study of nutritional factors in food allergies and food intolerance
DESCRIPTION
Study of Nutritional Factors in Food Allergies and Food IntoleranceTRANSCRIPT
ISSN 1018-5593
E U R O P E A N C O M M I S S I O N
Studies
Study of
nutritional factors
in food allergies and
food intolerances
Agro-industrial Research Division
EUR 16893 EN
European Commission
Study of nutritional factors in food allergies and food
intolerances In the framework of the agriculture and agro-industry
including fisheries programme, adopted by the Council of Ministers of the European Communities
Contractor
Prof. Claudio Ortolani Head of Department for Prevention,
Diagnosis and Treatment of Allergic Disease, Niguarda Hospital,
Milan, Italy.
Responsible for the study
Prof. Elide Anna Pastorello Associate Professor of Allergy and Clinical Immunology,
University of Milan-Policlinico Hospital, Milan, Italy.
Collaborators
Dr Raffaella Ansaloni Dr Cristoforo Incorvaia
Dr Marco Ispano Dr Valerio Pravettoni Dr Federica Rotondo
Dr Joseph Scibilia Dr Giuseppe Vighi
AIR1-93-8012-IT
Directorate-General XII Science, Research and Development
1997 EUR 16893 EN
Published by the EUROPEAN COMMISSION
Directorate-General XII Science, Research and Development
B-1049 Brussels
LEGAL NOTICE
Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use which might be made of the
following information
Cataloguing data can be found at the end of this publication
A great deal of additional information on the European Union is available on the Internet. It can be accessed through the Europa server (http://europa.eu.int).
Luxembourg: Office for Official Publications of the European Communities, 1997
ISBN 92-827-9554-3
© ECSC-EC-EAEC, Brussels · Luxembourg, 1997 Reproduction is authorized, except for commercial purposes, provided the source is acknowledged
Printed in Italy
Abbreviations AD AGA ARF ASA BHA BSA BIHT CAMP CD CIE CUE CNS CRIE DBPCFC DNCB EAACI eHF EIA ELISA FDA FEV1 GALT G6PD HR kd IBS IEL MAO MHC MSG MW NSAID OAS OME OSA OVA PCB PGE pHF PMN RIA SDS-PAGE SPT TCR
Atopic dermatitis Antigliadin antibodies Adverse reactions to food Acetylsalicilic acid Butylated hydroxyanisole Bovine serum albumine Butylated hydroxytoluene Cyclic adenosine monophosphate Celiac disease Crossed Immunoelectrophoresis Crossed line Immunoelectrophoresis Central nervous system Crossed radio-immunoelectrophoresis Double-blind placebo-controlled food challenges Dinitro chlorobenzene European Academy of Allergology and Immunology Extensively hydrolyzed formulae Exercise induced anaphylaxis Enzyme linked immuno sorbent assay Food and Drugs Administration Forced expiratory volume at 1st second Gut associated lymphoid tissue Glucose-6-phospho-deidrogenase Histamine release (test) Kilo Dalton Irritable bowel syndrome Intra epithelial lymphocytes Monoamine oxidase Major histocompatibility complex Monosodium glutamate Molecular weight Non-steroidal anti-inflammatory drugs Oral allergy syndrome Otitis media with effusion Ovine serum albumine Ovalbumine Parachlorobenzene Prostaglandine Partly hydrolyzed formulae Polimorphonuclear cells Radio-immunoassay Sodium dodecyl sulfate-polyacrilamide gel electrophoresis Skin prick tests Τ cell receptor
INDEX
SUMMARY 11
CLASSIFICATION AND TERMINOLOGY OF ADVERSE REACTIONS TO FOOD 15
1.1.
1.2.
Toxic food reactions
Non-toxic food reactions
1.2.1. IgE-mediated reactions
1.2.2. Non-lgE-mediated food allergy
16
16
16
16
GENERAL OUTLINE OF THE ROLE OF FOOD COVERING THE DIFFERENT HYPOTHESES 18
2.1.
2.2.
Toxic reactions
Non-toxic reactions
2.2.1. Immunological reactions (food allergy)
2.2.1.1. IgE-mediated food allergy
2.2.1.2. Non-lgE-mediated food allergy
2.2.2. Non-immune mediated adverse reactions to foods
2.2.2.1. Enzymatic food intolerance
2.2.2.2. Pharmacological food intolerance
2.2.2.3. Additive intolerance
18
19
19
19
20
21
21
21
22
3. SYMPTOMS OF FOOD ALLERGY AND FOOD INTOLERANCE 26
3.1.
3.2.
Oral allergy syndrome (OAS)
Extra oral symptoms
3.2.1. Rhinoconjunctivitis
3.2.2. Serous otitis media with effusion
3.2.3. Asthma
3.2.4. Urticaria and angioedema
26
28
28
28
29
29
3.2.5. Atopie dermatitis (AD) 30
3.2.6. Acute contact urticaria and angioedema 31
3.2.7. Systemic anaphylaxis 31
3.2.8. Exercise induced anaphylaxis (EIA) 33
3.2.9. Gastrointestinal hypersensitivity reactions to food 33
3.2.9.1. Gastrointestinal anaphylaxis 34
3.2.9.2. Infantile colics 34
3.2.9.3. Allergic eosinophilic gastroenteropathy 34
3.2.9.4. Food-induced enterocolitis syndrome 35
3.2.9.5. Food-induced colitis 35
3.2.9.6. Food-induced malabsorption syndrome 35
3.2.9.7. Lactose intolerance 35
3.2.9.8. Dermatitis herpetiformis 36
3.2.9.9. Celiac disease (CD) 36
3.2.9.10. Heiner's syndrome or food-induced pulmonary hemosiderosis 37
4. PATHOGENESIS OF FOOD ALLERGY 46
4.1.
4.2.
4.3.
4.4.
Introduction
Oral tolerance
Immaturity of the immune system
Role of allergens
46
46
50
51
FOOD ALLERGENS 58
5.1.
5.2.
Introduction
Allergens
5.2.1. Cow's milk
5.2.2. Hen's egg
5.2.3. Fish
58
59
59
59
61
5.2.4.
5.2.5.
5.2.6.
5.2.7.
5.2.8.
5.2.9.
5.2.10
Shrimp
Peanut
Soybean
Cereals
Apple
Celery
Prunoideae
62
62
63
63
64
65
65
6. PREVENTION OF FOOD ALLERGY 72
6.1.
6.2.
6.3.
6.4.
Introduction
Known risk factors for developing food allergy
Possible interventions aimed at preventing food allergy
6.3.1. Comparison between breast-feeding and cow's milk feeding
6.3.2. Comparison between soya feeding and cow's milk feeding
6.3.3. Comparison between hydrolyzed cow's milk formulae and other kinds of feeding
Conclusions
72
72
73
75
75
76
76
INTERACTION WITH LIFESTYLE AND PROFESSION 83
7.1.
7.2.
Interactions with lifestyle
Interactions with profession
7.2.1.
7.2.2.
7.2.3.
7.2.4.
7.2.5.
7.2.6.
7.2.7.
7.2.8.
Cereal flour
Hen's egg
Cow's milk
Seafoods
Legumes
Coffee
Garlic
Onion
83
84
84
85
86
86
86
87
87
87
7.2.9. Sesame seed 87
7.2.10. Others 87
7.3. Prophylactic measures 88
8. EPIDEMIOLOGY OF FOOD ALLERGY 93
8.1.
8.2.
8.3.
8.4.
Introduction
Epidemiology in adults
Epidemiology in children
Conclusions
93
93
94
95
CHANGING DIETARY HABITS 97
10. EFFECTS OF PROCESSING AND PREPARATION OF FOOD 104
10.1. Food allergens alteration by food processing and preparation
10.1.1.
10.1.2.
10.1.3.
10.1.4.
10.1.5.
10.1.6.
10.1.7.
10.1.8.
10.1.9.
10.1.10.
10.1.11.
10.1.12.
10.1.13.
10.1.14.
Fruit and vegetables
Cow's milk
Fish
Meat
Hen's egg
Shrimp
Microparticulated proteins
Peanut
Soybean
Corn
Sunflower oil
Sesame seed oil
Lupin seed
Food contaminants
104
105
105
106
107
107
108
108
109
110
110
110
111
111
111
10.2.
10.3.
10.4.
Food contaminants
Food additives
10.3.1.
10.3.2.
10.3.3.
10.3.4.
10.3.5.
10.3.6.
10.3.7.
10.3.8.
10.3.9.
10.3.10.
10.3.11.
Hidden
Preservatives
10.3.1.1. Benzoates and parabens
Antioxidants
Sorbic acid
Gallates
Tocopherols
Sulfiting agents
Colourants
Monosodium glutamate
Other additives and spices
Controversy in food additive intolerance
Diagnosis of food additive intolerance
allergens
114
117
119
119
120
121
121
121
121
123
125
126
126
127
136
11. DIAGNOSIS OF FOOD ALLERGY 140
11.1.
11.2.
11.3.
11.4.
11.5.
11.6.
Introduction
Clinical history
Elimination diets
Skin tests
In vitro tests
Double-blind placebo-controlled food challenge (DBPCFC)
140
140
141
142
144
144
12. CONTROVERSY ON ADVERSE REACTIONS TO FOOD 150
12.1. Non-validated methods 150
12.1.1. Cytoxicity test 150
12.1.2. Subcutaneous and sublingual provocation and neutralization 151
12.1.3. DRÍA test 152
12.2.
12.3.
12.4.
12.1.4.
12.1.5.
Electroacupuncture
Applied kinesiology
Inappropriate diagnostic tests
12.2.1.
12.2.2.
Serum IgG antibodies
Food immune complex assay
Clinical manifestations non-typical of food allergy
12.3.1.
12.3.2.
12.3.3.
12.3.4.
12.3.5.
12.3.6.
12.3.7.
12.3.8.
12.3.9.
Headache
Children's hyperactivity
Schizophrenia
Other neurologic and psychic disorders
Arthritis
Vasculitis
Irritable bowel syndrome
Otitis media with effusion
Allergy to twentieth century
Conclusions
152
153
153
153
153
154
154
155
156
157
158
158
159
159
159
160
13. POSITIVE APPROACHES 166
13.1. Hypoallergenic formulas 166
13.2. Non-allergenic food 171
13.3. Specific immunotherapy in food allergy 180
14. IMPORTANCE OF FOOD HYPERSENSITIVITY IN PUBLIC HEALTH, ECONOMIC EFFECTS, GROUPS AT RISK 183
14.1. The public health role 183
14.2. Groupsat risk 187
15. CONCLUDING REMARKS 194
10
SUMMARY
The recent Position Paper of the European Academy and Clinical Immunology Subcommittee on Adverse Reaction to Food (ARF) divided the ARF into toxic and non-toxic.
The latter are subdivided in immunomediated (in clinical practice represented quite exclusively by the IgE-mediated reactions) and non-immunemediated (enzymatic, pharmacologic and undefined intolerances).
Toxic reaction to food affects all human beings exposed. The major sources of toxicity of foodstuffs are the toxic substances induced in food processing, contaminants and additives.
IgE-mediated food allergy is the most frequent, the best known and the easiest to be diagnosed of the ARF. However the diagnosis of IgE-mediated food allergy must be made only when the relationship between the ingestion of a particular food and the symptoms is well established.
An evident role in clinical food allergy of non-lgE-mediated food allergy (i.e. IgG responses to foods, immune complexes with food allergens, cell mediated immunity to food), at the moment has not yet been demonstrated, and this topic maintains only theoretical importance.
Enzymatic food intolerances, except for lactase deficiency, are rare conditions, mainly due to inborn errors of metabolism. The pharmacological food intolerance includes: (1) the effects of vasoactive amine contained in some fruits; (2) the effects of mediator released by non-immunolo-gic mechanism and (3) the intolerances to food additives.
The symptoms of food allergy involve different organs. Oral allergy syndrome is frequent among patients with pollen allergy and it is provoked by sensitization to plant food allergens. This syndrome is frequently associated with birch or mugwort pollinosis. Rhinoconjunctivitis, asthma and otitis media with effusion are rarely due to food allergy. Acute orticaria/angioedema and atopic dermatitis frequently depend from food allergy.
Many foods have been reported to provoke fatal food-induced anaphylaxis: i.e. milk, egg, peanut, seafood, nut, legumes, spices and fruits. Hidden foods have been demonstrated to be frequently responsible for anaphylactic fatalities. Exercise-induced anaphylaxis may be related to a food allergy. In these patients the ingestion of the culprit food without exercise does not provoke symptoms.
Food allergy may provoke gastrointestinal reactions: gastrointestinal anaphylaxis is common in adults. In infancy, food intolerance may provoke some rare gastrointestinal syndromes, i.e. infantile colics, food-induced enterocolitis syndrome, food-induced colitis, food-induced malabsorption syndrome and food-induced hemosiderosis. Celiac disease and dermatitis herpetiformis are both gluten-related entero- and cutaneous-pathies in which a non-lgE mediated immune mechanism is probably involved. Allergic eosinophilic gastroenteropathy is a rare entity but only in some documented cases it is due to an IgE-mediated allergy. Lactose intolerance is a common disease due to acquired defect of intestinal lactase, more rarely the disease is dependent from an inborn lactase deficiency.
11
It is controversial whether clinical manifestations different from those listed above could be due to
one food allergy. Medical knowledge and clinical studies provided by the literature do not justify
the emphasis of some investigators and of the media in claiming the link between food allergy and
unusual symptoms. Among atypical complaints migraine is the most suitable for a relationship
with food intake. However the basic mechanism of the presumed foodadverse reaction is
unknown and a true food allergy is unlikely.
Among the immunologically mediated reactions to foods, IgEmediated food allergy is the most
exhaustively investigated regarding the pathogenesis. An important role in development of food
allergy is played by the break of oral tolerance, an immunologic mechanism mainly supported by
Tsuppressor lymphocytes leading to a systemic hyporesponsiveness but local IgA hyperrespon
siveness to antigens ingested in early infancy. Thus, immaturity of the immune system might
account for the higher prevalence of food allergy in children than in adults. Also the characteris
tics of some allergens, such as an enzymatic activity or the resistance to digestion, especially
occurring with sequential allergens, may be important in determining food sensitization. In
addition, recent studies showed that sensitization to crossreacting allergens present in food and
inhalant source may underlie the development of food allergy.
Compared with the vast number of aeroallergens as yet identified, only a few food allergens are
known, mainly because of the difficulty to recruit sufficient patients with positive IgE test and
DBPCFC and to perform the laboratory technique for detecting allergens. So far, food allergens
have been identified in cow's milk (alactoalbumin, ßlactoglobulin, caseins), in hen egg (ovomu
coid, ovalbumin, ovotransferrin in egg white, livetin in egg yolk), in fish (Gad c 1), in shrimp (Pen a
1, Pen a 2), in peanut (Ara h 1, Ara h 2), in soybean (Gly m 1), in cereals (a series of proteins with
m.w. from 26 to 79 kd as yet not named), in apple (Mal d 1), in celery (Api g 1), in fruits belonging
to prunoideae (an allergen of 13 kd proposed as Pru ρ 1).
Because of the importance of psychological factors in food allergy, great differences are observed
between the 'selfperception', accounting for 1520% of suspected allergy in the general popula
tion and the real prevalence of food allergy as established by DBPCFC. Recent studies reported
that the prevalence of true food allergy in adults was 1.41.8% in the United Kingdom, and about
1% in the Netherlands. In children a prevalence as high as 8% was reported, with major
importance for sensitization to cow's milk. As cow's milk allergy tends to outgrow with age, the
findings on children and adults seem to be consistent.
The diagnosis of food allergy should be based on clinical history and results of in vivo and in vitro
tests, but a number of factors make their value questionable. In fact, clinical history is biased by
the high 'selfperception' of food allergy, and skin tests and in vitro test have the drawback of
unsatisfactory sensitivity and specificity due to the lack of standardized food allergen extracts.
Thus, the 'gold standard' of diagnosis is the doubleblind placebocontrolled food challenge
(DBPCFC), the only test assessing the patient's reactivity to a suspected food in conditions free
from patient's and physician's subjective influences.
Epidemiological data on food allergy are few and incomplete, and there are no figures on the
changing prevalence of allergic reactions for each individual food. Particularly, there are no
studies on how food allergy has changed with respect to the changes in dietary habits. However
an increased risk for food allergy should be expected for several reason: (1) An increasing use of
12
domestic items within the household (e.g. freezer, microwave oven, frying devices, etc.); these items inevitably lead to the increased consumption of prepackaged food products, particularly frozen products and baked goods; (2) changes in life styles and work schedules facilitate the consumption of meals outside the household (e.g. fast-food restaurants, snack bars, etc.); (3) the increased distribution and availability of widespread food goods has reduced the boundaries of regional cooking habits and introduced new food products; (4) the food industry's expanding market of products that are processed and handled òn an industrial scale.
Methods that are not shown to be effective and safe by proper clinical trials should be considered 'unproven methods' or 'non-validated methods'. Non-validated methods are not recommended in clinical practice, because the literature does not provide convincing data on the reliability of these methods and, in some cases, well-conducted studies do not show any difference between the investigated method and the placebo. The most commonly employed non-validated methods are discussed in Chapter 12.
The only preventive measure able to interfere with development of food allergy is to postpone as much as possible the introduction into the child's diet of foods containing known allergens, such as cow's milk, egg, fish, and others. This is mainly done by prolonged breast-feeding; the preventive effect is improved by eliminating these foods from the mother's diet. Because of the difficulty to maintain such conditions it is not recommended to prolong breast-feeding over six months. As yet, there are not enough data to use hydrolyzed cow's milk formulas as a measure alternative to breast-feeding.
Food allergic patients need to change their eating habits, to a varying extent. Once diagnosed, the treatment of a food allergy is the avoidance of the sensitizing food in order to prevent further episodes of ARF. This measure is easy for foods not predominant in the diet, like exotic fruits. However, the interaction with the eating habit is stronger when patients have to eliminate from the diet predominant foods or foods which may be masked and hidden in food products and preparations. However food allergens, especially in an occupational setting, may induce allergic reactions even when inhaled or after skin contact. Foods most commonly involved in occupational food allergy are: cereal flour, egg, milk, seafoods and legumes. The most effective measure to prevent occupational diseases due to exposure to food allergens is primary prevention, that is prevention of exposure to food-related substances that can induce allergic reactions. A second step is secondary prevention, that is the detection of diseases at an early stage. The earlier the diagnosis is made, the more likely workers are to recover. Tertiary prevention consists in appropriate medical care of diseased workers. Due to that mentioned above, it is clear that any effort should be directed to primary and not to tertiary prevention.
There are two main problems that arise from food processing and preparation: (1) food processing may alter content and/or properties of food allergens, both reducing and increasing the allergeni-city of the starting material; (2) most processed, packaged and canned foods contain additives and other 'hidden' ingredients of both natural and synthetic origin. Common food allergens such as milk, egg, soya, and wheat are constituents of a wide variety of prepared foods, and in most cases labelling is incomplete and often misleading. This can have devesting consequences for a food-sensitive person. In fact almost all patients who died from food anaphylaxis had a history of allergic reactions to the food allergen responsible for the death, but they were unaware that the allergen was present in the food they ate. Therefore it is imperative that all processed foods sold
13
in the European Community be clearly labelled with the list of the ingredients and of the starting materials.
Hypoallergenic formulas (HF) may be used to treat allergic symptoms induced by cow's milk in sensitized children or to prevent food allergies in infants at high risk for the development of allergic disease. The important role that HF may play in the treatment of cow's milk allergy has been defined. In vitro and in vivo studies show that extensive casein hydrolysates are the less allergenic formulas in cow's milk allergic children. An elemental formula (Neocat) seems to be a good alternative as well. However it should be underlined that these formulas are hypoallergenic and not non-allergenic, because some highly sensitive milk-allergic infant may react adversely to being fed such formulas.
The role of HF in the prevention of allergic diseases is still controversial. Although some studies indicate a protective role of some H F in preventing allergic diseases in high-risk babies, further studies are needed to elucidate this point. In vitro and animal studies should select new formulas suitable for milk substitutes in cow's milk allergic children. Preclinical screening of these hydrolysates should demonstrate the absence of intact proteins and more than 99% of the peptides with molecular weight < 1.5 Kd, and non-anaphylaxis in animals challenged with the formula under investigation.
Hydrolysates selected by preclinical studies should then be screened by DBPCFC and open consumption, showing to be tolerated in cow milk allergic infants, in which the diagnosis of allergy to milk has been documented by positive DBPCFC.
The optimal treatment of food allergy is to avoid the culprit food, but this may be very difficult as masked foods are present in a number of preparations, exposing the allergic subject to unaware consumption. A series of fatal reactions derived from eating apparently unsuspected foods has been reported. In recent years, specific immunotherapy was considered as a treatment of food allergy and a first double-blind placebo-controlled study performed in patients allergic to peanut with a defatted peanut extract demonstrated, by a marked reduction of symptoms scores to DBPCFC and decrease of skin sensitivity to peanut extract in actively treated patients, that this treatment may be effective.
A new idea of prevention in food allergy must take into account the production of hypo- or non-allergenic food. Current means used to induce hypoallergenicity are heating, enzymatic hydrolysis and selection of vegetable stocks which synthesises little or no major allergenic protein (e.g. wheat deficient in gliadins). This last goal could be obtained by the biogenetic engineering with the production of transgenic plants.
Public health's role will be to make more effort than in the past to spread correct information on food allergy to the medical profession and to the public so as to provide an authoritative bulwark to the spread of unorthodox practices which are the main source of controversies on this topic. Measures will have to be taken to prevent or deal with serious allergic reactions, instructing those in charge of restaurants, hotels and school canteens on what should be done in cases of severe anaphylactic reactions. Constructive relations must be established with the food industry to make sure the user receives accessible information on food products, and jointly to promote studies to set in motion the farthest-reaching positive approaches.
14
C L A S S I F I C A T I O N AND T E R M I N O L O G Y OF A D V E R S E R E A C T I O N S TO FOOD
SYNOPSIS
The recent Position Paper of the European Academy and Clinical Immunology Subcommittee on adverse reaction to food (ARF) divided the ARF into toxic and non toxic.
The latter are subdivided in immunomediated (in clinical practice represented quite exclusively by the IgE mediated reactions) and non-immune mediated (enzymatic, pharmacologic and undefined intolerances).
The document, entitled 'adverse reactions to food' prepared by the American Academy of Allergy and Immunology Committee on Adverse Reactions to Foods and the National Institute of Allergy and Infectious Diseases in 1984, suggested an up-to-date terminology in the field of adverse reactions to food, with the aim of establishing a definite common meaning of all terms generally used by the medical community for food allergy and intolerance1 ·2.
Recently the European Academy of Allergy and Clinical Immunology (EAACI) Subcommittee on Adverse Reactions to Food presented a Position Paper with a new classification for adverse reactions to foods, based on pathomechanisms, that is the development of the American manual3
(Figure 1.1).
ADVERSE REACTION TO FOOD
^ ^ TOXIC
y
IMMUNE MEDIATED (FOOD ALLERGY)
^ / NON TOXIC
igE
NON-lgE
\ NON-IMMUNE MEDIATED (FOOD INTOLERANCE)
ENZYMATIC
PHARMACOLOGICAL
UNDEFINED
Figure 1.1.
According to this classification, adverse reactions to foods are divided into toxic and non toxic food reactions.
15
1.1. Toxic food reactions
Toxic food reactions are due to some substances that contaminate foods or that are naturally present in them, e.g. poison in non-edible mushrooms. Toxicity affects all human beings exposed to high doses of a certain toxin with the same mechanism and is not connected to an individual susceptibility. Allergists must be aware of toxic food reactions on account of their prevalence among adverse reactions to foods, in order to make a correct differential diagnosis, particularly when these reactions may mimic in some way an allergic symptomatology (e.g. scombroid syndrome).
1.2. Non-toxic food reactions
Non-toxic food reactions are due to an individual's susceptibility to certain foodstuffs and they are divided into immune-mediated and non-immune mediated reactions. Food allergy is the term commonly used for immune-mediated reactions, while food intolerance includes all non-immune mediated reactions. According to the immunological mechanism involved in the adverse reactions. Food allergy is defined IgE-mediated and non-lgE-mediated.
1 . 2 . 1 . IgE-mediated react ions
IgE-mediated reactions can be diagnosed in atopic patients when IgE antibodies specific to food, that significantly correlate with the symptoms and/or the provocative tests, are detected by in vivo and/or in vitro tests.
1 .2 .2 . Non- lgE-media ted food allergy
Non-lgE-mediated food allergy includes: (a) immune reactions caused by, other than IgE, specific to food allergen/s; (b) food immune-complexes; (c) cell-mediated immunity specific to food. Also in this case, a correct diagnosis needs the demonstration of the existence of an immune mediated mechanism (other than IgE) against the suspected food by in vivo and/or in vitro tests and the clinical evidence of a correlation between the symptoms evoked by the ingestion of the suspected food and the immune reaction. Up to now no clear demonstrations exist in respect of food allergy mediated by (a) and (b). Food intolerance, that is non-immune-mediated food adverse reactions, is a term used when the causative role of a food in provoking complaints is irrefutable, as clearly shown by the history and/or the provocative tests, but there is no evidence of an immunological mechanism. Two mechanisms are likely to explain these reactions; they are enzymatic defects and pharmacological actions of drugs or other pharmacological active substances added to the food or naturally present in it. In this case the reactions are therefore subdivided into enzymatic and pharmacological reactions; while the non-immune mediated food adverse reactions due to an unknown mechanism are classified in the group of undefined reactions.
Psychosomatic food-adverse reactions are not truly food dependent but are related to a primary mental disorder; therefore they are excluded in the EAACI classification. However, in clinical practice, most patients, who think they are allergic to some food, belong to this category4·5.
16
Unfortunately the individual beliefs of patients suffering from vague, recurrent symptoms, wrongly ascribed to some particular food, often find confirmation in many articles published in non-specialized newspapers, that attribute a lot of symptoms to food allergy simply on the basis of non-validated hypothesis and anecdotal reports. Moreover many of these patients find their assumptions guaranteed by physicians who apply unorthodox non-validated diagnostic procedures. In order to avoid these mistakes, official international allergy associations have published diagnostic protocols to be followed to diagnose adverse reactions to food3·6.
REFERENCES 1 Anderson J.A., Sogn D.D., eds. 'Adverse reactions to foods'. AAAI and NIAID, NIH publication
No 84-2442. 1984.
2 Anderson J.A. 'The establishment of common language concerning adverse reactions to foods and food additives'. J. Clin. Immunol. 78. pp. 140-144. 1986.
3 Bruijnzeel-Koomen C , Ortolani C , Aas K., Bindslev-Jensen C , Björksten B., Moneret-Vautrin D., Wuthrich B. 'Position Paper, Adverse reactions to foods'. Allergy, 50, pp. 623-635. 1995.
4 Pearson D.J., Rix K.J.B., Bentley S.J. 'Food allergy: how much in the mind?' Lancet, June 4, 1983. pp. 1259-1261.
5 Sloan A.E., Powers M.E. 'A perspective on popular perceptions of adverse reactions to food'. J. Allergy Clin. Immunol. 78. pp. 127-133. 1986.
6 Metcalfe D.D., Sampson H.A. Workshop on experimental methodology for clinical studies of adverse reactions to foods and food additives. J. Allergy Clin. Immunol. 86. pp. 421-442. 1990.
17
GENERAL O U T L I N E OF THE ROLE OF FOOD C O V E R I N G THE D I F F E R E N T H Y P O T H E S E S
SYNOPSIS
Toxic reactions to food affects all human beings exposed. The major sources of toxicity of foodstuffs are the toxic substances induced in food processing, contaminants and additives.
IgE-mediated food allergy is the most frequent, the best known and the easiest to be diagnosed of the ARF. However the diagnosis of IgE-mediated food allergy must be made only when the relationship between the ingestion of a particular food and the symptoms is well established.
An evident role in clinical food allergy (i.e. IgG responses to foods, immune complexes with food allergens, cell mediated immunity to food) has not been demonstrated conclusively, and this topic is still the object of investigation.
Enzymatic food intolerances, except for lactase deficiency, are rare conditions, mainly due to inborn errors of metabolism. The pharmacological food intolerance includes: (1) the effects of vasoactive amine contained in some fruits; (2) the effects of mediator released by non immunologic mechanism and (3) the intolerances to food additives.
2. 1 Toxic reactions
Many toxic substances may occur in foodstuffs. However, the amounts of these toxic substances are generally too small to cause symptoms, and habitual dietary variety keeps down the intake of any single toxin; this could explain the low prevalence of toxic reactions. Toxic substances in foodstuffs are:
1. Naturally occurring, both endogenous and exogenous;
2. Induced in food processing;
3. Contaminants;
4. Additives.1
Some examples of naturally occurring toxins in animal and vegetal foods are shown in Table 2.1.
Food toxicity mainly affects the CNS (headache, hallucination, incoherence and at times convulsions), liver and blood. Toxins induced in food processing, contaminants and additives are the major source of toxicity of foodstuffs today. Modern food technology enables us to produce, preserve and distribute large quantities of foods but there are frequent risks of breakdown in the food production and distribution chain, exposing many individuals to a high risk of food toxicity. The scombroid syndrome has become one of the major chemical food-borne illnesses reported in recent years.2·3
18
Table 2.1 Naturally occurring toxins in food (by C. May,1 modified)
TOXIN
Cyanide
Glucosinolites
Atropine
Pressor amines
Solanine
Aflatoxins
Colza toxins
Histidin & scombrotoxins
Paralytic shellfish toxins
FOOD
Prunoideae fruits
Cabbage
D. stramonium
Banana
Potato (raw), Jerusalem cherry, unripe tomato, etc.
Contaminants of corn, hypoallergenic milk
Colza oil
Spoiled fish
Shellfish
nuts and meats,
SYMPTOMS
Neuropathy, mental confusion
Goiter
Hallucination
Headache, hypertension
Headache, CNS depression, gastrointestinal
Reye's syndrome, gastrointestinal, hepatic
Gastrointestinal, CNS, muscular
Scombroid poisoning
CNS (paralysis), cardiovascular, gastrointestinal, respiratory
2.2. Non-toxic reactions
2 . 2 . 1 . I m m u n o l o g i c a l r e a c t i o n s ( f o o d a l l e r g y )
2.2.1.1. IgE-mediated food allergy
Type I, IgE-mediated, reactions in food allergy are the most frequent, the best known and the easiest to be diagnosed. The presence of IgE antibodies to specific offending food support the existence of an IgE mechanism, although clearly the diagnosis of IgE-mediated allergy can be made only when the relationship between the ingestion of a particular food and the onset of symptoms is well established. Double-blind placebo-controlled food challenge (DBPCFC) is the gold standard to demonstrate this relationship in order to exclude psychological reactions, and physician's and patient's prejudice. The result of DBPCFC is considered the only objective evidence in food allergy.
A variety of symptoms, likely to be secondary to an IgE-mediated response, are reported in controlled trials:4·5·6 anaphylaxis (associated with exercise in some cases); cutaneous manifestations, like urticaria-angioedema, atopic dermatitis and contact dermatitis; upper and lower respiratory symptoms, like rhinitis (rare), larynx edema and asthma; gastrointestinal disorders, like oral allergy syndrome (OAS), infantile colics, nausea, vomiting, diarrhoea and abdominal pain and neurological symptoms. However, in connection with these last complaints, there is no definitive evidence of a relationship between food and hyperactivity, depression or migraine.
19
Various foods have been found to cause most frequently IgE-mediated food allergy in a series of DBPCFC7 in adults and children. The foods found responsible of IgE-mediated food allergy listed in order of prevalence are: egg, milk, peanut, nuts, fish and soya in children, and peanuts, nuts, fish and shellfish in adults.
The prevalence of reactions to specific foods may depend on the eating habits or other peculiarities of a given population. For example soybean allergy is more common in Japan and fish allergy is more prevalent in Scandinavian countries. Patients suffering from allergy to certain pollens more often react with OAS to certain fresh fruits and vegetables.8·9 These patients with pollen allergy present very intense mucosal sensitivity to foods, such that local symptoms are evident within 15 minutes of food contact. OAS is IgE-mediated. The symptoms are generally localized in the oral cavity and pharynx, though more severe local or systemic manifestations may also occur, often within few minutes after the oral contact with the responsible food, they are angioedema of the oral cavity and pharynx, urticaria, conjunctivitis, orbital angioedema, asthma, gastrointestinal symptoms and even anaphylactic shock. The main foods inducing this IgE-mediated syndrome are apple, peach, cherry, nuts, celery, carrot, tomato and fennel.8·9
2.2.1.2. Non-lgE-mediated food allergy
Non-lgE-mediated food allergy provides the evidence that the adverse reaction is the consequence of an immune response, other than IgE-mediated specific for a certain food; immunoglobulins, belonging to a non-lgE class, food immune-complexes or cell-mediated immunity are directly involved in the mechanism provoking the symptoms. lgG4 to specific food antigens are frequently present in patients with adverse reactions to foods,10 but these antibodies are also often detected in normal subjects or in patients with inflammatory bowel disease, and their pathogenetic role has not been demonstrated. Their presence is likely to be the consequence of prolonged exposure to ubiquitous antigens resulting in an lgG4 restricted response.11 Circulating IgG and IgE immune-complexes containing food antigens may be found in patients with food allergy suffering from asthma and eczema,10·12 but their pathophysiological role has been rarely unequivocally demonstrated. Furthermore there is no definitive evidence that either IgG or IgE food-immune complexes cause human disease.10·12
There is ample indirect evidence that celiac disease (CD) may be provoked by a cell-mediated food allergy to gliadin, a prolamine contained in gluten.13·14 Τ cells appear to be involved in the pathogenesis of this disease,15·16 although, so far, there is no exhaustive proof that these immune phenomena are the direct original cause of the human disease. Recently an over-representation of one TCR variant of the lymphocytes present in the gut mucosa in CD was found, suggesting a role for these cells in the disease.17 Some experiments showed that the immune-mediated intestinal damage is similar to that provoked in the intestinal mucosa by the graft-versus-host reaction.18·19 As yet the role of the increased IgAand IgG antigliadin antibodies in the immunopathogenesis of this disease is still unclear.17·18
A clinical picture and histological alterations of the jejunal mucosa that mimic celiac disease are present in some infants with malabsorption syndromes; patchy villous atrophy with cellular infiltrate on jejunal biopsy is associated with the weaning period, and cow's-milk sensitivity is the most frequent cause of this syndrome.19 Sensitivity to soya, egg and wheat have also been
20
reported in this syndrome.20 Serum IgA and IgG antibodies specific to milk are elevated in cow's milk induced malabsorption.21 These abnormalities suggest both type-Ill (immunocomplexes) and type IV (cell-mediated) immunopathogenesis.
