Introduction

An update on food allergy
Introduction
Adverse reaction to food is a frequent clinical complaint, yet the subject of food allergy is one of the most misunderstood in clinical medicine. The wide array of symptoms ascribed to food ‘allergies’ often seem confusing to the clinician, and diagnostic tests are usually not easily available to non-specialists. This review will address the common clinical problems associated with food allergies, the approaches to establishing a diagnosis, and the available treatment strategies. Adverse reactions to food can present in many different ways. In order to make a correct diagnosis, some form of categorisation is necessary. The European Academy of Allergy and Clinical Immunology proposed a classification of adverse food reactions based on mechanism1. These reactions can be either toxic or non-toxic; toxic food reactions can occur in anyone, whereas non-toxic reactions require individual susceptibility and may or may not be immunologically-mediated. An example of toxic reactions is scombroid fish poisoning where bacteria in poorly preserved fish break down the amino acid histadine in muscles into histamine. The symptoms of this reaction are very similar to an IgE-mediated allergic reaction, but may occur in anyone provided a sufficient quantity of histamine is ingested. Food intolerances are non-immunologically mediated food reactions that occur in susceptible individuals. This may include flushing after alcohol, migraine headaches after ingesting tyramine-rich foods, arrhythmias after ingesting caffeine, and the Chinese restaurant syndrome after ingesting monosodium glutamate (MSG). The term food allergy should be confined to those clinical syndromes caused by immunological reactions to food proteins or chemicals. A substantial proportion of food allergic reactions are caused by immunoglobulin E (IgE) directed against food proteins. Such reactions are usually immediate, and may lead to GI symptoms, urticaria, angioedema, hypotension and frank anaphylaxis. Other reactions caused by IgA (coeliac disease) or cell-mediated immunity may also occur. The rest of this article will focus on immunologically-mediated food reactions. There is very little published data on food allergies in Southeast Asia. A prospective study of American children followed for the first three years of life revealed that 28% of parents reported food allergy in their children, but only 8% could be confirmed by challenge tests2. 2.5% of infants experience cow’s milk allergy in the first year of life3-5. 1.3% of young children are allergic to egg6, and 0.5% of them are allergic to peanut7,8. Surveys from the UK indicated that 1.4% to 1.8% of adults experience adverse food reactions9, and similar surveys from the Netherlands indicated a 2% adult prevalence10. In general, people with a strong personal or family history of atopic diseases such as asthma and atopic dermatitis have a significantly higher risk of developing food allergies. Experience from our allergy clinic in Hong Kong suggests that the pattern of food allergy may be different from the West. Whereas cow’s milk, egg, wheat, peanut, tree nuts, soy and fish constitute the majority of allergenic foods in the west, we see many more cases of shellfish allergies. Other more exotic foods rarely seen in the west, such as Chinese medicinal herbs, royal jelly11, limpets and fish sauce also cause a substantial number of allergies. Peanut allergy, though less common, is also seen in Chinese patients in Hong Kong and can be equally lethal. Gastrointestinal manifestations of food allergy
Since the GI tract is the first site to come into contact with food allergens, GI symptoms are frequent in patients with food allergy. IgE-mediated reactions that cause nausea, vomiting, abdominal pain and diarrhoea may occur sometimes within minutes of ingestion. Repeated ingestion of allergenic foods may lead to poor appetite, intermittent abdominal pain and malabsorption. Direct contact of allergenic food with the oral mucosa causing itching and swelling of the lips, tongue, palate and throat is called the oral allergy syndrome. This is usually caused by fresh fruits and vegetables, and patients with pollen allergy are especially susceptible. This is because there is substantial cross-reactivity in allergens found in ragweed pollen, melons and bananas12,13. There is also cross-reactivity between allergens found in birch pollen and apples, potatoes. hazelnut, celery, carrots