in severe AR are more frequent.

TABLE 1 Most Common Allergenic Foods/Causes of Food Allergy Worldwide, in the Order in which They Tend to Present Cow’s milk Hen’s eggs Soybean Wheat Peanuts Tree nuts (almonds, cashew nuts, walnuts, pecan nuts, Brazil nuts, pistachios, hazelnuts/filberts, pine/pinyon nuts, macadamia nuts, chestnuts, hickory nuts) Fish (all species of fin fish) Crustacea (shrimp, crab, lobster, crayfish)

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Asthma Asthma, most simply described as reversible airways obstruction, has proved notoriously difficult to define because there are many phenotypes. The interest in this chapter is on allergic asthma, which is the form that predominates in early life. The GINA [23] programme defines asthma as “a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest-tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment.” Inflammation makes the airways sensitive to stimuli such as allergens, chemical irritants, tobacco smoke, cold air, or exercise. In children up to about 5 years of age, the difficulty in distinguishing between an atopic phenotype and wheezing due to another cause has been recognised by a European Task Force [24], and the term “recurrent wheezing” is preferred to a diagnosis of asthma, particularly as there is no evidence that its pathophysiology is similar to that of asthma found in older children and adults [25].

Prevalence and Disease Burden of Allergy and Asthma Children bear the greatest burden of allergy and asthma, and for this reason, the emphasis of this chapter is to focus on allergic conditions that present in early life, and for which diet may have a role in primary prevention. The prenatal period and the first few months of life are a critical period, when there can be modulation of growth and development of the respiratory, immune, and gastrointestinal systems. Even delaying allergic disease onset in early life could have a significant public health impact, given, for example, the high prevalence of atopic eczema/dermatitis and that its earlier onset predicts a more severe disease course [16,26]. Furthermore, delaying allergic disease onset may shorten, or reduce the severity of, the atopic or allergic “march” [27]—the typical sequence of IgE-mediated responses that appear in early life, persist over subsequent years, and can recur in adult life (Figure 1). In recent decades, there has been a marked worldwide increase in allergy and asthma prevalence, especially in children [1,2]. Asthma is a public health concern, and it has been estimated that in the UK 1.1 million children and 4.1 million adults receive treatment for asthma. The cost of asthma for the UK economy was estimated to be £2.3 billion in 2001, including £1.2 billion in lost productivity, and £889 million in UK National Health Service expenditure [28,29]. Atopic dermatitis has a worldwide distribution; for example, it affects approximately 17.8 million people in the United States [30], has an estimated prevalence in the age group of 6–7 years of up to 23% in developed countries, and more recently high values in Asia and Latin America [31]. Globally, despite inadequate study coverage worldwide, difficulties with the range of outcome measures, and the possible changes in diagnostic criteria over time, Deckers et al. [32] reported increasing prevalence of eczema in Africa, eastern Asia, western Europe, and parts of northern Europe.

RISK FACTORS FOR THE DEVELOPMENT OF ALLERGIC DISORDERS It has long been recognized that allergic conditions have a tendency to cluster within individuals and families. Over the last two decades, there have been considerable advances in the understanding of the genetic basis of the tendency towards exaggerated IgE-mediated reactions and its clinical expression. Identification of the genes responsible has proved difficult, reflecting the conceptual and methodological problems that beset the study of complex genetic disorders. FIGURE 1 The allergic or atopic “march.” Source: Medical Observer, Allergic rhinitis, July 18, 2012.

Incidence Rhinitis

Asthma Eczema

Food allergy Age (years)

0

1

2

3

4

5

6

7

8

9

10 11

12

13

14

15

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Genome association analysis studies suggest the importance of epidermal barrier function and immune dysregulation in allergic disorders (e.g., van den Oord and Sheikh [33]; Paternoster et al. [34]) and the involvement of the ORMDL3 locus on chromosome 17 (e.g., Moffatt et al. [35]). Clearly, however, other factors are involved, and there is a pressing need to identify possible environmental risk factors and the ways in which they contribute to disease development and disease symptoms. The hypotheses-generating descriptive studies of the distribution and determinants of allergic disease frequency have, in the main, concentrated on upper airways (rhinitis) and lower airways (asthma) disorders, and include an assessment of how allergic disease frequency has varied over time (increased), the extent of demographic and socioeconomic variations in disease, and by geography (e.g., less prevalence in Mediterranean countries). International comparisons have been difficult to make, but two major initiatives have helped in this respect: the European Community Respiratory Health Survey (ECRHS) and the International Study of Allergies and Asthma in Childhood (ISAAC). Factors associated with a “Westernized” lifestyle, including dietary characteristics such as high fat and refined sugar intake, as well as a decrease in fruit and vegetable intake have been proposed as risk factors for allergic diseases.