The same mechanisms may be present in food-induced enterocolitis syndrome in infants.22 The jejunal biopsy shows flattened villi, edema and an increased number of lymphocytes, eosinophils and mast cells. The most prevalent responsible foods are cow's milk, soya protein or both together. These foods are also involved in food-induced colitis that differs from the above infantile syndromes in its mild clinical picture, generally characterized by the presence of gross or occult blood in the stools and a prominent eosinophilic infiltrate in the colonic mucosa.23 Heiner's syndrome, that is a food-induced pulmonary hemosiderosis, is very rare; it affects infants with non-lgE-mediated hypersensitivity to cow's milk; egg and pork have also been reported as the cause of this syndrome in some infants.24
2 . 2 . 2 . N o n - i m m u n e m e d i a t e d adve r se r e a c t i o n s to foods
2.2.2.1. Enzymatic food intolerance
Enzymatic food intolerance is present in patients affected by enzymatic defect that causes a clinically evident adverse reaction to certain foods or food additives. The most common conditions are: (1) disaccharidase deficiencies caused by a defect of lactase or sucrase; (2) galactosemia caused by a defect of galactose 1 phosphate uridyl transferase or uridine diphosphate-4 epimerase; (3) phenylketonuria due to phenylalanine hydroxylase deficiency; (4) alcohol intolerance consequent upon aldehyde dehydrogenase deficit; (5) favism due to a defect of glucose-6-phospho dehydrogenase (G6PD).
Except for lactase deficiency, these are very rare conditions or inborn errors of metabolism. However it is widely held that many undefined food intolerances may result from enzymatic defects. For example, a deficiency of diamine-oxidase has been postulated in patients with intolerance to histamine-containing foods,25 but clear evidence of a clinical syndrome due to this enzymatic defect has never been found.
2.2.2.2. Pharmacological food intolerance
The main substances that may be responsible for pharmacological food intolerance are: (1) vasoactive amines like histamine, octopamine, phenylephine and other biogenic amines: tyra-mine, phenylethylamine (in chocolate), tryptamine (in tomatoes), 5-hydroxytryptamine (in banana and avocado), spermidine (in pork and cereal germs); (2) releasing factors present in foodstuffs causing indirect pharmacological reactions such as protamine, basic peptides, diamines and polyamines and peptones (histamine releaser foodstuffs);26 (3) food additives.
Pharmacological food intolerance may depend on the direct effect of vasoactive amines naturally found in foods. Ingestion of large amounts of a food, containing one or more of these amines, will be followed by toxic symptoms. Some subjects, however, may have symptoms even after eating a very small amount of one of these substances. In particular, the threshold of susceptibility to
21
histamine may be lowered in some individuals, e.g. as stated above, subjects affected by diamine oxidase deficiency. Selected foods containing relatively large amounts of histamine or histidine or both can pose problems in these intolerant subjects.27 In scombroid poisoning factors potentiating histamine toxicity are involved and therefore this syndrome must be classified as a toxic food reaction.28
The largest amounts of histamine and tyramine are found in fermented foods, such as cheese, alcoholic beverages, tinned fish, fish autolysates (Nuoc-Mam), sauerkraut, tuna, dry pork and sausage.29·30·31·32 Grapes, potatoes, and cabbage are rich in tyramine.33
Some studies indicate that tyramine may play a role in migraine and chronic urticaria, especially in patients treated with a MAO inhibitor.27 In addition certain foods are said to have histamine releasing properties.27·34 Examples include egg white, shellfish, strawberries, tomatoes, chocolate, citrus fruit, fish and pork. However there is no evidence of this effect in vivo. Studies generally quoted to support histamine release by these foods are non-controlled, very old and performed in laboratory animals. More appropriate studies are therefore necessary to validate this hypothesis.
Pharmacological food intolerance might be evoked for the food intolerance present in patients with poor sulphoxidation ability. A poor sulphoxidation ability has frequently been documented in patients with ascertained food intolerance.35 The metabolism of foodstuffs containing sulphur, including thiophenes, sulphides and isothyocyanates might be impaired.
2.2.2.3. Additive intolerance
IgE-mediated additive allergy has been documented in some cases,36 but additive intolerance caused by non-toxic reactions does not seem to depend on immune-mediated mechanisms. Some observations suggest that additive intolerance may be consequent upon an enzymatic inhibition (e.g. sulphites and azo dyes).37 Other studies show non-specific mediator release in vivo induced by challenge with some additives (ASA, sulphites, etc.).38·39 So far, however, the mechanisms of additive intolerance remains largely unknown, therefore it seems more appropriate to include the adverse reactions to additives in the group of undefined food intolerance.
REFERENCES
1 May CD. 'Immunologic versus toxic adverse reactions to foodstuffs'. Ann. Allergy 51 (II): pp. 267-268. 1983.
2 Taylor S.L., Stratton J.E., Nordlee J.A. 'Histamine poisoning (scombroid fish poisoning): An allergy-like intoxication'. Clin. Toxicol. 27: pp. 225-240. 1989.
3 Morrow J.D., Margolies G.R., Rowland J., Roberts L.J. 'Evidence that histamine is the causative toxin of scombroid-fish poisoning'. N. Engl. J. Med. 324: pp. 716-720. 1991.
4 Sampson H.A. 'Food allergy' (review). J. Allergy Clin. Immunol. 84: pp. 1062-1067. 1989.
22
5 Bock S.A. 'Prospective appraisal of complaints of adverse reactions to foods in children during the first three years of life'. Pediatr. 79: pp. 683-688. 1987.
6 Hill D.J., Firer M.A., Shelton M.J., Hosking CS. 'Manifestations of milk allergy in infancy: clinical and immunologic findings'. J. Pediatr. 109: pp. 270-276. 1986.
7 Bock S.A., Sampson H.A., Atkins R.M. et al. 'Double-blind placebo-controlled food challenge as an office procedure: a manual'. J. Allergy Clin. Immunol. 82: pp. 986-997. 1988.
8 Ortolani C , Ispano M., Pastorello E., Bigi Α., Ansaloni R. 'The oral allergy syndrome'. Ann. Allergy 61 (II): pp. 47-52. 1988.
9 Pastorello E.A., Ortolani C , Incorvaia C , Bigi Α., Ispano M., Pravettoni V., Schilke M.L., Farioli L., Zanussi C 'IgE-mediated allergy from vegetable allergens'. Ann. Allergy 71: pp. 470-476. 1993.
10 Paganelli R., Quinti I., D'Offizi P., Papetti C , Carini C , Aiuti F. 'Immune complexes in food allergy: a critical reappraisal'. Ann. Allergy 59 (II): pp. 157-161. 1987.
11 Aalbersee R.C., Gaag Vander R., Leevwen Van J. 'Serologic aspects of IgG antibodies. I. Prolonged immunization results in an IgG-restricted response'. J. Immunol. 130: pp. 722-726. 1983.
12 Carini C. 'IgE-immune complexes in food allergy: significance, pathogenicity and clinical considerations'. Clin. Allergy 17: pp. 485-497. 1987.
13 Marsh M.N. 'Gluten, major histocompatibility complex, and the small intestine: a molecular and immunobiologic approach to the spectrum of gluten-sensitivity ('celiac sprue'). Gastroenterology 102: pp. 283-304. 1992.
14 De Ritis G., Auricchio S., Jones H.W., Lew E., Bernardin J.E., Kasarda D.D. 'In vitro (organ culture) studies of the toxicity of specific A-gliadin peptides in coeliac disease'. Gastroenterology 1994, pp. 41-49. 1988.
15 Marsh M.N. 'Studies of intestinal lymphoid tissue. XI. The immunopathology of cell-mediated reactions in gluten sensitivity and other enteropathies'. Scanning Microsc. 2, pp. 1663-1684. 1988.
16 Ferguson Α., Arranz E., O'Mahony S. 'Spectrum of expression of intestinal cellular immunity; proposal for a change in diagnostic criteria of celiac disease'. Ann. Allergy 71, pp. 29-32. 1993.
17 Arranz E., Ferguson A. 'Intestinal antibody pattern of celiac disease: occurrence in patients with normal jejunal biopsy histology'. Gastroenterology 104, pp. 1263-1272. 1993.
18 O'Mahony S., Arranz E., Barton J.R., Ferguson A. 'Dissociation between systemic and mucosal immune responses in coeliac disease'. Gut. 32, pp. 29-35. 1991.
23
19 Kuitunen P., Visakorpi J.K., Savilahti E., et ai. 'Malabsorption syndrome with cow's milk intolerance: clinical findings and course in 54 cases'. Arch. Dis. Child 50, pp. 351-356. 1975.
20 Goldman H., Proujansky R. 'Allergic proctitis and gastroenteritis in children'. Am. J. Surg. Path. 10, pp. 75-86. 1986.
21 Pearson J.R., Kingston D., Shiner M. 'Antibody production to milk proteins in the jejunal mucosa of children with cow's milk protein intolerance'. Pediatr. Res. 17, pp. 406-412. 1983.
22 Powell G.K. 'Milk and soya induced enterocolitis of infancy: clinical features and standardization of challenge'. J. Pediatr. 93, pp. 553-560. 1978.
23 Lake A.M., Whittington F., Hamilton S.R. 'Dietary protein-induced colitis in breast-fed infants'. J. Pediatr. 101, pp. 906-910. 1982.
24 Lee S.K., Kniker W.T., Cook CD., et al. 'Cow's milk-induced pulmonary disease in children'. Adv. in Pediatr. 25: pp. 39-57. 1978.
25 Wantke F., Götz M., Jarisch R. 'Histamine-free diet: treatment of choice for histamine-induced food intolerance and supporting treatment for chronical headaches'. Clin. Exp. allergy 23, pp. 982-985. 1993.
26 Schacter M. 'Histamine-release and the angfio-oedema type of reaction'. Histamine - Ciba Found Symp. pp. 167-169, London, Churchill. 1956.
27 Zeitz H.J. 'Pharmacologic properties of foods'. In Metcalfe D.D., Sampson H.A., Simon R.A. (eds.). 'Food allergy. Adverse reactions to foods and food additives': pp. 311-318, Blackwell Scientific Publications, Boston, 1991.
28 Taylor S.L. 'Histamine food poisoning: toxicology and clinical aspects'. CRC Crit. Rev. Toxicol. 17, pp. 91-128. 1986.
29 Monoret-Vautrin D.A. 'False food allergies: non-specific reaction to foodstuffs'. In Lessof MH (ed.): 'Clinical reactions to food', pp. 135-153, Chichester, Wiley. 1983.
30 Maga J.A. 'Amines in foods'. CRTC Crit. Rev. Food Sci. Nutr. 10, pp. 373-403. 1978.
31 lenistea C 'Bacterial production and destruction of histamine in foods, and food poisoning caused by histamine'. Nahrung 15, pp. 109-113. 1971.
32 Smith T.A. 'Amines in food'. Food Chem. 6, pp. 169-200. 1980.
33 Tarjan V., Janossy G. 'The role of biogenic amines in foods'. Nahrung 1978, pp. 22: 281-85.
34 Schacter M., Talesnik J. 'The release of histamine by egg-white in non-sensitized animal'. J. Phys. 118, pp. 258-263. 1952.
24
35 Scadding G.K., Ayesh R., Brostoff J., Mitchell S.C, Waring R.H., Smith R.L. 'Poor sulphoxida
tion ability in patients with food sensitivity'. BMJ 297, pp. 105107. 1988.
36 Kägi M.K., Wüthrich B., Johansson S.G.O. 'CampariOrange anaphylaxis due to carmine
allergy'. Lancet 344, pp. 6061. 1994.
37 Simon R.A. 'Sulfite sensitivity'. Ann. Allergy 56, pp. 281288. 1986.
38 Ortolani C , Mirane Α., Fontana Α., Folco G.L., Miadonna Α., Montalbetti Ν., Rinaldi M., Sala
Α., Tedeschi Α., Valenti D. 'Study of mediators of anaphylaxis in nasal wash fluids after aspirin
and sodium metabisulfite nasal provocation in intolerant rhinitic patients'. Ann. Allergy 59, pp.
106112. 1987.
39 Christie P.E., Tagari P., FordHutchinson A.W., Charlesson S., Chee P., Arm J.P., Lee T.H.
'Urinary LTE4 concentrations increase after aspirin challenge in aspirinsensitive asthmatic
subjects'. Am. Rev. Respir. Dis. 143, pp. 10251029. 1991.
25
3. S Y M P T O M S OF FOOD A L L E R G Y AND FOOD I N T O L E R A N C E
S Y N O P S I S
The symptoms of food allergy involve different organs. Oral allergy syndrome is frequent among patients with birch or mugwort pollinosis and it is provoked by sensitization to plant food allergens. Rhinoconjunctivitis, asthma and otitis media with effusion are rarely due to food allergy. Acute orticaria/angioedema and atopic dermatitis frequently depend from food allergy. Many foods have been reported to provoke fatal food-induced anaphylaxis: i.e. milk, egg, peanut, seafood, nuts, legumes, spices and fruits. Hidden foods have been demonstrated to be frequently responsible for anaphylactic fatalities.
Exercise induced anaphylaxis may be related to a food allergy.
Gastrointestinal anaphylaxis is common in adults. In infancy food intolerance may provoke some rare gastrointestinal syndromes, i.e. infantile colics, food-induced enterocolitis syndrome, food-induced colitis, food-induced malabsorption syndrome and food-induced hemosiderosis. Celiac disease and dermatitis herpetiformis are both gluten related entero- and cutan-eous-pathies in which a non-lgE-mediated immune mechanism is probably involved. Allergic eosinophilic gastroenteropathy is a rare entity but only in some documented cases is it due to an IgE-mediated allergy. Lactose intolerance is a common disease due to acquired defect of intestinal lactase, more rarely the disease depends from an inborn lactase deficiency.
Foods may induce the production of IgE towards specific protein antigens and release of mediators in allergic subjects after exposure to the sensitizing food. Food allergic symptoms involve different organs. Symptoms may appear in the organs that come in contact with the food (such as lips, mouth, pharynx) and/or in other target organs. We recognize therefore 'oral' and 'extra oral' symptoms.
Food allergy symptoms may also be subdivided according to the type of contact mode with the food: i.e. symptoms due to food ingestion, contact or inhalation.
3.1 Oral a l l e r g y s y n d r o m e (OAS)
OAS is a food allergy syndrome due to the contact of the oral mucosal with allergenic foods, particularly plant allergens. The term OAS was used first by Amlot et al.1 to identify immediate symptoms in the lip, mouth, pharynx and larynx in subjects sensitized to food allergens. The symptoms may be present in organs other than the oral cavity.
All foods may provoke this syndrome, however it is very common with fresh fruits and vegetables. This syndrome may be associated with pollinosis, particularly birch or mugwort pollen allergy. The first report of this association dates to 1942,2 but thereafter several clinical studies were conducted in Scandinavia,3·4·5 and in other European and American countries.6
Nearly 60-70% of allergic patients with OAS suffer from allergic pollen rhinoconjunctivitis.7 The contact between food and oral mucosa provokes itching and swelling of the lip, tongue, uvula, and larynx. Systemic reactions of different severity such as urticaria, rhinitis, asthma, laryngeal edema or anaphylactic shock may also occur.
26
The oral symptoms appear within a few minutes after having eaten the offending food. In some cases the symptoms may appear in organs other than the mouth or generalized; and may develop 30 to 60 minutes after contact with the offending food. This suggests that OAS may be defined as a variable syndrome in which immediate oral symptoms may be associated with delayed manifestation of symptoms in other organs.
The laryngeal edema may present as constriction of throat, cough, dysphonia, wheezing and tirage. The foods that more frequently cause OAS are apple, nuts, fruit, peach, fennel, cherry and celery. Some animal foods such as milk, egg and fish also may occasionally provoke OAS. Some patients have symptoms in response to more than one food, and a food may provoke different symptoms. Moreover some patients have symptoms only upon contact with fresh foods whereas they tolerate the same food when cooked.
In food-allergic patients it is possible to detect associations between hypersensitivity to different foods. Some of these associations occur very commonly. Therefore we can identify some definite 'clusters' of hypersensitivity. Some cross-reactivities respect the taxonomie classification, others do not. The clusters of food more frequently provoking OAS are:
(1) peach, plum, apricot, cherry;
(2) celery, carrot, fennel, parsley;
(3) apple, apricot, cherry, pear;
(4) hazelnut, pear;
(5) peanut, almond, hazelnut;
(6) watermelon, melon, tomato.
Allergy to prunoideae may not be associated to a pollen allergy; food allergy to watermelon, melon and tomato cluster may be associated with grass pollen allergy; all the other clusters are correlated with birch pollen allergy.
Several recent studies have investigated the immunological basis of these association. Andersen and Dreyfuss8 demonstrated a cross-reactivity between ragweed pollen and extracts of melon and banana; Hannuksela and Lahti,3 Eriksson and Formgren4 and Dreborg and Foucard5 found an association between birch pollen allergy and apple, nuts, peach, cherry pear, plum, carrot and potato allergy. Pauli and Bessot9 showed that a celery extract could inhibit RAST for birch and mugwort Staeger and Wuthrich10 confirmed the presence of common allergens between celery and birch and between celery, spices and mugwort. De Martino et al.11 found an association between grass pollen allergy and tomato allergy. Ortolani et al.7 found an association between grass pollinosis and tomato, melon and watermelon allergy.
OAS is frequently associated with respiratory allergy from grass, birch and mugwort pollen. The importance of the pollinosis in relation to the subsequent development of food allergy was further demonstrated by the observation that in a study group the prevalence of birch pollinosis was four
27
times higher than in a control group (patients with pollinosis regardless of whether they were or were not affected by OAS).
In conclusion OAS is a polymorphic disease related to IgE-mediated allergy in which local symptoms of the mouth may be associated with organ and systemic manifestations.
3 . 2 . E x t r a o r a l s y m p t o m s
3 . 2 . 1 . R h i n o c o n j u n c t i v i t i s
Ocular and nasal symptoms may be isolated or associated to OAS. DBPCFC have demonstrated the appearance of ocular itching, lacrimation, conjunctival hyperemia, nasal itching, rhinorrhea, sneezing, obstruction, cough, wheezing and bronchospasm; these symptoms occur within five minutes to two hours after food intake.
The frequency of respiratory symptoms due to IgE-mediated food allergy is higher in children. The temporal relation between food intake and the appearance of symptoms, and the ability to reproduce symptoms by DBPCFC, clearly attest to the food etiology.
Eriksson12 reported that 46% of food allergic patients have conjunctivitis and rhinitis. Ortolani et al.7 observed rhinitis in 10% of these patients, 3.5% conjunctivitis and 7% asthma. There are no data regarding the prevalence of food allergy as a cause of chronic sinusitis even if the repeated exposure to food antigen, which is typical of the allergic disease, may be important for the chronicity of sinusitis.
3 . 2 . 2 . S e r o u s o t i t i s m e d i a w i th e f f u s i o n
The relation between serous otitis media with effusion and food allergy remains controversial. Some studies13 show an increased prevalence of otitis media in allergic children, but the true prevalence is unknown. Bernstein14 points out the association between serous otitis media and IgE-mediated allergy only in 35-40% of patients; the symptoms may be associated to allergy to bacteria, viruses, or to a mucociliary clearance defect.
Milk, wheat, egg, peanut and soya may be etiologic factors in otitis media in children.15·16·17.18·19
In a recent investigation Nsouli et al.20 noticed that in 81/104 pediatric patients there is a statistical correlation between food allergy and recurrent serous otitis; 70/81 had clinical and instrumental improvement after a period of elimination diet, 66/70 reported otitis after an open challenge with the suspected food. These data may be confirmed with double-blind challenges. In agreement with the above authors, foods may provoke serous otitis media with several mechanisms; food causes nasal congestion and obstruction with nasopharyngeal pressure increase and then reflux of pharyngeal secretion; the food induced nasal obstruction gives rise to a different nasopharyngeal pressure, with eustachian tube dysfunction (otodynia, tinnitus hearing loss, vertigo); foods could cause edema of eustachian tube due to weakness of tensor veli palatini muscle, and finally the middle ear could be the shock target organ of food allergy. In conclusion the possibility of an IgE-mediated allergy should be considered in all pediatric patients with recurrent otitis media.
28
3 . 2 . 3 . Asthma
Patients spontaneously associate cutaneous symptoms to food allergy, whereas respiratory symptoms, particularly asthma, are rarely considered as associated to food allergy.24 Physicians must suspect food allergy when asthma appears in youth, when it is associated to atopic dermatitis with high levels of total IgE, and when asthma does not respond to treatment. Food allergic asthma is provoked in childhood by milk, egg, wheat and peanut.21·22 The disease appears in 4 to 6% of patients, whereas in asthmatic adults the prevalence of food allergic asthma is only 1-4%.23·25
Food additives may cause asthma, perennial rhinitis and urticaria-angioedema in sensitized subjects. Tartrazine, sodium metabisulphite and sodium benzoate are the most important additives responsible for intolerance.26
Respiratory symptoms may also be caused by inhalation of food allergens, particularly after industrial exposure in sensitized workers. In addition to the classic baker's asthma27 resulting from occupational airborne exposure to flour (wheat, but also alpha amylase), various agents may cause occupational asthma: hen egg,28 milk, vegetable dusts (green coffee, soya, castor bean), spices, and crustaceans. Some of these patients eat the foods which cause respiratory symptoms without problems. Allergic reactions to foods through inhalation of food particles have also been reported in housewives who were exposed to the steam from cooking legumes, chicken, peas, lentils, potatoes, or fish. In these cases most patients became sensitized in childhood via the gastrointestinal route and generalized symptoms usually occur after ingestion. The 'bird-egg syndrome' consists of respiratory symptoms following exposure to serum proteins from birds and then with allergy symptoms after egg ingestion. This phenomenon is caused by cross reactivity between bird proteins and egg yolk.29 The inverse situation was also described as 'egg-bird syndrome': (sensitization by the ingestion of egg proteins and reactions following inhalation exposure to birds and egg).30 In these cases, skin-prick tests (SPT) and serum IgE determination, are also essential to demonstrate an IgE-mediated mechanism.
3 . 2 . 4 . Urticaria and angioedema
Urticaria is a well-demarcated skin reaction clinically characterized by erythematous palpable lesions called wheals: these are evanescent areas of edema of the dermis that resolve within hours. Angioedema is characterized by a deeper swelling of the subcutaneous or submucosal tissues, often with normal-appearing skin, accompanied by a tingling or burning sensation rather than pruritus.31 If symptoms recur for less than six weeks the urticaria-angioedema is defined as acute, if the lesions persist or recur for more than six weeks, it is defined as chronic. Acute symptoms are generally provoked by food intake or contact. The most important foods are egg, milk, peanut, fish, cereals, crustacean and vegetables. Symptoms of OAS may precede the cutaneous symptoms.32 Chronic urticaria is rarely due to food allergy and an IgE-mediated allergy has been demonstrated only in a small percentage of patients with chronic recurrent urticaria (mainly due to cereals and legumes).
Symptoms can appear an hour or more after a meal. The association between food intake and urticaria may not be made when symptoms are caused chronically by foods consumed on a daily basis. Moreover, the patient's response to the food may vary according to how the food is prepared: for example, some fruits may cause symptoms when raw and not when cooked.
29
3 . 2 . 5 . Atopie dermatit is (AD)
AD is a chronic inflammatory skin disorder that occurs in 10% of the pediatric population;33 it is characterized by pruritus, patterned distribution and a chronic relapsing course. The pathogenesis of AD remains unknown. Recent studies on bone marrow transplantation suggest that the basic defect in AD resides in a bone marrow derived cell.34 It has been reported that patients with Wiskott Aldrich syndrome, who have eczema and elevated serum IgE that are comparable to AD, were noted to show clearing of their cutaneous symptoms and normalization of serum IgE titer after successful bone marrow transplantation.35
Individuals receiving bone marrow from atopic donors developed atopic symptoms after transplantation. Histological studies of skin lesions demonstrated cellular infiltration that is suggestive of a type IV cell-mediated hypersensitivity reaction. However, the exact relationship between AD and IgE-mediated sensitivity remains unclear. Approximately 2/3 of the children with AD have a positive family history for atopic disease; 50-80% of these children have or will develop allergic rhinoconjunctivitis and/or asthma.36·37 In 80% of the patients with AD serum IgE concentrations are elevated and skin tests and serum-specific IgE are positive for a large number of allergens. Many inhalant allergens cause eczematous cutaneous skin lesions: pollens,38·39·40·41 animals42
and mould.43 The first studies concerning the first comprehensive description of AD and relationship between house dust mite allergens and AD were published by Rost44 and Besnier;45
thereafter, Piatt Mills et al.46 confirmed the importance of mites in AD. The above observations considered both the clinical improvement after mite allergen control measures and the appearance of cutaneous symptoms after mite allergen exposure. The histological analysis of the eczematous lesions in AD demonstrate a prominent T-lymphocytes cellular infiltration.
Investigators47·48·49·50·51 have carried out patch tests (evaluated after 48 to 72 hours) in AD subjects to demonstrate that such allergens may also cause delayed reactions and eczematous lesions. Several studies52 suggest that the application of mite allergens on the skin of subjects with AD may cause binding to allergen-specific IgE situated on Langherans' cells, thereby delaying the reaction to the patch tests. The recruitment of eosinophils may occur by the release of chemotactic factors by mast cells and Langheran's cells.53 Over 50 years ago Brunner, Waltzer and Wilson54·55 demonstrated that many food antigens cross the gastrointestinal barrier and come into conctact with cutaneous mast cells within minutes to hours after food intake.56
Thereafter a large number of studies were aimed at clarifying the pathogenesis of food allergy in AD. Afterwards an attempt was made to establish the presumed prevalence of food allergy in AD. According to some authors nearly 1/3 of the patients evaluated in the dermatology and/or allergology clinic complained of the exacerbation of cutaneous symptoms after food intake. The frequency of food allergy in children with AD has been reported to be 5-20%. Other studies have reported a frequency of 60% independently of serum-lgE values.57 The latter study investigated the role of oral challenges in AD. The population described by Sampson was made up of young patients with AD and respiratory symptoms (47% had rhinitis and asthma, 28% only rhinitis, and 4% only asthma); nearly all had reported an extensive history of cutaneous symptoms. The choice of food allergens used in the challenges was based upon the results of the diagnostic tests and/or a positive history of food allergy. The symptoms began within 15 to 120 minutes after the challenge, and were characterized by morbilliform rash and urticaria which resolved after 1 to 3 hours. After this period of time the only lesions observed were those caused by scratching
30
(plasma histamine was monitored during the challenge to demonstrate that the symptoms were secondary to IgE mediated mast cell activation). Skin reactions were seen in 70% of the patients challenged; only 30% of the patients had an isolated cutaneous response.37 Studies performed on other patient groups revealed gastrointestinal symptoms in 55% of the cases and upper respiratory complaints in 39%. The high frequency of gastrointestinal symptoms has lead many authors to search for a defect in intestinal permeability by the lactulose/rhamnose test.58·59 These authors have demonstrated an increase of lactulose uptake and excretion, suggestive of malabsorption, only in those patients with food hypersensitivity. Egg, peanut, and milk are the foods that more frequently account for positive challenge in AD patients (70% of the cases).57 The latter three foods along with soya, fish, and wheat account for 90% of the food allergic reactions seen in patients with food allergy. Of these children, 38% did not have an allergic reaction to food, 28.5% reacted to one food, 20% to two foods, 9.5% to three foods, and 4% to four foods or more. This study demonstrated that eliminating the allergen from the diet for a period of one to two years allowed for the development of tolerance to the food eliciting the symptoms. There was a correlation between the development of tolerance and the type of food: less than 25% of the cases of hypersensitivity to egg, peanut, and milk, were lost during the dietary period, while one third of wheat sensitivity cases and one half of soya sensitivity cases were outgrown after one to two years of elimination diet.57
3 . 2 . 6 . Acute contact urticaria and angioedema
This syndrome appears 10 to 30 minutes after skin exposure to some foods.60 It can be provoked by an IgE-mediated mechanism and disappears within 24 hours. Contact urticaria may appear at the point of skin contact or in other cutaneous regions. In these patients the contact with the offending food may at times cause systemic effects in other target organs (e.g. rhinitis, conjunctivitis, asthma, anaphylactic shock). The term 'contact-urticaria syndrome' coined by Maibach61
indicates the above systemic reactions that appear in hypersensitized subjects after exposure and cutaneous absorption of the allergen. The symptoms consist of itching, tingling, erythema, and wheal formation; the erythematous reaction can be localized or systemic. The foods most commonly involved are egg, milk, wheat, peanut, vegetable, and fish. Most of these individuals handle food products through occupational exposure for extended periods of time before complaining of symptoms.
The name 'protein contact dermatitis' was suggested by Hjorth and Roed-Petersen62 to describe patients with chronic eczema who complained of exacerbations within 30 minutes after exposure of the affected skin to certain food protein such as those found in fish, wheat, milk, vegetable, and spices.63 The symptoms consist of itching, erythema, urticarial swelling of the fingers or extensor surface of the hand.
3 . 2 . 7 . Systemic anaphylaxis
Systemic anaphylaxis is a dreadful allergic reaction that usually occurs 1 to 30 minutes after food exposure, but may also take place up to two hours after the meal. Systemic anaphylaxis can be the initial manifestation of food allergy, or it may develop in subjects with previously documented reactions io a known food.
31
The term 'anaphylaxis'64 is used to describe a generalized and severe reaction that follows the release of various mediators that are able to provoke cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms. Anaphylaxis can be fatal when severe symptoms rapidly progress and proper assistance is delayed. Many foods have been reported to cause anaphylaxis: milk, egg, peanut, seafood, nut, legumes, spices, and some exotic fruits.
There is no reliable data on the prevalence and incidence of fatal and near fatal anaphylactic reactions.
Yunginger et al. described seven cases of fatal food-induced systemic anaphylaxis that occurred immediately after intake (fish, peanut).65·66 These reactions did not occur at home and patients were unaware that the food they had eaten contained the responsible allergen. All had experienced a previous, less severe anaphylactic reactions to the same food. Sampson et al. described six fatal cases due to the ingestion of either peanut, nut, or egg.67 Five patients initially had oral and abdominal symptoms, later they developed various combinations of cutaneous, respiratory, gastrointestinal, and cardiovascular signs and symptoms. Dutau et al.68 described four cases of food-induced anaphylaxis: the offending food was milk in two cases, egg in one case, and snail in the other. Previously, the same author had pointed out the occurrence of severe symptoms after peanut intake in 7.5-25% of pediatric patients.69 Sampson et al.70 has reported that 50% of the children with peanut-induced anaphylaxis have symptoms so severe that oral challenges with peanut are not possible. A retrospective analysis of American and European studies on anaphylaxis shows that peanut is responsible in 50% of the cases. Milk71 ·72 and egg 73 are also known to cause severe reactions especially in pediatric patients; these reactions sometimes can follow unknown inhalation of food allergens. Ansaloni et al.74 reported 24 patients who had severe systemic reactions to food, of these patients nine had had anaphylactic shock and 13 laryngeal edema that were supported by medical records. The foods eliciting the severe symptoms were milk (three cases) and hazelnut (three cases); peach, cherry, kiwi, egg, fish, food crustácea (two cases for each food); apple, wheat, maize, mustard, pear, fennel, legumes (one case for each food). Symptoms appeared within 1 to 60 minutes after food intake. In this study laryngeal edema was the most frequently reported severe reaction, and milk and hazelnut were the foods most frequently responsible. The anaphylactic reactions due to milk are generally provoked by casein.
Due to the increasing use of vegetarian foods, sesame seeds induced anaphylaxis75·76 has recently been described. Spices that are included in sauces and other foods, such as mustard77·78·79·80 and coriander, can also provoke anaphylactic symptoms. It is important to consider a diagnostic protocol in order to reach a diagnosis of food induced anaphylaxis or other food induced life threatening reactions. The following are the main points of the diagnostic work-up:
• verify the life-threatening event (anaphylactic shock, laryngeal edema, or severe asthma that requires emergency treatment) and substantiate it with medical documentations;
• exclude other causes of anaphylaxis (insect sting, concurrent diseases, etc.);
• determine the likelihood that the food eaten is the cause of the life threatening reaction;
• positive skin tests and/or RAST to the suspected food(s) can confirm the IgE mediated mechanism.
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3 . 2 . 8 . Exercise- induced anaphylaxis (EIA)
EIA has been recognized as a distinct form of physical allergy characterized by flushing or urticaria associated with symptoms of the upper respiratory tract and/or gastrointestinal tract that in some cases can precede cardiovascular failure.81-82
The intake of an offending food can elicit severe anaphylactic reactions when followed by exercise, whereas the ingestion of the food alone or exercise alone do not provoke symptoms. At times the offending food alone does not cause anaphylaxis but symptoms of anaphylaxis are elicited only when the food is combined with exercise. The pathogenesis of this syndrome remains unknown but it probably involves the degranulation of mast cell and an abnormal response of the autonomic nervous system.
There are rare reports of this disease: Maulitz et al.83 report one reaction of exercise-induced anaphylaxis to shellfish; Kidd and Cohen81 report three cases after celery intake. In these patients symptoms appeared within 2 to 15 minutes after initiating exercise. In one patient it was clearly shown that exercise without prior food ingestion or exercise occurring two hours after an offending meal did not produce an anaphylactic reaction. Other cases have reported a delay in the onset of symptoms: usually apparent 1-4 hours after physical exercise. The diagnosis should become evident if DBPCFC is followed by exercise.
