PAEDIATRIC RESPIRATORY REVIEWS (2003) 4, 205–212 doi: 10.1016/S1526–0542(03)00058-7 SERIES: DIFFICULT ASTHMA Food allergy and asthma—what is the link? Graham Roberts1 and Gideon Lack2* 1 Paediatric Respiratory Medicine, Royal London Hospital, Whitechapel, London E1 1BB, UK; 2Paediatric Allergy, Asthma and Immunology, Imperial College at St Mary’s Hospital, Praed Street, London W2 1NY, UK KEYWORDS asthma; food allergy Summary Food allergy and asthma are both atopic diseases and therefore frequently co-exist. Food allergy is common in childhood, affecting approximately 8% of infants. The diagnosis is based on a suggestive history supported by skin-prick testing, serum specific IgE or food challenge. The role of diet in the aetiology of asthma and as a precipitant of exacerbations has been investigated extensively. Many people perceive diet as being an important precipitant of their asthma but objective testing suggests that it is only important in a minority. Meanwhile, there is considerable epidemiological evidence to suggest that there is a link between asthma and food allergy. Food can induce bronchospasm and food allergy has been implicated as a risk factor for life-threatening asthma. Additionally, asthma also seems to be a risk factor for life-threatening food allergy. The mechanism underlying this connection is unclear. The co-existence of food allergy should be considered in any child with asthma. Where food allergy is confirmed, steps should be taken to avoid these foods as this may considerably improve asthma control. ß 2003 Elsevier Science Ltd. All rights reserved. INTRODUCTION Food allergy and asthma are both atopic diseases and therefore frequently co-exist. Given this relationship, there has been much interest in recent years in the role of diet in the development of asthma and as a precipitant of exacerbations. Additionally, there is now evidence to suggest that food allergy may be a risk factor for life-threatening asthma and asthma may be a risk factor for life-threatening food allergy. This statistical association between these two allergic diseases may be due to their common atopic basis or may reflect a close inter-relationship in their pathogenesis. FOOD ALLERGY Defining food allergy Food allergy is a common childhood manifestation of atopy. It is most common in early life, affecting up to 8% of infants.1 Food allergies are defined as any immunologically mediated adverse reaction to food which is reproducible under blinded * Correspondence to: Gideon Lack. Tel.: þ44 (0) 20 7886 6384; Fax: þ44 (0) 20 7886 1129; E-mail: [email protected] 1526–0542/$ – see front matter conditions.1 Only a minority of adverse reactions to food constitute food allergies. Other mechanisms relate to toxins, pharmacologically active chemicals, enzymatic deficiencies or psychological reactions. Food allergy can itself be divided into IgE- and non-IgE-mediated reactions. IgE-mediated reactions involve the release of mediators (e.g. histamine) from mast cells and result in symptoms within 2 h of exposure.1 Other mediators (e.g. prostaglandins) attract a local infiltrate of inflammatory cells which may lead to the onset of late-phase symptoms after 4–8 h. Symptoms from non-IgE-mediated food allergy typically take 12–24 h to develop and consist of a cell-mediated hypersensitivity reaction.1 Presentation and natural history of food allergy The usual allergenic foods are hens’ eggs, cows’ milk, soy, wheat, tree nuts, peanuts, fish and shellfish.1 The age of onset of food allergy depends on the individual food and the age at which it is typically introduced into the child’s diet. Cows’ milk, egg, soy and wheat allergy all usually present in the first year of life. Fish, peanut and tree nut allergy typically present later. The presenting features of food allergy usually involve the skin (urticaria, angioedema, eczema) or gastrointestinal ß 2003 Elsevier Science Ltd. All rights reserved. 206 tract (nausea, vomiting, abdominal pain, diarrhoea). Frequently though, there is upper airway (sneezing, rhinorrhoea, nasal congestion, change in voice, stridor), pulmonary (cough, wheeze) and cardiovascular (collapse due to hypotension) involvement.1 The natural history of food allergy in childhood can be divided into two groups: cows’ milk, egg, soya and wheat, where resolution of the allergy is seen in most children by 5 years of age; and peanuts, tree nuts, fish and shell fish where the problem is thought to be generally life-long.1,2 Diagnosing food allergy The diagnosis of food allergy can be difficult as presenting symptoms have many potential causes and there is often not a clear temporal link between the ingestion of a single food and the development of symptoms. It is further complicated in that almost all young children outgrow their food