GEOGRAPHICAL VARIATION AND RELATIONSHIPS BETWEEN DIET AND ALLERGY There are large geographical differences in the prevalence and incidence of allergy and asthma, with higher prevalence rates in English-speaking countries and lower prevalence rates in, for example, the Mediterranean region [36,37]. Diet has emerged as a factor of considerable interest in explaining the different risks of allergy and asthma between countries, and, as a result of the high intake of olive oil, vegetables, and fruit, whole-grain cereals and bread, a low intake of dairy products, some fish consumption, and only small amounts of red meat, a Mediterranean diet, being rich in antioxidants, has been proposed as being a contributory factor in lower allergy incidence. The Mediterranean diet also has a high content of complex carbohydrates, fiber, and unsaturated fatty acids and is low in saturated fatty acids. The implication of a low intake of antioxidant vitamins (i.e., vitamins A, C, and E) and mineral co-factors (i.e., selenium, zinc, and copper) essential for antioxidant defense mechanisms being related to an increase in allergy and asthma concurs with a Mediterranean diet being of potential benefit in the prevention of allergy and asthma. Of the dietetic hypotheses put forward to explain a link with allergy, the Mediterranean diet is not on its own, and other exposure/intervention candidates studied include type of maternal antenatal diet (such as maternal dietary antigen avoidance); infant feeding (e.g., breast versus formula milk), early versus delayed weaning, diversity of early life food exposure; food groups such as fruits, vegetables, fish, milk; nutrient type such as long-chain polyunsaturated fatty acids (LCPUFA); “fast” food; and single micronutrients such as vitamin A, vitamin D, vitamin E, folic acid, selenium, and zinc. Some of these have a strong relationship to the Mediterranean diet. Predisposition to allergy may already be determined at birth, and therefore diet during pregnancy presents a window for intervention in the prevention of allergic disorders. Studies focused on single nutrients or food items may fail to account for the interactions between nutrients and do not take into account that some nutrients are interrelated [9]. It is for this reason that interest has recently shifted to dietary patterns that represent a broader picture of food and nutrient consumption and may therefore be more predictive of disease risk, fitting well in the context of assessing the overall effect of adherence to a dietary pattern on the occurrence of a disease [10]. Epidemiological studies suggest that deficiencies of the aforementioned nutrients and/or vitamins may be associated with an increased risk for the development of allergy and asthma; however, in general, there are inadequacies, biases, and methodological weaknesses in these studies, such as cross-sectional designs that do not reflect causal relationships (Table 2), making it difficult to dissect out temporal relationships which are of pivotal TABLE 2 Possible Deficiencies, Biases, and Methodological Flaws in Primary Prevention, Studies of Diet and Allergy Limited sample sizes Lack of randomized controlled trials Cross-sectional studies that do not reflect causal relationships Variable dietary and biomarker assessment Variable disease and outcome measure definition Variable identification of those (e.g., children) at high risk of atopy Variable timing of exposure or intervention—prenatal, postnatal, infancy, adult Biases—participation, memory recall, reverse casuality, confounding factors, etc. Modified from Ref. [25]

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importance in assessing causality. Furthermore, there is a lack of mechanistic evidence for causality. Hypotheses on the effects of diet on allergy and asthma in a variety of population subgroups have included factors such as excess sodium intake; antioxidant imbalance; dietary lipid intake, e.g., increased saturated fat intake; change in the ratio of n
3 LCPUFA (i.e., decrease) to n
6 LCPUFA (i.e., increase); alteration of early life immune profiles; early life fever and infection; and, early life exposures impacting on the intestinal microbiota (including mode of infant delivery, infant diet, and use of antibiotics).