In conclusion exercise-induced anaphylaxis is the result of an IgE-mediated reaction to a sensitizing food, occurring when physical exercise is performed after the ingestion of that food in a previously sensitized individual.
3 . 2 . 9 . Gastro intes t inal hypersens i t iv i ty react ions to food
Some diseases of the gastrointestinal tract can be caused by allergic reactions to food allergens. The gastrointestinal system converts the ingested foods into simple elements which are easily absorbed. During the digestive process immunological (GALT) and physiological mechanisms act to hinder the passage of foreign antigens through the gastrointestinal mucosal barrier. Food-specific IgA antibodies that are secreted by the lymphatic structure into the lumen, aid in hindering the absorption of food antigens. In fact proteins or their fragments that cross the mucosal barrier are then inactivated in the systemic circulation mainly by Kuppfer cells of the liver and phagocytic cell of the retículo endothelial system. Disorders of intestinal barrier can allow macromolecules easily to reach the systemic circulation, triggering clinical reactions locally or at sites distant from the site of absorption.84
Some allergic reactions of the gastrointestinal tract can be caused by more than one immunological mechanism. Nonetheless, most reactions are IgE-mediated: i.e. oral allergy syndrome; gastrointestinal anaphylaxis (malaise, abdominal pain, vomiting, and/or diarrhoea) and infantile colic.
Other adverse reactions to food depend on a non-lgE-mediated immunological mechanism: i.e. food-induced enterocolitis syndrome, allergic eosinophilic gastroenteropathy; food-induced colitis, malabsorption syndromes, intolerance to lactose; dermatitis herpetiformis; celiac disease and food-induced pulmonary hemosiderosis.
33
3.2.9.1. Gastrointestinal anaphylaxis
This disease is an IgE-mediated gastrointestinal hypersensitivity that accompanies allergic manifestations in other target organs.37 This results in a variety of symptoms that generally develop within minutes to two hours after food intake, mainly nausea, abdominal pain, vomiting, and/or diarrhoea. In children with atopic dermatitis and food allergy,59 the frequent ingestion of food allergens may induce partial desensitization of gastrointestinal mast-cells resulting in less pronounced symptoms (poor appetite, periodic abdominal pain). In these patients the abnormal gut permeability has been shown to be related to histological alterations of the gastrointestinal tract.
3.2.9.2. Infantile colics
This is a syndrome characterized by a unrestrainable crying and intractability that develop during the first 3-4 months of life.85 A possible cause of the pain could be the hypersensitivity to cow's milk.86 In fact, psychosocial and dietary factors have been implicated in the etiology of this syndrome. However, recent double-blind crossover trials in bottle-fed and breast-fed infants suggest that IgE mediated hypersensitivity may be a pathogenic factor in some infants.87 This mechanism accounts for only 10-15% of all colicky infants, the etiopathology of the remaining cases remain unclear.88
3.2.9.3. Allergic eosinophilic gastroenteropathy
This disorder is characterized by peripheral eosinophilia, eosinophilic infiltration of gastric and intestinal mucosa, and exacerbation of symptoms.89
A large number of gastropathies fall under the heading of 'eosinophilic gastroenteropathy', but an IgE-mediated food allergy has been recognized only in the disorder with the characteristics described by Waldman.90 Their patients simultaneously showed other atopic diseases.
The eosinophilic infiltrate involves various gastric and intestinal layers. Eosinophilic invasion of the muscular layer lead to thickening and rigidity of the stomach and intestinal walls, along with eosinophilic infiltration of the serosal cells. Symptoms are post-prandial nausea and vomiting, abdominal pain, diarrhoea (occasionally steatorrhoea), weight loss in adults or failure to thrive in young infants.
These patients have a form of the disease that is mainly localized to the mucosa; an IgE-mediated reaction to food has been identified as the cause of this disorder. This form of allergic eosinophilic gastroenteropathy can be accompanied by elevated IgE antibodies in duodenal and jejunal tissue, elevated serum IgE titres, positive prick tests to inhalant and foods allergens, peripheral blood eosinophilia, iron deficiency anemia, and hypoalbuminemia. Edema secondary to hypoal-buminemia may occur in infants with protein-losing enteropathy with minimal gastrointestinal symptoms. A small number of patients have an improvement of symptoms after an elimination diet. Symptoms may resolve after eliminating the responsible food from the diet for a period of 6 to 12 weeks.
34
3.2.9.4. Food-induced enterocolitis syndrome
This disorder is seen in children within the third month of life; it is characterized by vomiting, diarrhoea, and malabsorption. Symptoms are provoked by hypersensitivity to cow-milk and soya proteins.91 The damaged intestinal mucosa and accompanying malabsorption may also be caused by intolerance to chicken, rice, fish, and egg. Stools may contain occult blood, eosinophils, neutrophils, and may also test positive for sugar malabsorption. Skin-prick tests for food are generally negative. Jejunal biopsy also shows mild atrophy of the mucosa that is similar to that seen in celiac disease. Vomiting and diarrhoea may occur within minutes to hours after a food-challenge test. However, opinions regarding the pathogenesis of this syndrome remain discordant. Although many authors consider this enteropathy as non-lgE mediated, an increase in IgE antibodies has been demostrated after challenge with the suspected foods.92-93 Studies performed on intestinal biopsies showed evidence of an increase in plasma cells producing IgM and IgA.94·95 Recent investigations report the IgE-mediated activation of intestinal mast-cells.
A milk-free diet induces a quick resolution of symptoms and many children tolerate milk by their first year of life, also in the presence of moderate abnormalities of the jejunal mucosa.
3.2.9.5. Food-induced colitis
This is a disorder that develops in the first few months of life; symptoms are caused by hypersensitivity to milk and soya proteins.96·97 The most important complaint is bloody diarrhoea; histologic lesions are seen in the large bowel and primarily consist of mucosal edema and eosinophilic infiltration of the epithelium and lamina propria.
In these children, symptoms improve after eliminating cow's milk or soya from their diet or the mother's diet if the infant is being breast-fed. These children tolerate milk by the age of two.
3.2.9.6. Food-induced malabsorption syndrome
This disorder is present in the first several months of life and is characterized by diarrhoea, poor weight gain, and carbohydrate malabsorption.98 These patients are generally intolerant to either cow's milk proteins, soya, egg, or wheat. Jejunal biopsy is typically defined by patchy villous atrophy and cellular infiltration. Moreover these patients show elevated serum IgA and IgG antibodies specific for cow's milk proteins.
3.2.9.7. Lactose intolerance
Intestinal lactase is an enzyme able to hydrolyze lactose and glycosilceramide found in human milk. 99,100
Isolated deficiency of this enzyme is rare and is usually manifested at birth. On the other hand, the acquired deficiency is frequently seen in adults, often after disease of the small bowel. The concentration of lactase in the intestinal brush-border cells tends to decrease in the long run. The prevalence of acquired lactase deficiency is elevated in Orientals, Negroes, and American
35
Indians (90%);101 in subjects of Northern Europeans the prevalence is only about 5%. In Italy the prevalence of lactase deficiency has been reported to be 4, 52, 55,102 and 78%, according to the different studies performed on healthy adults. Secondary lactase deficiency is present in some inflammatory bowel disorders, untreated celiac disease, bowel reactions in chronic alcoholism, and after anti-neoplastic chemotherapy. Identification of these patients is possible with the use of indirect methods: measuring glycemia after lactose load and H2 concentration assay in expiratory air after lactase ingestion (H2 breath test).103 The latter test is very sensitive for quantifying the lactose that is not absorbed.
Management of the lactose intolerant patient is based on educating the patient on what foods reduce symptoms rather than instructing the patient to exclude those foods that contain lactose. It has been verified that lactase is an induceable enzyme and that patients with lactase deficiency can induce acquired tolerance to lactose by drinking large quantities of milk, thereby selecting the development of a bacterial flora that metabolizes lactose in the presence of an acidic environment.104
3.2.9.8. Dermatitis herpetiformis
This disease is a papular-vesicular skin disease often associated with gluten sensitive enteropathy (85% of patients).
Dermatitis herpetiformis, as celiac disease, has an increased association with specific cellular surface antigens: 80-90% of these patients have the HLA B8 and DRW3 haplotype.10·69 The histology of the skin lesions is characterized by infiltration of PMN in the dermoepidermal junction. The derma of 85-90% of the patients with dermatitis herpetiformis reveals granular deposits of IgA with J-chains. This suggests that the IgA antibodies most probably originate from the mucosal surface of the small bowel.
Linear IgA deposist without J-chains can be found in 5% of the patients, suggesting non-mucosal origin of these immune globulins.107'108 Intestinal biopsy in patients with granular IgA deposits indicates injury that is similar to celiac disease.109 On the contrary, patients with linear IgA deposits do not show the typical intestinal defects.
Elimination of gluten from the diet leads to resolution of skin symptoms and normalization of intestinal intercellular structures over several months; and this permits the tapering of sulfones.
3.2.9.9. Celiac disease (CD)
CD is a gluten sensitive enteropathy caused by an abnormal intestinal immune response to gluten.110·111 It appears in individuals with genetic susceptibility and the haplotype HLA B8 DW3. interaction between gluten and the immune system not only involves intestinal mucosa but also the skin, oral mucosa, kidney, and joints. In the intestinal mucosa T-cell mediated immunity accompanies the histological and functional alteration: flat mucosa or normal crypts and villi with an intraepithelial lymphocytic infiltration of the villi. A clear correspondence between histological alteration and symptoms is not always present: therefore celiac disease has been defined as active, silent, latent, and potential celiac disease.
36
Villous atrophy, crypt hyperplasia, gastrointestinal symptoms, and malabsorption characterize the active form. In silent disease there is a scarcity of symptoms and the mucosa is flat. In latent celiac disease the intestinal mucosa is normal when on a free diet, but these patients can or will develop a flattened mucosa that normalizes after a gluten-free diet. The immunopathogenesis is not evident but recent studies suggest a cell-mediated mechanism. Pathological lesions of the small intestine consist of neutrophilic and eosinophilic infiltration of the mucosa with edema and increased vascular permeability. Subsequently the mucosa is infiltrated by mononuclear cells, plasma cells, and lymphocytes. In chronic celiac disease one sees a reduced flat intestinal mucosa with villous athrophy, plasma cells, and lymphocytic infiltration of the lamina propria. The increased antibody response (antigliadin antibodies or food-antigen antibodies) is a consequence of anti-inflammatory activity. It is unlikely that antigliadin antibodies (AGA) play an important role in the mucosal damage, although an activated complement system is evident in these patients. Some authors consider celiac disease to be an autoimmune disease caused by gluten ingestion, the target organ being the protein of the lamina propria after identification of Ab antireticuline, Ab-antiendomysium, Ab-antijejunum.112·113·114'115
The active form of celiac disease occurs in the first two years of life and is characterized by chronic diarrhoea, weight loss, vomiting, and anorexia. If extensive mucosal damage is present the patients may suffer from steatorrhoea, peripheral edema, pallor due to food loss caused by vitamin-K deficiency, and tetany due to calcium and magnesium deficiency. Recent instrumental investigations have shown new forms of the disease. These forms are frequent during late infancy and in adults with extraintestinal symptoms: iron deficency anemia (resistant to iron replacement therapy), retardation of puberty and low stature. The association between celiac disease and joint disease and the evidence of elevated transaminase levels and chronic hepatitis has also been reported. Moreover, an association has been indicated between celiac disease and epilepsy in patients with bilateral occipital calcifications. Dentinoenamel hypoplasia and recurrent aphtous ulcers can be symptoms of celiac disease. Granular IgA accumulations have been found in celiac patients.
Treatment for celiac disease consists of a gluten-free diet. Clinical improvement, particularly in children, can be seen within days of dietary treatment and morphologic abnormalities are reversed in a matter of weeks. A life-long gluten-free diet is recommended for celiac disease patients regardless of symptoms.
3.2.9.10. Heiner's syndrome or food-induced pulmonary hemosiderosis
This is a syndrome characterized by recurrent episodes of pneumonia associated with pulmonary infiltrates caused by hemosiderosis, iron deficiency anemia due to gastrointestinal blood loss, failure to thrive, vomiting, cough, and dysplasia. Hemosiderin-laden macrophages may be found in the gastric fluid or on biopsy specimens of the lung; multiple serum precipitins to cow's milk may also be seen in the peripheral blood.116·117
This rare syndrome is often associated with a non-lgE-mediated hypersensitivity to cow's milk but reactivity to egg and pork has also been reported: the immunological mechanisms are not known.
37
Rare studies report deposits of IgG, IgA, and C'3 in lung biopsy specimens. Antigen antibody complexes and lymphocyte mediated hypersensitivity responses to milk are postulated in the immunopathogenesis of this disorder. This hypothesis is based on the presence of elevated serum levels of milk specific IgG antibodies. The elimination of milk or other foods responsible resolves symptoms.
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55 Wilson S.J. and Walker M. 'Absorption of undigested proteins in human beings. The absorption
of unaltered egg protein in infants'. Am. J. Dis. Child 50, pp. 4954. 1935.
56 Burk A.W., Mallory S.B., Williams L.W. et al. 'Atopic Dermatitis: clinical relevance of food
hypersensivity reactions'. J. Pediat. 113, pp. 447451. 1988.
41
57 Sampson H.A. 'Food hypersensitivity and atopic dermatitis'. Allergy Proc. 12, 5, pp. 327331.
1991.
58 Jackson P.G., Baker R.W.R., Lessof M.H. et al. 'Intestinal permeability in patients with eczema
and food allergy'. Lancet 1, pp. 12851286. 1981.
59 Flick J.A., Sampson H.A., Perman J.A. 'Intestinal permeability to carbohydrates in children with
atopic dermatitis and food hypersensitivity'. Pediatr. Res. 23, p. 303 A. 1988.
60 Lahti Α., Maibach H.I. 'Contact skin allergy: urticaria'. Clinical Science 61, pp. 14631469.
1987.
61 Maibach H.I. 'Immediate hypersensitivity in hand dermatitis'. Arch. Dermatol. 112, pp. 1289
1291. 1976.
62 Hjorth Ν., Roed Petersen J. 'Occupational protein contact dermatitis in food handlers'. Contact
Dermatitis 2, pp. 2842. 1976.
63 Hafner J., Riess CE., Wutricht B. 'Protein contact dermatitis from paprika and curry in
cooking'. Contact Dermatitis 26, pp. 5152. 1992.
64 Settipane R., Settipane G.A. 'Anaphylaxis and food allergy'. Clinical Science 11, pp. 150163.
1991.
65 Junginger J.W. et al. 'Fatal foodinduced anaphylaxis'. YAMA 260, pp. 14501452. 1988.
66 Junginger, et al. 'Fatal anaphylactic reactions induced by peanuts'. Allergy Proceed. 10, 4, pp.
249253. 1989.
67 Sampson H. et al. 'Fatal and near fatal anaphylactic reaction to food in children and adoles
cents'. New England J. Med. 327, pp. 380384. 1992.
68 Dutau G. et al. 'Chocs anaphylactiques par allergies alimentaires'. Rev. Fr. Allerg. 34(5): pp.
409417. 1994.
69 Dutau G. et al. 'L'arachide: allergène d'avenir chez l'enfant et l'adolescent'. Sem. Hop. Paris
26, pp. 16261665. 1991.
70 Sampson H.A. 'Peanuts anaphylaxis'. J. Aller. Clin. Immunol. 86, pp. 13. 1990.
71 CollinsWilliams C 'Acute allergic reaction to cow's milk'. Ann. Allergy 13, pp. 415421. 1955.
72 Vargiu Α., Vargiu E., Locci F., Del Giacco S., Del Giacco G.S. 'Hypersensitivity reactions from
inhalation of milk proteins'. Allergy 49, pp. 386387. 1994.
73 Dutau G., Juchet A. 'Allergie alimentaire à l'oeuf'. Arch. Fr. Pediatr. 50, pp. 185186. 1993.
42
74 Ansaloni R., Ispano M., Ortolani C. 'Reazioni allergiche ad alimenti pericolose per la vita'. Atti Meeting Annuale SIAIC, Napoli, 1993.
75 Chiù J.T. et al. 'Sesame seed oil anaphylaxis'. J. Allergy Clin, immun. 88, pp. 414-415. 1991.
76 Kaegi M., Wuhtrich B. 'Falafel-burger anaphylaxis due to sesame seed allergy'. Lancet 388, p. 582. 1991.
77 Panconesi et al. 'Anaphylactic shock from mustard after ingestion of pizza'. Contact Dermatitis 6, pp. 294-295. 1990.
78 Raneé F., Dutau G. 'L'allergie à la moutarde chez l'enfant'. Rev. Fr. Allerg. 33, pp. 292-294. 1993.
79 Raneé F. et al. 'Allergie aux épiées chez l'enfant'. Rev. Fr. Allerg (a paraître).
80 Monreal P., Botey J. et al. 'Mustard allergy. Two anaphylactic reactions to ingestion of mustard sauce'. Ann. Allergy 69, pp. 317-320. 1992.
81 Kidd J.M., Cohen S.H. 'Food-dependent exercise anaphylaxis'. J. Allergy Clin. Immun. 71, pp. 407-411. 1983.
82 Martin Munoz et al. 'Exercise-induced anaphylactic reaction to hazelnut'. Allergy 49, pp. 314-316. 1994.
83 Maulitz R.M. et al. 'Exercise-induced anaphylactic reaction to shellfish'. J. Allerg. Clin. Immunol. 63, p. 433. 1979.
84 Gallo C et al. 'Modelli di allergia alimentare non IgE mediata'. Corso di allergia ed intolleranza alimentare, pp. 51-59, Società' Italiana di Allergologia e Immunologia clinica, Milano, 1994.
85 lllingsworth R.S. 'Three month's colic'. Arch. Dis. Child 29, pp. 165-174. 1954.
86 Lothe L., Lindberg T. 'Cow's milk whey proteins elicits symptoms of infantile colic in colicky formulae-fed infants. A double-blind cross-over study'. Pediatr. 83: pp. 262-266. 1989.
87 Jakobsson I., Lindberg T. 'Cow's milk proteins cause infantile colic in breast-fed infants. A double cross-over study'. Pediatric 71, pp. 268-271. 1983.
88 Sampson H.A. 'Infantile colic and food allergy: Fact or fiction?'. J. Pediatr. 115, pp. 583-584, 1989.
89 Klein N.C., Hargrave R.I. et al. 'Eosinophilic gastroenteritis'. Medicine 49, pp. 299-319. 1970.
90 Waldman T.A., Wochner R.D. et al. 'Allergic gastroenteropathy: A cause of excessive gastrointestinal protein loss'. New Engl. J. Med. 276, pp. 761-769. 1967.
43
91 Powell G.K. 'Milk and soy induced enterocolitis of infancy: Clinical features and standardization of challenge'. J. Pediatr. 93, pp. 553-560. 1978.
92 Goldman A.S., Andersen D.W. et al. 'Milk allergy I. Oral challenge with isolated milk proteins in allergic children'. Pediatr. 32, pp. 425-443. 1963.
93 Mc Donald P.J. et al. 'Food protein-induced enterocolitis altered antibody response to ingested antigen'. Ped. Res. 18, pp. 751-755. 1984.
94 Boch S.A., Remigio L.K. et al. 'Immunochemical localization of proteins in intestinal mucosa of children with diarrhoea'. J. Allergy Clin. Immunol. 72, pp. 262-268. 1983.
95 Pearsons J.R., Kingston D. et al. 'Antibody production to milk proteins in the jejunal mucosa of children with cow's milk protein intolerance'. Pediatric Res. 17, 406-412. 1983.
96 Gryboski J.D. 'Gastrointestinal milk allergy in infants'. Pediatrics 40, pp. 354-362, 1967.
97 Goldman H. et al. 'Allergic proctitis and gastroenteritis in children'. Ann. J. Surg. Pathol 10, pp. 75-86. 1986.
98 Kuitunen P., Visakorpi J.K., Savilahti E. et al. 'Malabsorption syndrome with cow's milk intolerance: Clinical findings and course in 54 cases'. Arch. Dis. Child. 50, pp. 321-356. 1975.
99 Saavedra J.M., Perman J.A. 'Current concepts in lactose malabsorption and intolerance'. Ann. Rev. Nutr. 9, pp. 475-502. 1989.
100 Buller H.A., Grand R.J. 'Lactose intolerance'. Ann. Rev. Med. 41, pp. 141-148. 1990.
101 Bayless T.M., Christopher N.L., Boyer S.H. 'Autosomal recessive inheritance of intestinal lactase deficiency: Evidence from ethnic difference'. J. Clinic. Invest. 48, A6. 1969.
102 Bozzani Α., Penagini R. et al. 'Lactose malabsorption and intolerance in Italians'. Dig. Dis. Sci. 31, pp. 1313-1316. 1986.
103 Sciaretta G., Giacobazzi G., Verri Α., Zanirato P., Garuti G., Malaguti P. 'Hydrogen breath test quantification and clinical correlation of lactose malabsorption in adult irritable bowel syndrome and ulcerative colitis'. Dig. Dis. Sci. 29, pp. 1098-1114. 1984.
104 Benati G., Stracchi A. et al. High prevalence of lactose malabsorption in the elderly does not facilitate dietetic deficiency'. It. J. Gastroent. 25, p. 519. 1993.
105 Hall R.P. 'The pathogenesis of dermatitis herpetiformis: Recent advances'. J. Am. Acad. Dermatol. 16, pp. 1129-1144. 1987.
106 Solheim B.G., Ek J., Thume P.O. et al. 'HLA antigens in dermatitis herpetiformis and coeliac disease. Tissue antigens'. 7, pp. 57-59. 1976.
44
107 Unsworth D.J., Payne A.W. et al. 'The IgA in dermatitis herpetiformis skin is dimeric'. Lancet
1,p. 478. 1982.
108 Leonard J.N., Haftenden G.P. et al. 'Evidence that the IgA in patients with IgA disease is
qualitatively different from that of patients with dermatitis herpetiformis'. Br. J. Dermat. 110: p.
315. 1984.
109 Laweley T.S., Straber W. et al. 'Small intestinal biopsies and HLA types in dermatitis herpeti
formis patients with granular and linear IgA skin deposits'. J. Invest. Dermatol. 74: p. 9. 1980.
110 Straber W. 'Glutensensitive enteropathy: An abnormal immunologic response of the gastroin
testinal tract to a dietary protein'. In Shorter R.G. and Kirsner J. editors: Gastrointestinal
immunity for the clinician. Grune & Stratton Orlando, p. 75. 1985.
111 Ferguson Α., Arranz E. et al. 'Clinical and pathological spectrum of coeliac disease: Active,
silent, latent, patient'. Gut. 34, pp. 150151. 1993.
112 Ferguson A. 'Models of immunologically driven small intestinal damage'. In Marsh M.N. editor:
Immunopathology of the small intestine. Marsh M.N. (ed.) Wiley J. and Co., Chichester, pp.
225252. 1987.
113 Maki M., Hallstrom O., Vesikari J.K. 'Evaluation of serum IgA class reticulin antibody test for
the detection of childhood celiac disease'. J. Pediatric. 105, pp. 901905. 1984.
114 Chorzelski T.P., Beutner E.H., Suley J. et al. 'IgA antiendomysium antibody. A new immuno
logical marker of dermatitis herpetiformis and coeliac disease'. Br. J. Dermat. 111, pp. 395
402. 1984.
115 Karpati S., Bürgin Wolff Α., Krieg T. et al. 'Binding to human jejunum of serum IgA antibody
from children with coeliac disease'. Lancet 366, p. 1335. 1990.
116 Heiner D.C., Sears J.W. 'Chronic respiratory disease associated with multiple circulating
precipitins to cow's milk'. Am. J. Dis. Child. 100, pp. 500502. 1960.
117 Lee S.K., Kniker W.T., Cook CD. et al. 'Cow's milkinduced pulmonary disease in children'.
Adv. Pediatr. 25, pp. 3957. 1978.
45
4. P A T H O G E N E S I S OF FOOD ALLERGY
S Y N O P S I S
Among the immunologically-mediated reactions to foods, IgE-mediated food allergy is the most exhaustively investigated regarding the pathogenesis. An important role in development of food allergy is played by the break of oral tolerance, an immunologic mechanism mainly supported by T-suppressor lymphocytes leading to a systemic hyporesponsiveness but local IgA hyperre-sponsiveness to antigens ingested in early infancy. Thus, hyperresponsiveness to antigens and immaturity of the immune system might account for the higher prevalence of food allergy in children than in adults. Also the characteristics of some allergens, such as an enzymatic activity or the resistance to digestion, especially occurring with sequential allergens, may be important in determining food sensitization. In addition, recent studies showed that sensitization to cross-reacting allergens present in food and inhalant sources may underlie the development of food allergy.
4.1 Introduction
Adverse reactions to foods can be classified in two main groups, the immunologically-mediated and the not-immunologically-mediated reactions, the latter comprising: (1) adverse reactions due to intolerance to carbohydrates, intestinal lactase deficiency being the most common cause of adverse reactions to foods; (2) toxic reactions to food contamination by pathogenic microbes or their toxins; (3) pharmacological reactions due to substances naturally occurring in foods such as caffeine and tyramine, or added in food preparation such as nitrites, or developing during storage such as histamine.
Immunologically-mediated reactions comprise: (1) IgE-mediated reactions, the only ones that have been exhaustively evaluated from all clinical and pathogenetic aspects, since the results of double-blind placebo-controlled food challenge (DBPCFC) show they are the only reactions really reproducible in controlled conditions. IgE-mediated reactions cause symptoms such as urticaria, atopic dermatitis and asthma, but also anaphylactic shock and gastrointestinal symptoms such as vomiting and diarrhoea; (2) cell-mediated reactions, including gluten enteropathy and probably the child-at-breast enteropathies, whose typical histological aspects include atrophic villus and hyperplastic crypta, elicited by foods such as soya, fish and milk.
IgE-mediated reactions are properly defined as allergic and are part of the large group of atopic diseases, involving both the exposure to certain antigens and a particular genetic disposition. However, a third factor is also likely to play a pivotal role in the case of IgE-mediated sensitization to foods, known as oral tolerance.1
4.2. Oral tolerance
The existence of oral tolerance has been known for a long time, but its mechanisms are only partially recognized. By this phenomenon the exposure to an antigen by the enteral route induces a specific systemic immunologic hyporesponsiveness, limited to IgE-mediated and cell-mediated
46
immunity, to subsequent exposures to the same antigen also by other routes, such as the parenteral one. Oral tolerance can be easily induced, especially with soluble antigens, but does not occur with replicant antigens and therefore oral tolerance cannot be induced to viral antigens. Oral tolerance has been demonstrated by a series of experimental models. For example some chemical aptens able to elicit contact dermatitis if administered in the experiment animal by the gastroenteric route significantly inhibited the contact sensitization compared to the control animals.2 First studies were performed by DNCB and demonstrated an inhibition of cell-mediated reactivity.3 Regarding food antigens, the most reproducible model is the oral tolerance to ovalbumin in mice, which can be induced by a single administration and can last up to two months. In a study a single administration of ovalbumin at different amounts induced a well-measurable suppression of cell-mediated reactivity.4 This obviously gave rise to various theoretical speculations about the most convenient rhythms of feeding in man and on the importance of the so-called 'priming' effect.5 This is a well reproducible and measurable phenomenon, the mechanisms of which are incompletely known, regulating the immune response to antigenically intact absorbed proteins. However absorption of intact proteins occurs only rarely, since some mechanisms globally defined as mucosal barrier are aimed at interfering with the intake of macromolecules. The gut is constantly exposed to large amounts of soluble and particulate antigens, mostly derived from foods. To avoid massive absorption followed by non-selective immunization, particular mechanisms have developed in the intestine, some non-immunologic forming a barrier to the passage of macromolecules, and others immunologic regulating the immune response if this barrier is broken.6
The intestinal barrier consists of mucus, gastric acid, duodeno-pancreatic enzymes. Gastric digestion by acid secretion and pepsinic hydrolysis provides a first degradation of food proteins, then completed by proteolytic enzymes determining a digestion in to simple peptides to be absorbed by the bowel. Therefore, the small bowel is reached only by a few intact proteins, the absorption of which is further prevented by the presence of the intestinal mucus. This is continuously produced by the mucus-secreting cells scattered in the intestinal epithelium and forms a viscous barrier trapping all the proteins with a molecular weight higher than 17 kd. However its major efficacy relies in being constituted by large glycoproteins with a prateie core and a carbohydratic contour. The latter account for about 80% of the molecular weight and have monosaccharidic terminal residues such as fucose and sialic acid. Many antigens, even of foods, adhere by such carbohydratic residue to enter in the enterocytes and thus the mucus acts by competition, blocking the food proteins as well as the cell walls of many microbes. The mucus, once trapped all refused substances, flows by peristaltic mechanisms. Another non-immunologic mechanism is represented by the selective permeability of the microvillum membrane of the enterocytes, which largely depends on age and maturation of the subject.
Also an immunologic mechanism consisting in the immunoexclusion by secretory IgA antibodies can concur to the intestinal barrier. They are prevalently represented by the lgA2 subclass, probably because of its greater resistance to enzymatic degradation compared to lgA1 subclass. If secretory IgA certainly block some antigens, especially bacterial,7 their role with food protein is yet unclear. So far a correlation between deficiency of secretory IgA and food allergy has not been reported, however this mechanism is under continuous investigation because of the theoretical importance of the block by IgA to antigen intake. This block occurs at three levels, namely in the lumen where IgA are secreted, in the epithelium and in the lamina propria. Despite this, a small
47
quota of macromolecules, corresponding to about 2%, physiologically reach the intestine, on one hand giving rise to further production of secretory IgA and on the other the development of oral tolerance, which is an anergic mechanism but involves many regulatory mechanisms.
Regulation of the immune response is based on the activity of anatomical structures such as Peyer's patches, M (microfold) cells, and other components of the immune system in the intestinal mucosa grouped under the umbrella term GALT (gut associated lymphoid tissue).8
Intestinal lymphatic tissue is one of the most abundant in the human organism and its basic elements are Peyer's patches and a specialized epithelium represented by M cells in the ileum. Peyer's patches are certainly an unique element in lymphatic system and can be defined as sites of induction of IgA response. They are complexly structured and include three main areas: so-called dome zones, in which are contained macrophagic dendritic cells and scattered Τ and Β lymphocytes, and two other well organized zones. These are the parafollicular zone where the Τ lymphocytes (T areas) are found and the follicular zone with two germinative centers where the Β lymphocytes (B areas) are the type of lymphocytes in the parafollicular zones which has been investigated in a number of studies and it has been possible to define, at least partly, the phenotype functions of these cells. Being Peyer's patches sites preferentially inductive of IgA response, they are provided of all the immunocompetent cells helping this response. Thus, in parafollicular zones Τ lymphocytes are essentially of CD4 phenotype with helper function, with only a small quote of CD8 lymphocytes.9 CD4 cells are lymphocytes regulating isotypic switch of Β cells from BlgM to BlgA. Peyer's patches are a site with a large concentration of BlgA, i.e. already capable of IgA production, however these are only 40% of resident Β cells, being 60% represented by cells that await the signal for switching.10
Also other types of lymphocytes are present. Recent studies reported the presence of subtype TH2 of CD4 cells, as demonstrated by the model of immunization with heterologous red cells in mice showing that, once the switch has occurred, lymphocytes producing cytokines such as IL-4, IL-5 and IL-6 (characteristic of the TH2 pattern) were found.11 In particular, IL-5 is involved in further development and differentiation of Β lymphocytes in plasma cells producing IgA.12
In Peyer's patches, an antigen-specific as well as an antigen-non-specific suppression may occur. The latter is demonstrated by the increase of oral response to certain antigens, the decrease of suppressor Τ cell response after oral challenge, and by the lack of oral unresponsiveness in animals genetically unresponsive to lipopolysaccharide.1
Once the sensitization to the antigen has occurred a specific Β IgA (with its TCD4) leaves through the efferent lymphatics, arrives to mesentheric lymph nodes, passes in the thoracic duct and reaches the bloodstream, then homing in the lamina propria of the different secretory sites, where the effector IgA response is effective. Therefore, most Β IgA cells return to the intestinal lamina propria (which is the induction site), where they develop to plasma cells and produce the dimeric IgA which adhere by their secretory or J component and are transported to the luminal surface. However, Β IgA cells may also reach different sites located in the respiratory, urogenital and mammary tissues, being influenced by endothelial factors such as addressins.13
48
This gives rise to the concept of a common mucosal system,14 which makes it reasonable that a sensitization that occurred in the GALT can account for antigen-specific IgA in all secretory apparata.
Considering the epithelium above Peyer's patches, M cells are caliciform cells lacking lysosomial organelles, thus allowing an unaffected passage of antigens, which reach intact macrophages, dendritic cells, and the dome zone of Peyer's patches, where they are processed and elicit the immune response. However M cells are only a minority in the intestinal epithelium, where the most common cell is the enterocyte. This cell absorbs the antigens and certainly plays an important role in the regulation of the immune response to food antigens because (1) it carries secretory IgA and joins them to J component (2) it has a rich lysosomial apparatus and expresses class II MHC antigens (3) it is in continuous contact with intraepithelial lymphocytes (IEL), to which deep investigation have been devoted from many years.15 These lymphocytes are an homogeneous group of Τ cells with CD3 + CD8 + phenotype, thus showing a suppressor/cyto-toxic function, which represent 70-90% of human IEL16; those cells recently were attributed the function of suppressing the immune response at a systemic level.17 In rats and humans, antigen presentation by epithelial cells expressing class II MCH antigens is likely to induce a selective stimulation of CD8+ suppressor cells with subsequent block of the immune response to that antigen.18'19 It is reasonable to suppose that these activated CD8+ cells are IEL.
From a theoretical point of view, as enterocytes present the antigen in conjunction with class II MHC molecules a preferential stimulation of CD4+ cells, i.e. helper lymphocytes, should occur, but on the contrary a suppressor stimulation takes place. This fact has not yet been explained, however recent studies reported that antigens produced by immature IEL can stimulate Τ suppression.20 Moreover, enterocytes express anomalous class II antigens and may produce tolerogenic substances.9 It is possible that the type of antigen presentation by the enterocyte may condition the activation of CD8+ lymphocytes, which once migrated in the spleen should induce anergy.