allergy. Skin-prick testing is performed by puncturing the skin through a drop of allergen using a lancet with the weal diameter being measured after 15 min. It is important that the results are interpreted in the light of a negative saline control (ruling out dermatographism) and positive histamine control (ruling out the presence of any antihistamine). The predictive value of weal diameter of 3 mm or larger for food allergy is only approximately 50%, although the negative predictive value of a negative result is in the order of 99%.3 Recent work though has suggested that larger weal diameters give better predictive values.4 A weal diameter of at least 7 mm for egg and 8 mm for cows’ milk or peanuts had a 100% positive predictive value for clinical allergy. When skin-prick testing is impossible due to extensive eczema, antihistamine use in the previous 72 h, or nonavailability of relevant allergen preparation, specific serum IgE can be measured. The best validated system is the Pharmacia CAP method. Again the level of specific IgE has been shown to be related to probability that a child is clinically allergic.5,6 Values at or above which there is a 95% chance of clinical allergy are 6 kU/l for egg, 32 kU/l for milk, 15 kU/l for peanut and 20 kU/l for fish. A number of tests are often promoted as being useful for diagnosing food allergy. Examples are food-specific IgG or IgG4 antibodies, provocation–neutralisation testing and applied kinesiology. None of these tests are supported by any scientific testing and therefore should be avoided.7 The gold standard for diagnosing food allergy is the double-blind, placebo-controlled food challenge.1 Increasing amounts of the disguised food or a suitable placebo are given at 15–30 min intervals under careful supervision. The placebo is used to ensure against a false-positive outcome. Assuming that the maximum dose given is equivalent to a normal meal size portion, there is a low false-negative rate.8,9 Open challenges are also clinically useful when subjects present with objective symptoms. G. ROBERTS AND G. LACK ROLE OF DIET IN ASTHMA The role of diet in the aetiology of asthma has become a popular avenue of speculative research in recent years.10,11 Investigators have focused on a number of the constituents of our diet including potassium, magnesium, antioxidants such as vitamins C and E, and fatty acids. Results from cross-sectional epidemiological studies have suggested that wheeze or increased bronchial reactivity are related to low magnesium, potassium, vitamin C or fatty acid intake.12–14 However, when an effect on lung function is seen, it is very small.10,11 Additionally, there is limited convincing interventional data examining the effect of dietary manipulation of asthma. For example, a Cochrane review of the effect of marine n–3 fatty acid supplementation in asthma examined nine randomised controlled trials.15 The authors could not find any consistent beneficial effect of supplementation of fish oil over placebo. The other dietary target of investigators looking for links between diet and asthma has inevitably been food additives. Many thousands of chemicals are added to foods to enhance flavour or act as preservatives. As many as 50% of asthmatics perceive that their asthma is exacerbated by these.16,17 Monosodium glutamate is perhaps the best known as the cause of the ‘Chinese restaurant syndrome’ of paraesthesia, palpitations and a burning sensation of the neck, chest and limbs. The relationship between monosodium glutamate and asthma is less clear. There are studies both confirming and ruling out the association.18 There is also some evidence to suggest that adverse reactions to both tartrazine19 and sulphites20,21 may induce lower airway symptoms. Food additives would seem to be a problem for a few asthmatic subjects investigated in tertiary clinics.18–21 However, there is no good epidemiological data demonstrating that food additives play an important role in community-based asthma. While the role of diet and food additives in asthma has attracted considerable interest, the inter-relationship between food allergy and asthma has received scant attention. The evidence that does exist suggests that there is likely to be very important interplay between these two diseases. The relationship between food allergy and asthma will be discussed in the rest of this review. First, we will examine the evidence that paediatric asthma is an allergic disease, and then we will look at the association between asthma and food allergy and how they may inter-relate. ROLE OF ALLERGENS IN CHILDHOOD ASTHMA Over the last two decades, asthma has been increasingly considered to be a disease which very often has an important allergic component.22,23 This view is supported by a number of lines