and kiwi14,15. Since these allergens are heat labile, patients can usually eat these foods without symptoms if they are cooked. By the same token, it is best to use fresh food extracts for skin testing in this Aside from IgE-mediated reactions, food allergies may cause other forms of GI pathologies. Eosinophilic oesophagitis or gastroenteritis is sometimes seen in infants with cow’s milk allergy. Symptoms include gastroesophageal reflux16, vomiting, abdominal pain, failure to thrive, hypoalbuminaemia, haematamesis and intestinal obstruction17. Other food proteins may cause similar symptoms in older children. Elimination of the offending foods will lead to resolution of symptoms in 3 to 8 Food proteins can also induce enteropathy in children; while cow’s milk is most frequently implicated, soy, egg, chicken, rice and fish have also been reported. There is overlap between food protein enteropathy and celiac disease, with small bowel injury being a prominent feature19. Affected infants usually present gradually with malabsorption, and cow’s milk intolerance also predisposes to soy protein enteropathy. As soy protein is equally allergenic, hydrolysed formula should be used in cow’s milk allergic infants. After the age of 1 year, cow’s milk can be re-introduced gradually. Gluten-sensitive enteropathy or celiac disease appears to be rare in Chinese. Food-induced enterocolitis has a more acute and severe presentation, and can start within the first few days of life. Affected infants develop protracted bloody diarrhoea, vomiting and dehydration. Small bowel injury leads to anaemia, hypoproteinaemia, malabsorption and failure to thrive. An extensively hydrolysed formula should be Cutaneous manifestations of food allergy
IgE-mediated reactions to food often present as urticaria and angioedema. Onset of symptoms is rapid, sometimes within minutes of ingestion, and usually last for less than 24 hours. Patients are usually able to identify and avoid the offending foods. Food allergy is rarely a cause of chronic urticaria,20 although salicylates and food additives have been implicated. Food allergy as a factor in the development of atopic dermatitis (AD) is still a matter of debate especially amongst dermatologists. In a recent study, 37% of children with moderate to severe AD were found to be allergic to food by serum IgE tests and food challenge21. In a study of 55 children with severe AD and egg allergy, those children randomised to an egg elimination diet improved significantly compared to those children undergoing conventional treatment alone22. The good news is, one-third of children with AD and food allergies “outgrow” their allergies over 1 to 3 years23, with the exception of peanut, nuts, fish and shellfish allergies. It is therefore pertinent that all children with moderate to severe AD should be tested for food allergies, and if present, dietary advice should be given. A two to three week elimination diet followed by gradual reintroduction of suspected foods one by one while keeping a symptom diary is often sufficient for diagnosis. In some severe cases, a trial of an elemental (antigen-free) diet may be warranted. Elemental formulas from Alpha Nutrition, Vivonex or Neocate would be appropriate for this Respiratory tract manifestations of food allergy
Respiratory symptoms are common in patients who develop food-induced anaphylaxis, and are invariably present in fatal or near-fatal cases. Patients with a history of asthma or a history of previous severe reactions are especially susceptible to severe anaphylaxis. Food allergy is a rarely a factor in allergic rhinitis; a survey of 323 patients with chronic rhinitis revealed that only 2 patients had nasal symptoms during blinded food challenges24. Most cases of food-induced asthma occur in early infancy in relation to cow’s milk allergy. Estimates of asthma prevalence in milk- allergic infants vary from 7% to 29% depending on the definition of milk allergy. A study of 88 children with AD and asthma revealed that 15% wheezed during food challenge, and 8% demonstrated a greater than 20% drop in FEV 25 induced respiratory symptoms appear to be rare in patients without AD. There have been anecdotal reports of asthma caused by food additives such as the yellow dye tartrazine, monosodium glutamate (MSG) and sulphites. Sulphite-induced asthma is well recognised, and can cause severe or even fatal reactions. Sulphites are found in dried fruit and wine, and are sometimes