The phenomenon of oral tolerance is currently under thorough investigation because it has been found that it can be used in treatment of immunologic diseases. For example in experimental allergic encephalopathy of the mouse, equivalent to multiple sclerosis in man, administering basic myelin by feeding made it possible to stop the demyelination lesions.21 Moreover, oral immunization with allogeneic splenocytes was able to inhibit accelerated rejection of cardiac graft.22
Therefore oral tolerance seems to be a very important immunologic mechanism mainly supported by T-suppressor lymphocytes, as demonstrated by its inhibition by T-suppressor depletion made with cyclophosphamide.23 It occurs quickly following a single assumption and depends on the animal's age, doses and times of administration, developing according to a sequence in which the antigen uptake by M cells in intestinal Peyer's patches is followed by local production of secretory IgA antibodies accompanied by suppression of the systemic response by T-suppressor lymphocytes. This gives rise to a systemic hyporesponsiveness of IgM, IgG and IgE but local hyperre-sponsiveness of antigen-specific secretory IgA, which then helps block further antigen absorption. Though it has not been proved that IEL are solely responsible for oral tolerance, considering their phenotype and the contiguity with epithelial cells and mucosal lymphatic system, they are probably the cells most involved.
49
These observations suggest that any break in this sequence of events, even partial or short-lasting, can cause the loss of oral tolerance, resulting in sensitization to foods.
4.3 Immaturity of the immune system
The dependency of oral tolerance on the animal's age suggests the importance of maturation of the immune system in this mechanism. It has been found that a too early feeding with solid foods in respect to the animal's age can determine an activation of IEL antigens, resulting in the abolition of tolerance also to soluble antigens.24 Thus, in humans an inadequacy of the mechanisms underlying oral tolerance might account for the higher prevalence of food allergy among children, especially in the very first years when factors regulating the intestinal barrier are not yet fully developed.25 The final maturation of the specialized structures of the intestinal barrier would thus explain the spontaneous resolution of food allergy in the first three years of life, which occurs, as demonstrated by Bock, very commonly.26 By contrast, a food allergy arising after this age is unlikely to resolve spontaneously. It is thus conceivable that in infancy the lack of fine regulation of IgA synthesis and of full maturation of enterocyte microvillus membrane may condition a high passage of food antigens and, as a consequence, a sensitization to foods caused by a breakdown of tolerance.
The overall immaturity of the immune system in the first months of life might explain the high prevalence in early infancy of atopic eczema, a disorder often related to food allergy. True immunodeficiency diseases involve eczema and dysregulation of IgE and IgA antibodies. Among these are some diseases due to the presence of dysfunctional Β cells, such as Wiskott-Aldrich syndrome and hyper-lgE syndrome in which both eczema and high levels of IgE are likely to be related to an impaired function of the Τ suppressor cells.27 Thus in a child with no true immunodeficiency a transient slowing or arrest of the maturation of these cells might cause eczema symptoms and/or an increase of IgE (even specific) which will disappear when the immune system matures.
Recent studies underlined the importance of intestinal mast cells. In the gut there is a vast number of both mucosal and connectival mast cells, though in humans this distinction is not as clear-cut as in rats since the two types may have similar characteristics according to the conditions of the environment.28 In the regulation of IgE sinthesis two signals are required: the presence of IL-4 and the T-B interaction, which may be cognate (i.e. with interposition of the antigen) but also non-cognate.29 Recently the mechanism of non-cognate interaction was identified as the ligand CD 40 on the Τ cell and this ligand was found also on mast cells and basophils, thus these cells can determine, in cooperation with Β cells, the production of IgE with no Tcells.30
This has to be carefully considered to explain why sensitization is particularly important in sites with the most abundance of mast cells, such as the intestinal and respiratory mucosa.
However food allergy does not always occur in the first three years of life. In patients with allergic symptoms after this age it is difficult to lay the blame on factors such as impairment of the gastroenteric barrier or of immunecompetent cells, and other mechanisms are more likely to be involved, such as the exposure to certain food allergens.
50
4.4. Role of allergens
Pathogenetic mechanisms linked to food allergens, or even to allergens from other sources, are
still largely unknown, but on the basis of recent data some hypotheses can be proposed.
It is likely that in adults with a mature intestinal immune system, only some characteristics of the
allergens might favour the sensitization. The pivotal characteristic that makes an antigen aller
genic is still unidentified, however general characteristics of allergens include the glycoprotein
nature, a molecular weight ranging from 5 to 50 kd (but reaching also 8090 kd) and a variable
resistance to heat and digestion. The latter is related to the antigenic determinants, many of
which have particular functional properties, sometimes linked to an enzymatic nature. For
example, the soybean tryptic inhibitor31
and the major allergens of dermatophagoides mites32
are enzymes and the enzymatic activity may account for an easier sensitization. Of particular
importance in providing the allergenicity of an antigen are some reaction sites with Τ and Β
lymphocytes as well as with IgE antibodies. There are continuous allergenic sites represented by
an epitopes formed by a unbroken segment of polypeptide chain, that is a series of aminoacids,
which are defined as sequential allergens. This kind of allergens is almost indestructible, being
very small and hardly affected by proteolytic activity. By contrast discontinuous allergenic sites
are formed by epitopes obtained by justa/position of aminoacids caused by folding of the peptidic
chain and their activity is linked to tertiary proteic structure. They are defined as conformational
allergens and are more easily denatured by chemical procedures or digestion.
Among sequential allergens the most investigated is allergen M from codfish (Gad c 1 from the
taxonomie name Gadus callarías according to current allergen nomenclature), which is a low
molecular weight protein, of 12.3 kd, formed by a sequence of 113 aminoacids. The IgE reactive
epitope is formed by two tetrapeptides separated by an inert aminoacidic sequence33
and this
structure accounts for the sequential nature and makes the allergen in toto resistant to heat and
proteolysis. Another sequential allergen is ovalbumin, one of the major allergens of chicken's
egg, in which a reactive epitope formed by a sequence of 10 aminoacids was identified34
. A very
important allergenic source, especially in USA, is peanut (Arachis hypogea). All the proteins
contained in the hydrosoluble globulinic fraction are allergens and Ara h 1 and Ara h 2 were
recognized as major allergens.35
·36
So far, no sequential allergen has been identified, however
the peculiar allergenicity of peanut is indicated by the particular natural history of peanut allergy,
showing, differently from other food allergies, no tendency to be outgrown with time.37
Among conformational allergens it is known that the allergens contained in the albuminic fraction
of wheat flour are responsible for sensitization by the inhalant route, causing the socalled baker's
asthma, but are unable to resist to digestion and thus allergic subjects can eat bread with no
reaction.38
Upon different conditions, a sensitization route other than the gastroenteric one could be
important in determining food allergy. Some patients may be sensitized by inhalation, inducing
IgE production toward foods sharing allergens or epitopes with inhalant sources such as pollens,
mites or animal hair and dander. This seems true for the most common food allergy in adults, the
oral allergy syndrome, which especially involves vegetable foods.39
This syndrome is very
frequently associated with pollinosis and allergy to certain vegetable foods is related to allergy to
51
certain pollens, as reported since 194240 and confirmed in a number of studies.41 Well-known associations between foods and pollens are: apple and birch;42 celery and birch and mugwort;43
melon and banana and ragweed;44 tomato and peanut and grass;45 kiwi and grass and birch.46
Recent studies investigated the pathogenetic basis of these clinical associations and in some cases it has been possible to identify the allergen determining IgE cross-reactivity. For example the major allergen of birch (Betula verrucosa) Bet ν 1, with a molecular weight of 17 kd, was found as the allergen causing clinical reaction to apple in subjects allergic to birch pollen.42 Bet ν 1 and its iso-allergen in apple demonstrated an homology of about 75% at nucleic acid level, thus making it reasonable to suppose that, considering the diffusion of birch pollinosis, most subjects allergic to apple are sensitized to the 17 kd allergen by the inhalant route.
Allergy to kiwi fruit also seems conditioned by sensitization to allergens cross-reactive with grass and birch pollens, as demonstrated by the inhibition of immunoblotting, which causes a complete disappearance of some allergens demonstrating an almost identical structure.46 Patients with allergy to vegetable foods and pollens always report that pollinosis began before, often many years before, the oral allergy syndrome, thus indicating the route of sensitization as the inhalant one.
Another model of cross-sensitization is allergy to avian proteins occurring in bird breeders, or in whatever subjects exposed to birds, conditioning hypersensitivity to egg.47 Also in this case, which has been defined as 'bird-egg syndrome', the homology between the two allergenic sources was demonstrated in the laboratory by a very high inhibition of RAST, and in particular the cross-reactive allergen was identified in egg yolk α-livetin, homologous to chicken serum albumin.48 Similarly to oral allergy syndrome and pollinosis, sensitization to avian proteins precedes allergy to egg, confirming the importance of the inhalant route.
In some cases ubiquitous antigens are involved, these are defined as panallergens, that is allergens extremely diffuse in both the vegetable and animal kingdoms. This is true for profilin, a well-known protein with a molecular weight of about 14 kd, determining in animals actine polymerization and involved in macrosomial reaction of spermatic cells.
This kind of sensitization occurs in birch and mugwort pollinosis, both conditioning hypersensitivity to celery due to profilin.49 In birch, profilin has been identified as the major allergen Bet ν 2,50
but its presence has been recognized in a number of vegetable foods, and in some cases monoclonal antibodies have demonstrated the identity of the two profilins.51 Being reported a homology of 34% also with human profilin, it cannot be excluded that in some cases the IgE reactivity to this allergen may be maintained by an autosensitization.51
Other ubiquitous proteins accounting for sensitization by different routes are lectins. These constitute a heterogeneous group of glycoproteins which have the characteristic to specifically bind with very high avidity to a single monosaccharide.52 Lectins are extremely diffuse in the vegetable kingdom but were identified also in animals.53 Due to their high affinity for carbohydrate residues, lectins were suspected to induce degranulation of basophils by IgE-binding,54 but in in vitro studies RAST-inhibition with specific sugars failed to demonstrate such a mechanism.55
Thus sensitization to lectins is likely to occur by other mechanisms, such as intracellular
52
penetration by their ability to adhere to free monosaccharidic residuals. Because of this ability lectins are commonly used in immunologic research as mitogens.
Recent evidence has been added to our knowledge of the ubiquitous allergens tropomyosin, a protein involved in actine activation during muscle contraction, which has been identified as a cross-reactive allergen in shrimp, mites, and several insects.56 It is conceivable that in a number of patients allergic to mites, sensitization to tropomyosin, representing for shrimp its major allergen Pen a 1, 5 7 may trigger the development of food allergy to shrimp.
REFERENCES
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2 Strobel S. 'Oral tolerance'. In Auricchio S., Ferguson Α., Troncone R. (eds.): 'Mucosal immunity and the gut epithelium. Interactions in health and disease'. Dyn. Nutr. Res. Basel, Karger, 1995, vol 4, pp. 65-75.
3 Lowney E.D. 'Tolerance of a contact sensitizer in man'. Lancet 1968, 1, p. 1377.
4 Bruce M.G., Ferguson A. 'Oral tolerance to ovalbumin in mice: Studies of chemically modified and "biologically filtered" antigen'. Immunology 1986, 57, pp. 627-630.
5 Strobel S., Ferguson A. 'Immune responses to fed protein antigens in mice. III. Systemic tolerance or priming is related to age at which antigen is first encountered'. Pediatr. Res. 1984, 18, pp. 588-594.
6 Walker W.A. 'Role of mucosal barrier in antigen handling by the gut'. In Brostoff J., Challa-combe S.J. (Eds.): 'Food allergy and intolerance'. Bailliere Tindall, London, 1987, pp. 209-222.
7 Brandtzaeg P., Nilssen D.E., Rognum T.O., Thrane P.S. Ontogeny of the mucosal immune system and IgA deficiency'. Mucosal immunology. I. Basic principles. Gastroenterol Clin. North Am. 1991,20, pp. 397-439.
8 Kagnoff M.F. 'Immunology of the intestinal tract'. Gastroenterology 1993, 105, pp. 1275-1280.
9 Kaiserlian D. 'The intestinal epithelial cell: a nonconventional type of antigen-presenting cell'. In Auricchio S., Ferguson Α., Troncone R. (eds.): 'Mucosal immunity and the gut epithelium. Interactions in health and disease'. Dyn. Nutr. Res. Basel, Karger, 1995, vol. 4. pp. 32-39.
10 Straber W., James S.P. 'The mucosal immune system'. In Stites D.P., Terr A.I., Parslow T.G. (eds.): 'Basic and clinical immunology'. Lange, East Norwalk, 1994. pp. 541-551.
11 Guy-Grand D., Vassalli P. 'Gut intraepithelial Τ lymphocytes'. Curr. Opin. Immunol., 1993, 5, pp. 247-252.
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12 Harriman G.R. 'The role of IL-5 in IgA Β cell differentation'. J. Immunol. 1988, 140, pp. 3033-3039.
13 Picker L.J., Treer J.R., Ferguson-Darnell B., Collins P., Buck D., Terstappen L.W.M. 'Control of lymphocyte homing in man: I. Differential regulation of the peripheral lymph node homing receptor L-selection on T-cells during the virgin to memory transition'. J. Immunol. 1993, 150, pp. 1105-1121.
14 Bienenstock J., Mc Dermott M., Befus AD. 'A common mucosal system'. In Ogra PL, Dayton D (eds.): Immunology of breast milk. Raven Press, New York, 1979, pp. 135-151.
15 Ferguson A. 'Progress report. Intraepithelial lymphocytes of the small intestine'. Gut 1977, 18, pp. 921-37.
16 Dobbins W.O. 'Human intestinal intraepithelial lymphocytes'. Gut 1986, 27, pp. 972-85.
17 Barrett T.A., Gajewski T.F., Danielpour D., Chang E.B., Beagley K.W., Bluestone J.A. 'Differential functions of intestinal intraepithelial lymphocytes subsets'. J. Immunol. 1992, 149, pp. 1124-1130.
18 Bland P.W., Warren L. 'Antigen presentation by epithelial cells of the rat small intestine. II. Selective production of suppressor Τ cells'. Immunology 1986, 58, pp. 9-14.
19 Mayer L., Shlein R.C. 'Evidence for function of la molecules on gut epithelial cells in man'. J. Exp. Med. 1987, 166, pp. 1471-83.
20 James S.P. 'Mucosal T-cell function'. Gastroenterol Clin. North Am. 1991, 20, pp. 597-612.
21 Whitacre C.C., Gienapp I.E., Orosz CG., Bitar D.M. 'Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy'. J. Immunol. 1991, 147, pp. 2155-2163.
22 Hancock W.W., Sayegh M.H., Zhang Z.J., Kwok CA., Weiner H.L., Carpenter C.B. 'Oral immunization with allogeneic spenocytes inhibits development of accelerated but not acute rejection of cardiac grafts: Analysis of intragraft effector mechanisms'. Transplant Proc. 1992, 24, pp. 250-251.
23 Mowat A.M., Strobel S., Drummond Η.E. 'Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide'. Immunology 1982, 45, pp. 105-13.
24 Hanson D.G., Vaz N.M., Maia L.C.S. 'Inhibition of specific immune responses by feeding protein antigens. III. Evidence against maintenance of tolerance to ovalbumin by orally induced antibodies'. J. Immunol. 1979, 123, pp. 2337-43.
25 Taylor B., Norman A.P., Orgel M.A. 'Transient IgA deficiency and pathogenesis of infantile atopy'. Lancet 1973, 2, pp. 111-13 .
54
26 Bock S.A. 'The natural history of severe reactions to foods in young children'. J. Allergy Clin. Immunol. 1985, 107, pp. 676-80.
27 Vercelli D., Jabara H.H., Arai K., Geha R.S. 'Induction of human IgE synthesis requires interleukin 4 and T/B cell interactions involving the Τ cell receptor/CD23 complex and MHC class II antigens'. J. Exp. Med. 1989, 169, pp. 1295-1307.
28 Gauchat J.F., Henchoz S., Mazzel G., Aubry J.P., Brunner T., Blasey H., Life P., Talabot D., Flores-Romo L., Thompson J., Kishi K., Butterfield J., Dahinden C , Bonnefoy J.Y. 'Induction of human IgE synthesis in Β cells by mast cells and basophils'. Nature 1993, 365, pp. 3409-3413.
29 Parronchi P., Tiri Α., Macchia D. 'Non-cognate contact-dependent Β cell activation can promote IL-4 dependent in vitro human IgE synthesis. J. Immunol. 1990, 144 pp. 2102-2108.
30 Noelle R.J., Ledbetter J.A., Aruffo A. CD40 and its ligand: an essential figand-receptor pair for thymus-dependent B-cell activation. Immunol. Today, 1992, 13, pp. 431-437.
31 Moroz L.A., Yang W.H. 'Kunitz soybean tripsyn inhibitor: A specific allergen in food anaphylaxis'. N. Engl. J. Med. 1980, 302, pp. 1126-1128.
32 Yasueda H., Mita H., Akiyama K. 'Allergens from dermatophagoides mites with chymotryptic activity'. Clin. Exp. Allergy 1993, 23, pp. 384-390.
33 Elsayed S., Somes S., Apold J. 'The immunological reactivity of the three homologous repetitive tetrapeptides in the region 41-64 of allergen M from cod'. Scand. J. Immunol. 1982, 16, pp. 77-82.
34 Elsayed S., Holen E., Haugstad M.B. 'Antigenic and allergenic determinants of ovalbumin. II. The reactivity of the NH2 terminal decapeptide'. Scand. J. Immunol. 1988, 27, 587-591.
35 Burks A.W., Williams L.W., Helm R.M. 'Identification of a major peanut allergen, Ara h I, in patients with atopic dermatitis and positive peanut challenge'. J. Allergy. Clin. Immunol. 1991, 88, pp. 172-179.
36 Burks A.W., Williams L.W., Connaughton C. 'Identification and characterization of a second major peanut allergen, Ara h II, with use of sera of patients with atopic dermatitis and positive peanut challenge'. J. Allergy Clin. Immunol. 1992, 90, pp. 962-969.
37 Bock S.A., Atkins F.M. 'The natural history of peanut allergy'. J. Allergy Clin. Immunol. 1989, 83, pp. 900-904.
38 Sutton R., Hill D.J., Baldo B.A. 'Immunoglobulin E antibodies to ingested cereal flour components: studies with sera from subjects with asthma and eczema'. Clin. Allergy, 1982, 12, pp. 63-74.
39 Ortolani C , Ispano M., Pastorello E.A., Bigi Α., Ansaloni R. 'The oral allergy syndrome'. Ann. Allergy, 1988, 61, pp. 47-52.
55
40 Tuft L., Blumstein G.I. Studies in food allergy. II. Sensitization to fresh fruits: clinical and experimental observations'. J. Allergy, 1942, 13, pp. 574-582.
41 Ortolani C , Pastorello E.A., Farioli L., Ispano M., Pravettoni V., Berti C , Incorvaia C , Zanussi C. 'IgE-mediated allergy from vegetable allergens'. Ann. Allergy, 1993, 71, pp. 470-76.
42 Ebner C , Birkner T., Valenta R., Rumpold H., Breitenbach M., Scheiner O., Kraft D. 'Common epitopes of birch pollen and apples'. Studies by Western and Northern blot. J. Allergy Clin. Immunol. 1991, 88, pp. 588-94.
43 Pauli G., Bessot J.C, Dietermann-Molard A. 'Celery sensitivity: clinical and immunological correlations with pollen allergy'. Clin. Allergy, 1985, 15, pp. 273-279.
44 Anderson B.L., Dreyfuss E., Logan S. 'Melon and banana sensitivity coincident with ragweed pollinosis'. J. Allergy, 1970, 45, pp. 310-319.
45 De Martino M., Novembre E., Cozza G., De Marco Α., Bonazza G., Vierucci A. 'Sensitivity to tomato and peanut allergens in children monosensitized to grass pollen'. Allergy, 1988, 43, pp. 206-213.
46 Pastorello E.A., Ortolani C , Pravettoni V., Farioli L., Ispano M., Asman I., Bengtsson Α., Incorvaia C. 'Identification of the allergenic components of kiwi fruit and evaluation of their cross-reactivity with timothy and birch pollens'. Submitted.
47 Hoffman D.R., Guenther D.M. Occupational allergy to avian protein presenting as allergy to ingestion of egg yolk'. J. Allergy Clin. Immunol., 1988, 81, pp. 484-88.
48 Szepfalusi Z., Ebner C , Pandjaitian R., Orlicek F., Scheiner O., Boltz-Nitulescu G., Kraft D., Ebner H. 'Egg yolk α-livetin (chicken serum albumin) is a cross-reactive allergen in the bird-egg syndrome. J. Allergy Clin. Immunol., 1994, 93, pp. 932-942.
49 Valuer P., Dechamp C, Valenta R., Vial O., Deviller J. 'Purification and characterization of an allergen from celery immunochemically related to an allergen present in several other plant species. Identification as a profilin'. Clin. Exp. Allergy, 1992, 22, pp. 774-782.
50 Valenta R., Duchene M., Ebner C , Pettemburger K., Scheiner O., Kraft D. 'Profilins constitute a novel family of functional plant pan-allergens'. J. Exp. Med., 1992, 2, pp. 377-385.
51 Valenta R., Duchene M., Pettemburger K., Sillaber P., Valent P., Bettelheim P., Breitenbach M., Rumpold H., Kraft D., Scheiner O. 'Identification of profilin as a novel pollen allergen; IgE autoreactivity in sensitized individuals'. Science, 1991, 253, pp. 557-60.
52 Summer J.B., Howell S.F. 'Identification of hemagglutinin of jack bean concanavalin'. A. J. Bacteriol., 1936, 32, pp. 227-237.
53 Freed D.L.J. 'Dietary lectins and disease'. In Brostoff J., Challacombe S.J. (eds.): Food allergy and intolerance, Bailliere Tindall, London, 1987, pp. 375-400.
56
54 Siraganian R.P., Siraganian P.A. 'Mechanism of action of concanavalin A on human basophils'. J. Immunol., 1975, 114, pp. 886-893.
55 Barnett D., Howden M.E.H. 'Lectins and the radioallegosorbenttest'. J. Allergy. Clin. Immunol., 1987,80, pp. 558-561.
56 Witteman A.M., Akkerdaas J.A., van Leeuwen J., van der Zee J.S., Aalberse R.C 'Identification of a cross-reactive allergen (presumably tropomyosin) in shrimp, mite and insects'. Int. Arch. Allergy Appi. Immunol., 1994, 105, pp. 56-61.
57 Shanti K.N., Martin B.M., Nagpal S., Metcalfe D.D., Subba Rao P.V. 'Identification of tropomyosin as the major shrimp allergen and characterization of its IgE-binding epitopes'. J. Immunol., 1993, 151, pp. 5354-5363.
57
FOOD A L L E R G E N S
SYNOPSIS
Compared with the vast number of aeroallergens as yet identified, only a few food allergens are known, mainly because of the difficulty to recruit sufficient patients with positive IgE test and DBPCFC and to perform the laboratory technique for detecting allergens. So far, food allergens have been identified in cow's milk (alactoalbumin, ßlactoglobulin, caseins), in hen's egg (ovomucoid, ovalbumin, ovotransferrin in egg white, αlivetin in egg yolk), in fish (Gad c 1), in shrimp (Pen a 1, Pen a 2), in peanut (Ara h 1, Ara h 2), in soybean (Gly m 1), in cereals (a series of proteins with m.w. from 26 to 79 kd as yet not named), in apple (Mal d 1, Mal d 2), in celery (Api g 1), in fruits belonging to Prunoideae (an allergen of 13 kd proposed as Pru ρ 1).
5 . Í Introduction
Allergens are polypeptide molecules of molecular weight (MW) ranging from 5 to 100 kd, able to
elicit a specific IgE response. Differently from inhalant allergens, that have been thoroughly
investigated, and the major, intermediate, and minor allergens1 have been identified, the process
of identification of food allergens is ongoing and only a limited number of foods has been
evaluated. This is mainly due to the difficulty, given the relative rarity of food allergy as compared
to inhalant allergy, in recruiting a reasonable population size of subjects with specific IgE tests
and doubleblind placebocontrolled food challenge (DBPCFC) positive for a given food, in order
to perform the laboratory techniques necessary to detect the allergens and to determine their
clinical importance.2
So far, this has been possible for some of the foods most frequently responsible for food allergy
such as cow's milk, hen's egg, fish, shrimp, peanut, wheat, soybean, and for some vegetable
foods frequently involved in oral allergy syndrome (OAS), such as apple, celery, and Prunoideae
fruits.
In recent years considerable efforts have been made to identify the major allergens of legumes,
cereals, fruits and vegetables. This has been possible for some of the above mainly by using
SDSPAGE and immunoblotting on the sera of patients with OAS, the most common form of food
allergy in adults, especially prevalent in subjects with pollinosis. A number of observations
indicate that the majority of allergens in fruits and vegetables are crossreactive with homologous
allergens in pollens, and that some allergens are particularly frequent. This is true for profilin, a
substance involved in fertilization of plants, and for the allergens related to the major allergen of
birch, Bet ν 1, which can be considered panallergens in the vegetable kingdom. On the other
hand, allergens not crossreacting with pollens are surely involved in clinical symptoms, as
demonstrated for fruits of the Prunoideae subfamily.
58
5.2. Allergens
5 . 2 . 1 . Cow's milk
Since the 1960s it has been found that cow's milk contains about 20 proteins able to elicit the
specific IgE synthesis.3 These proteins can be divided into caseins, representing about 80% of
the protein fraction of milk, and whey proteins, representing about 20%. The casein fraction is
comprised of five distinct proteins, namely αcasein (MW 27 kd), ascasein (23 kd), ßcasein (24
kd), Kcasein (19 kd), and γcasein (21 kd). The whey proteins comprise ßlactoglobulin (36 kd), of
which three genetic variants with different electrophoretic mobility, but with no immunological
differences, have been reported,4 alactoalbumin (14.4 kd), bovine serum albumin (69 kd),
peptone (420 kd), as well as bovin immunoglobulins, lactoferrin, tranferrin, and lipase.
Carbohydrates contained in cow's milk have no allergenic activity, but it has been reported that
the allergenicity of cow's milk proteins can be enhanced by a nonenzymatic reaction with lactose,
resulting in the coupling of the sugar to the protein, as demonstrated by a greater skin reactivity to
ßlactoglobulin treated with lactose onehundredfold higher than seen with untreated ßlactoglo
bulin in milk allergic patients.5
Caseins are heatstable if boiled, whereas ßlactoglobulin is partially denatured and the other
whey proteins are almost completely denatured.6 ßlactoglobulin was stable to digestion in a
gastric model in vitro, the whole protein resisted 60 minutes to digestion, casein whole protein
was stable two minutes, while its fragments 15 minutes.7
The availability of the various cow's milk proteins allowed to evaluate their allergenic importance
by testing patients with demonstrated allergy to cow's milk. Out of 45 children who underwent
challenges with the individual milk protein, 28 (62%) had a positive response to ßlactoglobulin,
27 (60%) to casein, 24 (53%) to alactalbumin, and 23 (51%) to bovine serum albumin.8
In vitro investigation by crossedradioimmunoelectrophoresis (CRIE) found that alactalbumin, ß
lactoglobulin, bovine serum albumin and bovine gamma globulin act as major allergens as
assessed by the IgEbinding of most sera of milk allergic patients.9 In addition, studies by SDS
PAGE/immunoblotting have detected in milks of various animals proteins that crossreact, as
demonstrated by IgEbinding of sera of sensitized individuals with this component in milk from
cows, goats, and sheep.10
5 . 2 . 2 . Hen's egg
Most protein components determining allergic sensitization are contained in egg white, which
comprises more than 20 proteins. Major allergens are ovalbumin, ovomucoid (Gal d 1), and
ovotransferrin (Gal d 3), previously known as conalbumin,11
as demonstrated by CRIE12
and
SDSPAGE immunoblotting.13
Ovalbumin, named Gal d 2, according to the current allergen nomenclature14
based on the
accepted taxonomie denomination of the animal or vegetal species representing the allergen
59
source (which in this case is Gallus domesticus), has a molecular weight of 45 kd and comprises more than 50% of egg's white proteins. Its complete aminoacid sequence has been described,15
and a terminal decapeptide able to specifically bind with the IgE in sera of egg-allergic patients and to inhibit further binding with whole ovalbumin in RAST-inhibition experiments, was identified.16 The allergenic activity of ovalbumin was found to be resistant to both thermal and trypsin denaturation, as shown by negligible RAST-inhibition following these treatments, whereas pepsin hydrolysis caused an inhibition of 50%, demonstrating significant alteration of the antigenic structure.17 Gal d 2 was stable 60 minutes to digestion in a gastric model in vitro, the Gal d 1 whole protein resisted eight minutes and the Gal d 3 whole protein was instable to gastric digestion, while its fragments were stable after 15 minutes.17 The cleavage of ovalbumin with cyanogen bromide resulted in four fractions, all binding specific IgE in the sera obtained from egg-sensitive individuals.17 A recent study was aimed at defining the allergenic epitopes of ovalbumin by using two preparations either physically and chemically denatured or containing ovalbumin fragments obtained by enzymatic digestion.18 Analysis of the sera of patients with egg allergy by SDS-PAGE followed by an ELISA technique showed that the primary structure of ovalbumin was retained after both types of denaturation, whereas the conformational structure was modified only by physical denaturation by heat, as demonstrated by differences in fine specifities of IgE compared to IgG and IgA against ovalbumin. Another study investigated the epitope mapping of ovalbumin using synthetic peptides comprising a segment of 70 aminoacid residues located at the N-terminal.19 It was observed that the allergenicity, tested by inhibition of ovalbumin binding by specific IgE from allergic patients, was distributed in the 11-70 region, being the 11-19 peptide able to inhibit IgE-binding despite a weak antigenicity. The 11-70 region seemed to contain conformational rather than continuous allergens.
Ovomucoid (Gal d 1) has a molecular weight of 28 kd, comprises about 10% of egg's white proteins, is heat stable20 and not denaturated by chemical procedures.21 Because of these characteristics, ovomucoid seems particularly involved also in the allergic reactions that occur when cooked eggs are eaten. A recent study investigated a group of 18 children with egg allergy in relation to the in vivo and in vitro response to ovalbumin and ovomucoid.22 Wheals elicited by skin test with ovomucoid were significantly greater than those elicited by ovalbumin, and ovomu-coid-specific IgE concentrations in serum were significantly higher than ovalbumin-specific IgE concentrations. In addition, in two groups of patients respectively with persistent egg allergy and with development of tolerance to egg, specific IgE to ovomucoid were significantly higher in the former, whereas no difference was found in specific IgE to ovalbumin. These findings led the authors to suggest that, contrary to what is commonly thought, ovomucoid is the immunodominant protein fraction in egg white.
Ovotransferrin or conalbumin (Gal d 3) has a molecular weight of 78 kd, theoretically precluding penetration in the intestinal mucosa, however its ability to react with specific IgE was demonstrated in vitro by CRIE and in vivo by skin tests performed in 15 patients clinically sensitive to egg.23
Lysozyme (Gal d 4) has a molecular weight of 15 kd and comprises about 3% of egg white proteins. This allergen cannot be considered a major allergen, since lysozyme-specific IgE have been found only rarely.24
60
Very recently, ovalbumin, ovomucoid, ovotransferrin, and lysozyme were purified and character
ized by raising specific antibodies in immunized rabbits and performing immunoblots with sera
from patients with a positive DBPCFC25
Purification of the four proteins allowed the observation
that apparent positivity of IgE tests to ovotransferrin, and especially to lysozyme, are caused in
most cases by the presence of contaminating proteins in crude preparations. In fact, only one
serum showed a positive IgE reaction to purified lysozyme. Interestingly, ovomucoid was detected
in at least two homologous variants, ranging from 32 to 46 kd in molecular weight, varying in N
glycosilation of the third domain.
Egg yolk contains three main protein fractions, namely globulins, livetins, and lowdensity
lipoprotein, which were found to bind IgE in sera from patients allergic to egg.24
The authors of
this study could not exclude that the binding was due to presence of contaminants, however at
least livetin was successively demonstrated as an allergen. In fact, αlivetin was identified as the
allergen crossreacting with chicken serum albumin in subjects with allergic reaction to egg and
respiratory allergy to bird feathers defining the socalled birdegg syndrome.26
Another study from the Netherlands performed SDSPAGE/immunoblotting and confirmed the
presence, in the sera of adult patients with respiratory allergy to birds, of an allergen cross
reacting with egg yolk, but found that sera from exclusively foodallergic children mainly reacted
with a component of 35 kd, which is likely to represent another allergen of egg yolk.27
The
different pattern of IgE binding makes it reasonable to suppose that in adult patients sensitization
to αlivetin occurs through the respiratory route by inhalation of avian proteins.
5 . 2 . 3 . Fish
The most extensively characterized allergen of fish is represented by a parvalbumin (i.e. a
sarcoplasmic protein from muscle tissue of fish not present in mammals) contained in the myogen
fraction of the meat of codfish, initially described as allergen M28
and actually named Gad c 1
(from the taxonomie name Gadus callarías) following the current allergen nomenclature. This 12.3
kd allergen is formed by 113 aminoacids and is particularly resistent to heat and proteolysis,
maintaining its allergenic properties after cooking and enzymatic digestion.29
It has been also
possible to define its threedimensional structure, which has three domains,30
as well as to
identify the IgEreactive epitope, which constitutes a sequential linear antigen, being formed by a
repetitive group of a few aminoacids, unlikely to be altered.