of epidemiological evidence. FOOD ALLERGY AND ASTHMA 207 Increased total IgE levels and cutaneous reactivity to aeroallergens are both associated with an increased risk of asthma.24 A number of case-controlled studies have demonstrated a link between house dust mite reactivity and asthma.25 Associations have been seen between reactivity to indoor allergens and presentation to hospital with asthma.26 There are seasonal changes in the rates of asthma exacerbations related to seasonal increases in levels of environmental aeroallergens such as grass pollen27 and Alternaria.28 Morphological studies of the asthmatic airways demonstrate an inflammatory infiltration, hyperplasia of mucous-secreting goblet cells, disruption of epithelial cells and marked thickening of the laminar reticularis.23 These inflammatory changes are even seen in mild paediatric asthma.29 The inflammation in asthma is often but not invariably characterised by eosinophils, mast cells and T lymphocytes.23 Lastly, perhaps the most compelling line of evidence for the allergic nature of asthma is the effect of anti-IgE on asthma. This agent is a humanised mouse monoclonal antibody that binds to free IgE. In recent randomised controlled trials in both childhood30 and adult31 moderate to severe asthma, antiIgE has been shown to be a steroid-sparing agent and to reduce the rate of exacerbations. The success of anti-IgE treatment in asthma is a persuasive argument for the role of IgE in the pathogenesis of asthma. However, recent epidemiological data would suggest that there is not a straightforward relationship between atopy and asthma, and other additional factors may play an important role. For example, rates of sensitisation to aeroallergens and asthma, diagnosed using a symptom- and exerciseinduced bronchospasm, have been compared in Albania and the UK.32 The prevalence of atopy was similar in both countries but asthma was more than three times more prevalent in the UK. A similar pattern was observed when Nigerian and Australian children were compared.33 Additionally, rates of atopy have been shown to be increasing in East Germany over the past few years, whereas the prevalence of asthma has remained static.34 Thus while atopic status and allergen exposure are impor- Table 1 tant factors in childhood asthma, there are other important genetic and environmental factors that remain to be determined. THE EPIDEMIOLOGICAL LINK BETWEEN FOOD ALLERGY AND ASTHMA Epidemiological studies looking at the prevalence of asthma are unfortunately complicated by the lack of a diagnostic test, leading to non-specific questionnaire-based definitions that are likely to overestimate rates.35 Similar problems exist with food allergy, as the positive predictive value of a history of an allergic reactions is only 50%.1 Cross-sectional epidemiological studies involving double-blinded, placebocontrolled food challenges are expensive and time consuming, and therefore rarely attempted. Co-existing asthma and food allergy There is a perception amongst the general public that foods are frequently implicated in precipitating exacerbations of asthma. In surveys of patients attending asthma clinics in both Australia and the UK, over two-thirds believed that food induced their asthma.16,36 Even in a community sample, 21% of subjects considered diet as a precipitant for their asthma.37 As can be seen in Table 1, the real picture is very variable with 2–24% of asthmatics experiencing food-induced bronchospasm within a challenge situation. The reason for the failure to substantiate the link in so many individuals is apparent from some of the items cited as inducing asthma: ice cream, cold water and carbonated drinks.38 For these items, the mechanism responsible for generating the bronchospasm is more likely to be cold or acid than an allergic reaction.36 When food challenges have been employed, the food implicated in food-induced episodes of asthma were peanut, milk, egg, tree nuts, soy, wheat, legume, bean and turkey.39,40 Such studies also suggest that food-induced asthma is Prevalence of food allergy in asthmatic children. Author (year) Number Subjects Food allergy Bock and Atkins 199042 410 Novembre et al. 198840 140 Oehling and Baena Cagnani 198067 Onorato 198641 284 Children with asthma in an allergy clinic Children (2–9 years) with asthma Children and teenagers with asthma Children and adults with asthma in a respiratory clinic 279 (68%) reported food-induced wheezing, 98 (24%) confirmed in DBPC food challenge 32 (23%) reported history suggestive of food allergy, eight (5.7%) had positive DBPC food challenges Food-induced bronchospasm seen in 24 (8.5%) 300 DBPC, double-blind, placebo-controlled. 