used as antioxidants in salads and potato fries. Intense bronchospasm may occur within minutes of ingestion in susceptible individuals. It has been estimated that 5% of asthmatics are sensitive to sulphites26. Data on other additives are less clear-cut. In one study, 11 out of 277 (4%) asthmatics challenged with tartrazine experienced a significant response27. In another study, only one out of 28 patients with possible food-additive asthma reacted to tartrazine28. In another recent study, 100 asthmatics including 30 with a history suggestive of MSG sensitivity were challenged with MSG and no significant response was seen29. MSG is widely used in restaurants in Hong Kong, and we rarely encounter patients with a history of MSG-induced asthma. Such complaints seem to be more prevalent in western countries, where MSG use is not as widespread. Systemic manifestations to food allergies
Systemic anaphylaxis is the most dangerous of all allergic reactions, and food allergy is the most common cause of anaphylaxis30. Any food protein can theoretically cause anaphylaxis but certain foods are more likely. These include peanut, tree nuts, fish, shellfish, cow’s milk, egg, seeds, beans, fruits and cereals. Reactions invariably occur within 60 minutes and may include urticaria, angioedema, bronchospasm, hypotension, laryngeal oedema, abdominal pain, emesis and diarrhoea. Severe reactions will lead to asphyxia, vascular collapse, cardiac arrhythmia or myocardial infarction. The quantity of food required to induce a reaction is dependent on patient sensitivity, potency of the food allergen and other unknown factors. Some food such as peanut and fish may invoke a fatal reaction in microgram amounts. It is well known that some patients react to plain M&Ms because these were produced in vats that previously contained peanut M&Ms. Peanuts are now banned on domestic flights in the US because some patients developed reactions when neighbouring passengers opened their packets of peanuts. One of my paediatric patients develops bronchospasm whenever his neighbour fries fish next door. The sensitivity of individual patients may change with time. Some patients might have tolerated a certain amount of a particular food without significant ill effects in the past, but nevertheless developed a severe reaction when they tried to ingest a similar amount One interesting form of anaphylaxis is the food-associated exercise-induced anaphylaxis. These patients develop anaphylaxis if they exercise within 2 to 4 hours of ingesting a food that they are allergic to. However, ingesting the same food without exercise will not elicit a reaction. Most of these patients will have a positive skin test reaction to that particular food. There are also some patients who would develop anaphylaxis if they exercise after eating; this may be a form of exerice- induced anaphylaxis, and not a food allergy. I have also seen a patient who develops anaphylaxis if she eats a certain food after exercising. Diagnosis and management of food allergies
The history is the most important tool in the diagnosis of food allergy, yet it is frequently inaccurate and only about 40% of such histories can be verified by food challenges31. Important points to note in the history include the nature of the reaction, the foods ingested at the time, the timing of the reaction relative to food ingestion, repeatability and frequency of the reaction, and other exacerbating factors such as exercise. Knowledge of the pattern of food allergy in the community is also helpful in discerning the likely culprit. One must also bear in mind the “hidden allergens”, especially in processed food. The Chinese diet is incredibly varied, and it is often extremely difficult, if not impossible, to uncover all the food allergens present during a restaurant meal. Persistent food-allergic symptoms without a clear pattern suggest reactions to additives or spices. A food diary is often a helpful tool in revealing these hidden allergens. If an IgE-mediated food allergy is suspected, skin prick tests (SPT) are useful in screening for likely culprits. One must bear in mind that SPT have a low positive predictive value (hence high false-positive rate) but a high negative predictive value. Treatment based solely on positive SPT results would subject patients to unnecessary food avoidance, but negative SPT will almost completely exclude food allergies. Sources of false negative reactions include the intake of anti- histamines