A recent study demonstrated by SDSPAGE/immunoblotting that protein components cross
reactive with Gad c 1 are present in a number of common fish species.31
However other
allergenic proteins, though as yet not isolated, different from Gad c 1, are likely to be involved in
allergic reactions. This is suggested by the findings of a study of RASTinhibition performed with
sera from 20 children with a positive history for fish allergy and positive skin tests for 17 fish
species, showing a high crossreactivity between the antigens from cod, bass, dentex and eel, but
a lower one with sole and tuna; only two children had a IgEreactivity for dogfish.32
In addition, the
inability of lyophilized fish to provoke symptoms during challenge in patients otherwise reactive to
unmanipulated fish, strongly suggests the involvement of unstable allergens, which have yet to be
identified.33
61
5 . 2 . 4 . Shrimp
Allergens of shrimp have been thoroughy investigated, and by CRIE at least seven allergenic components were detected, comprised in three main fractions, respectively located at pi of 4.5-5, 5-5.5, and 5.5-6.34 A more recent study conducted by SDS-PAGE/immunoblotting with material obtained from boiling shrimps (including the water in which they were boiled) and sera from 13 patients allergic to shrimp found nine IgE-binding components.35 A successive study on the same sera found that 92% of them bound to a component of 36 kd, which thus acted as an important major allergen and was named Pen a 1 from the taxonomie name Penaeus aztecus.36 This allergen is a protein with an aminoacid composition rich in glutamic and aspartic acid, representing about 20% of the shrimp's extract and inhibiting 75% of RAST to shrimp.36 Pen a 1 is similar to a protein of 34 kd previously isolated from the species of shrimp Penaeus indicus and preliminarily named Sa (i.e. shrimp allergen)-ll.37 In that study, another allergen of 8.2 kd, named Sa-I, was found, but inhibition studies showed a 54% sharing of allergenic epitopes, suggesting the possibility that Sa-I might be simply a fragment of Sa-ll.
Evidence for allergens common to other crustácea, such as lobster, crawfish, and crab, was provided by positivity of IgE-tests for these crustácea in patients allergic to shrimp but with no exposure to other crustácea and by RAST-inhibition experiments.38 Monoclonal antibodies to Pen a 1 were found to react against a 36 kd protein present in crustácea as well as in other seafood such as oyster, squid, and scallop.36 Finally, the 36 kd shrimp allergen, that is, Pen a 1, was identified as tropomyosin, a protein involved in activation of actin during muscle contraction present in all vertebrates, as revealed by equal molecular mass, isoelectric point, and high homology in amino acid sequences.39 Tropomyosin was then found to be a cross-reactive allergen in a number of arthropods including mites and insects,40 but not to cross-react with tropomyosin molecules from vertebrates of phylogenetically distinct species.39
A study investigated the possible species-specific shrimp allergens by evaluating in 31 patients allergic to shrimp the IgE reactivity to white shrimp (Penaeus setifecus) and brown shrimp (Penaeus aztecus). Specific IgE in serum were found in most patients to both shrimp, whereas in two subjects there were IgE only to brown shrimp and in one only to white shrimp.41 RAST-inhibition in two individuals revealed qualitatively different allergens in the different species, supporting the existence, even rarely, of species-specific shrimp allergens, which have yet to be identified.
5 . 2 . 5 . Peanut
Allergens of peanut are essentially contained in water-soluble fraction, constituted by globulins which in turn are divided in two fractions, arachin and conarachin, according to their precipitation in ammonium sulphate.42 By CRIE, 16 allergenic fractions have been detected, with molecular weight ranging from 15 to 66 kd.43 A study conducted on nine patients with a positive DBPCFC to peanut identified as major allergen a 63.5 kd protein, thus named, from the taxonomie name Arachis hypogaea, Ara h i . 4 4 This protein showed characteristics similar to a glycoprotein of about 65 kd previously described as an important peanut allergen.45 Very recently, the cDNA coding for Ara h 1 was cloned and sequenced, and it was found that this allergen has multiple IgE-binding domains.46 Other studies identified a second major allergen, Ara h 2, as a component of
62
17 kd,47 and peanut agglutinin, with a molecular weight of 31 kd, as an intermediate allergen, being recognized by 50% of sera from patients with a positive challenge to peanut.48 As reported in a study of RAST-inhibition, peanut contains one or more allergens cross-reacting with tomato as well as with grass pollen.49 The clinical significance of this cross-reactivity has yet to be determined, whereas it has been demonstrated that the cross-allergenicity observed by skin tests and RAST among peanut and other members of the legume family, such as various beans, soybean, and pea, is not clinically important, as assessed by a positive response to DBPCFC to more than one legume in only 5% of 69 patients with apparent multiple sensitization.50
5 . 2 . 6 . Soybean
This member of the legume family contains water-soluble proteins, which are albumins, and salt-soluble proteins, which are globulins, the latter constituting about 90% of soybean proteins.51
Ultracentrifugation further separates four fraction respectively with a sedimentation rate of 2S (whey fraction), 7S (a-conglycinin), 11S (glycinin), and 15S (aggregated glycinin). Glycinin has a molecular weight of 320 kd and includes six subunits, each containing one acidic and one basic polypeptide; these polypeptides are heterogeneous and have molecular weights from 34 to 45 kd for the acidic polypeptide and from 19 to 22 kd for the basic one.52 ß-conglycinin has a molecular weight of about 180 kd and is composed of three subunits, with a respective molecular weight of 76, 72, and 53 kd.53 The first study on the allergenicity of the fractions 2S, 7S, and 11S was conducted by RAST and RAST-inhibition with sera from patients with suspected allergy to soybean, and found that the three fractions were cross-reactive as to IgE-binding, but the 2S showed the highest inhibiting potency.54 The IgE-binding was reduced by heat treatment for the 7S and 11S fractions, but not for the 2S one. Thus, this fraction, i.e. the whey fraction, which is known to include components such as the Kunitz trypsin inhibitor and cytochrome c, seemed to be the most allergenic. In particular, the trypsin inhibitor, of molecular weight of about 20 kd, was reported in the same year as responsible of anaphylaxis in one patient.55 However, a study conducted with sera from nine patients with atopic dermatitis and positive DBPCFC to soybean, investigating the IgE-binding to a crude soya extract and to the 2S, 7S, and 11S fractions found no difference in allergenicity of the different fractions.56 In addition, trypsin inhibition was recently demonstrated to represent only a minor allergen of soybean, showing an IgE-binding in only 20% of sera from patients positive to DBPCFC to soybean.48 A study in patients with allergic reactions to ingestion of soybean establishing its major, intermediate, and minor allergens, and thus attributing their allergen nomenclature, is as yet unavailable, whereas in patients suffering from asthma to inhalation of soybean, the major allergen has been identified as a component of 14 kd and named Gly m 1 from the taxonomie name of Glycine maxima.57 This component, contained in the hull of soybean, is likely to represent an allergen not inducing food allergy, though this hypothesis has not been definitely demonstrated. Another study performed on asthmatic patients reported a protein of 21 kd, a molecular weight similar to that of trypsin inhibitior, as an allergen cross-reacting between soya and wheat flour.58
5 . 2 . 7 . Cereals
It has been long known, on the basis of their solubility, that cereals contain four different protein fractions.59 Albumins and globulins are soluble in neutral solutions, glutenins In acid solutions,
63
and prolamines in ethanol. The first studies on allergens of cereals were conducted on sera from patients with respiratory allergy to flour, the so-called baker's asthma, and found that IgE-binding occurred mainly to proteins of molecular weight ranging from 12 to 20 kd present in neutral solution.60·61 More recent investigations found other major allergens as components of the neutral fraction of 47 kd62 and 66 kd.63 A study comparing the IgE-binding in patients with asthma to that in patients with eczema due to the ingestion of wheat flour, found that allergenic fractions of cereals seemed represented by albumins when regarding asthma, and by globulins and glutenins regarding skin symptoms.64 Recently, SDS-PAGE/immunoblotting with sera from 35 patients with atopic dermatitis and positive skin tests and RAST for one or more cereals (wheat, rye, barley, and oats) revealed that the most frequent IgE-staining occurred with proteins of 26, 28-30, 40-50, 69, and 79 kd.65 A similar IgE-binding, suggesting cross-allergenicity, was observed with wheat, rye and barley, but not with oats, which appeared to cross-react only weakly. An extensive cross-reactivity between wheat, rye, and barley, as assessed by RAST-inhibition experiments, was observed using sera of patients with wheat-induced asthma.58 Major allergens of wheat were proteins with molecular weight of 12, 21, 26, 33, and 69 kd, whereas in rye they were proteins of 12 and 21 kd and in barley they were proteins of 10, 52, and 69 kd. These findings were partly confirmed in a study of sequence analysis of wheat allergens separated by two-dimensional electrophoresis, which found a major IgE-binding in the area of 14-18, 27, and 37 kd.66 Recently, the major wheat allergen of 15 kd was identified as α-amylase inhibitor, belonging to the family of a-amylase/trypsin inhibitors acting on mammalian and insect α-amylases.67 This allergen seems mainly involved in baker's asthma,68 but it has been also reported as responsible for food allergy.69
5 . 2 . 8 . A p p l e
Using CLIE, antigens of apple were found to have structural similarities with antigens of birch and grass pollen.70 Apple allergens in the range of 17-18 kd were detected by immunoblotting in 81 patients allergic to birch. In particular, a 17 kd allergen was found highly homologous, by sharing of common epitopes, with the major allergen of birch Bet ν 1.7 1 These allergens seem to belong to the group of 'pathogenesis-related proteins' involved in resistance to diseases of plants.72 By microsequencing, it was found that the apple allergen cross-reacting with Bet ν 1 has identical but also different antigenic determinants compared to Bet ν 1, such as the three consecutive proline residues in position 14-16.73 This might account for variation in sensitization patterns in individuals sensitized or not to birch pollen.
Recently the major allergen of apple, Mal d 1 (allergen 1 from Malus domestica), has been purified and its characteristics were studied:74
1. Bet ν 1 has all allergenic epitopes of Mal d 1, but Mal d 1 is only a weak inhibitor of IgE reactivity with Bet ν 1 ;
2. Mal d 1 represents the main allergenic activity of apple;
3. Mal d 1 is extremely labile due to interactions with phenols present in the fruit.
64
The complete DNA sequence of Mal d 1 has been obtained: it is a 158 residue protein with M. W.
of 17.5 kda.75
"76
In SDSPAGE Mal d 1 has an apparent higher molecular weight. The amino acid
sequence of Mal d 1 is 63% identical to Bet ν 1.
5 . 2 . 9 . Celery
A study used SDSPAGE to separate the protein components of celery, which were detected in
the range from 15 to 90 kd. The 15 kd allergen was analyzed by twodimensional electrophoresis,
which showed the presence of isoallergenic forms, and purified. By using a specific rabbit
polyclonal antibody recognizing a recombinant birch profilin, this allergen was identified as
profilin. Profilin is present in mugwort, which cross reacts via profilin with celery.77
A second major allergen of celery is Api g 1, (allergen 1 from Apium graveolens) an allergen
related to Bet ν 1 and belonging to a group of 'pathogenesis related proteins'. By preincubation
with recombinant Bet ν 1 it was possible to reduce IgE binding to homologous proteins in celery.78
Api g 1 has recently been cloned and sequenced showing a high immunological and structural
relationship to Bet ν 1 and Bet ν 1 related allergens.76
5 . 2 . 1 0 . Prunoideae
SDSPAGE/immunoblotting in 23 patients with OAS from peach and skinprick tests, RAST and
oral challenge positive for peach and other fruits of Prunoideae such as apricot, plum and cherry,
detected at least 10 allergenic components, of molecular weight ranging from 13 to 70 kda, three
of them acting as major allergens. The 13 kd component, detectable by IgEbinding in 90% of
allergic patients, was found to be the most relevant major allergen of peach, thus deserving the
denomination of Pru ρ 1 (major allergen 1 of Prunus persicus), shared by other Prunoideae but not
by grass and birch pollens, otherwise widely crossreacting with Prunoideae as regards the other
allergens.79
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71
P R E V E N T I O N O F F O O D A L L E R G Y
SYNOPSIS
The only preventive measure able to interfere with development of food allergy is to postpone as much as possible the introduction into the child's diet of foods containing known allergens, such as cow's milk, egg, fish, and others. This is mainly done by prolonged breast-feeding; the preventive effect is improved by eliminating these foods from the mother's diet. Because of the difficulty to maintain such conditions it is not recommended to prolong breast-feeding over six months. As yet, there are not enough data to use hydrolyzed cow's milk formulae as a measure alternative to breast-feeding
6 . 7 . Introduction
A disease can be successfully prevented when the factors underlying its occurrence are fully understood. This is not the case of food allergy, the pathogenesis of which is largely unknown. However, the important increase in recent years of the prevalence, especially in children, of diseases related to food allergy such as atopic dermatitis or asthma1 has made it worthwhile to perform a series of studies on the prevention of food allergy based on the knowledge of the factors involved in the development of this clinical condition.
6.2. Known risk factors for developing food allergy
The major risk factors connected with the development of food allergy are represented by a reliable parental history of atopic diseases and by an early exposure to sensitizing antigens contained in particular foods. As regards the first point, a series of studies investigated both retrospectively and prospectively the frequency of atopic diseases in children with a uniparental or biparental history of atopy. It has been found that a uniparental history of atopy is associated with a risk ranging from 20 to 38% when evaluated retrospectively2"5 and from 13.5 to 58% when evaluated prospectively.6"11 In these studies, as well as in other studies,12"13 it has been reported that a biparental history of atopy increases the risk up to 100%.
In newborns with a parental history of atopy, the decision to establish preventive measures can also be based on some immunological parameters, the most important of which is generally thought to be the detection of IgE antibodies in cord blood or in blood during the first week of life. This parameter has been initially described as a good predictor of future allergic diseases,14·15
however recent studies demonstrated that its predictive accuracy is less than satisfactory.16·17 In particular, the sensitivity of this test, ranging from 14 to 74%, was found to be not significantly better than that of a family history of atopy.17 Detection of high levels of total IgE in children up to 14 years selected by a negative family history of atopy, resulted a good predictive factor, as in one study 75% of children with high IgE levels had atopic disorders, during the follow-up compared to 6% of those with low IgE levels.18 However, more recent studies investigating the diagnostic accuracy of this parameter in populations of children with positive or negative family history of atopy reported unsatisfactory sensitivity and specificity.19"20 Regarding the value of specific IgE
72
to foods in infancy as a risk factor for food allergy a study claimed that positivity of skin tests to
egg was associated to subsequent food allergy also to other foods and to respiratory disorders as
well.21
Nevertheless, in another study, positivity of both skin test and RAST to ovalbumin and ß
lactoglobulin showed a specificity close to 100% but a very low sensitivity.17
Because of the overall unsatisfactory predictive value of total or specific IgE measurements,
which led Kjellman to conclude that they are not suitable for allergy risk screening on an
individual basis,22
other parameters have been considered as possible predictors of food allergy.
They consist of: (1) assessment of the number of CD4+ and CD8+ lymphocyte subpopulations
and their ratio, which are of pivotal importance in the regulation of IgE synthesis;23
this parameter
resulted in acceptable specificity but poor positive predictive value;17
(2) platelet counts, as
platelets seem involved at various levels in atopic disorders;24
in one study, conducted on a small
number of newborns, all subjects developing atopy within the following 18 months had low
platelet counts in cord blood; however, an overlapping of values with newborns not developing
atopy was observed;25
(3) histamine release by cord blood basophils, which was not found to be
independently helpful;26
(4) content in linolenic acid of cord blood lecithin, which was found
higher in children with atopic dermatitis than in healthy controls;27
levels of phosphodiesterase in
leukocytes, which are inversely correlated with intracellular levels of cAMP, a basic mechanism
underlying regulation of lymphocytes, and possibly IgE production; high levels of phosphodiester
ase were found in newborns with family history of atopy and children with atopic dermatitis.28
A recent study investigated several of these parameters, as well as that of IgE and of skin tests
with histamine and allergens, and found that neither single parameter nor any combination of
them provided acceptable predictive capacity to be used for routine screening of allergy risk at
birth.29
6.3. Possible interventions aimed at preventing food allergy
Due to the obvious importance of allergen exposure in determining food allergy, the infant at risk
should avoid coming in contact with food known to be allergenic. In particular, cow's milk contains
foreign proteins, such as ßlactoglobulin, αlactalbumin, and casein, which elicit in all human
subjects an antibody response including IgG, IgA, IgM, and IgG isotypes,11
these proteins are
also important allergens and thus trigger the IgE response. The optimal preventive measure is
thought to be prolonged breastfeeding, which however induces a weaker response not only of
IgE but also of the other immunoglobulin classes; this does not result in a less efficient defence
from infections.30
In order to avoid an early exposure to food allergens, the mother should not eat
foodstuffs known to contain allergens able to pass in human milk, whereas dietary restriction
during pregnancy is unnecessary: it is broadly accepted that intrauterine sensitization does not
occur.31
Various allergens of cow's milk and hen's egg have been detected in human breast
milk,11
though it has never been clearly demonstrated that they cause allergic sensitization. In
particular a study investigated the secretion of ßlactoglobulin in milk of mothers of infants with
cow's milk allergy and found different patterns of secretion, some with an increase, others with a
decrease and others with no detectable ßlactoglobulin, after an oral cow's milk load.32
The factor
underlying these different patterns was unknown, as no difference in intestinal absorption of
macromolecules was found between the three groups of mothers.
73
However there is evidence that passage of food antigens in breast milk can cause allergic
symptoms in previously sensitized children33
·34
and that elimination of the offending foods from
the mother's diet gives an improvement of symptoms.35
Various studies reported a sensitization
to foods such as cow's milk, egg, and peanut in children believed to be exclusively breast
fed, 33,34,36 but ¡t has not been possible to ascertain whether the sensitization occurred by
passage in the mother's milk or by inadvertent ingestion of small amounts of these foods by the
children. Another possibility is provided by crosssensitization to allergens shared by inhalant and
food sources. This has been reported for allergic reactions to egg yolk, induced by sensitization to
antigens of bird's serum, inhaled when birds are present in dwellings.37
Recently, the cross
reacting allergen was identified as egg yolk αlivetin, corresponding to chicken serum albumin.38
In any case, avoidance of cow's milk (including maternal avoidance) in infants at risk was able to
reduce the overall prevalence of both IgE sensitization and cow's milk allergy in a controlled
study.19
Under conditions of uncertainty regarding the introduction of small amounts of potentially
sensitizing foods, it is inadvisable to prolong breastfeeding excessively. It has been reported that
exclusive breastfeeding for periods longer than three months was associated to a higher
frequency of positive skin tests to egg and milk.39
As regards solid foods, it has been observed that the number of foods added to the diet during the
first months of life correlated with the development of eczema, within the age of 10 years;40
though the causative role of food allergy was not demostrated, because food challenges were not
performed. Another study suggested that the elimination of solid foods in the first year of life can
only postpone the onset of food allergy, since no differences in positive food challenges at the age
of three years were observed between two groups of children in which specific foods (fish and
citrus) were eliminated or not from the diet during the first year.41
A recent study reported that measures of allergen avoidance including aeroallergens, had
beneficial effects in highrisk infants, at least at the age of two years.42
In fact, a group of children
receiving breast milk and living in houses in which extensive measures for preventing indoor
allergens were performed, had significantly lower prevalences of eczema and rhinitis (but not
asthma) and of positive skin tests than children conventionally fed and with no environmental
control.
Other factors, such as the antigen absorption in infants, may be involved in the development of
food allergy. It has been reported that preterm newborns had a higher antigen absorption than
term newborns.43
The absorption is likely to be influenced by the antigen's characteristics, as
suggested by the differences in the various antigens (and specific antibodies) of cow's milk found
in serum of preterm newborns.44
A controlled study demonstrated that early exposure to cow's
milk increases the risk of preterm newborns to develop allergic diseases within 18 months.45
It is
possible to hypothesize, despite contrasting observations, that breast milk, and particularly its IgA
immunoglobulins, may oppose the intestinal absorption of antigen.11
This was indirectly support
ed by the observation that children with IgA deficiency had an increased absorption, as demon
strated by precipitins or immune complexes, of various food antigens.46
74
A number of studies was addressed to compare the effects of different feeding during the first year of life on the development of atopic diseases. In particular, they investigated the decrease or the delayed onset of atopy in children fed with breast milk, soya milk or hydrolysate formula compared to those fed with cow's milk. However, because of the impossibility to organize random double-blind studies, the data provided by these investigations have a limited value. In fact, as underlined by Zeiger,11 some differences in psychological and social characteristics between families of children differently fed may bias the results obtained, for example by modifying other factors such as the time of introduction of solid foods or the exposure to viral infections.
6 . 3 . 1 . Comparison between breast - feeding and cow's milk feeding
There is a similar number of studies reporting the favourable effects of breast-feeding on allergic manifestations as compared to cow's milk feeding14·47"54 and no difference between the two methods.8·55"59 The studies that reported positive results also found significant decreases of serum IgE levels in breast-fed infants within six months48·51 or one year.49 However, in the study by Chandra et al.54 cord blood IgE levels correlated with the development of allergy within two years from birth (being higher in subjects with subsequent allergic diseases than in those without allergic manifestations) in a group of breast-fed infants with no family history of allergy, but not in a group with family history of allergy.
A prospective study from Denmark reported that in a cohort of 1 749 newborns there was a significant difference in adverse reactions to cow's milk between breast-fed and cow's milk formula-fed infants regarding intolerance, meaning with no positive skin test and/or RAST, but not allergy to cow's milk.60 Some of the studies reporting negative results may be criticized because of the too short duration of breast-feeding, corresponding to 1-2 months,8·55.56 but some recent studies fulfilling the same criteria used in the 'positive studies' observed no differences between breast-fed and bottle-fed infants in development of atopic diseases57-59 as well as in IgE levels.57·58
6 . 3 . 2 . Comparison between soya feeding and cow's milk feeding
Soya milk was introduced in the 1950s following the observations of the reduced incidence of atopic dermatitis and hay fever in infants fed with soybean milk compared to those fed with cow's milk.61 However a number of randomized prospective studies was unable to demonstrate the beneficial effects of soya feeding on allergic manifestation,6·12·52·54·56·62"64 except a significant decrease of perennial rhinitis and asthma in the study by Johnstone and Dutton.62 One study considered also immunological parameters demonstrating atopy and found no difference in the development of atopic diseases within four years from birth between soya-fed and cow's milk-fed infants.12 A recent study reported that soya-protein-based formula sensitized atopic children, and especially those with gastrointestinal allergy.65 On the other hand it is now well known that soybean is an important allergenic source and a number of allergens have been identified.66·67
Thus, feeding with soya-milk in infants at risk of atopic diseases is no longer indicated.
75
6 . 3 . 3 . Comparison between hydrolyzed cow's milk formulae and other kinds of feeding
Cow's milk protein hydrolysates, and particularly the casein hydrolysate Nutramigen®, were introduced into the market in 1942 in order to reduce the allergenicity of cow's milk. This product was made by hydrolyzing the milk into small peptides with molecular weight lower than 1 500 daltons, providing nutritional adequacy but resulting non-immunogenic in animal experiments.11
Hydrolyzed formulae are obtained by heat or enzymatic hydrolysis, the former affecting the conformation of milk proteins, resulting in a decrease of allergenicity of whey but not of casein, whereas the latter breaks all the allergenic proteins including sequential epitopes.68
The hydrolysis can be extensive or partial and the hydrolyzed formulae thus obtained present important differences regarding taste and smell (better for partly hydrolyzed formulae, pHF) and allergenicity (lower with extensively hydrolyzed formulae, eHF). A significant proportion of proteins with molecular weight from 8 to 40 kd can be found in pHF, which instead are absent in eHF. Various studies evaluated the residual in vivo allergenicity of hydrolyzed formulae by skin tests and/or double-blind placebo-controlled food challenge.69"71 An effective hypoallergenicity of casein eHF was demonstrated by the negativity of these tests in children with cow's milk allergy, whereas whey eHF was reported to be as allergenic as casein eHF72 but as yet there is not such a direct demonstration. In vitro, RAST-inhibition and ELISA-inhibition experiments showed that whey pHF was 60 times less allergenic than cow's milk and whey eHF was 20 million times less allergenic than cow's milk.69"73
Some prospective studies evaluated the preventive effect on development of allergic diseases of pHF and eHF and reported favourable results.19·72·74"76 However, as stated in a recent position paper of the European Society of Pediatric Allergy and Clinical Immunology, none of these studies can be considered definitive, as they lack some or more requisites such as an adequate selection of high-risk infants, the statistical demonstration of a significant reduction of prevalence of cow's milk allergy as determined by DBPCFC, or the prospective randomized blind design of the study for a period long enough to develop atopic disease, that is, at least 18 months.68 In this position paper future studies fulfilling such prerequisites were strongly recommended.
6.4. Conclusions
To date, the only measure with a sure preventive effect on development of allergic diseases, and particularly of food allergy, in infants at high risk, as defined by a biparental history of atopy or by an uniparental history and an high level of IgE in cord blood, is breast-feeding. Some studies suggested that such preventive effect can be improved if during breast-feeding foods containing known allergens, such as cow's milk, egg, the 'nuts' group, fish, and seafood, are eliminated from the mother's diet. Being difficult to maintain such conditions for more than six months, it is not recommended to prolong breast-feeding beyond this period. To date there are not enough data to propose the use of hydrolyzed cow's milk formulae as an alternative to breast-feeding in the prevention of food allergy. When introducing solid foods into the infant's diet, food items known as allergenic sources should be postponed as late as possible.
76
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82
I N T E R A C T I O N W I T H L I F E S T Y L E A N D P R O F E S S I O N
S Y N O P S I S
Food allergic patients need to change their eating habits to a varying extent. Once diagnosed, the treatment of a food allergy is the avoidance of the sensitizing food in order to prevent further episodes of ARF. This measure is easy for foods not predominant in the diet, like exotic fruits. However, the interaction with the eating habit is stronger when patients have to eliminate from the diet predominant foods or foods which may be masked and hidden in food products and preparations. However food allergens, especially in an occupational setting, may induce allergic reactions even when inhaled or after skin contact. Foods most commonly involved in occupational food allergy are: cereal flour, egg, milk, seafoods and legumes. The most effective measure to prevent occupational diseases due to exposure to food allergens is primary prevention, that is prevention of exposure to food-related substances that can induce allergic reactions. A second step is secondary prevention, that is the detection of diseases at an early stage. The earlier the diagnosis is made, the more likely workers are to recover. Tertiary prevention consists of appropriate medical care of diseased workers. Due to that reported above, it is clear that any effort should be directed to primary and not to tertiary prevention.
7.1 Interactions with lifestyle
Food allergic patients need to change their eating habits, to a varying extent. Once diagnosed, the treatment of a food allergy is the avoidance of the sensitizing food in order to prevent further episodes of adverse reactions to foods. This measure is easy for foods not predominant in the diet, like exotic fruits. However, the interaction with the eating habit is stronger when patients have to eliminate from the diet predominant foods or foods which may be masked and hidden in food products and preparations. This is particularly true for highly sensitive patients and for food-allergic children. In these cases, a restaurant meal or a meal not consumed at home may be very dangerous, sometimes life threatening, for food-allergic persons and therefore the restriction of their lifestyle is very remarkable. The limitations concern a small number of individuals, who nevertheless should be protected to the maximum possible extent. In a descriptive study on fatal and near-fatal food-induced anaphylaxis, five of six fatal cases occurred in schools or public places, whereas all the non-fatal reactions occurred in private homes. Moreover, a delay in the administration of epinephrine was likely to be associated with a fatal outcome.1 This suggests the need for educating school personnel, day-care providers and restaurant personnel about food-induced anaphylaxis. For instance, the Canadian Restaurant and Food-service Association has instituted an allergy awareness programme in which participating restaurants agree to maintain lists of food ingredients and to designate one on-site employee to answer customers' questions about ingredients.2
Patients highly sensitive to food must be taught the importance of having and using emergency kits containing epinephrine. In the case of food-allergic children, parents and child-care personnel should be trained in the appropriate administration of this medication. The American Academy of Pediatrics Committee on School Health has recommended that schools be equipped to treat anaphylaxis in children.3·4 A Position Statement from the American Academy of Allergy and Immunology on the use of epinephrine in the treatment of anaphylaxis states that epinephrine
83
must be available in many first-aid situations for use by trained personnel.4 However many States of the USA do not permit non-medical personnel to administer epinephrine.2
Apart from the small number of food-allergic individuals, it is estimated that more than one quarter of Americans alter their eating habits based on misperceptions of food allergy.5 A study on women's opinions of food allergies indicated that 22% of women avoid particular foods on the mere possibility that the food may contain an allergen. Moreover 19% of family members were on diets to control food allergies.6 Another study investigating whether food avoidance in adults with self-reported food allergy leads to an unbalanced diet, indicated that, even after calcium supplementation, the mean calcium intake of patients who completely avoided milk and milk products was unacceptably low (441 mg/day). Only a small minority (<8%) of the patients recruited were on a diet as a result of a correct diagnostic procedure (food challenge).7
7.2. Interactions with profession
Generally, food allergic patients experience adverse reactions after the ingestion of non-tolerated foods. However food allergens may induce allergic reactions even when inhaled or after skin contact. Moreover, the inhalation of food antigens is more likely to induce sensitization than the ingestion, which is normally the route of the development of tolerance to the antigens. It seems that the allergy to vegetable foods in patients with oral allergy syndrome and pollenosis arises from the sensitization to inhalant allergens which share common epitopes with vegetable foods (e.g. birch and apple).8
7 . 2 . 1 . C e r e a l f l o u r
In baker's asthma the exposure to wheat flour through inhalation elicits asthma, however bakers with inhalant allergy to wheat proteins can usually eat wheat flour and wheat products without experiencing adverse reactions. It has been shown that among new workers, who had been in the baking industry for one year, 9% had positive SPT results, although symptoms were present only in 5%. Among veteran workers with 20 years in the industry, 34% had positive SPT result, although only 20% were symptomatic.9
Prichard et al.10 investigated 176 male bakers. Fifteen per cent of subjects showed positive SPT to wheat extracts. These subjects had increased prevalence of respiratory symptoms and of bronchial responsiveness to metacholine. Thirty per cent of bakers had negative SPT to wheat extracts, but positive SPT to common allergens. There was a significant association between SPT responses to whole wheat and SPT responses to common allergens, suggesting that bakers with pre-existing sensitivity to common allergens are at increased risk of developing wheat flour sensitization.Thus atopic subjects should be informed of that risk, before deciding to undertake the profession of baker.
Popp et al.11 investigated the factors that may contribute to the sensitization to flour in bakers' apprentices: 20.9% of 258 had specific IgE against flour allergens (wheat, rye and/or barley). A correlation was found between sensitization to flour and specific IgE to grass and tree pollen, total lung capacity, radiographic shadowing of the paranasal sinues. Based on the presence or
84
absence of these parameters, the authors were able to predict flour sensitization with a sensitivity of 63%, a specificity of 90% and an efficiency of 84%.
The sensitization of bakers is especially toward water-soluble wheat proteins.11 The major allergen recently characterized is a 27 kd which had even been purified and sequenced.12 Also a 15 kd protein, an α-amylase inhibitor protein, has been recently identified as a major allergen of wheat flour.13 In addition, different kinds of common flour14-15 and other baking ingredients may induce sensitization in bakers, α-amylase from Aspergillus oryzae, which is widely used as a baking additive has been identified as an important causative allergen in bakers' asthma.16·17
Other allergens described as causing bakers' asthma are mould18, mites19, and dust flour obtained from non-cereal sources such as buckwheat20 and chickpea.21 Soybean lecithin, a common additive in bakery, has also been recently shown to be involved in baker's asthma.22
Lachance et al.23 described a case of occupational asthma in a 29-year-old female working in a company producing biscuits. It had been shown that an alkaline hydrolysis wheat gluten derivative that was incorporated into marshmallow, was the causative agent.
A method for measurement of airborne proteins involved in baker's asthma has been recently developed.24 The assay can identify airborne proteins from several flours with a detection limit of 1 pg ml" 1 . The method could be of value both in epidemiological studies and in examining the effectiveness of interventions to reduce the concentration of flour in the air.
Rarely, bakers may experience skin-contact allergy from wheat, rye and malt flour.25
Apart from the widely investigated baker's asthma, many other foods and food products have been reported as occupational allergens.
7 . 2 . 2 . Hen's egg
Twenty-five employers of an egg-processing factory were evaluated for respiratory sensitization to inhaled egg proteins.26 Occupational asthma was found in five workers, who showed skin reactivity to one or more egg allergens. Egg specific IgE for different allergens were detected in four patients. Blanco Carmona and co-workers described a patient with asthma induced by occupational exposure to egg used to spray cakes before baking, in a confectionary industry.27
The sensitization was shown to be against egg white.
Several cases of egg allergy in adults as a result of sensitization through inhaled bird antigens have been reported.28·29 The association between allergy to avian proteins and allergy to egg has been called 'bird-egg syndrome'.28 Allergy to the ingestion of egg yolk may develop in patients with occupational allergy to avian proteins. The reactivity to egg yolk seems to be the result of avian serum sensitization, as suggested by RAST-inhibition studies. Similarly De Maat-Bleeker et al.31 described the case of an old woman who developed hypersensitivity to ingested hen's egg yolk coincidently with the acquisition of a parrot, in a non-occupational setting. IgE antibodies from this patient demostrated cross-reactivity between bird sera and egg yolk.
85
Recently egg yolk αlivetin (chicken serum albumin) has been identified as a crossreactive
allergen in the birdegg syndrome, by using immunoblot technique to investigate sera of 31
patients with clinical history of egg allergy, bird allergy, or bird and egg allergy.32
7 . 2 . 3 . C o w ' s mi lk
Hypersensitivity to milk proteins is a relatively common clinical condition, especially in infancy.