25 (8%) had a history of food-induced asthma; food-induced wheezing seen in only six (2%) challenges, all were children or teenagers 208 seen more frequently in children than adults.41 The rate of food-induced bronchospasm in asthma is also very different in studies because of selection bias operating in different clinical settings. Thus the higher rate of confirmed food-induced wheezing in the Bock and Atkins paper42 compared with other studies may be explained by the recruitment of these children from an allergy clinic. Studies that have failed to detect an effect of foods on pulmonary function could conceivably have shown effects on other endpoints that were not measured. Thus exposure to food products in some subjects does not alter their lung function but can result in increased bronchial hyper-reactivity.43 It is possible that the link between asthma and food allergy is merely a statistical association given that both have a common atopic background. Alternatively, there may be a causal pathophysiological link with clinical implications. RESPIRATORY REACTIONS ASSOCIATED WITH ALLERGIC REACTIONS TO INGESTED FOOD Respiratory reactions to ingested food A number of investigators have looked at the extent to which allergic reactions to food involve the lower respiratory tract. In one study, 100 small children with IgE- and non-IgE-mediated milk allergy (mean age 16 months) were challenged with milk.44 Regardless of the immunological mechanism, one-fifth developed lower respiratory tract symptoms during the challenge. In a larger study, 320 subjects (6 months to 30 years of age) with atopic dermatitis and possible food allergy underwent placebo-controlled, blinded food challenges. Food allergy was confirmed in 205 (64%) with one-quarter experiencing lower airway problems during the food challenge.39 These respiratory reactions are typical early-phase responses seen within 2 h of exposure.39 Late-phase asthmatic responses have also been seen after ingestion of a food allergen.45 With a prolonged time interval between ingestion and the onset of asthma, it has been suggested that this form of allergic reaction to food is often misdiagnosed as asthma.46 This group also demonstrated that even when acute asthma symptoms are not seen, there was an increase in airway hyper-responsiveness. For example, when 26 children with asthma and food allergy were assessed before and after placebo-controlled, blinded food challenges, there were 22 positive reactions, 12 of which involved lower respiratory symptoms. Seven of these 12 subjects experienced an increase in hyper-responsiveness despite the minimal decreases in lung function.47 The mechanism of food-induced asthma The mechanism of food-induced asthma is unclear but there are a few possibilities. Firstly, small particles of G. ROBERTS AND G. LACK ingested food may be inhaled into the airway during mastication. Alternatively, food may enter the airway within the context of gastro-oesphageal reflux. In this way, food allergens would be able directly to stimulate airway mast cells inducing a lower airway reaction. Secondly, potentially allergenic proteins may also be able to reach the lungs via the circulation, having been absorbed intact from the gut. A last possibility is that allergenic protein may act indirectly on the lower respiratory tract via inflammatory mediators released from the skin or gastrointestinal tract and circulating in the blood. These mechanisms require further elucidation. RESPIRATORY REACTIONS ASSOCIATED WITH AEROSOLISED FOOD Aerosolised food as a cause of asthma There are many case reports in the literature of bronchial reactions associated with aerosolised food proteins, for example aerosolised fish.48 It would seem that fish protein can become aerosolised though boiling, frying or simply by being exposed to the atmosphere. Thus, Taylor et al. have been able to detect fish allergen using a competitive IgE immunoassay from air samples collected in a fish market.49 It has also been reported that peanuts and tree nuts can become aerosolised within a confined space, causing both mild and severe symptoms in allergic subjects.50 Many airlines have now stopped including nuts within snacks. Lastly, food allergens have been known to behave as more general aeroallergens. For example, in the past, Barcelona has been affected by episodic epidemics of sudden, severe and, in some cases, fatal asthma. Affected individuals showed evidence of specific IgE to soya. Careful investigation concluded that these episodes were related to unloading soya at the port, and were abolished when unloading practices were altered.51 Occupational asthma in the food industry The issue of aerosolised food allergens as precipitants of asthma in childhood has not been examined systematically. There are, however, observations about occupational asthma in adults that have implications for the