POTENTIAL MECHANISMS OF ACTION OF THE MEDITERRANEAN DIET ON ALLERGY PREVENTION The Mediterranean diet has been proposed to potentially impact inflammatory disorders such as asthma through immunomodulation and/or by modulation of oxidative stress. The antioxidant richness of the Mediterranean diet is believed to protect against endogenous and exogenous oxidative damage in the airways. In the context of the developing fetus, dietary antioxidants may influence atopy possibly by affecting the first interactions between the fetal and neonatal immune system and allergens [38], which subsequently plays a role in chronic inflammatory processes such as asthma. The increased consumption of fish, a source of n
3 (omega) fatty acids and the potential anti-inflammatory active ingredient, eicosapentaenoic acid (EPA), may reduce airway inflammation and bronchoconstriction. Docosahexaenoic acid (DHA) and EPA are termed the LCPUFA, the most widely available dietary source being from oily fish. It is believed that the allergic phenotype may be determined in utero or early infancy and that in the atopic phenotype, the immune system can have a T helper cell type 2 (Th2) dominance/response to common allergens with more secretion of interleukin 4 (IL-4), rather than the attenuation of immune response (immune tolerance) or the deflection of a response to a Th1 dominant pattern (immune deviation), where cytokine balance is towards interferon gamma (IFN-g) production (Figure 2). Animal models have been used to better understand key events of allergic disease development and to identify and develop therapeutic agents, and the mouse has become the species of choice for asthma research involving animals. There is, however, no animal model that can replicate the multifaceted dietary and environmental exposures of free-living humans. Furthermore, it is suggested that asthma seems to be a uniquely human disease that is not spontaneously developed by animals, the most similar conditions being “heaves” in horses and an allergic syndrome in cats [39]. Nevertheless, the growing number of genetically modified mouse strains and the development of germ-free mice have increased the understanding of the events causing allergic reactions (for a review, see Corazza and Kaufmann [40]). Hollingsworth et al. [41] demonstrated enhanced allergic airway disease in mice after in utero supplementation with methyl donors. Epigenetic methylation changes were associated with decreased transcriptional activity and increased disease severity as a result of methyl donor supplementation, indicating that dietary factors can modify the heritable risk of allergic airway disease during a vulnerable period of fetal development [41], which may arise through an imbalance of the T-cell mediated proinflammatory cytokine response. The high n
3/n
6 polyunsaturated fatty acids (PUFAs) ratio potentially brought about by a high consumption of fish as part of the Mediterranean diet reduces the level of proinflammatory cytokines (that have been shown to be induced in asthmatic patients) and influences the differentiation of Th lymphocytes. The result of a reduced consumption of fruit and vegetables, a major component of the Mediterranean diet, has been associated with asthma prevalence, and the Th1/Th2 paradigm has been investigated in mice with reference to vitamin A intake. It was shown that vitamin A deficiency diminished the development of experimental asthma (and IgE response) in the OVA-induced mouse model of allergic pulmonary inflammation and hyper-responsiveness [42], while a high-level of vitamin A enhanced the experimental asthma (and increased serum IgE). Translating this to humans suggests that a relatively high intake of vitamin A may contribute to a Th2 bias and an increased risk of asthma. A vitamin A “dose-response” effect remains to be tested in any experimental trial but, based on epidemiological studies, there may be some substance to it, given that a multivitamin supplement containing vitamin A within the first 6 months of life was associated with an increased risk for asthma [43], while the use of a high bioavailability combined vitamin A and D supplement in water-soluble form (but not if given in peanut oil) has been associated with increased risk of allergic disease in infancy [44]. The potential failure of immune maturation in early life, with both genetic and environmental (including dietary) factors operating as causes, combined with the development of the immune capability and physiology in utero, makes the investigation of prenatal diet pertinent—a period that, alongside the first months of life, offers a window of opportunity to modulate the development of the immune, respiratory, and digestive systems. Once the “atopic march” has begun, there appear to be few, if any, dietary strategies that have been found to be effective as secondary (reducing morbidity) measures, or tertiary (mitigating disease complications) preventive measures.

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FIGURE 2 Th1/Th2 cytokine balance before, during and after pregnancy. Naı¨ve T helper cells (type 0; Th0) are considered precursors to the other Th cell types. In a basal state, Tregs (specialized T cells that inhibit the proliferation and activation of effector T cells), including Th3 cells and the cytokine transforming growth factor b (TGF-b), support the immune “balance.” One of the major classes of Tregs is CD4+CD25+ T cells, which play a major role in this maintenance of self/immune tolerance. Pregnancy is characterized by Th2 predominance, which counters the Th1 responses that can prove toxic for the placenta/result in immune rejection. After delivery, a shift toward Th1 occurs as a consequence of microbial stimuli that provide protection, with a reduction in Th2 reactivity responsible for allergic processes. In the atopic phenotype, the immune system can have a Th2 dominance/response to common allergens with more secretion of IL-4, rather than the extinction of immune response (immune tolerance) or the deflection of a response to a Th1 dominant pattern (immune deviation) where cytokine balance is towards IFN-g production. Chronic inflammatory diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis have been described as Th1 dominant conditions, whereas atrophy and allergy are considered to be Th2 dominant conditions. Adapted from Allergy on-line clinic (2013), http://allergyclinic.wordpress.com/2012/04/01/clinical-aspect-in-th1-and-th2-balance/, accessed March 2013.