Although milk and milk derivatives are not included among agents causing occupational
asthma,33
recently some cases of workrelated asthma, with or without rhinoconjunctivitis caused
by inhalation of milk have been demonstrated: casein,35
·36
·37
alactoalbumin36
·38
and ßlactoglo
bulin34
·37
were the causative milk proteins. Symptoms were elicited by milking sheep,37
, by
preparing salted meats in a delicatessen factory,36
by sprinkling confectionery with driedmilk
powder.38
One patient was a tanner35
and one patient an employee of the cheese industry.34
7 . 2 . 4 . Sea foods
Allergic reactions to seafoods in the occupational setting have been reported among seafood
processors, fishermen, oyster shuckers, seafood caterers, and cooks in restaurants.39
Allergenic
agents include snowcrabs,40
shrimp, oysters, shell products, rubber boots, and fishing nets.39
The prevalence of occupational asthma was investigated in 313 employees of two snow crab
processing industries.40
Occupational asthma was demonstrated in 46 (15.6%) workers accom
panied in several patients with rhinitis and/or rhinoconjunctivitis, and with skin rash. Positive skin
tests to crab were related to the presence of occupational asthma suggesting an IgE sensitization
to crab in these workers. Subsequently, a group of workers was reexamined using different snow
crab extracts for SPT and specific IgE measurements.41
Cooking water and snow crab meat
extracts were more sensitive than commercial preparations, water extract being more potent and
more sensitive than meat extract. Respiratory and, to a lesser extent, dermatological reactions to
other crustaceans, to fish, and to molluscs have been documented too.42
One case of occupa
tional asthma caused by exposure to cooking lobster in the work environment has been
reported.43
Colas Des Francs et al.44
reported a case of anaphylactic shock caused by accidental ocular
projection of defrosted raw shrimp juice in a woman previously sensitized cutaneously. Peeling of
raw shrimps had for several months already caused an urticarial rash of the hands and forearms
of this woman working as cook in a Vietnamese restaurant. An IgEmediated mechanism has
been documented in this case.
7 . 2 . 5 . Legumes
Bush et al.45
described a case of a 43yearold women who developed asthma six years after
beginning work in a foodprocessing plant in which soybean flour was used as a protein
extender. Positive SPT, RAST and bronchial challenge with soya flour confirmed the diagnosis of
occupational asthma. The role of soybean in eliciting asthma attacks through inhalation is
supported by recurrent asthma outbreaks in Barcelona, Spain, provoked by dust generated by the
86
unloading of soybeans in the harbour.46 High levels of specific IgE to soybean present in 84.9% of the sera from patients with asthma attacks during an asthma outbreak and in only 5.8% of controls, confirmed the diagnosis. Igea et al.47 describe a case of occupational asthma in a homemaker, who experienced rhinoconjunctivitis, asthma attacks, and contact urticaria when trimming raw green beans. Positive SPT, RAST, basophil histamine release, and bronchial challenge with green bean confirmed the diagnosis of IgE-mediated allergy to the legume. The patient was able to eat and touch cooked green beans without experiencing adverse reactions.
7 . 2 . 6 . Coffee
Several reports of occupational allergic reactions among coffee workers have been made.48
Coffee industry workers develop occupational asthma, rhinitis, or dermatitis. Most reports concern coffee workers during manufacturing rather than in growers. SPT and specific IgE to green coffee bean have been demonstrated in symptomatic coffee workers, but not in asymptomatic workers. A prevalence of positive RAST to castor bean has been also documented among workers in the green coffee bean exposure, suggesting an exposure to castor bean allergen through handling contaminated sacks.48
7 . 2 . 7 . Garlic
Rare cases of occupational asthma induced by inhalation of garlic dust have been reported.49·50
In these cases, an IgE-mediated allergy to garlic has been demonstrated by in vivo and/or in vitro tests.
7 . 2 . 8 . Onion
Recently some cases of bronchial asthma, rhinoconjunctivitis, and contact dermatitis caused by onion has been descibed.51 An IgE-mediated mechanism has been shown for respiratory symptoms and a type IV mechanism for contact dermatitis. One patient was a cook in a restaurant and the others homemakers.
7 . 2 . 9 . Sesame seed
A case of occupational allergy due to sesame seed has been reported.52 The patient worked in a mill, in which waste bread was ground for animal food. He had asthma, rhinitis and urticaria from inhalation of sesame seed dust.
Positive SPT, RAST and provocation test with sesame seed confirmed the IgE mediated mechanism for the symptoms developing on the workplace.
7 . 2 . 1 0 . Others
Food service workers are more likely to have irritant than allergic skin reactions.53 Fruit, vegetable, and seafood are involved in IgE-mediated reactions. Delayed hypersensitivity, less common,
87
may be caused by onion, garlic, spices and food additives.25 A phytophototoxic dermatitis has been reported in grocery workers, caused by skin contact with high natural concentrations of furanocumarins in celery.54 Furanocumarins are a subgroup of psoralens, naturally occurring components found in celery, parsnip and citrus fruits. Exposure to these plants followed by exposure to ultraviolet radiation can cause Photodermatitis. A careful investigation showed that a certain brand of celery was implicated in the contact dermatitis in grocery workers and that such a brand contained significantly higher native levels of furanocumarins than other brands.54
7.3. Prophylactic measures
The most effective measure to prevent occupational diseases due to exposure to food allergens is primary prevention, that is prevention of exposure to food-related substances that can induce allergic reactions.55 In fact, retrospective studies have clearly shown that occupational asthma can lead to permanent asthma even after removal from exposure.33 Primary prevention is easier to practice when a new manufacturing process is being planned. A second step is secondary prevention, that is the detection of diseases at an early stage.
The earlier the diagnosis is made, the more likely workers are to recover. Factors influencing a less-favourable prognosis include the duration of the exposure, the severity of asthma at the time of removal, and the duration of exposure after onset of symptoms. Moreover wearing a facemask does not seem significantly to improve the outcome.42
Tertiary prevention consists in appropriate medical care of diseased workers. Due to that reported above, it is clear that any effort should be directed to primary and not to tertiary prevention.
Once the diagnosis of occupational disease is confirmed, satisfactory provision for removing affected workers from the workplace should be offered.
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additives αamylase from Aspergillus oryzae (Asp o II)'. Clin. Exp. Allergy 24, pp. 465470,1994.
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caused by alpha amylase'. Ann. Allergy 73, pp. 337342, 1994.
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aspergillus in baker's asthma'. Clin. Allergy 7, pp. 227233, 1977.
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buckwheat flour'. Ann. Allergy. 63, pp. 149152, 1989.
21 Valdivieso R., QuirceS., Sainz T. 'Bronchial asthma caused by Lathyrus sativus flour'. Allergy
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22 Lavaud F., Perdu D., Prévost Α., Vallerand Η., Cossart C , Passemard F. 'Baker's asthma
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23 Lachance P., Cartier Α., Dolovich J., Malo L. 'Occupational asthma from reactivity to an
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24 Sandiford C.P., Nieuwenhuijsen M.J., Tee R.D., Newman Taylor A.J. 'Measurement of airborne
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25 Adams R.M. 'Dermatitis in food service workers'. Allergy Proc. 11, pp. 123124, 1990.
26 Bernstein D., Smith A.B., Moller D.R., Gallagher J.S., Tar Ching A.W., London M., Kopp S.,
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27 Blanco Carmona J.G., Juste Picon S., Garces Sotillos M., Rodriguez Gaston P. Occupational
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275278, 1991.
30 Hoffman D.R., Guenther D.M. 'Occupational allergy to avain proteins presenting as allergy to
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31 MaatBleeker F.D., Van Dijk A.G., Berrens L. 'Allergy to egg yolk possibly induced by sensitiza
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32 Szépfalsi Ζ., Ebner C , Pandjaitan R., Orlicek F., Scheiner O., BoltzNitulescu G., Kraft D.,
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33 ChanYeung M., Lam S. 'Occupational asthma'. Am. Rev. Respir. Dir. 133, pp. 686690,1986.
34 Moneret Vautrin D.A., Pupil P., Courtine D., Grilliat J.P. 'Asthme professionnel aux protéines
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35 Olaguibel J.M., Hernandez D., Morales P., Péris Α., Basomba A. 'Occupational asthma caused
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36 Rossi G.L., Corsico Α., Moscato G. 'Occupational asthma caused by milk proteins. Report on a
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37 Vargiu Α., Vargiu G., Locci F., Del Giacco S., Del Giacco G.S. 'Hypersensitivity reactions from
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38 Bernarola G., Echechipia S., Urrutia I., Fernandez E., Audicana M., Fernandez de Corres L.
'Occupational asthma and rhinoconjunctivitis from inhalation of dried cow's milk caused by
sensitization to alactalbumin'. Allergy 49, pp. 189191, 1994.
39 Lehrer S.B. 'Hypersensitivity reactions in seafood workers'. Allergy Proc. 11, pp. 6768, 1990.
40 Cartier Α., Malo J.L., Forest F., Lanfrance M., Pineau L., StAubin J.J., Dubois J.Y. 'Occupa
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42 Malo J.L., Cartier A. 'Occupational reactions in the seafood industry'. Clin. Rev. in Allergy 11,
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43 Patel P.C., Cockcroft D.W. 'Occupational asthma caused by exposure to cooking lobster in the
work environment: A case report'. Ann. Allergy 68, pp. 360361, 1992.
44 Colas Des Francs V., Kopferschmitt Kubier M.C., Kopferschmitt J., Gourdon C , Pauli G. 'Choc
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45 Bush R.K., Schroeckenstein D., Meier Davis S., Balmes J., Kempel D. 'Soyabean flour asthma:
Detection of allergens by immunoblotting'. J. Allergy Clin. Immunol. 82, pp. 251255, 1988.
46 Rodrigo M.J., Morell F., Helm R.M., Swanson M., Greife Α., Anto J.Μ., Sunyer J., Reed CE.
'Identification and partial characterization of the soyabeandust allergens involved in the
Barcelona asthma epidemic'. J. Allergy Clin. Immunol. 85, pp. 778784, 1990.
47 Igea J.M., Fernandez M., Quirce S., de la Hoz Β., Diez Gomez M.L. 'Green bean hypersensiti
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48 Lehrer S.B. 'Bean hypersensitivity in coffee worker's asthma: A clinical and immunological
appraisal'. Allergy Proc. 11, pp. 6566, 1990.
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8. E P I D E M I O L O G Y OF FOOD A L L E R G Y
SYNOPSIS
Because of the importance of psychological factors in food allergy, great differences are observed between the 'self-perception', accounting for 15-20% of suspected allergy in the general population and the real prevalence of food allergy as established by DBPCFC. Recent studies reported that the prevalence of true food allergy in adults was 1.4-1.8% in-United Kingdom, and about 1% in the Netherlands. In children a prevalence as high as 8% was reported, with major importance for sensitization to cow's milk. As cow's milk allergy tends to outgrow with age, the findings on children and adults seem to be consistent.
8.1. Introduction
It is harder to establish the prevalence of food allergy in the general population than other kinds of allergy. This is mainly due to the poor reliability of answers to the standardized questionnaires commonly used in the epidemiology of allergic diseases, because of the greater importance of psychological factors1 in suspected food allergy, especially in adults, which lead to a self-perception of food allergy much higher than the real prevalence, measured against a 'gold standard' such as the double-blind placebo-controlled food challenge (DBPCFC).
8.2. Epidemiology in adults
The differences between self-assessed prevalence of food allergy and demonstration by DBPCFC first emerged in the 1960s. On simply asking people whether they had ever had adverse reactions to foods, a prevalence ranging from 4.9 to 33% was found,2 5 higher in women than men. By contrast, DBPCFC found a prevalence of 1 % of food allergy.5
A recent study in the United Kingdom on about 20 000 people confirmed this, the self-perception of food allergy in answers to a questionnaire amounting to 20.4%, whereas the prevalence of true allergy established by DBPCFC was 1.4%-1.8%.6 This study questionnaire focused on the relationship between ingestion of a food and occurrence of typical allergic symptoms such as itching, urticaria/angioedema, eczema, asthma, rhinitis, and gastrointestinal symptoms, but also non-specific symptoms such as joint symptoms, behavioural disorders, and headaches. The most frequent typically allergic reaction was rhinitis (28%), followed by eczema (17%) and itching (16%), while among the other symptoms 20% of subjects reported headaches, 15% joint symptoms, and 13% behavioural changes. The female predominance reported in previous studies was confirmed. A number of foods was reported as causes of symptoms, chocolate being the most frequently suspected (6%). Out of the 20 000 subjects initially surveyed, only 93 agreed to DBPCFC to confirm their reactions to foods. Eight foods were selected for the challenge, including cow's milk, hen's egg, wheat, soya, citrus fruit, and fish/shellfish, excluding foods usually not involved in food allergy even though frequently reported by the subjects. Eighteen of the 93 people (19.4%) who underwent DBPCFC had a positive reaction, and the authors used a statistical model to extrapolate a prevalence rate in the general population from 1.4 to 1.8%.
93
However, out of the 18 reactors to challenge, 12 had not typically allergic symptoms, such as joint symptoms, headaches and behavioural changes, so it is likely that the prevalence of true food allergy in the population considered is lower.
In the Netherlands the magnitude of both self-perception and true food allergy seems to be even lower, as in a sample of about 1 500 adults self-perception of food allergy corresponding to 12.4% was confirmed by DBPCFC only in 0.8% of cases.7 Most of the 12 patients reacting to challenge had symptoms in response to chemicals such as additives, glucose, and histamine, and only one patient reacting to kiwi had a demonstrable IgE-mediated allergy, as shown by positive skin test and RAST.
Thus, from these recent studies, it seems conceivable that the overall prevalence of food allergy in the general population may currently correspond to less than 1%.
However, for one particular form of food allergy, the oral allergy syndrome, in which symptoms mostly develop in the oropharynx when certain fresh fruits or vegetables are eaten, frequently encountered in patients suffering from pollinosis because of cross-reacting allergens in pollens and vegetables, a prevalence of 40% in pollinotic patients was reported.8 Considering in turn the estimated prevalence of 7-8% pollinosis in the general population in civilized areas,9 hypersensitivity to vegetables may involve about 3% of the population. However, no epidemiological study on the prevalence of oral allergy syndrome in the general population is yet available.
8.3. Epidemiology in children
The question of excessive self-perception also affects the evaluation of food allergy in children, because their parents mainly suspected foods as triggers of allergic symptoms. In a prospective study in 480 children during the first three years of life, Bock demonstrated that out of 133 (28%) children suspected by their parents to have food allergy, only in 37 (8%) were the symptoms elicited by the suspected food administered as an oral challenge in controlled conditions.10 The foods most commonly assumed to induce symptoms were milk (72 cases), egg (11), soya (11), chocolate (8), and peanut (6). The blind challenge confirmed the suspicion in 11 cases for milk, three for peanut, two for soya, and one for egg. Bock considered separately the reactions to fruits and fruit juices, which were complained of by the parents of 75 children and confirmed by an open challenge in 56 cases; the fruits most frequently responsible were orange and tomato (14 cases), apple (7), and grape (4). Symptoms confirmed by the challenge were diarrhoea, vomiting, abdominal pain, skin symptoms such as urticaria-angioedema and erythema, and nasal congestion.
The overall prevalence of true food allergy of 8% in this study was higher than in adults, but the natural history of food allergy may explain the difference, as children tend to outgrow sensitization to most foods with time.11 In fact, only in four of the children of Bock's study was the reaction to food confirmed by a further blind challenge in their third year.
In view of its overwhelming importance in causing allergy, some studies have investigated the prevalence of adverse reactions to cow's milk in children. A first study, based only on historical data as reported by children's parents, found a prevalence of 7.5%,12 whereas in studies based
94
on elimination/challenge procedures the prevalence was, as expected, lower. In Sweden, out of 1 079 infants about 2% had skin or gastrointestinal symptoms related to cow's milk13 and comparable figures were found in the United Kingdom, where a prevalence of 2.5% of cow's milk intolerance in infants was reported.14
Two recent studies prospectively evaluated the prevalence of cow-milk allergy in the first years of life. In Denmark a cohort of 1 749 infants was followed for three years, establishing adverse reactions to cow's milk by an elimination/challenge procedure in the first year and repeating the challenge at 6-12 month intervals until the third year of age.15 The first challenge showed 39 of the 1 749 (2.2%) infants allergic to cow's milk, 64% presenting skin symptoms, 59% gastrointestinal and 33% respiratory symptoms. Among these 39 positive children, 21 (54%) had an IgE-mediated allergy, as assessed by positive skin tests and RAST to cow milk. On repetition of the challenge symptoms had disappeared in 22 of the 39 (56%) at one year, in 30 (77%) at two years, and in 34 (87%) at three years of age.
The other study was conducted in the Netherlands and was limited to the first year of life.16 Two positive elimination/challenge tests showed 26 of 1 158 (2.3%) infants were allergic to cow's milk. Of these, 50% had gastrointestinal, 3 1 % dermatological, and 19% respiratory symptoms. Twenty children were then followed for four years, by which time 75% were tolerant to cow's milk.
These findings clearly illustrate the tendency to outgrow milk allergy with age, unlike other foods, to which adverse reactions tend to persist. For example, a Canadian study reported that out of 480 children suffering from food allergy tested by DBPCFC in the first year of life 186 (39%) were allergic to milk, 236 (49%) to egg, and 120 (25%) to peanut. After five years only six of 186 children (3.2%) had a positive DBPCFC to milk, compared to 19 of 236 (8%) for egg and to 68 of 120 (56.6%) for peanut.17
8.4. Conclusions
The prevalence of food allergy in the general population tends to decline with age, from about 8% in children to less than 1 % in adults. Patients tend to outgrow the clinical sensitization with time, which explains this decrease. This natural history is particularly evident for cow milk's allergy, which is the most common in infancy, but only a small number of children with adverse reactions to milk in the first three years of life still present the clinical reactivity after three to five years. On the other hand, the prevalence in adults of allergy to fresh fruits and vegetables has yet to be fully estimated; preliminary studies report it as very common in subjects suffering from pollinosis because of cross-sensitization between the allergens of pollens and vegetables.
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3 Burr M.L., Merret T.G. 'Food intolerance: A community survey'. Br. J. Nutr., 1983, 49, pp. 217-219.
4 Cohen M., Splansky G.L., Gallagher J., Bernstein D.I., Bernstein I.L. 'Epidemiologic survey and validation of adverse food reactions (AFR) in adults populations'. J. Allergy Clin. Immunol., 1985, 75, pp. 206.
5 Sloan A.E., Powers M.E. 'A perspective on popular perceptions of adverse reactions to foods'. J. Allergy Clin. Immunol., 1986, 78, pp. 127-133.
6 Young E., Stoneham M.D., Petruckevitch Α., Barton J., Bona R. 'A population study of food intolerance'. Lancet, 1994, 343, pp. 1127-1130.
7 Niestijl Jansen J.J., Kardinaal A.F.M., Huijbers G., Vlieg-Boerstra B.J., Martens B.P.M., Ock-huizen T. 'Prevalence of food allergy and intolerance in the adult Dutch population'. J. Allergy Clin. Immunol., 1994, 93, pp. 446-456.
8 Bircher A.J., Van Melle G., Haller E. 'IgE to food allergens are highly prevalent in patients allergie to pollens, with and without symptoms of food allergy'. Clin. Exp. Allergy, 1994, 24, pp. 367-372.
9 Evans R. III. 'Epidemiology and natural history of asthma, allergic rhinitis, and atopic dermatitis'. In Middleton E., Reed CE., Ellis E.F., Adkinson N.F., Yunginger J.W., Busse W.W., (Eds): 'Allergy. Principles and practice'. Mosby Year Book., St. Louis, 1993, pp. 1109-1136.
10 Bock S.A. 'Prospective appraisal of complaints of adverse reactions to foods in children during the first three years of life'. Pediatr., 1987, 79, pp. 683-688.
11 Bock S.A., Atkins F.M. 'Patterns of food hypersensitivity'. J. Pediatr., 1990, 54, pp. 561-567.
12 Gerrard J.W., Mackenzie J.W.A., Goluboff N. 'Cow's milk allergy: Prevalence and manifestations in an unselected series of newborns'. Acta Paediatr. Scand., 1973 (Suppl), 234, pp. 3-21.
13 Jakobsson I., Lindberg T. 'A prospective study of cow's milk protein intolerance in Swedish infants'. Acta Pediatr. Scand., 1979, 68, pp. 853-859.
14 Hide D.W., Guyer B.M. 'Cow milk intolerance in Isle of Wight infants'. Br. J. Clin. Prac. 1983, 37, pp. 285-287.
15 Host Α., Halken S. 'A prospective study of cow milk allergy in Danish infants during the first three years of life'. Allergy, 1990, 45, pp. 587-596.
16 Schrander J.J.P., van den Bogart J.P.H., Forget P.P., Schrander-Strumpel C.T.R., Kuijten R.H., Kester A.D.M. 'Cow's milk protein intolerance in infants under one year of age: A prospective epidemiological study'. Eur. J. Pediatr., 1993, 152, pp. 640-644.
17 Chandra R.K. 'Natural history of food allergy'. Pediatr. Allergy Immunol, (submitted).
96
C H A N G I N G D I E T A R Y H A B I T S
SYNOPSIS There are no figures on the changing prevalence of allergic reactions for each individual food. Particularly, there are no studies on how food allergy has changed with respect to the changes in dietary habits. However an increased risk for food allergy should be expected for several reasons: (1) an increasing use of domestic items within the household (e.g. freezer, microwave oven, frying devices, etc.); these items inevitably lead to the increased consumption of prepackaged food products, particularly frozen products and baked goods; (2) changes in life styles and work schedules facilitate the consumption of meals outside the household (e.g. fast-food restaurants, snack bars, etc.); (3) the increased distribution and widespread availability of food goods has reduced the boundaries of regional cooking habits and introduced new food products; (4) the food industry's expanding market of products that are processed and handled on an industrial scale.
Epidemiological data on food allergy are few and incomplete, and there are no figures on the changing prevalence of allergic reactions for each individual food. Particularly, there are no studies on how food allergy has changed with respect to the changes in dietary habits. Quantitative data on the changes in the consumption of individual foods or food groups is available for EC countries;1 part of the available data are reported in the tables (Tables 9.1 to 9.9).
In the past 31 years there was general increase of food consumption in every EC country. Milk and egg consumption increased in Greece, Portugal and Spain; in all the other countries the increase was poor except in Denmark, Finland and Ireland for milk, and in Benelux, Ireland and Sweden for eggs. Fish consumption doubled in Finland, Ireland, Italy and Spain; did not change in Germany, Netherlands, Norway and Sweden; it was slightly increased in all the other countries. Crustaceans consumption increased in all EC countries: it grew from 0 to 0.4 in Austria; moreover this increased seven times in Denmark, six in Spain and Portugal, five in the Netherlands, four in France, Italy and Sweden. Tomato consumption increased in all the EC countries, particularly in Scandinavia (10 times in Finland and eight times in Sweden). A general increase of consumption was registered for banana which grew three times in Greece and six in Finland.
Nut consumption increased in all EC countries except in Ireland and Portugal for treenuts, and Spain for groundnuts where consumption fell.
Nevertheless, food allergy being a phenomenon primarily directed by qualitative changes, the modified foods eaten can act on the prevalence of food allergy.
In some countries and concerning some particular food the change of dietary habit was important; i.e. in Finland the tomato consumption per capita grow from 1.3 kg/year to 13.1. Provided that tomato is an allergic food we can expect an increase of the incidence of allergies to tomato in Finland. However, no incidence data are available for either food allergy in general or allergy to a single food. The study of this topic is not easy to develop, moreover the cross reactivity between some food isoallergens may complicate the understanding of this phenomenon.
97
Precise data on this matter are lacking, but a clear tendency toward changing life styles is taking place, especially in regard to food habits and the recent expansion of the food industry.
In particular the following points need to be underlined:
1. There has been an increase in the use of domestic items within the household (e.g. freezer, microwave oven, frying devices, etc.). These items inevitably lead to the increased consumption of prepackaged food products, particularly frozen products and baked goods.
2. Changes in life styles and work schedules facilitate the consumption of meals outside the household (e.g. fast-food restaurants, snack bars, etc.).
3. The increased distribution and widespread availability of food goods has reduced the boundaries of regional cooking habits and introduced new food products. Examples are the availability of exotic fruits all year round, and the presence of fresh fruits and vegetables (of Mediterranean origin) in northern European countries.
4. The food industry's expanding market of products that are processed and handled on an industrial scale.
In recent years some European countries have expanded their cultivation of kiwi fruit, this has made kiwi largely available, making it part of the regular diet of many Europeans. Kiwi fruit is allergenic, and its introduction into the European diet has increased the number of patients who complain of food allergy to this fruit; symptoms are not infrequently life threatening.2"6
Pizza is a food of Italian origin and its consumption has spread to other countries, and it is not infrequent to encounter allergy to this food (personal observation). The allergen responsible is not always identifiable: some cases can be due to wheat flour or tomato; other cases may be due to components found in the flour mixtures, and these ingredients may prove difficult to identify.
Crustaceans constitute another food group that causes allergy; the consumption of crustaceans has increased in Europe during the period 1961 -92 : 1 : see Table 9.4.
The large use of soya by the food industry for the preparation of foods has significantly influenced the growth of allergy to this food. Soya is one of the main allergens in the food industry and the unreported presence of soya in food products can be responsible for serious allergic reaction that are sometimes fatal.7
Similarly, the use of peanut has increased in the food industry and its widespread consumption has made it the principal food allergen in the United States; peanut has the highest prevalence for death resulting from food allergy.8"10
In general, as discussed in Chapter 10, food processing and preparation can increase the risk of sensitization to foods and this can give rise to severe allergic reactions, at times fatal, when an allergic patient inadvertently ingests the offending food.7 For this reason the allergenic potential of products such as Simplesse® must not be underestimated.11
98
In conclusion, the qualitative modifications of food (and to a lesser degree the quantitative modifications) increase the risk that the susceptible population has of developing allergy when eating a food. In fact this latter tendency makes it absolutely important to produce guidelines that safeguard the food-allergic patient, as indicated in Chapter 10.
REFERENCES 1 FAO computerized information series No 6: Food balance sheets (floppy disks). Food and
Agriculture Organization of the United Nations; Rome, 1995.
2 Fine A.A. 'Hypersensitivity reaction to kiwi fruit'. J. Allergy Clin. Immunol., 1978, 58, pp. 500-515.
3 Niestijl Jansen J.J., Kardinaal A.F.M., Huijebers G., Vlieg-Boerstra B.J., Martens B.P.M., Ockhuizen T. 'Prevalence of food allergy and intolerance in the adult Dutch population'. J. Allergy Clin. Immunol., 1994, 93, pp. 446-56.
4 Dutau G., Juchet Α., Rance F., Fejji S., Nouilhan P., Bremont F. 'Chocs anaphylactiques par allergies alimentaires'. Rev. fr. Allergol., 1994, 34, pp. 409-417.
5 Gall H., Klaveram K.J., Forck G., Sterry W. 'Kiwi fruit allergy: A new birch pollen-associated food allergy'. J. Allergy Clin. Immunol. 1994, 94, pp. 70-76.
6 Ortolani C , Ispano M., Pastorello E.A., Bigi Α., Ansaloni R. 'The oral allergy syndrome'. Ann. Allergy 1988, 61 (Part two), pp. 47-52.
7 Yman I.M., Eriksson Α., Everitt G., Yman L., Karlsson T. 'Analysis of food proteins for verification of contamination or mislabelling'. Food & Agricultural Immunology 1994, 6, pp. 167-172.
8 Yunginger J.W., Squillace D.L., Jones R.T., Helm R.H. 'Fatal anaphylactic reactions induced by peanuts'. Allergy Proc, 1989, 10, pp. 249-253.
9 Sampson H.A., Mendelson L., Rosen J.P. 'Fatal and near-fatal anaphylactic reactions to food in children and adolescents'. N. Engl. J. Med. 1992, 327, pp. 380-382.
10 Junginger J.W., Sweney K.G., Sturner W.Q., Giannandrea L.A., Teigland J.D., Bray M., Benson P., York J.A., Biedrzycki L., Squillace D.L., Helm R. 'Fatal food-induced anaphylaxis'. JAMA 1988, 260, pp. 1450-1452.
11 Sampson H.A., Cooke S. 'The antigenicity and allergenicity of microparticulated proteins: Simplesse®. Clin. Exp. Allergy 22, pp. 963-969, 1992.
99
Table 9.1 Consumption of milk (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
218.9
185
222.2
358.1
227.6
172.5
125.4
279
150.1
282.9
250.5
64.5
80.7
297.3
1971
219.2
190
208.8
326.6
244.6
176.9
161.3
308.6
187.7
279.8
250.4
78.4
114.2
308.2
1981
244.4
198.3
212.1
329.5
295
196.8
204.4
317.8
256.7
313.3
316.6
106.4
370.9
370.9
1992
267.8
208.6
175.7
307.9
283.9
245
231.9
257.8
267.8
317.8
235.8
183.9
359.9
359.9
Table 9.2 Consumption of eggs (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
13
15.2
10.5
7.4
10.6
12.7
5.5
14
8.9
12.7
8.5
3.3
7.9
11.5
1971
13.6
13.1
11.2
10
12.2
15.9
10.7
11.2
10.6
12.2
9.6
3.5
13.5
11.9
1981
14.4
13.9
14.2
10.4
14.7
17
10.6
13.9
11.4
13.3
11.1
5.4
15.9
12.7
1992
13.3
12.9
15.4
10.5
15
13.8
10.1
9
12.3
11.9
10.9
7.7
15.1
12.4
100
Table 9.3 Consumption offish (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
7
17.7
16.6
17.5
18.8
20.7
19.1
7.1
12.7
10.7
38.7
55.8
26.7
25.8
1971
7.8
17.1
19.8
22.8
20.6
23.9
16.6
10.3
12.8
13
30.3
62.9
35.6
29.4
1981
5.7
18.1
18.9
27.5
24.7
21
17
16.3
13.8
10.5
42.6
29.6
31
26.8
1992
9.1
19.2
18.8
31
30.5
20.3
23
17.6
21.1
10.8
44.1
49.2
38.8
27.6
Table 9.4 Consumption of crustacean (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
0
1.5
0.2
0
0.8
0.5
0.2
0.3
0.4
0.3
1.2
0.1
0.6
1.4
1971
0.2
1.6
1.8
0.2
1.3
0.6
0.2
1.1
0.4
0.5
0.9
0.2
1.4
2.8
1981
0.3
2.6
1.7
0.5
2.7
0.6
0.3
0.8
0.6
0.9
5.7
0.2
1.5
3.5
1992
0.4
2.4
1.5
1.7
3
0.8
0.6
0.7
1.8
1.5
3.6
0.6
3.4
5.2
101
Table 9.5 Consumption of tomato (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
3
6.1
5.4
1.3
11.4
4
38.3
5.1
32.3
4.1
4.4
12.6
27.8
2.4
1971
5.8
10.7
7.5
4.7
13.4
7.1
97
6.8
41.6
7.3
5.2
23.1
37
6
1981
9.9
13.1
9.4
9.1
19.6
9
137.4
9.3
49
9.4
8.6
17.5
36.9
9.6
1992
13.2
24.3
13.9
13.1
22.8
14.2
113.4
8.8
61.3
19.9
10.6
27.9
40.4
18
Table 9.6 Consumption of banana (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
3.8
6.4
5.9
2.5
7.5
6.2
0.5
3.4
2.1
5.6
7.2
3.6
5.8
5.3
1971
8.4
7.9
7.4
6
8.4
8.1
1.4
8.2
4.5
7.4
9.9
7.9
9.8
9.2
1981
9.5
7.1
4.6
8.3
7.9
6.9
0.2
4.5
4.3
7
7.7
3.3
11.2
8.2
1992
14.4
22.1
10.6
15.1
8.2
12.2
4.4
9.2
8.6
10.1
13.4
12.7
8.2
17.7
102
Table 9.7 Consumption oftreenuts (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
2.2
1
0.9
0.2
2.6
1.9
7.5
0.7
5.1
0.9
1.7
10
6.2
1.7
1971
2.6
1.7
1.4
0.2
2.6
2.2
6.9
1.1
4.6
1.5
1.8
4.8
5.3
2.1
1981
3.5
2.5
1.8
0.4
3
2.7
9.1
1.3
5.4
0.2
2.7
2.9
6.3
3
1992
6.1
4.1
3.6
1.2
3.2
4.6
9.2
0.4
5.2
3.3
2.7
4
7.8
3
Table 9.8 Consumption of groundnuts (kg/year per capita)
COUNTRY
AUSTRIA
BELGIO-LUXEMBOURG
DENMARK
FINLAND
FRANCE
GERMANY
GREECE
IRELAND
ITALY
NETHERLANDS
NORWAY
PORTUGAL
SPAIN
SWEDEN
1961
0.2
0
0
0.2
0.4
0.2
0.3
0.1
0.2
0.2
0
0.1
0.8
0.1
1971
0.3
0
0
0.1
0.3
0.3
0.5
0.1
0.2
0.1
0.1
0.2
0.9
0.1
1981
0.3
0
0
0.2
0.4
0.3
0.2
0.3
0.2
0.3
0
0.1
0.5
0.2
1992
0.6
0.3
3
0.5
1
0.4
0.3
0.5
0.2
0.6
0.3
0.1
0.6
0.8
103
10 . EFFECTS OF P R O C E S S I N G AND P R E P A R A T I O N OF FOOD
SYNOPSIS
There are two main problems that arise from food processing and preparation: (1) food processing may alter content and/or properties of food allergens, both reducing and increasing the allergenicity of the starting material; (2) most processed, packaged and canned foods contain additives and other 'hidden' ingredients of both natural and synthetic origin. Common food allergens such as milk, eggs, soya, and wheat are constituents of a wide variety of prepared foods, and in most cases labelling is incomplete and often misleading. This can have devastating consequences for a food-sensitive person. In fact almost all patients who died from food anaphylaxis had a history of allergic reactions to the food allergen responsible for the death, but they were unaware that the allergen was present in the food they ate. Therefore it is imperative that all processed foods sold in the European Community countries be clearly labelled with the list of the ingredients and of the starting materials.
There are two main problems arising from processing and preparation of food:
1. Food processing may alter content and/or properties of food allergens, both reducing and increasing the allergenicity of the starting material.
2. Most processed, packaged and canned foods contain additives and other 'hidden' ingredients of both natural and synthetic origin. Common food allergens such as milk, eggs, soya, and wheat are constituents of a wide variety of prepared foods, and in most cases labelling is incomplete and often misleading. This can have devastating consequences for a food-sensitive person. In fact almost all patients who died from food anaphylaxis had a history of allergic reactions to the food allergen responsible for the death, but they were unaware that the allergen was present in the food they ate.1
10.1. Food allergens alteration by food processing and preparation
Several studies have been performed in evaluating the change of food allergen properties during processing and preservation of food.