role of environmental exposure to food allergens in children with asthma. Occupational exposure to aerosolised food can lead to the development of asthma in adult life. An example is baker’s asthma caused by occupational exposure to airborne cereal grain.52 Workers with this problem cough and wheeze only in association with exposure to aerosolised wheat proteins and have positive skin prick or serum specific IgE to wheat proteins. Other examples of occupational asthma are milk powder,53 egg54 or carob bean flour.55 Overall, the food industry accounts for 10% of occupational asthma.56 Data reported by occupational physicians suggest that the annual risk of a baker developing baker’s asthma is approximately FOOD ALLERGY AND ASTHMA 0.3%, which represents a considerable risk over a 30-year career as a baker.56 The pathophysiology of occupational and allergic asthma are very similar. Histologically, an inflammatory eosinophilic infiltrate, oedema and airway smooth muscle hypertrophy are seen in both.57 The possibility of occupational exposure must always be considered in any adult with persistent asthma. Although children do not suffer from occupational exposure to food allergens, they may be exposed to aerosolised food allergens at school and home, particularly in the kitchen. Bronchial challenges with aerosolised foods We investigated a group of 12 children who presented to our clinic over a 2-year period.58 All had proven IgEmediated food allergy in addition to asthma that seemed to worsen on environmental exposure to the food to which they reacted. The implicated foods were fish, milk, chickpeas, buckwheat and eggs. Although the children were practising dietary avoidance, the families continued to cook the foods and the children continued to have symptoms of chronic asthma. Nine subjects consented to a bronchial challenge. Five of these developed an earlyphase response characterised by objective asthmatic signs and lung function changes on bronchial food challenge. The early-phase response is normally associated with specific IgE-mediated release of mediators, such as histamine and tryptase, from mast cells. Two subjects also developed late-phase responses which are known to be related to an influx of inflammatory cells, oedema and increased mucous secretion. When the families of these children stopped cooking the food in the house, there was a considerable reduction in both their child’s symptoms and inhaled steroid requirements. IS THERE A LINK BETWEEN SEVERE ASTHMA AND FOOD ALLERGY? Food allergy as a risk factor for life-threatening asthma In a cohort study of peanut-allergic children, four of the 46 subjects in the cohort died of an exacerbation of asthma over the 2–14-year follow-up period.59 This is a substantially higher fatality rate than one would expect in any high-risk asthmatic population. This suggests that subjects with food allergy may have a greater risk of dying from asthma than from anaphylaxis and that food allergy may be a risk factor for life-threatening asthma. This is an important issue; despite the improvement in therapies for asthma, there continue to be approximately 50 childhood deaths a year in the UK.60 It has been reported that half of adults with brittle asthma report co-existent food allergies.11 This risk factor for lifethreatening asthma in adults has been investigated in a number of studies. In one, Ernst et al. aimed to investigate 209 whether frequent inhaled beta-agonist use was associated with life-threatening asthma. In their study, the second most significant factor associated with life-threatening asthma was a history of asthma attacks being precipitated by food (odds ratio, 5.1; 95% CI, 2.4–11.1).61 We examined this issue in a group of children ventilated for a life-threatening exacerbation of asthma. Using a case–control design, 19 cases were compared with 38 matched controls with milder exacerbations. Subjects and controls were matched for age, gender and ethnicity. Half the cases had persisting food allergy compared with only 10% of the controls. Even after logistic regression analysis for all potential risk factors, food allergy remained a significant factor.62 Asthma as a risk factor for anaphylaxis Asthma also seems to be a key factor associated with poor outcome in children with food allergy. In published series of subjects with fatal anaphylaxis, almost all subjects had asthma.45 Respiratory rather than cardiovascular problems were responsible for the severity of these reactions. The foods responsible for these reactions were tree nuts, peanuts, egg and milk.1,45 The results of these case series have led many paediatric allergists to prescribe a selfinjectable epinephrine device (e.g. EpiPen) to any patient with both asthma and food allergy.1 Explanations for the association