ALLERGY PREVENTION THROUGH DIET Primary Prevention Given the increasing evidence suggesting that prenatal and early life exposures influence the development of asthma and allergic disease, interest has converged on the possible role of the diet during pregnancy and early life. It has been hypothesized that maternal diet during pregnancy modulates the development of allergy and asthma by influencing fetal airway and/or immune development [45]. Birth cohort studies have reported associations between aspects of maternal diet during pregnancy and childhood asthma and allergic outcomes (e.g., Erkkola et al. [46]), as has a cohort study that evaluated maternal dietary intake (e.g., Mediterranean diet adherence) with follow-up of the children born [10].

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The Mediterranean Diet and Allergy Prevention An extensive and rigorous systematic review and meta-analysis examined the strength of the scientific evidence for associations between dietary intake of foods and nutrients by pregnant women and children and the risk of children developing asthma and other allergic disorders [47]. Of nearly 15,000 potentially relevant articles, 62 satisfied the inclusion criteria. Included studies were all those relevant to children (i.e., pregnant women, infants, and children 16 years) that investigated the role of nutrients and foods for the primary prevention of asthma and atopic disorders in children. There were no randomized controlled trials (RCTs); all were cohort, case-control, or cross-sectional studies. Although these study designs are potentially at high risk of bias in assessing the effectiveness of dietary constituents/patterns, the review results found a potentially substantial protective role for vitamins A, D and E, zinc, fruit and vegetables, and a Mediterranean diet for the prevention of allergy and allergic disorders. Of these dietary candidates, vitamin A, vitamin D, and vitamin E, and possibly others are under investigation. Of the five observational Mediterranean diet studies in the review (Table 3), one used a cohort design [10], and four were cross-sectional studies [48–51]. The higher quality cohort study of Chatzi et al. [10], reviewed by Nurmatov et al. [47] reported that high adherence to a Mediterranean diet was found to be protective against persistent wheeze (OR ¼ 0.22, 95% CI 0.08, 0.58), atopic wheeze (OR ¼ 0.30, 95% CI 0.10, 0.90), and atopy (OR ¼ 0.55, 95% CI 0.31, 0.97). Although observational studies have therefore reported potentially beneficial associations with a Mediterranean diet, it is not known whether an intervention to promote the Mediterranean diet reduces the likelihood of childhood allergy and asthma. Of particular interest would be a primary prevention strategy in those at high risk of developing allergy and asthma. It has been suggested that in atopy prevention studies to date there may have been inconsistency in study methodology with regard to defining high-risk populations and disease outcomes [52], so this should be a consideration in any design. There are currently no RCTs testing the hypothesis that a Mediterranean diet of the mother decreases the risk of asthma and allergic disease in children; however, there is a need for a well-designed, adequately powered RCT of the Mediterranean diet and allergy, and we have started a program of work to lead into this. We have recently reported our pilot study protocol to investigate rates of maternal recruitment and retention of women at high allergy risk for the fetus, to assess the acceptability of a dietary advice intervention, to evaluate any change in the Mediterranean diet score, and to measure adherence to a Mediterranean diet during pregnancy [53]. The intervention was a 15-min structured dietary advice

TABLE 3 Studies Evidencing Modification of Allergy and Asthma Risk in Children Brought About by Mediterranean Diet Adherence Number of Participants (Age)

Outcome Measures

Main Findings of the Highest Quality Study

Risk of Bias

Reference

Moderate

[10]

Wheeze

High

[48]

690 (7–18 years)

Allergic rhinoconjunctivitis wheeze

High

[49]

Cross-sectional

1476 (6–7 years)

Allergic rhinoconjunctivitis wheeze asthma

High

[50]

Cross-sectional

20,106 (6–7 years)

Allergic rhinoconjunctivitis asthma

High

[51]

Country

Design

Spain

Cohort

460 (0–6.5 years)

Atopy wheeze

Spain

Cross-sectional

1784 (4.1 years)

Crete, Greece

Cross-sectional

Mexico

Spain

Protective for childhood atopy, atopic wheeze and persistent wheeze at age 6.5 years