prior to testing, and the use of commercial extracts for labile allergens such as some fruits and vegetables32; under these circumstances, fresh food extracts should be used. Children under the age of two may also lack skin reactivity33. For patients who are on anti-histamines, have significant skin pathologies that preclude the use of skin tests, or if there are a limited number of suspicious culprits, measurement of serum food-specific IgE by the radioallergosorbent test (RAST) or the Pharmacia CAP test is warranted. A recent study of children with AD showed that quantitation of food-specific IgE improved the positive predictive value of SPT34. When a list of possible candidate food allergens can be established, a diagnostic elimination diet is helpful in supporting the diagnosis. There should be significant improvement in symptoms if the offending allergens are eliminated. After two weeks of allergen elimination, food challenge should be carried out. In cases where there is a risk of severe anaphylaxis, or if the history is strongly supported by SPT results, food challenge can be omitted. Food challenges can be done open, single-blind or double-blind. Double-blind, placebo-controlled food challenge (DBPCFC) is the gold standard for the diagnosis of food allergies and should be used if several foods are suspected, or when patient perception may significantly influence symptom assessment. The time to reaction depends on the type of reaction expected; it may take several minutes for an IgE-mediated reaction to occur, but up to 3 days for some Elimination of allergenic foods is the only effective treatment for food allergies. Patient education is extremely important, especially in identifying hidden allergens. All patients at risk of anaphylaxis must carry injectible epinephrine. The dose of epinephrine is 0.3mg for adults, and 0.15mg for children to be given intramuscularly. If several foods are involved, the help of a dietician is invaluable in designing a diet that will prevent malnutrition. In general, most children grow out of their food allergies after several years, with the exception of peanut, nuts and shellfish allergies. A prospective study of milk allergy in infants showed that 85% of the children lost their milk allergy by three years of age35. In older children and adults, a substantial proportion will lose their clinical sensitivity to a food after one to two years of complete allergen elimination, again with the exception of peanut, nuts and shellfish allergies. Skin test sensitivity tends to remain, however. Allergies can be prevented or delayed by dietary control during the first few years of life, and is a worthwhile endeavour in patients with a strong family history of atopy. The use of whey-hydrolysate for infant feeding is associated with a reduction in the risk of asthma and AD during the first five years of life36. A 17-year prospective study on breastfeeding concluded that prolonged breastfeeding (>6 months) is associated with a significant and long-lasting reduction in the risk and severity of atopic diseases including AD, food allergies and respiratory allergies37. Infants with cow’s milk allergy have an increased risk of developing allergies to other foods. They are also at risk of developing other allergies and asthma later on in life. Highly allergenic foods such as peanut, nuts, fish and shellfish should therefore be avoided in such patients until at least their third birthday. Conclusion
In this review, we have summarised briefly the major clinical syndromes associated with food allergies, including the various enteropathies, atopic dermatitis, asthma and anaphylaxis. A rational approach to the diagnosis of food allergy is outlined, in order to avoid unnecessary food avoidances, psychological trauma, and disruption in the patient’s lifestyle. The treatment of food allergy is avoidance, but this can be difficult especially in teenagers where peer pressure and the urge to conform is strong. Work on immunotherapy with mutated allergens and peptide epitope vaccines is underway and may become a viable treatment alternative in the future. Proper dietary management during the early years of life is effective in reducing the risk of allergic diseases in high-risk individuals, and should be practised whenever possible. Table 1. Possible symptoms of cow’s milk allergy in infants
Table 2. Common allergenic foods
Cow’s milk
Fig. 1 Diagnosis of food allergies in children with atopic dermatitis.