The authorities responsible for the safety assessment of food and food products pay careful attention to microbiologic contamination, toxicity and risk of cancer developing in food consumers, whereas the allergenic content of food is not taken into account except, indirectly, for the food ingredient labelling.
The food allergens are mainly proteins or glycoproteins which in many cases are not lost in food processing and preparation. However the allergenic content and properties may vary notably.2
More details are given in Section 5 (Food allergens).
104
1 0 . 1 . 1 . Fruit and vegetables
It is well known, although not widely investigated, that allergens from fruits and vegetables are generally labile and easily denaturated by food processing and preparation. Cooking a carrot or an apple will destroy the food allergens, allowing the sensitized person to eat the food.3
It is sufficient to cut an apple and store it minutes to hours to largely decrease the allergenicity of the fruit. This phenomenon depends on the interaction between proteins and polyphenols. Polyphenols, natural constituents of many plants, can, in the presence of oxygen, be oxidized to the corresponding quiñones. These quiñones can polymerize into brown pigments of large size or can react with the residues of certain amino acids. In the latter case, condensation may take place between quiñones and either lysine or cysteine residues, and/or oxidation reactions may occur with methionine residues or possibly with cysteine and tryptophan residues.2 The condensation of proteins in vegetable foods reduces the allergenicity.
On the contrary, the allergens of milk, egg and fish are quite stable to cooking and digestion.4
Moreover cooking the food may, in some cases, increase the allergenic properties.
1 0 . 1 . 2 . Cow's milk
In general heat treatment reduces the allergenicity of milk proteins,5 but may increase the allergenicity of some milk proteins, such as beta-lactoglobulin.6 Moreover one study suggests that pepsin tryptic digests of beta-lactoglobulin result in new antigens: while only 4/10 cow-milk allergic patients had IgE antibodies to indigested beta-lactoglobulin, all 10 patients had IgE antibodies to beta-lactoglobulin digests.7 These data however have not been confirmed by Fallstrom et al., who did not find significant differences in the IgE levels against natural cow's milk proteins, processed cow's milk proteins, native beta-lactoglobulin and pepsin digested beta-lactoglobulin in children sensitized to cow's milk proteins.8
Low pasteurization (75° C for 15 seconds) of cow milk does not seem to cause any significant reduction of the antigenicity. A stronger heat treatment (121 ° C for 20 minutes) may exacerbate allergic reactions.9 However, severe heating detroyed the anaphylactic sensitizing capacity of whey proteins (a-lactoalbumin and beta-lactoglobulin) and reduced that of casein in experiments in guinea pigs.9
Interestingly, Enomoto et al.10 showed that milk whey protein fed to mice elicited a systemic humoral response, whereas, when heat-denaturated whey protein was fed, the animals showed only a poor serum response, while oral tolerance was induced to a similar degree as that of natural whey protein diet.
Host and Samuelsson11 studied five children with IgE-mediated adverse reactions to cow's milk. The children were orally challenged double-blind with three different milk preparations processed from the same bath of milk: (1) raw untreated milk; (2) pasteurized cow milk; (3) homogenized and pasteurized cow milk. Skin-prick tests with the same preparations were also performed. Skin-prick tests and oral challenges were positive in all children with all the three different milk preparations. However tendency towards a lower threshold of reactions and larger skin reactions
105
induced by processed-milk preparations indicate an increased ability of pasteurized and homogenized/pasteurized milk to elicit allergic reactions in sensitized patients. These results are in agreement with animal studies showing increased anaphylactic reactions to intravenously injected homogenized milk in cow milk sensitized mice.12
During homogenization the fat globules are split into many smaller parts; this procedure causes an increase of the total surface area of the fat globules. About 25% of the casein micelles, and to same extent the whey proteins, are adsorbed to these new fat globules. Thus the amount of proteins increases in homogenized milk from 3.4 to 6.9% if the fat content is 3.5%. This might explain the abovementioned results.12
1 0 . 1 . 3 . F i s h
Gad d from codfish, the best characterized food allergen, resists digestion, cooking and proteolysis; its primary structure is allergenic.13 However, given the stability of Gad c1, Bernhisel Broadbent et al.14 found seven of 33 (21%) false-negative, double-blind, placebo-controlled, oral challenges (DBPCFC) with cooked lyophilized fish. In an effort to elucidate this discrepancy, the authors compared cooked lyophilized fish extracts used in DBPCFC with cooked non-lyophilized fish extract (used in positive open challenges) by SDS PAGE, immunoblot and ELISA-inhibition assays.15 Minor differences were apparent between the cooked non-lyophilized and the cooked lyophilized flounder extract: bands at 23 kd and 15 kd were prominent in the non-lyophilized lane but were absent in the lyophilized lane. Three of the seven false-negative DBPCFC were with flounder. With the exception of the flounder extracts on SDS-PAGE, the authors were unable to demonstrate a change in allergenicity of the fish extracts as a result of lyophilization. However the authors conclude that the seven false-negative DBPCFC to fish were the result of lyophilization and not dose-related, since the positive open challenges often occurred with the first dose of the cooked non-lyophilized fish. They suggest that the in vitro methods performed lacked the sensitivity to detect this subtle, clinically relevant change in allergenicity. In the same study15
altered fish allergenicity as a result of food processing was examined with canned tuna and salmon. All the 18 patients with IgE-mediated allergy to fish had negative challenges with canned tuna and the two patients with IgE-mediated allergy to salmon had negative challenge with canned salmon. SDS-PAGE of tuna and salmon extracts revealed a striking loss of definable protein fractions in the canned fish extract when compared with raw and cooked fish extracts. A 100 to 200 times higher concentration of canned salmon was required to achieve 50% inhibition of an ELISA inhibition assay when compared with cooked salmon. In a separate paper Bernhisel Broadbent et al. depict the results of SDS-PAGE and immunoblot analyses on raw and cooked protein extracts from nine fish species, performed with sera of 10 patients with positive oral challenge to fish.14 Several protein bands in the raw-fish extracts appeared to denature with cooking and form high molecular weight conglomerates. Seven of nine fish species had a prominent band at 20 kda in cooked, but not the raw, lanes (with exception of tuna and salmon). Four cooked fish extracts (tuna, salmon, codfish and flounder) formed high (> 115 kda) molecular weight complexes, not present in the raw material lanes. The protein bands in the molecular weight range of 40 to 90 kda appeared especially sensitive to heat denaturation, and many bands present in the lanes performed with raw fish were not present in the lanes containing cooked fish.
106
Hansen et al. also investigated the allergenic activity of processed fish:16 extracts of fresh, raw codfish, mackerel, herring and plaice were compared with extracts of boiled fish and water from boiling after 6 minutes, 1 hour, and 4 hours by using histamine release test (HR), SDS-PAGE, and immunoblotting. Sera from two adults clinically allergic to codfish and a control person were investigated. In HR the allergenic activity of all extracts was unchanged, except in mackerel. Here a decrease in allergenicity could be seen already at 6 minutes. No major differences were noted in SDS-PAGE between raw and boiled extract of each fish, but bands > 40 kda appeared more sensitive to heat. Fewer bands were seen in water from boiling after 6 minutes than 4 hours, but all extracts contained a band < 14 kda (Gad c 1) except water for boiling of mackerel. However, immunoblotting with patients' sera demostrated IgE-specific binding to that band in all extracts. The authors conclude that boiling fish for up to 4 hours does not significantly reduce allergenicity, however, it cannot be excluded that prolonged boiling may alter the allergenic profile of fish proteins.
Mata et al. investigated the allergenicity of a Japanese food product named surimi17 which is minced and thoroughly washed fish meat. Surimi is a mixture of small fish of many species. It lacks most soluble sarcoplasmic proteins and is composed mainly of myofibrillar proteins. The production of surimi has greatly increased and it uses cryoprotectors which slow the denaturation of frozen proteins. Surimi may have added starch, egg white, and other ingredients forming an elastic gel after cooking. Its applications in the food industry are numerous. The allergenicity of codfish and surimi was compared by skin tests, RAST and HR in six fish allergic patients. Skin-prick tests were positive for codfish and, to a lesser extent, for surimi in the allergic patients. Both codfish and surimi RAST were positive in the six patients. HR test were also positive for both surimi and codfish in 5/6 patients. The eluate from codfish contained several proteins ranging from 13 (probabily Gad c1) to 63 kda, while the eluate from surimi contained a single 63 kda protein, showing an extensive alteration in protein contents of surimi when compared with codfish.
1 0 . 1 . 4 . Meat
A decrease in allergenicity of processed beef and mutton when compared with non-processed meat was demostrated by Fiocchi et al.18 in 12 children with IgE-mediated allergy to beef. The peptic digestion of bovine serum albumin (BSA) and ovine serum albumine (OSA) strongly reduced the number of positive skin-prick tests and RAST when compared with native BSA and OSA in the 12 children. All children were skin-prick tests positive to native BSA and OSA whereas only 1/12 had a positive prick tests with lyophilized and homogenized beef and 1/12 with lyophilized mutton, showing an extensive reduction in allergenicity of the processed meat.
1 0 . 1 . 5 . Hen's egg
Elsayed et al.19 showed that thermal denaturation of egg white ovalbumin by heating to 80° C for 10 minutes or treating with trypsin had no direct effect on the antigenic reactivity as shown by crossed immuno-electrophoresis (CIE). Furthermore, trypsin hydrolysis of carboxymethy ovalbumin (OVA) did not abolish the activity of IgE antibodies in patients with egg allergy.19 Similarly, the patients' IgE showed reactivities on IEF immunoprints for cleavage products of OVA.20
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In a recent study21 the SDS-PAGE results indicated that the primary structure of OVA was retained when OVA was treated with dithiothreitol, urea or hydrochloric acid. Meanwhile, the binding activities of heterologous rabbit or mouse anti-OVA antibodies to denatured OVA were not identical with those to native OVA, indicating that denaturation of OVA modified the conformational structure.
1 0 . 1 . 6 . S h r i m p
Rosen et al.22 describe a patient with an anaphylactic reaction after shrimp ingestion and with negative skin-prick test (SPT) performed with commercially available shrimp extracts. The SPT performed with the natural food gave a negative result with raw shrimp, whereas the SPT result with the cooked (steamed) shrimp was unequivocally and repeatedly positive. The authors conclude that it appears that cooking the shrimp did not destroy all of the allergens but rather produced new ones not present in the raw shrimp, possibly by altering existing allergenic proteins or by exposing allergenic epitopes already present in the shrimp.
1 0 . 1 . 7 . M i c r o p a r t ¡ d i l a t e d p r o t e i n s
Sampson and Cooke evaluated the allergenicity of Simplesse®, a microparticulated product derived from egg and milk proteins.23
Microparticulated proteins may develop naturally in some foods or may be secondary to processing techniques used in the food industry, like blending, mixing, pasteurization, pH alteration, baking. Recently a technique utilizing heat and a high-shear processor has been developed to coagulate food proteins into microparticles that are uniform in particle distribution, size and quality. These microparticles are 0.1-3 mm in diameter and when placed in the mouth are perceived as fat. The resulting material, Simplesse®, may be used to replace the fat in various fat-laden foods, greatly reducing the fat, cholesterol and caloric content of these foods. It is used in cream-based foods such as frozen desserts, ice creams, cream cheeses, soft cheeses, sour cream, etc., and oil-based products such as mayonnaise and salad dressings, where it comprises 7 to 40% of total protein.23 Simplesse® has been approved for use in most EC countries. In addition, other protein sources (e.g. soya) could be utilized in this process.The major allergenic proteins in egg and milk are largely resistent to heating and to break-down by proteases. Simplesse® which is made from ultra-filtered egg white and skim milk proteins or whey concentrate, is subjected to heat and high shear forces to form microparticles. In the Sampson and Cooke study,23 soluble protein fractions of Simplesse® and its respective starting materials were compared to egg white, cow's milk protein, an ultra-filtered egg white condensed milk mixture, and/or a whey concentrate by SDS-PAGE. In addition, sera from 16 patients with documented egg and/or cows' milk hypersensitivity were used to assess potential allergenicity of these products by immunoblot analysis.
The use of Simplesse® may provide a significant advance in preventive health management of cardiovascular disease, by lowering the amount of fat and the calories of the food products when compared with butterfat containing food products. However, the Sampson and Cooke study23
clearly indicates the high risk for cow's milk or egg allergic individuals when eating Simplesse® containing food products. Since the greatest danger to patients with food allergy is the unknowing
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ingestion of a food allergen,1·24 it is of paramount importance that Simplesse® and all food products containing microparticulated proteins, be clearly labelled to indicate the presence of egg and milk.
1 0 . 1 . 8 . Peanut
Nordlee et al.25 tested extracts of 19 different peanut products and peanut oil for their allergenicity by the radioallergosorbent test (RAST) inhibition assay using a crude peanut extract'from raw peanuts as the standard for comparison. The IgE antibody pool was comprised of the combined sera obtained from five individuals highly sensitive to peanuts. The eight peanuts flours prepared from the cotyledons of the peanut were allergenic.The slopes of the RAST inhibition line for five of the eight flours did not vary significantly from the slope of the RAST inhibition line of the standard raw peanut extract, whereas the slopes of the RAST inhibition lines for the three remaining flours were significantly different. The authors suggest that this variance may be related to the impact of processing on certain allergenic determinants or to some difference between the allergenic determinants of distinct source varieties of peanuts.
The four peanut butter extracts were somewhat more allergenic, accordingly with the higher amount of peanut protein contained in the peanut butter when compared with the raw peanut.
Oil roasted and dry roasted peanuts had approximately the same degree of allergenicity as the standard raw peanut extract. The peanut hull flour extract showed only small amounts of the peanut allergen, whereas peanut oil and the extract from hydrolyzed peanut protein did not inhibit binding, suggesting that these products are not allergenic.25
To quantify trace amounts of peanut allergens in food processing materials and finished foods, Keating et al.26 performed a radioimmuno-assay (RIA) inhibition using pooled sera from peanut-sensitive individuals and roasted peanut meal extract. The peanut allergen content of test samples was expressed relative to a reference extract of roasted peanut meal that was assigned an arbitrary potency of 100 000 U/ml. In confectionary products spiked with varying amounts of peanut the recovery of peanut allergen ranged from 31 to 94%. Peanut allergens were undetectable in vegetable oil used to roast peanuts, but 600 to 700 U/mg of dry weight were present in oil after varying periods of use.26
Burks et al.27 investigated the change in IgE specific binding to peanut allergens altered by either chemical or thermal denaturation. The serum of 10 patients allergic to peanut were used for ELISA inhibition analyses. Heating the peanut extracts at varying temperatures and time intervals did not significantly change the IgE specific binding of the peanut positive pooled serum.
When these same extracts were treated with enzymes in the immobilized digestive assay system employed to mimic human digestion, a 100-fold reduction in IgE binding was observed when compared with the crude peanut extracts.27
It is generally accepted that peanut oil ingestion does not pose a risk to peanut-sensitive individuals.28 Taylor et al.29 performed skin-prick test (SPT) with peanut oil and DBPCFC with 1.2, and 5 ml of peanut oil in 10 adult patients highly sensitive to peanut. SPT and DBPCFC were
109
negative in all patients. However, some reports of allergic reaction to peanut oil are reported. Children allergic to peanut may experience adverse reactions to milk formulas containing peanut 0j|.30,31
Recently in vitro investigations with immunoblot analyses confirmed the absence of detectable amounts of peanut allergen in high temperature processed peanut oils from three different manufacturers.32 However, highly significant amounts of peanut allergen were found in two brands of cold-pressed peanut oil, and a trace amount was present in a third. A fourth brand appeared to be free of detectable allergen. The authors suggest that individuals highly sensitive to peanut should also avoid foods prepared in or with peanut oils, especially 'health foods' which may be prepared with cold-pressed or unrefined peanut oil that may be contaminated with peanut protein.32
1 0 . 1 . 9 . Soybean
Burks et al.27 investigated the allergenicity of soya bean extract altered by chemical or thermal denaturation in two patients with positive food challenge. Heating the soya proteins at various temperatures and time intervals did not significantly change the IgE specific binding to the soya positive pooled serum. When soya proteins were treated with enzyme assay system the binding of IgE to crude soya extract was only minimally reduced (10 fold).27
In the processing of soya bean oils the allergenic portion is removed. Bush et al.33 found that soya bean oil is not allergenic to soya bean-sensitive individuals: 7/7 subjects had negative challenge with oil. However the number of patients challenged with soya oil is not sufficient to state that soya oil is safe in all patients highly sensitive to soya bean.
1 0 . 1 . 1 0 . Corn
Corn is widely used in food products, mainly for oils and as corn sweeteners or cornstarch. In the processing of corn oil the allergenic portion is removed and therefore corn oil is considered safe in patients allergic to corn. Loveless showed that corn-allergic patients tolerated a challenge with corn oil and corn sugar and syrup.34 However, occasional patients sensitive to corn may have a positive blinded challenge to corn starch.28·34
1 0 . 1 . 1 1 . Sunflower oil
The safety of sunflower oil in patients sensitized to sunflower seeds is controversial. Halsey et al.35 investigated the allergenicity of sunflower seed oil in two patients allergic to sunflower seeds. Specific IgE to refined or cold-pressed sunflower oil were not detectable. Although the cold-pressed sunflower oil was found to contain a minute amount of protein (2-8 pg/ml), open challenge with the derivative oils resulted negative.35 In contrast Kanny et al.36 describe a case of allergic reaction to sunflower oil in a patient with mugwort hay fever.
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1 0 . 1 . 1 2 . Sesame seed oil
Another report describes a case of anaphylactic reaction to sesame seed oil in a patient highly sensitive to sesame seed.37 Moreover, sesame seed oil provoked in this patient anaphylactic reactions more severe than raw sesame seed and other sesame-seed products.
1 0 . 1 . 1 3 . Lupin seed
Heflie and coworkers38 describe a case of a girl with peanut and green peas sensitivity, who experienced urticaria and angioedema after ingestion of spaghetti-like pasta fortified with sweet lupin seed flour. The skin-prick test with the lupin pasta extract was positive and immunoblotting studies of the extract showed IgE-binding protein bands.
1 0 . 1 . 1 4 . Food contaminants
In addition to food itself, food contaminants may be responsible for some anaphylactic reactions. Erben et al.39 describe a patient not sensitive to food allergens, but highly sensitive to dust mite, who experienced an anaphylatic reaction shortly after ingestion of homemade beignets prepared from a commercial mix, which resulted in the beignets being contaminated with Dermatofha-goides farinae. Antibiotics may account for some adverse reaction to foods, due to contaminants.
REFERENCES 1 Sampson H.A., Mendelson L., Rosen JP. 'Fatal and near-fatal anaphylaxis reactions to food in
children and adolescents'. N. Engl. J. Med. 327, pp. 380-384, 1992.
2 Bender A.E. Food processing and nutrition. Academic Press, London, New York, S. Francisco, 1978.
3 Ortolani C , Ispano M., Pastorello E.A., Ansaloni R., Magri G.C. '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., 83, pp. 683-90, 1989.
4 Taylor L., Lemanske F., Bush K., Busse W. 'Food allergens: structure and immunologic properties'. Ann. Allergy, 59 (Part two) pp. 93-99, 1987.
5 Gjesing Β., Osterballe O., Schwartz Β., Wahn U., Lowenstein H. 'Allergen-specific IgE antibodies against antigenic components in cow milk and milk substitutes'. Allergy, 41, pp. 51-56, 1986.
6 Bleumink E., Oung E. 'Identification of the atopic allergen in cow's milk'. Int. Arch. Allergy, 34, pp. 521-543, 1968.
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7 Haddad Z.H., Kaira V., Verma S. 'IgE antibodies to peptic and peptictryptic digests of beta
lactoglobulin: significance in food hypersensitivity', Ann. Allergy, 42, pp. 368371, 1979.
8 Fallstrom S.P., Ahlstedt S., Carlsson B., Lonnerdal B., Hanson L.A. 'Serum antibodies against
native processed and digested cow's milk proteins in children with cow's milk protein intoler
ance'. Clin. Allergy, 16, pp. 417423, 1986.
9 Kilshaw P.J., Heppel L.M., Ford J.E. 'Effects of heat treatment of cow's milk and whey on the
nutritional quality and antigenic proprieties'. Arch. Dis. Child. 57, pp. 842847, 1982.
10 Enomoto Α., Konishi M., Hachimura S., Kaminogawa S. 'Milk whey protein fed as a constituent
of the diet induced both oral tolerance and a systemic humoral response while heat denatured
whey protein induced only tolerance'. Clin. Immunol. Immunopathol, 66, pp. 136142, 1993.
11 Host Α., Samuelsson E.G., 'Allergic reactions to raw, pasteurized and homogenized pasteur
ized cow milk: A comparison'. Allergy, 43, pp. 113118, 1988.
12 Poulsen Ο.M., Hau J., Kollerup J. 'Effect of homogenization and pasteurization on the allergen
icity of bovine milk analysed by a murine anaphylactic shock model'. Clin. Allergy, 17, pp. 449
458, 1987.
13 Elsayed S., Apold J. 'Immunochemical analysis of cod fish allergen M: location of the immun
oglobulin binding sites as demonstrated by the native and synthetic peptides'. Allergy, 38, pp.
44959, 1983.
14 Bernhisel Broadbent J., Scanion S.M., Sampson H.A. 'Fish hypersensitivity'. J. Allergy Clin.
Immunol. 89, pp. 730737, 1992.
15 Bernhisel Broadbent J., Strause D., Sampson H.A. 'Fish hypersensitivity. II Clinical relevance
of altered fish allergenicity caused by various preparation methods'. J. Allergy Clin. Immunol.,
90, pp. 622629, 1992.
16 Hansen T.K., Skov S.P., Poulsen L.K., Bindslev Jensen C. 'Allergenic activity of processed
fish'. ACI News Suppl., 2, p. 445, 1994.
17 Mata E., Favier C , Moneret Vautrin D.A., Nicolas J.P., Han Ching L., Guèant J.L. 'Surimi and
native codfish contain a common allergen indentified as a 63 kda protein'. Allergy, 49, pp. 442
447, 1994.
18 Fiocchi Α., Restani P., Riva E., Restelli A.R., Biasucci G., Galli CL., Giovannini M. 'Allergia alla
carne. Effetto del trattamento tecnologico e della digestione enzimatica sulle proprietà aller
geniche della sieroalbumina bovina ed ovina Riassunti' 21 ° Congresso della Società Italiana di
Allergologia e Immunologia Clinica, Milano, 912 November, 1994.
19 Elsayed S., Hammer A.S.E., Kalvenes Μ.Β., Florvaag E., Apold J. Vik H. 'Antigenic and
allergenic determinants of ovalbumin. I. Peptide mapping cleavage at the methionyl peptide
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bonds and enzymic hydrolysis of native and carboxymetyl OA'. Int. Arch. Allergy Appi. Immunol., 79, pp. 101-107, 1986.
20 Kahlert H., Peterson Α., Becker W.M., Schlaak M. 'Etiope analysis of the allergen ovalbumin (Gad dll) with monoclonal antibodies and patients' IgE'. Mol. Immunol., 29, pp. 1191-1201, 1992.
21 Honma K., Kohno Y., Saito K., Shimojo N., Tsunoo H., Numi H. 'Specificities of IgE,. IgG and IgA antibodies to ovalbumin'. Int. Arch. Allergy Immunol., 103, pp. 28-35, 1994.
22 Rosen J.P., Selcow E.J., Mendelson L.M., Grodofsky M.P., Factor J.M., Sampson H.A. 'Skin testing with natural foods in patients suspected of having food allergies: Is it a neccesity?' J. Allergy Clin. Immunol., 93, pp. 1068-1070, 1994.
23 Sampson H.A., Cooke S. 'The antigenicity and allergenicity of microparticulated proteins: Simplesse'. Clin. Exp. Allergy, 22, pp. 963-969, 1992.
24 Yunginger J.W., Sweeney K.G., Stumer W.Q., Giannandrea L.A., Tiegland J.D., Bay R.M., Benson P.A., York J.A., Biedzycki I., Squillance D.L., Helm R.M. 'Fatal food-induced anaphylaxis'. J. Am. Med. Assoc, 260, pp. 1450-1452, 1988.
25 Nordlee Α., Taylor L., Jones R.T., Yunginger W. 'Allergenicity of various peanut products as determinated by RAST inhibition'. J. Allergy Clin. Immunol., 68, pp. 376-382, 1981.
26 Keating M.U., Jones R.T., Worley N.J., Shively C.A., Yunginger J.W. 'Immuno-assay of peanut allergens in food-processing materials and finished foods'. J. Allergy Clin. Immunol., 86, pp. 41-44, 1990.
27 Burks A.W., Williams L.W., Thresher, Connaughton C , Cockrell G., Helm R.M. 'Allergenicity of peanut and soyabean extracts altered by chemical or thermal denaturation in patients with atopic dermatitis and positive food challenge'. J. Allergy Clin. Immunol., 90, pp. 889-97, 1992.
28 Koerner C.B., Sampson H.A. 'Diets and nutrition'. In Metcalfe D.D., Sampson H.A., Simon R.A., (eds) 'Food Allergy. Adverse reactions to food and food additives' pp. 332-354, 1991.
29 Taylor S.L., Busse W.W., Sachs M.I., Parker J.L., Yunginger J.W. 'Peanut oil is not allergenic to peanut-sensitive individuals'. J. Allergy Clin. Immunol., 83, pp. 900-904, 1989.
30 Moneret Vautrin D.A., Hatahet R., Kanny G., Aitdjafer Z. 'Allergenic peanut oil in milk formulas'. Lancet 338, pp. 1149, 1991.
31 Morrow-Brown H. 'Allergenic peanut oil in milk formulas'. Lancet, 338, p. 1523, 1991.
32 Hoffman R., Williams Collins C. 'Cold-pressed peanut oils may contain peanut allergen'. J. Allergy Clin. Immunol., 93, pp. 801-802, 1994.
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33 Bush R.K., Taylor S.L., Nordlee J.A., Busse W.W. 'Soy bean oil is not allergenic to soyabean-sensitive individuals'. J. Allergy Clin. Immunol., 76, pp. 242-45, 1985.
34 Loveless M.H. 'Allergy for corn and its derivatives: Experiments with a masked ingestion test for its diagnosis'. J. Allergy, 21, pp. 500-511, 1950.
35 Halsey A.B., Martin M.E., Ruff M.E., Jacobs F.O., Jacobs R.L. 'Sunflower oil is not allergenic to sunflower seed-sensitive patients'. J. Allergy Clin. Immunol., 78, pp. 408-10, 1986.
36 Kanny G., Fremont S., Nicolas J.P., Moneret-Vautrin D.A. 'Food allergy to sunflower oil in patients sensitized to mugwort pollen'. Allergy 49, pp. 561-564, 1994.
37 Chiù J.T., Haydik B. 'Sesame seed oil anaphylaxis'. J. Allergy Clin. Immunol., 88, pp. 414-15, 1991.
38 Helfe S.L., Lemanske R.F., Bush R.K. 'Adverse reactions to lupin-fortified pasta'. J. Allergy Clin. Immunol., 94, pp. 167-72, 1994.
39 Erben A.M., Rodriguez J.L., McCullough J., Ownby D.R. 'Anphylaxis after ingestion do beignets contaminated with Dermatofagoides farinae'. J. Allergy Clin. Immunol., 92, pp. 846-9, 1993.
10.2. Food contaminants
The most common food contaminants are bacterial toxins, moulds, metals, biogenic amines, chemical compounds that have accidentally polluted the food (environmental pollution) or that have been deliberately used in the cultivation, i.e. pesticides, insecticides, fungicides, etc. Contaminants can cause untoward reactions by toxic or non-toxic non-immunological mechanisms, less frequently by a immunological mechanism. Botulism is an example of acute toxic reactions where flaccid paralysis is caused by the Clostridium toxin contained in a food.
Other bacterial contaminants can produce enterotoxins such as Staphylococcus pyogenes, salmonella and yersinia species. Fungal contamination of cereals by Clavlceps purpurea may provoke ergotism.1
Methylalcohol or ethylene glycol toxicity is another example of acute toxic reaction caused by fraudulent introduction of these substances in alcoholic drinks.
Scombroid fish poisoning is the most common cause of ichthyotoxicosis worldwide.2 The scom-brotoxin is not present when the fish are caught but it is produced subsequently during spoilage.3
Scombroid fish contain substantial amounts of free histidine in the muscle tissues that can be decarboxylated to form histamine by enteric bacteria present in spoiled fish.4·5 This clinical syndrome results from the ingestion of spoiled fish, usually of the families Scombridae and Scomberesocidae (tuna, mackerel, bonito, skipjack, saury).6 However non-scombroid fish, such as anchovies, sardine, herring, bluefish, yellow tail and amberjack as well as cheese, especially
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Swiss cheese, can also be the cause of this poisoning.7·8 Cheddar cheese and Gouda cheese have been implicated in single accidents of histamine poisoning.7·9 Scombroid fish most commonly implicated are tuna, skipjack and mackerel.9·10 Among non-scombroid fish, bluefish (Pomatomous saltatrix) and mahi-mahi (Coryphaena hippurus) are the most common in the US, while sardines, pilchards and herrings are commonly implicated in Europe, but so far not in the US.9·10
The risk of histamine poisoning arises when the content of histamine exceeds 450 mmol per 100 g of fish according to the FDA estimation7 (fresh tuna contains less than 9 mmol per 100 g). Symptoms begin in less than one hour after the ingestion of spoiled fish and last for several hours. The symptoms include an oral burning sensation or a peppery taste, sweating, nausea, vomiting, diarrhoea, flushing, tachycardia, headache and rarely hypotension and bronchospasm.
There is no doubt about the role of histamine in scombroid poisoning.9·11 Indeed the clinical picture is the same, experimentally obtained during intravenous infusion of histamine, and urinary levels of histamine in the affected persons far exceed those associated with symptoms of histamine excess. Moreover symptoms usually improve with the administration of H1-receptor-antagonist drugs.12 Symptomatic improvement was also described after the administration of an H2-antagonist drug.13 Therefore recommended treatment is an association of antagonists to both H1 and H2 receptors.9·11
It is not clear how histamine can pass through intestinal mucosa without being inactivated by diamine oxidase as it happens in normal subjects who do not present symptoms when experimentally fed with high doses of histamine.
Scombroid poisoning can be prevented effectively by handling and refrigerating fish appropriately. Warming facilitates bacterial overgrowth with production of high quantities of histamine without macroscopic evident alterations of the organolectic properties of the fish. It is probably for this reason that it is one of the most common causes of ichthyotoxicosis.
Among the foodborne disease outbreaks reported to the Center of Disease Control (USA) between 1970 and 1974, 48.9% of these were caused by toxic fish, followed by mushroom poisoning (16.5%) and heavy metal poisoning (10.9%: copper, zinc, iron, etc.).14
In patients treated with a drug that is a potent inhibitor of histamine metabolism (e.g. isoniazide dihydralazine, clavulanic acid, promethazine, verapamil, metoclopramide and ambroxol hydrochloride), ingestion of food containing large amounts of histamine might produce allergy-like symptoms such as sneezing, flush, skin itching, diarrhoea and even shortness of breath or might even mimic a scombroid poisoning.9,11,19,20,21,22 Histamine formed by bacteria decarboxylating histidine act as indicator of freshness and hygienic handling of food.9 Food rich in histamine or red wine (see Table 10.2.1.) may cause allergy-like symptoms or headache in some subjects even if it is not associated with the abovementioned drugs.23 There is some evidence that these patients with intolerance to histamine could have a deficiency or a reduced activity of diamine oxidase.23
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Table 10.2.1 Food rich in histamine
Fish Tunny Sardine Anchovy Mackerel
Cheese Emmenthal Hard cheese Gouda Roquefort Tilsiter Camembert Cheddar
Hard-cured sausages Salami Dried ham
Vegetables Pickled cabbage Spinach Tomatoes (ketchup)
Alcoholic beverages Red wine White wine Sparkling wine Beer
In normal human physiology histamine is metabolized by diamine oxidase, a soluble copper-containing enzyme and by histamine N-methyl-transferase.24·25·26 Methylation is the principal route of metabolism for both orally and intravenously administrated histamine. By blocking diamine oxidase histamine uptake is enhanced inducing elevated plasma histamine level which cause inhibition of methyl-transferase.27 In some cases other substances, often naturally present in the same foods rich in histamine, could cooperate to produce symptoms, such as putrescine or tyramine (occurring in red wine or cheese), that are catabolized by diamine oxidase causing competitive inhibition of the enzyme.27 Alcohol is another example of a remarkable inhibitor of diamine oxidase.27 An evidence of the role of diamine oxidase is the remission of symptoms occurring in pregnancy in women intolerant to food.28 As diamine oxidase levels are massively enhanced in pregnancy, a deficiency of the enzyme in these food-intolerant patients appears likely. In patients suffering from headache or itching of the skin after drinking red wine, plasma histamine did not decrease to basal level after 30 minutes as observed in controls but showed an increase.23 Symptoms of wine intolerance could be eliminated by H1 and H2 blockers premedication.29·30 The same persistent elevated histamine level is seen in patients with intolerance to histamine after eating food rich in this biogenic amine (Table 10.2.1.) and antihistamine premedication prevent symptoms also in these patients.31
Besides causing acute toxic reactions mentioned above, some food contaminants can have a long-term toxicity that is often less evident but more and more dangerous because they determine severe and often irreversible diseases that mainly affect the liver and neurological system. Moreover some contaminants are known for their carcinogenicity.
The European alimentation is exposed to carcinogenic risk connected with nitrosamine.
The risk of liver toxicity, induced by moulds such as Aspergillus Flavus in peanuts or Aspergillus Parasiticum (both containing aflatoxins), Fusarium and Pénicillium in cereals or rice, is well identified.1 Another example of long-term toxicity is the paralysis caused by the ingestion of Lathyrus sativus, due to a toxin that interferes with glutaminergic neurotransmission.15 Other
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Chemical contaminants that have a long-term toxicity are: heavy metals, nitrites, nitrates, pesticides, insecticides, fungicides. They form complexes with proteins and inhibit enzymatic activités and can also cause immunosuppression. Except for mercury, aflatoxin and PCB in Western countries the trend in contaminant levels is generally downward.16
Some contaminants can provoke an allergic reaction of type I or type IV. Even if rarely, type I reaction (IgE mediated) may be due to a food contaminant.