The cohort study was considered higher quality than the other studies as a result of the study of clinically relevant outcomes, long duration of follow-up, good completeness of follow-up and appropriate adjustment for potential confounding. Modified from Ref. [47]

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session at 12 weeks of pregnancy, encouraging the consumption of particular foods that are consistent with the Mediterranean diet. The intervention was directed at increasing consumption of fruit, vegetables, legumes, nuts, seeds and fish, using olive oil as a dressing and for cooking, and eating leaner and/or less red meat. A Mediterranean diet pyramid was contained in a participant resource booklet used to deliver the intervention, and goals were discussed, and then followed up with supportive telephone calls at 16, 20, and 28 weeks of pregnancy. A Mediterranean diet score (based on Castro-Rodriguez et al. [48]) was obtained preintervention and at 24 and 36 weeks of pregnancy. The inclusion of certain nutrients in the diet, or a greater adherence to a particular dietary pattern, is of particular interest; however, one aspect of primary prevention that has also been investigated is that of food allergen avoidance in pregnancy and lactation. Ironically, some of the potentially antigenic foods that have been excluded as an intervention strategy to investigate primary prevention of atopic diseases are components of the Mediterranean diet (e.g., nuts, fish). It is known that maternal dietary antigens cross the placenta and are able to pass into breast milk, and a review of maternal diet (i.e., antigen avoidance) during pregnancy or lactation (or both) has recently been carried out [54]. The evidence from five trials involving 952 participants did not suggest a protective effect of maternal dietary antigen avoidance during pregnancy on atopic eczema/dermatitis in the first 18 months of life, and the authors concluded that there is insufficient evidence to draw meaningful inferences regarding AR or conjunctivitis, or urticaria. Overall, it was concluded that dietary antigen avoidance during pregnancy is unlikely to substantially reduce the child’s risk of atopic disease, and that such avoidance may adversely affect maternal or foetal nutrition. Interest has also increased in the potential of dietary interventions related to key nutrients of the Mediterranean diet during pregnancy to decrease the risk of allergy and asthma, such as those related to antioxidant intakes. Small numbers of cohort studies have highlighted associations between reduced maternal intake of some nutrients (vitamin E, vitamin D, PUFA [and zinc and selenium]) during pregnancy and childhood asthma [55]. In contrast, in an assessment of maternal antioxidant intakes (b-carotene, vitamin C, vitamin E, copper, and zinc) and infant allergy outcomes (n ¼ 420 pregnant women, n ¼ 300 infant allergic outcomes at one year), vitamin E and zinc intakes showed no association with allergic outcomes [56]. The main associations with allergic outcomes were seen with vitamin C and copper, despite the systematic review of Nurmatov et al. [47] concluding that the evidence for the role of vitamin C (and selenium) in the primary prevention of allergy and asthma was less encouraging/suggestive compared with vitamins A, D, and E; zinc; fruits and vegetables; and the Mediterranean diet. In a longitudinal pre-birth cohort of 1376 mother-infant pairs studied in the first and second trimester, and the infants at 3 years of age [57], maternal dietary pattern as determined by Mediterranean diet score using food frequency questionnaire data was not associated with recurrent wheeze in the infants after adjustment for confounders. The authors suggested that maternal intake of individual nutrients may be more important determinants of offspring wheeze-associated illness than is dietary pattern. Vitamin D trials are ongoing, and, two intervention trials suggest that PUFA manipulation during pregnancy may be associated with improved allergy outcomes [55]. Of course, a key component of the Mediterranean diet is the use of olive oil, rich in monounsaturated fatty acids rather than PUFA. High-quality intervention trials of maternal nutrient intake during pregnancy are required to see if they can be used as low-cost, healthy, public health measures to reduce allergy and asthma prevalence. The association of fish consumption with the Mediterranean diet makes intervention trials of PUFA in pregnancy and infancy of interest. Palmer et al. [58] carried out an intervention (n ¼ 368 pregnant women) of 900 mg of n
3 LCPUFA daily from 21 weeks’ gestation to birth compared with a control group (n ¼ 338) who received matched vegetable oil placebo capsules without n
3 LCPUFA. This was therefore a reasonably large RCT, which reported low attrition. There was no difference in IgE-associated allergic disease between the groups at 1 year of age, although the percentage of infants diagnosed as having atopic dermatitis and egg sensitization were lower. In a smaller study, Furuhjelm et al. [59] reported their follow-up of infants at 2 years of age, born to mothers (n ¼ 145) at high risk of having an allergic infant, who were randomized to daily supplementation with 1.6 g EPA and 1.1 g DHA (n ¼ 70) or placebo (n ¼ 75) starting at 25 weeks’ gestation and continuing through to 3.5 months of breastfeeding. No difference in the prevalence of allergic symptoms in the infants at 2 years of age was found between the groups, but the decrease in IgE-associated disease seen during the first year remained until 2 years of age. Willers et al. [60] showed that there was no association between maternal intake of several foods during pregnancy and asthma, respiratory, and allergic outcomes in 5-year old children; however, apple and fish consumption appeared to have a protective effect against the development of allergy and asthma, in agreement with Erkkola et al. [46], who suggested that low maternal consumption of leafy vegetables and maleceous fruit (e.g., apple, apricot, peach, pear, plum) and chocolate were positively associated with the risk of wheeze in children. High maternal consumption of fruit and berry juices was positively associated with the risk of AR in children. Certainly a diet rich in leafy vegetables and malaceous fruit fits well into the positive associations with the Mediterranean diet, and the high sugar content of fruit juices, despite being from