Skin prick tests +/- patch skin tests with food extracts. suspected, keep food diary and re-evaluate. Symptoms recur. Diagnosis confirmed. Eliminate allergenic foods for 1 – 2 years. References
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Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 13. Anderson L, Dreyfuss E, Logan J, et al. Melon and banana sensitivity coincident with ragweed pollinosis. J Allergy Clin Immunol 1970;45:310 14. Andersen K, Lowenstein H. An investigation of the possible immunological relationship between allergen extracts from birch pollen, hazelnut, potato, and 15. Dreborg S, Foucard T. Allergy to apple, carrot, and potato in children with birch- 16. Iacono G, Carroccio A, Cavataio F, et al. Gastroesophageal reflux and cow’s milk allergy in infants: a prospective study. J Allergy Clin Immunol 1996;97:822-7. 17. Snyder JD, Rosenblum N, Wershil B, Goldman M, Winter HS. Pyloric stenosis and eosinophilic gastroenteritis in infants. J Pediatr Gastroenterol 1987;6:543-7. 18. Kelly KJ, Lazenby AJ, Rowe PC, Yardley JH, Perman JA, Sampson HA. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino-acid based formula. Gastroenterology 1995;109:1503-12. 19. Kuitunen P, Visakorpi JK, Savilahti E, Pelkonen P. Malabsorption syndrome with cow’s milk intolerance: clinical findings and course in 54 cases. Arch Dis Child 20. Volonakis M, Katsarou-Katsari A, Stratigos J. Etiologic factors in childhood chronic urticaria. Ann Allergy 1992;69:61-5. 21. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BD, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. 22. Lever R, MacDonald C, Waugh P, Aitchison T. Randomized controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs. Pediatr Allergy Immunol 1998;9:13-9. 23. Sampson HA, Scanlon S. Natural history of food hypersensitivity in children with atopic dermatitis. J Pediatr 1989;115:23-7. 24. Simpson S, Somerfield S, Wilson J, Hillas J. A double-blind study for the diagnosis of cows’ milk allergy. N Zealand Med J 1980;92:457-9. 25. James JM, Eigenmann PA, Eggleston PA, Sampson HA. Airway reactivity changes in food-allergic, asthmatic children undergoing double-blind placebo- controlled food challenges. Am J Respir Crit Care Med 1996;153:597-603. 26. Bush RK, Taylor SL, Holden K, Nordlee JA, Busse WW. Prevalence of sensitivity to sulfiting agents in asthmatic patients. Am J Med. 1986;81:816-20. 27. Spector SL, Wangaard CH, Farr RS. Aspirin and concomitant idiosyncrasies in adult asthmatic patients. J Allergy Clin Immunol 1979;64:500-6 28. Tarlo SM, Broder I. Tartrazine and benzoate challenge and dietary avoidance in chronic asthma. Clin Allergy 1982;12:303-12. 29. Woessner KM, Simon RA, Stevenson DD. Monosodium glutamate sensitivity in asthma. J Allergy Clin Immunol 1999;104:305-10 30. Yocum MW, Khan DA. Assessment of patients who have experienced anaphylaxis: a 3-year survey. Mayo Clin Proc 1994;69:16-23. 31. Bock SA, Atkins FM. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges. J Pediatr 1990;117:561-7. 32. Ortolani C, Ispano M, Pastorello EA, Ansaloni R, Magri GC. Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 33. Menardo J, Bousquet J, Rodiere M, et al. Skin test reactivity in infancy. J Allergy 34. Sampson H, Ho D. Relationship between food-specific IgE concentration and the risk of positive food challenges in children and adolescents. J Allergy Clin 35. Host A. Cow’s milk protein allergy and intolerance in infancy. Pediatr Allergy 36. Chandra RK. Five-year follow-up of high-risk infants with family history of allergy who were exclusively breast-fed or fed partial whey hydrolysate, soy, and conventional cow's milk formulas. J Pediatr Gastroenterol Nutr. 1997;24:380-8. 37. Saarinen UM, Kajosaari M. Breastfeeding as prophylaxis against atopic disease: prospective follow-up study until 17 years old Lancet. 1995;346:1065-9. Further reading
1. Sampson HA. Food allergy. Part 1: Immunopathogenesis and clinical disorders. J Allergy Clin Immunol 1999;103:717-28. 2. Sampson HA. Food allergy. Part 2: Diagnosis and management. J Allergy 3. Metcalfe DD, Sampson HA, Simon RA. Food allergy: Adverse reactions to foods and food additives. Oxford; Blackwell Science, 1997.

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