between severe asthma and food allergy There are a number of possible explanations for the association between severe asthma and food allergy. The first possibility is that anaphylaxis is misdiagnosed as asthma. This is plausible since food-induced bronchospasm is often seen in anaphylaxis, and there may be a delay between allergen exposure and the development of respiratory symptoms.46 Studies have also documented life-threatening asthma symptoms within an hour of the onset of the exacerbation,63 a short time frame that is consistent with anaphylaxis. In this study, no subject had a history suggestive of anaphylaxis as a cause of the asthma exacerbation. A second explanation for the observed association is that food allergy may be a marker for severe asthma. The persistence of food allergy in this group of children suggests that they may be more atopic than other asthmatics. Lastly, chronic inhalation of aerosolised food may worsen asthma in subjects with food allergy. IS THERE ANY ROLE FOR DIETARY MANIPULATION IN MANAGING ASTHMA? The place of exclusion diet in the management of asthma There seems to be no universal role for a standard exclusion diet in most asthmatics. For example, despite the 210 popular thought that dairy products are associated with increased mucous, exclusion of cows’ milk in adults with asthma has no significant effect on their asthma.64 Additionally, exclusion diets in childhood may compromise a child’s nutrition and therefore growth and development.1 However, there is a rationale for the rigorous and complete removal of any food allergen that has a significant role in a child’s asthma. The removal of such an allergen in subjects with asthma will reduce their chance of experiencing a severe allergic reaction and potentially improve their asthma control.58,65 MANAGING AN ASTHMATIC WITH POSSIBLE CO-EXISTING FOOD ALLERGY A history of unexplained sudden asthma exacerbations suggests that there may be an allergic trigger. Although foods are implicated in only a minority of cases of childhood asthma, a high index of suspicion must be maintained as elimination of a significant allergen can lead to a rapid improvement in symptoms. A careful history will usually point to the presence of food allergy in a child with asthma. Detailed questioning may be required where patients are avoiding a food to decide whether this represents allergy or is due to cultural or psychological reasons. It is important though that such a suspicion should be supported by objective evidence given the high rate of false-positive diagnoses based on history alone.1 The use of skin-prick testing, serum specific IgE or food challenges are recommended. Also, it must be kept in mind that there are many potential precipitants of asthma that can confound any potential relationship between a food allergen and asthma symptoms. Other diagnoses should also be considered; examples are gastro-oeosphageal reflux, vocal cord dysfunction and exercise-induced anaphylaxis.66 Once food allergy is confirmed, careful questioning is required to determine whether continued hidden food exposure is responsible for a subject’s continued exacerbations. The help of a dietician is invaluable in these circumstances. CONCLUSIONS Food allergy may be an important factor only in a minority of children with asthma. However, for these children, it is important to identify the problem and take steps to avoid direct and indirect exposure. This may lead to a significant improvement in their asthma control. Furthermore, this important minority may represent the more severe end of the disease spectrum. Food allergy has been implicated as a risk factor for life-threatening asthma and asthma also seems to be a risk factor for life-threatening food allergy. These are further reasons why coexisting asthma and food allergy should be identified and managed effectively. G. ROBERTS AND G. LACK PRACTICE POINTS Generalised dietary exclusions do not have a proven role in the majority of childhood asthma. Foods should be considered as potential precipitants of asthma when exacerbations are sudden in onset, particularly when the child has a known food allergy. Removal of environmental food allergens may lead to improvement in asthma control in selected children. Food allergy is a risk factor for severe asthma. Asthma is a risk factor for life-threatening food allergy. RESEARCH DIRECTIONS Clarification of the role of food allergens in lifethreatening asthma. Definition of the mechanism by which food allergens induce asthma. Clarification of the significance of diet in asthma. REFERENCES 1. Sicherer SH. Food allergy. Lancet 2002; 360: 701–710. 2. Hourihane JO, Roberts SA, Warner JO. Resolution of peanut allergy: case–control study. 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