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fruits, fits into a negative association. However, in a prospective study of maternal food consumption during pregnancy, there were no associations between maternal vegetable, fish, egg, milk or milk products, and nut consumption and longitudinal childhood asthma outcomes (n ¼ 2832 children) over 8 years [61], and a crude association between maternal fruit intake during pregnancy and childhood wheeze lost significance when adjusted for confounding variables.

Dietary Intervention in Infancy and Childhood While the benefits of breastfeeding per se are well recognized for other health outcomes, and possibly for allergy, there appear to be no intervention trials to promote the Mediterranean diet in women while breastfeeding in relation to allergy. An RCT has recently been carried out in a small number of overweight breastfeeding women [62] and both a Mediterranean diet and a MyPyramid diet were reported to support postpartum weight loss and reduce TNF-a and IL-6, biomarkers of inflammation, though these are not cytokines implicated in Th1/Th2 balance. The landmark study of Grulee and Sanford [63] was probably the first attempt to examine closely the relationship between diet and allergy [64]. It was a large study (over 20,000 children participated) in which there was substantial clinical protection from atopic dermatitis between 5 and 9 months of age as a result of breastfeeding up to 6 months, compared with those infants artificially fed (essentially with boiled cow’s milk with the addition of cane sugar—a 1930s forerunner to formula milk, which has become popular since the 1950s). Confounding variables such as maternal diet, weaning age, and socioeconomic status were not the type of characteristics that were commonly measured at the time, and may be of importance; however, a 0.3% incidence at 8 months in the breastfed group compared with a 4.6% incidence in the artificially fed is remarkable. Perhaps less remarkable, given our current knowledge, is the impact that cow’s milk has on infant atopic eczema/dermatitis. Of the large number of studies carried out since to assess the protective effect of breastfeeding on atopy and allergy, systematic reviews and meta-analyses of prospective studies have suggested an overall protective effect of breastfeeding exclusively for at least 3–4 months on atopic eczema/dermatitis during early childhood, particularly in children at high risk of developing allergy, that is, when one or both parents are atopic. Other conclusions have been reached; the overall allergy consensus appears to be that breastfeeding may not affect allergy risk to any great extent, but that it should be promoted because of the other associated benefits. The most effective dietary strategy in early life appears to be breastfeeding for 4–6 months, or, in the absence of breast milk, formula with reduced allergenicity for at least the first 4 months, combined with the avoidance of solid food and cow’s milk for the first 4 months [65]. Strategies for the primary prevention of diseases by definition involve intervening in healthy individuals and should therefore be based on robust evidence from clinical trials, though in the case of breastfeeding, randomization is unethical, and therefore primary prevention recommendations, by necessity, need to be based on high quality systematic reviews of high quality cohort studies. Evidence from two trials of maternal antigen avoidance in lactation involving 523 participants did not suggest a significant protective effect on the incidence of atopic eczema/dermatitis during the first 18 months or on SPTs to the most common food allergens at 1, 2, or 7 years [54], but a large RCT is needed if allergen avoidance remains a potential preventive strategy. Recent work on a Finnish child cohort (n ¼ 3781) investigating the timing of infant feeding in relation to allergy and asthma has concluded that the early introduction of foodstuffs, including three of the most common allergenic foods (egg, wheat, and fish; see Table 1) appear to decrease the risk of asthma, AR, and atopic sensitization in children [66]. Longer duration of total breastfeeding, rather than its exclusivity, was protective against the development of non-atopic but not atopic asthma [66]. The early introduction of foods may protect against atopic sensitization, particularly in high-risk children, while the risk of atopic sensitization might be increased by less food diversity as early as at 3 months of age [67]. Peanut is one of the most common allergenic foods, and insight is now becoming available with regard to peanut avoidance versus measured repeated consumption of peanut in infancy [68] as a result of an ongoing study (Learning Early About Peanut Allergy study “LEAP,” e.g., Du Toit et al. [69]). Nurmatov et al. [47] excluded the field of dietary fats because systematic reviews of this literature had recently been carried out [70,71]. The Childhood Asthma Prevention Study (CAPS) [72] was possibly the first RCT of the effectiveness of a nutritional intervention (modification of dietary intake of fatty acids through supplementation with n
3 PUFA; 500 mg tuna fish oil from 6 months of age) in combination with house dust mite avoidance, implemented from birth, for the prevention of asthma and other allergic disorders. The study started in 1997, was completed in 2000 and recruited 616 participants who were followed up at 18 months [73], 3 years [74], and 5 years [75]. At the 5-year follow-up (n ¼ 516), the combined HDM avoidance measures and dietary fatty acid modification implemented in infancy and early childhood had not prevented the onset of eczema, asthma, or atopy in high-risk children.

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In an ongoing RCT, infants at high atopic risk who received a combined DHA (280 mg) and EPA (110 mg) or control oil daily from birth to 6 months have been reported to show increased PUFA levels with some lowered Th2 and elevated Th1 responses on follow-up at 6 months of age [76]. At 12 months of age follow-up (n ¼ 323), the improved infant n
3 PUFA status was still evident, but allergic disease was not prevented [77]. Further follow-up of these infants is planned at 18, 30, and 60 months of age [78]. In an intervention composed of increasing maternal and infant intake of n
3 PUFAs and oily fish, reducing parental smoking, and reducing indoor dampness, the data suggest sex differences in the potential effectiveness of the intervention to reduce the incidence of asthma at 2 years of age [79]. This study included participants regardless of parental history of atopy, on the basis that a larger number of people at low risk may give rise to more disease cases than a smaller number of participants at high risk. The cross-sectional primary prevention studies of the Mediterranean diet and allergy and asthma identified by Nurmatov et al. [47] (see Table 3) looked at diet in children of about 4 years of age [48], 7–18 years of age [49], and 6–7 years old [50,51]. The quality of these studies was not adjudged to be as high as the cohort study [10], but the overall conclusion was that though the epidemiological evidence is weak, it is potentially supportive of a Mediterranean diet for the prevention of asthma, and that well-designed RCT’s are needed. Arvaniti et al. [80] reviewed the scientific evidence for the effects of dietary habits on asthma using studies published between 1985 and 2009, based on child and adult sample populations. They selected 43 studies for review, 38 of which were cross-sectional, 4 case-control, and 1 longitudinal. None were RCTs. Five Mediterranean diet studies were highlighted in this review, four in children [24,49–51] and one secondary prevention study in adults [81]. The authors concluded that there is a generalized consistency in the evidence that a Westernized diet seems to be associated with an increased risk of asthma; however, the mechanism and importance of the association remains to be resolved [80].

Secondary and Tertiary Prevention Research suggests that there is an association between diet and allergic disease; however, there is little evidence that any food, nutrient, or dietary pattern has an impact on allergy and asthma after early infancy. While primary prevention aims to eliminate or reduce factors related to disease incidence, secondary prevention aims to screen for/detect preclinical disease and reduce morbidity. There would appear to be few dietary strategies that have been found to be effective as secondary prevention measures, however, Barros et al. [81] found that a high adherence to Mediterranean diet increased the likelihood of asthma being under control in adults—high adherence had a 78% reduction in the risk of having noncontrolled asthma (OR ¼ 0.22, 95% CI ¼ 0.05–0.85), with a higher consumption of fresh fruit decreasing the probability of having noncontrolled asthma. A higher intake of ethanol had the opposite effect. It would appear that there is no benefit of dietary supplements in the treatment of established atopic eczema/dermatitis [82]. In mitigating disease, that is trying to prevent progression or complications (tertiary prevention) again, few, if any, dietary strategies are thought, or indeed evidenced to be effective. In any tertiary allergy preventive program, smoking cessation is a key, and partially reversible influence on the respiratory symptoms of allergic diseases, however, as smoking becomes less common, allergic sensitization, and other influences on adult asthma, possibly dietary influences, may attain greater relative importance. An impact is likely to be confined to the prenatal stage and the early stages of the lifespan. It has been said that once the atopic process has started, no nutritional strategies have been found to be effective as secondary or tertiary preventive measures [25], though there appear to be few secondary and no tertiary prevention trials of the Mediterranean diet and allergy.

CONCLUSIONS There is consistent epidemiological evidence that the Mediterranean diet in early childhood may have a protective effect against atopic sensitisation and the development of allergic diseases such as atopic eczema/dermatitis, food allergy, AR, and asthma. Mother/infant cohort studies of maternal dietary nutrients and infant dietary nutrient intervention studies have not culminated in a consensus for a benefit in the primary prevention of allergy and asthma. Supplementation with n
3 or n
6 PUFA in pregnancy, lactation, or infancy seems unlikely to play an important role as a strategy for the primary prevention of atopic sensitisation or allergic disease. There is relevant evidence from basic science studies to suggest that effects of diet may be biologically plausible, possibly exerting their effect through epigenetic mechanisms in high-risk individuals; however, there is little evidence regarding the effects of maternal dietary intervention on allergy and asthma. Dietary antigen avoidance during pregnancy is unlikely to substantially reduce the child’s risk of atopic disease, and such avoidance may adversely affect maternal or foetal nutrition [54].

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There are no RCTs of a Mediterranean diet intervention during pregnancy, hence the need for a large-scale RCT that follows a framework for developing and evaluating complex interventions. We have used the knowledge base to formulate the theory that diet has a role in the primary prevention of asthma and allergic disease in order to inform a systematic review and meta-analysis [47]. Based on the Mediterranean diet being one of the evidential candidates, and that a dietary pattern represents a broad picture of food and nutrient consumption, we have modeled a potential intervention and are in the feasibility and piloting stage of this work, which will refine the practicality of the intervention (e.g., recruitment, retention, sample size determinants). Given the need for sufficiently high-powered longitudinal experimental studies in cohorts of pregnant women, we are developing a large-scale, multicenter RCT in pregnant high-risk women to test the hypothesis that greater adherence to a Mediterranean diet during pregnancy will reduce the risk of allergy in newborns, testable only in a RCT with follow-up of the infants, i.e., until at least age 5 to enable a diagnosis of asthma to be securely made. As with any primary prevention intervention, adverse events should also be studied, as should health economic considerations. Given that the available epidemiological evidence supports a link between a Mediterranean diet and the prevention of allergy, the trial we are developing has the potential to offer a brief, effective and cost-effective intervention at a key stage in the lifespan, which may reduce the allergy burden on individuals and on healthcare providers.

SUMMARY POINTS l

l l

l

l

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There has been a rapid increase in the incidence and prevalence of allergic diseases in many parts of the world, and one in three people in developed countries manifest one or more allergic condition at some point in their lives. Children bear the greatest burden of allergy and asthma. Diet may have epigenetic and regulatory effects that modulate development of the immune system along with other pre- and postnatal influences and immune stimuli. Studies suggest both association and a lack of association of prenatal and postnatal nutrient intake and diet on the development of childhood allergy and asthma. Some associations of diet with allergy prevention are better documented, by cross-sectional and cohort studies, and appear to have beneficial effects, such as the Mediterranean diet. Strategies for the primary prevention of diseases, by definition, involve intervening in healthy individuals and should therefore be based on robust evidence from clinical trials. The available epidemiological evidence, supportive of a link between a Mediterranean diet and the prevention of allergy and asthma, suggests that there is a pressing need for a large-scale intervention in a cohort of pregnant women with follow-up of the newborn infants, which should help to clarify whether the Mediterranean diet is a primary preventive measure for allergy and asthma.

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3 LCPUFA intervention trial in term infants. Contemp Clin Trials 2011;32(5):771–8. [79] Dotterud CK, Storro O, Simpson MR, Johnsen R, Oien T. The impact of pre- and postnatal exposures on allergy related diseases in childhood: a controlled multicentre intervention study in primary health care. BMC Public Health 2013;13:123. [80] Arvaniti F, Priftis KN, Panagiotakos DB. Dietary habits and asthma: a review. Allergy Asthma Proc 2010;31(2):e1–e10. [81] Barros R, Moreira A, Fonseca J, de Oliveira JF, Delgado L, Castel-Branco MG, et al. Adherence to the Mediterranean diet and fresh fruit intake are associated with improved asthma control. Allergy 2008;63(7):917–23. [82] Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC. Dietary supplements for established atopic eczema. Cochrane Database Syst Rev 2012;2: CD005205.