10.3. Food additives
Food additives together with natural salicilates have been associated with allergy, intolerance and behavioural disorders like hyperactivity. Food intolerance to additives were first described by Lockey in 1959: urticaria after ingesting a formula containing tartrazine.32 Additives were first associated with behavioural disturbances in 1973, in a study that recorded an improved behaviour in 50% of hyperactive children after elimination of natural solicylates and natural or artificial food colours from their diet.33 Controlled human studies have been performed only since 1978.34·35
Although the list of additives used by the food industry is very extensive most of them have not been implicated in adverse food reactions. Moreover many reports of additive adverse reactions were not controlled and/or anecdotal.
The particular category of inadvertent additives or contaminants has been previously treated in this chapter. Food additives can be classified as preservatives (antimicrobials), antioxidants, colouring agents, flavours, spices, sweeteners, emulsifiers, stabilizers, fillers, séquestrants, anticaking agents, humectants, firming agents, cresping agents, thickeners, enzymes, acids, buffers, bases and nutritive agents.36·37
The self-diagnosis of additive intolerance has become very common. Additive intolerance is supposedly responsible for urticaria angioedema, anaphylaxis, asthma, atopic dermatitis, gastrointestinal disturbances (nausea, vomiting, diarrhoea, abdominal pain) and many other complaints such as migraine and hyperkinetic syndrome for which no evident cause has been identified. Accurate prevalence studies are very rare. However the dimension of this phenomenon seems overestimated as the prevalence of food additive intolerance in a recent study of Fuglsang on schoolchildren range between 1 to 2%,38 and in general population it is lower (0.01-0.23%) according to Young.39 In 1981 the Commission of the European Communities suggested a prevalence of food additive intolerance of 0.03-0.15%.40 Many estimates of the prevalence of food additive reactions have been based on selected populations. The prevalence of additive reactions in chronic urticaria angioedema based on DBPCFC range widely from 2.3 to 55.8%,41·42·43·44 being strongly influenced by the lack of an objective method to assess the cutaneous lesions and by the different selection of the population. Until now only two DBPCFC studies have evaluated the prevalence of additive intolerance in atopic dermatitis with results surprisingly different, being in the first study45 confirmed in 100% of suspected additive intolerant patient while in the second study46 only 8.5% of suspected patients were confirmed by DBPCFC.
In Table 10.3.1. are listed the categories of food additives most often involved in adverse reactions.
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Table 10.3.1 Categories of food additives
Preservatives (antimicrobials) Benzoate/hydroxybenzoic acid (E 210 - E 213) Parabens (esters) (E 214 - E 219) Sorbate/sorbic acid (E 200 - E 203)
Antioxidants Bisulfites/metabisulfites (E 220 - E 224) Butylated hydroxyanisole (BHA) (E 320) Butykated hydroxytoluene (BHT) (E 321) Tocopherols (E 306 - E 309) Gallates (E 310-E 312)
Colourants
Azodyes Tartrazine (FD&C yellow // 5) (E 102) Sunset yellow (FD&C yellow // 6) (E 110) Ponceau (FD&C red // 4) (E124)
Non-azodyes Erytrosine (FD&C red // 3) (E127) Cochenille, carmin red (E 120) Indigotine (FD&C blue) (E 132)
Chlorophyll (E 140) Carotinoid bixin (Annatto) (E 160b)
Emulsifiers/Stabilizers Ethylene diaminetetracetic acid (EDTA) Gum arabic (acacia) (E 414)
Fillers Tragacanth, guar, bean gum
(E 407-E 416) Propylene glycol alginate (E 400 - E 405)
Flavours/Sweeteners Aspartame Monosodium glutamate Saccharin Vanillin
Contaminants (inadvertent additives) Toxins Biogenic amines Pharmaceuticals
The mechanisms of action of additives in triggering adverse reactions are uncertain. Most evidence suggests that the action is pharmacological36 rather than immunological even if in few cases a clear IgE-mediated reaction has been demonstrated, for example in some sulfite reactions47 and in adverse reactions to carmine red colourant.48 IgE are certainly involved in immunological contact urticaria.36 Some additives, as azodyes, have a low molecular weight and so can act only as apten; indeed IgD antibodies against tartrazine has been found in allergic patients49 and IgE antitartrazine can be experimentally induced.50 The other suggested mechanisms include cell-mediated immune response, non-specific release of mediators, enzyme deficiency, anticyclooxygenase activity and cholinergic defect.36 Cell-mediated immune response may be involved mainly in occupational contact dermatitis in subjects developing sensitization after skin contact with additives present in foods, ointments and cosmetics. Some of these subjects might present eczema also after ingestion of additives such as azodyes, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), parabens, etc.51
Some evidence has been obtained in favour of a non-specific release of mediators in patients with food additive intolerance.52 However the results of the studies on direct mediator release by sulfiting agents are controversial.53·54·55 Histamine release from leukocytes has been described following ASA, benzoate, BHT and BHA, and azodyes.56 Plasma and urine histamine increase after azodyes challenge has been reported as well as urine prostaglandin increase.57
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Enzyme deficiency, namely sulfite oxidase deficiency, has been proposed for some adverse reaction to sulfites,54 while hepatic aldehyde dehydrogenase deficiency seems responsible for some vasomotor and cardiac problems ensuing after alcohol ingestion.58
Some food additive adverse reactions show a strong association with ASA intolerance.37 It seems due to the same inhibitory activity to Cyclooxigenase with the consequent decrease of some prostaglandins, such as PGE that act as a bronchodilator, and increase of leukotrienes, bradikinin and other mediators responsible for immediate reactions that mimic IgE mediated, immune response.36 However tartrazine does not inhibit cyclooxygenase pathway, but it could act like some NSAIDs without anticyclooxygenase activity that mantain the same properties of ASA, inducing Pseudoallergie reactions such as asthma or urticaria in sensitive subjects.59·60 Non-immunological contact urticaria can be elicited by some additives,36 and can be abolished by aspirin oral pre-treatment suggesting a causative role of prostaglandins in these reactions.61
Asthmatic reactions to additives as seen above can be elicited by the inhibition of Cyclooxigenase pathway, but the ingestion of metabisulfite may also evoke a cholinergic reflex that cooperates in provoking asthma.54 It is not clear why sulfur dioxide can elicit bronchospasm when inhaled only in some asthmatic subjects. Moreover this mechanism does not explain how sulfur dioxide provoke asthma when parenterally administered.
Various mechanisms may be simultaneously responsible for adverse reactions to some foods. It is the case of adverse reactions to wine, where sulfite agents account for asthma and urticaria, but other substances like tyramine or phenylethylamine can cause vascular headache.62·63
Fermentation of wine does not ordinarily produce tyramine. However contamination with other than usual fermenting organisms may produce appreciable amounts in various red wines, especially chianti and sherry, and could occur in any red wine. This vascular headache is more common in patients receiving monoamine oxidase inhibitors after they had eaten tyramine-rich food (wine, aged cheese, fermented sausages, sour cream, pickled herring, and pods of broad beans).63·64 Phenylethylamine is present in some red wines, chocolate and some cheeses and double-blind control studies demonstrated convincingly that this can provoke migraneous attacks in patients suffering from vascular headache. Ethyl alcohol may occasionally cause urticaria or bronchospasm mediated by its histamine releasing action. Benzoates, present in great quantities in certain grapes, and quinine, present in many aperitifs, may be responsible for intolerance with an unknown mechanism.65
1 0 . 3 . 1 . P r e s e r v a t i v e s
May be antimicrobials, that prevent bacterial or fungal spoilage or antioxidants, that prevent rancidity and offcolours or tastes.
10.3.1.1. Benzoates and parabens
Sodium benzoate and benzoic acid are antimicrobials, effective against bacteria and yeasts.
Parabens (closely related to benzoic acid) are aliphatic esters of parahydroxybenzoic acid and include methyl, ethyl, butyl and propylparaben. They are more effective against yeasts and
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moulds. Benzoates and parabens are widely used as preservatives in food and drugs and are often reported cross-reactivities among different components of this group.37 They are clearly recognized as a cause of severe contact dermatitis.66 In well-documented reports, parabens have been associated with immediate hypersensitivity reactions resulting in diffuse urticaria and angioedema.67 These reports involved parabens used as preservatives in drugs, not in foods. Benzoates and parabens are respectively the first and second most frequent cause among the preservatives implicated in drug adverse reactions in the UK.67
Sodium benzoate and hydroxybenzoic acid have been often reported to cause skin reactions.37
They are responsible for urticaria and angioneurotic edema more often in ASA sensitive patients than in ASA tolerant patients.68 Non-immunologic contact urticaria from benzoates is also reported. Although parabens give allergic contact dermatitis among workers in the cosmetic industry and, occasionally, in the food industry, they do not affect consumers, even those who are sensitized.69 Controlled studies have also demonstrated that benzoates can be involved in atopic dermatitis.45 Sodium benzoate and hydroxybenzoic acid have been reported to cause asthmatic or even anaphylactoid reactions.70 The prevalence of the asthmatic response to benzoate in different studies ranges widely from 2 to 11.5%,36·71·72 according as the method used (double-blind or open challenge respectively). The incidence of benzoate-induced asthma based on DBPCFC studies ranges from 0 to 6.5% in asthmatic patients.73 Benzoate intolerance is present in about 2.5% of rhinitis.36 It has been estimated that ingestion of benzoic acid and other additives may exacerbate the skin lesion in at least 5% of all children with atopic dermatitis and Van Bever, challenging a selected population of 24 children, recorded that DBPCFC with additive aggravate atopic dermatitis in six of them, being sodium benzoate responsible in three children.45
It is not clear if additives have a direct role in atopic dermatitis or if they simply aggravate atopic dermatitis by inducing erythema and urticaria, which seems to be the most likely explanation.74
1 0 . 3 . 2 . Ant iox idants
Chemical action of oxygen, heat, moisture or enzymes on food fat is the cause of rancidity. Unsaturated fats are more susceptible to these changes than saturated fats. Unsaturated fats are prevalent in vegetable oils but these food are protected by the presence of naturally occurring antioxidants. On the contrary lower amounts of natural antioxidants are present in meat where saturated fats are prevalent. Therefore animal fats are at greater risk of rancidity. The same chemical changes may cause fruits and vegetables to lose their freshness and change colour ('browning action'). Antioxidants avoid these events and may even restore 'freshness' in some cases.
(BHA) and butylated hydroxytoluene (BHT) are often used in foods containing oil and fat, frequently associated with other antioxidants, such as propyl gallate, citric acid, phosphoric acid and ascorbic acid, in order to enhance their activities. BHA and BHT were originally developed as antioxidants for petroleum and rubber products and only in the mid 1950s were their effectiveness on animal fats discovered. These compounds are now added to various foods, cosmetics and pharmaceuticals to prevent oxidation of unsatured fatty acids. The US average daily intake per person of BHT alone was estimated as 2 mg in 1970.75 With the greater present relevance of the American diet on processed and package foods, currently intake of BHA and BHT may be substantially larger. Despite a wealth of animal toxicology literature on these antioxidants, there
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are only rare reports of adverse reactions to BHA and BHT in humans.51·76 The most frequent clinical features are recurrent or chronic urticaria,77·78 while eczematous dermatitis due to dietary ingestion is rare,51 and contact urticaria and acute urticaria vasculitis are anecdotically reported.79 Controlled studies failed to show a relationship between asthma or rhinitis and BHT or BHA as previously suggested by other open studies.80·81 Two studies suppose that adverse reactions to BHA and BHT may be immunologically mediated.51·76 Until 1989 13 drug formulations containing BHA and BHT have been implicated in adverse reaction in UK.67
1 0 . 3 . 3 . Sorbic acid
Sorbic acid is widely used as preservatives in bakery products. Sorbic acid and potassium sorbate have the advantage of a best effectiveness against moulds over a wider pH range than sodium benzoate. Sorbic acid and sorbates are among additives causing or aggravating urticaria and angioneurotic edema.36·78·82·83 They can also produce non-immunologic contact urticaria.84
The concentration of sorbic acid evoking wheal and flare reaction is 5% in petrolatum.36 A few people react to 0.2% mixture. Contact allergy is rare and is mainly due to the use of creams containing sorbic acid. Its ingestion does not provoke or worsen atopic dermatitis.
1 0 . 3 . 4 . Gal lates
Gallates present in margarine and peanut butter are not harmful when ingested even in subjects with occupational hand dermatitis.85
1 0 . 3 . 5 . Tocophero l s
Tocopherols are vitamin E related antioxidants commonly used in baked goods, cereals, soups and milk products. Tocopherols may be naturally present in some foods such as nuts, cereals and vegetable oils. Although tocopherols are potent contact allergens they do not provoke allergic reactions when ingested.86
1 0 . 3 . 6 . Sulf i t ing agents
Sulfating agents belong to antioxidant which have antimicrobials action as well. A variety of sulfiting agents, including S02, sodium and potassium bisulfite, sodium and potassium metabi-sulfite, and sodium sulfite are widely used as food additives.
Sulfiting agents control microbial growth and spoilage, prevent browning, modify the texture of certain types of flour doughs and bleach certain foods. Sulfites are widely used in the food and beverage industry. FDA has recently restricted the use of sulfiting agents previously considered safe for all food uses except their use on fresh fruits and vegetables. These restrictions in the use and the duty of declaring the presence of sulfiting agents on the label of packaged foods when residue levels exceeded 10 ppm of sulfite expressed as total S02, stem from the new awareness of their potential role in provoking adverse reactions, sometimes severe, in sensitive patients. The maximum quantity of sulfur dioxide in foods is reported in Table 10.3.2.
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Table 10.3.2 Maximum quantity of sulfur dioxide infoods
Food
Dehydrated peas Gelatine Dehydrated vegetables Pickles Sausages (and sausage meat) Cheese mixture and paste Glucose, syrup, and solid Wine Cordials Cider Fruit juices and soft drinks Potatoes (whole, peeled, or sliced) Beer Vinegar
Maximum amount of S02 (mg/kg)
1 000 1 000
500 to 1 500 750 525 300 300 300 230 200 115 50 25 25
Most people tolerate sulfite but a lot of studies have shown sulfite sensitive subjects who experienced adverse reactions on ingestion of sulfiting agents.53·54·87 Asthma is the most common symptom evoked by sulfites while other symptoms are reported only occasionally, even if in the study of Van Bever sodium metabisolfite was responsible for exacerbation for atopic dermatitis in two out of six children intolerant to additives according to DBPCFC.45 Anaphylactic reactions to sulfites have been described.55·88 Such patients may have a positive SPT to sulfites and their attacks are characterized by flushing, urticaria, angioedema as well as bronchospasm. Asthmatic reactions to ingestion of metabisulfite-containing foods are usually rapid, frequently occurring within one to two minutes of ingestion.
The prevalence of sulfite sensitivity is higher among steroid-dependent subjects with asthma (8.4%) than among overall asthmatic population (3.9%).89 Moreover sulfite use is prohibited in thiamine-containing food such as fresh red meat because thiamine is destroyed by sulfiting agents. Sulfites are often present in fresh and dried fruits and vegetables, potatoes (baked, fried, chips, salad), citrus drinks, beer and wine, cellophane packaged vegetables, salad, ready-made foods, avocado, cider and vinegar, and fresh red meat in spite of legal prohibition of the use of sulfites in the last case. Despite well-defined levels of allowed sulfiting agents, their food concentrations vary widely mainly when poorly trained and monitored individuals are entrusted with their use, as it sometimes occurs for lettuce, mushrooms and shrimps. Such occurrences are unlikely with dehydrated potatoes, dried apricots and white grape juice in which the sulfite application is done by large food companies with good quality assurance programmes that would monitor the levels of sulfites. Adding excessive amount of sulfite may alter the fate of sulfite in the food system because it might lead to greater amounts of free sulfite in the food that is definitely a hazardous form of food-borne sulfite. Sulfite concentrations are often very high in potatoes particularly if peeled, because potatoes are often soaked in sulfite solutions for prolonged time. Indeed the worst asthmatic reactions in a sulfite sensitive patient reported in literature occurred after ingestion of potato.54 These potatoes were treated with sulfites but their presence were not listed on the package label. After the ingestion of potatoes the patient suffered a severe asthmatic
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reaction culminating in respiratory arrest that was solved by admitting the patient in an intensive care unit on a ventilator for two weeks. Residual motor and neurological deficits recovered only l1 /2 years after the acute reaction.
Another patient suffered a fatal asthmatic reaction after having eaten some canned mashed potatoes that contained sulfite.54 The mechanism of this greater sensitivity is unclear but a partial deficiency of sulfite oxidase has been postulated to obstacolate the proper metabolism of sulfites. It has been estimated that every day sulfite ingestion is about only 2 to 3 mg if foods have been prepared at home.54 Beer and particularly wine can add 15, 30 or even more mg/100 gr. A restaurant meal can contain 25 to even 200 mg of sulfites, not including the wine.
Sulfites are also used as antioxidants by the pharmaceutical industry. Until 1989 sulfites had been implicated in adverse reactions caused by 5I drug formulations in UK, being third for frequency among preservatives following benzoates and parabens.67
Simon underlined the importance to asthmatics of some drugs such as bronchodilator solutions, epinephrine, corticosteroids that in some formulations contain paradoxically sulfites.54·90 Sulfites are also present in some antibiotics, local anaesthetics, antiarhythmics, analgesic, antishock, eye drops and in solutions for total parenteral nutrition and dialysis. Reviewing the literature an association between ASA sensitivity and sulfite intolerance seems unlikely.91
1 0 . 3 . 7 . C o l o u r a n t s
Azodyes and non-azodyes are both involved in adverse reactions to additives. As we list in Table 10.3.3. azodyes include tartrazine, sunset yellow and ponceau. Non-azodyes include erythrosine and indigotine. Other natural colourants are often used in food preparations (also in other manufactures such as cosmetic industry) that may be responsible for adverse reactions to food or drugs.
A survey of adverse reactions to drug additives in UK showed that a lot of colouring agents may cause adverse reactions.67 The list is reported in Table 10.3.3.
Table 10.3.3 Drug colourings that have been identified causing adverse reactions in UK (from I. Pollock, BMJ, 1989)
Amaranth Blake PN Blue (colour index No 12196 and 16383) Brilliant black CF Brown FK Brown HT Brown (colour index No 18285) Buff (colour index No 17175) Quinoline yellow Red2G Sunset yellow FCF Tartrazine
Carmoisine Disperse blues Disperse pinks Erythrosine BS Green S Indigo carmine Patent blue V Ponceau 4R Yellow 2G Various commercial mixes containing the above colourings
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In the same study the authors verify the number of drug formulations that contained various colourings implicated in adverse reactions; erythrosine was the most common (191 cases) followed by sunset yellow (187 cases), indigo carmine (142 cases), quinoline yellow (123 cases), tartrazine (124 cases), amaranth (97 cases) and ponceau 4 R (95 cases). Azodyes, other synthetic colourings (quinoline yellow, patent blue, amaranth, indigo carmine) and natural colourings (cantaxanthine, ß-carotene, annatto, beet colouring, turmeric) are among food additives causing or aggravating urticaria or angioneurotic edema.32·42·68·78·82·83 Azodyes can also be a rare cause of occupational allergic hand dermatitis in bakers.92
Cantaxanthine is artificially added to the diet of farmed salmon in order to obtain the same colours of wild fresh salmon due to astaxanthin, a pigment found in small shellfish that make part of the diet of wild salmon. Cantaxanthine may cause or aggravate urticaria and angioneurotic edema.36·37 Other natural colourings seldom implicated in food-adverse reactions are ß-carotene (carrot), betanine (beet), annatto (bixa orellana seeds), turmeric (curcuma or indian saffron), and indigo carmine.38·93
In 1987 a study was published by Young et al. that started with the forwarding of 11 388 questionnaires to families involving an estimated 30 000 people.39 Subsequently 1 223, whose replies indicated suspected food adverse intolerance, were interviewed and 132 of those were selected with a possible food allergy/intolerance. DBPCFC additive challenge was performed in 81 patients with 11 different additives and aspirin. Three subjects showed consistent reactions: annatto was responsible for symptoms in two patients respectively, provoking headache in one and upper abdominal pain in the other one. The third patient had a reaction to azodyes which resulted in a change in mood. The features reported in this study are as different from those commonly expected in food additive intolerance that are skin and respiratory disorders as different are the additives from those more commonly reported responsible for adverse reactions in other studies.
Carmine (E120) has been recently reported as the cause of an IgE-mediated severe anaphylaxis in a patient after drinking Campari.48 It is a natural red dye widely used as a food colouring agent, mainly in butchery and confectionery and for cosmetic products, pharmaceutical industry and as an histologic dye. It is obtained from the dried females of Dactylopius coccus var. Costa (cocchineal). Carmine was previously known for occupational asthma94 and extrinsic allergic alveolitis secondary to its inhalation,95 and for allergic cheilitis due to lip salve containing it.96 IgE-mediated allergy to carmine was shown in three out of nine patients with occupational asthma and RAST inhibition studies indicated that the main allergen had a MW from 10 to 30 kd.97 No evidence of asthma triggered by carmine oral challenge could be elicited but only with its inhalation asthma could be evoked. However Bürge et al. reported two patients who after carmine oral challenge presented respectively gastrointestinal symptoms and asthma.94
Colouring agents were also predominant in provoking adverse reactions in the study of Fuglsang on all schoolchildren in Viborg (Demmark).38 Based on a questionnaire 271/4 274 children were selected to follow an elimination diet for two weeks and successive open challenges with a mixture of preservative, colouring (natural or synthetic) and flavour. Open challenge was positive in 17 children and 12 out of them went through a DBPCFC additive challenge which was positive in six; five to colouring mixture and one to citric acid. This study did not explain if colouring agent
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or agents responsible for adverse reactions had been subsequently identified among those used in the colouring mixture.
While natural colourings are rare causes of adverse reactions to additives, synthetic colourings are more commonly involved in food and drug intolerance. Azodyes and non-azodyes may both provoke urticaria.
Among azodyes possessing a nitrogen-nitrogen double link, tartrazine has been the most studied colouring in the last decades.
In 1958 asthma exacerbation was for the first time associated to food colours.98 In 1959 Lockey reported urticaria due to tartrazine.32 Since then many studies have been performed to look for the actual prevalence of tartrazine and other colourings in patients suffering from asthma or skin disorders or other disturbances.
Tartrazine-induced asthma was described in 1967 in a patient whose steroid dependent asthma was also worsened by aspirin, acetaminophen and sodium benzoate.99 Since then other studies evaluated the association existing between aspirin and tartrazine in asthmatic patients and in patients with chronic urticaria and angioedema.42·60·68·72·100·101·102·103·104·105·106
The studies based on DBPCFC with tartrazine showed an incidence of tartrazine-induced asthma in 0 to 4% asthmatic patients.71·104·105 This is the evidence that the role of tartrazine intolerance in asthma was previously overestimated by non-controlled studies. Indeed Weber et al. could not confirm tartrazine intolerance in asthmatic patients previously diagnosed under single-blind conditions when they were double-blind rechallenged; three patients responded to ponceau (azo dye), erythrosine (non-azo dye), or sodium benzoate on repeated double-blind challenge.71
The same statement is true for chronic urticaria and angioedema even if the actual prevalence of tartrazine intolerance is probably higher in patients with skin disorders than in asthmatic patients ranging for the former between 8 to 26% in double-blind studies.41 • 4 2 · 4 4 ASA sensitive asthmatics who react to tartrazine range between 8 to 50% according to different studies.72·105 But further studies did not find a significative prevalence of tartrazine intolerance among ASA sensitive asthmatic patients. Morales found only one subject out of 47 ASA-sensitive asthmatic patients who reacted to tartrazine ingestion and this is what was expected by chance.60 Tartrazine may exacerbate the skin lesions in some children with atopic dermatitis and Van Bever reported that it was responsible for symptom exacerbation in two of six children intolerant to additives.45
1 0 . 3 . 8 . Monosodium glutamate
Monosodium glutamate (MSG) is the sodium salt of glutamic acid, a non-essential amino acid that forms 20% of dietary protein. It is artificially added to foods in order to enhance their flavour. The average daily intake in western countries is estimated to be 0.3 to 1 g, but as much as 4 to 6 g and more may be present in Chinese restaurant meals.107 The 'Chinese restaurant syndrome'108
consists of a warmth or burning sensation, especially over the head and shoulders, stiffness or tightness, weakness in the limbs, pressure, tingling, headache, lightheadedness, and gastric discomfort occurring approximately within 15-20 minutes after ingestion. Although the rapid
125
outbreak of symptoms is usual, sometimes they can be delayed. For instance angioedema many hours after ingestion of MSG is described.109 In a graded challenge monosodium glutamate alone produced angioedema 16 hours after ingestion of at least 250 mg. However quantities of MSG required to precipitate symptoms are usually greater and in susceptible individuals range from 1.5 to 12 g and the severity of symptoms are usually dose dependent.107 MSG-induced asthma was also reported and confirmed by blind-provocation challenge.107 Also in MSG-induced asthma both early and late asthmatic response can be present, the onset of wheezing ranging from 1 up to 12 hours. Therefore there may be certain individuals who respond to monosodium glutamate with complaints that do not appear until hours after ingestion, thus making diagnosis more difficult. MSG is also reported to cause epileptic-like shudder attacks in children.110
1 0 . 3 . 9 . Other addit ives and spices
The additives most frequently involved in food intolerance have already been described above. Other additives and/or spices can be rarely the cause of adverse food reactions. Food additives causing or aggravating urticaria and angioneurotic edema are sorbic acid, sorbate, azodyes, canthaxanthine, beta-carotene, annatto, quinoline yellow, nitrites and nitrates, artificial sweeteners such as saccharin111 and aspartame,112 spices such as cinnamon, clove, white pepper.36
These spices are also reported as the cause of chronic urticaria, nasobronchial and gastrointestinal complaints, and shock.83·113·114·115 Spice-lgE-mediated allergy is more common in patients with hypersensitivity to some pollens, mainly to birch,36·83 cinnamon, cayenne and mustard may produce both immunological and non-immunological contact urticaria; other spices such as coriander, caraway and cardamon may prevalently cause immunological contact urticaria.36·116·117 Inhalation of spices such as powder coriander, curry and paprika, has been described as also causing occupational asthma.118·119
1 0 . 3 . 1 0 . Controversy in food addit ive intolerance
In the last decades some studies have suggested a role of food additive in the genesis of some 'neurological' disturbances. Headache, epilepsy and childhood behavioural disorders, such as hyperkinetic syndrome, childhood hyperactivity and attention deficit syndrome, are the main entities reported as being likely related to a food additive intolerance. Headaches associated with tightness around the face is a relatively common symptom in 'Chinese restaurant syndrome' provoked by MSG. Susceptible subjects have different thresholds of reaction as the quantities of MSG required to precipitate symptoms range widely from 1.5 to 12 g.120
Other dyes and preservatives have been reported only anecdotally as a cause of migraine; this is the case of aspartame121 which however in double-blind placebo-controlled studies showed no difference in headache frequency compared with placebo.122
The relationship between food intolerance and some 'neurological' disturbances, that is epilepsy, migraine or hyperactivity, were studied by Egger and colleagues in 63 children.123·124 They found that 18 children with epilepsy alone did not improve under oligoantigenic diet, while a subgroup of children with epilepsy associated to migraine improved on the oligoantigenic diet. Double-blind placebo-controlled challenges showed that additives (tartrazine and benzoic acid) can be responsible for epilepsy associated to migraine or hyperactivity in some of these children.
126
Attention deficit syndrome, synonymous with hyperkinetic syndrome and childhood hyperactivity, was related to food intolerance by Shannon in 1922 for the first time.125 In 1975 Feingold wrote a book based on a few observations which asserted that food additives could cause attention deficit syndrome.33 Two groups of scientists were charged by FDA and the Nutrition Foundation respectively to review available data on additive intolerance and hyperkinetic syndrome. Both groups reached the same conclusion: (1) no controlled studies showed an association between hyperkinesis and food additives; (2) there was as yet no confirmation that hyperactive behaviour improved on the salycilate, dye, and preservative-free diet; (3) controlled studies needed to be done.34
Since this time several behavioural studies have generally shown no effect of artificial food colours or only suggested an effect on children under five years of age, when the doses of these food additives were similar at the average daily intake of a non-restricted diet.35·126·127·128·129
Even with large doses of tartrazine and benzoic acid, administered in double-blind placebo-controlled challenges, David showed no change in behaviour in 24 children who were on a diet avoiding these items and that had previously shown a clear behavioural reaction within two hours of open challenges.130 Twenty-two patients returned to a normal diet without problems.
Large doses of artificial food colours were used also by Pollock in a DBPCFC study on 19 children,131 whose behaviour was observed by their parents to improve on an artificial food additive-free diet and to deteriorate with dietary lapses. He showed a significant difference in Conner's rating of behaviour during the challenge with additives compared with the placebo period. But most parents could not detect these changes. Pollack suggests that pharmacological mechanism may be responsible for food-additive intolerance. There is an experimental evidence that large doses of both aspartame and monosodium glutamate can be excitogenic in animals, and can also lower the seizure potential.132
A recent review suggests that there is substantial data to conclude an effect of diet on children affected by attention deficit syndrome, but it does not mean that foods or food additives are the cause of this syndrome.133 In fact only children with the milder behavioural changes seem to benefit on elimination diet alone, while more severe alterations of behaviour require other means of treatment.
A case of Melkersson-Rosenthal syndrome related to the exposure of food additives (tartrazine and sodium benzoate) is reported in literature, but the etiology of this syndrome is still widely unknown.74
1 0 . 3 . 1 1 . Diagnos i s of food addit ive into lerance
The algorithm of the diagnosis of adverse reaction to food additives provides three sequential steps to reach a certain diagnosis. The first step is an elimination diet (diet without additives). The disappearance of disturbances on elimination diet is necessary to begin the second step that is an open challenge with the suspected additive(s). If this challenge is positive, a double-blind placebo-controlled challenge with the suspected additive is performed. The gold standard for the diagnosis is a positive double-blind placebo-controlled challenge with the suspected additive.
127
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69 Schorr W.F. 'The skin and chemical additives to foods'. Arch. Dermatol., 1972, 105, pp. 131.
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72 Rosenhall L. 'Evaluation of intolerance to analgesics, preservatives and food colourants with
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74 Pachor M.L., Urbani G., Cortina P., Lunardi C , Nicolis F., Peroli P., Corrocher R., Gotte P. 'Is
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75 Babich H. 'Butylated hydroxytoluene (BHT): A review'. Environ. Res., 1982, 29, pp. 1-29.
76 Osmundsen P.E. 'Contact urticaria from nickel and plastic additives (butylhydroxytoluene, oleylamide)'. Contact Dermetitis, 1980, 6, pp. 452-4.
77 Goodman D.L., McDonnell J.T., Nelson H.S., Vaughan M.D., Weber R.W. 'Chronic urticaria exacerbated by the antioxidant food preservatives, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT)'. J. Allergy Clin. Immunol., 1990, 86, pp. 570-5.
78 Juhlin L. 'Recurrent urticaria: Clinical investigation of 330 patients'. Br. J. Dermatol., 1981, 104, pp. 369-81.
79 Moneret-Vautrin D.A., Faure G., Bene M.C. 'Chewing-gum preservative induced toxidermic vasculitis'. Allergy 1986, 41, pp. 546-8.
80 Cloninger P., Novey H.S. 'The acute effects of butylated hydroxyanisole ingestion in asthma and rhinitis of unknown etiology'. Ann. Allergy, 1974, 32, pp. 131-3.
81 Fisherman E.W., Cohen G.N. 'Chemical intolerance to butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) and vascular response as an indicator and monitor of drug tolerance'. Ann Allergy., 1973, 31, pp. 126-33.
82 Hannuksela M. 'Food allergy and skin diseases'. Ann. Allergy., 1983, 51, pp. 269-72.
83 Warin R.P., Smith R.J. 'Chronic urticaria. Investigations with patch and challenge tests'. Contact dermatitis, 1982, 8, pp. 117-21.
84 Lahti A. 'Non-immunologic contact urticaria'. Acta Derm. Venereol. (Stock.), 1980, 60 (suppl.), p. 91.
85 Van Ketel W.G. 'Dermatitis from octyl gallate in peanut butter'. Contact Dermatitis, 1978, 4, pp. 60-1.
86 Fisher A.A. 'Reactions to antioxidants in cosmetics and foods'. Cutis, 1976, 17, pp. 21-8.
87 Taylor S.L., Bush R.K., Seiner J.C., Nordlee J.A., Wiener M.B., Holden K., Koepke J.W., Busse W.W. 'Sensitivity to sulfited foods among sulfite-sensitive subjects with asthma'. J. Allergy Clin. Immunol., 1988, 81, pp. 1159-67.
88 Prenner B.M., Stevens J.J. 'Anaphylaxis after ingestion of sodium bisulfite'. Ann. Allergy, 1976, 37, pp. 180-82.
89 Bush R.K., Taylor S.L., Holden K., Nordlee J.A., Busse W.W. 'Prevalence of sensitivity to sulfiting agents in asthmatic patients'. Am. J. Med., 1986, 81, pp. 816-20.
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90 Baker G.J., Colile« P., Allen D.H. 'Bronchospasm induced by metabisulfitecontaining foods
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91 Towns S.J., Mellis CM. 'The role of acetylsalicylic acid and sodium metabisulfite in chronic
childhood asthma'. Pediatrics, 1984, 73, pp. 6317.
92 Fisher A.A. 'Hand dermatitis — A: "Baker's dozen"'. Cutis, 1982, 29, pp. 21421.
93 Nish W.A., Wishman B.A., Goetz D.W., Ramirez D.A. 'Anaphylaxis to annatto dye: A case
report'. Ann. Allergy, 1991, 66, pp. 12931.
94 Bürge P.S., O'Brien I.M., Harries M.G., Pepys J. 'Occupational asthma due to inhaled car
mine'. Clin. Allergy, 1979, 9, pp. 1859.
95 DietemannMolard Α., Braun J.J., Sohier B., Pauli G. 'Extrinsic allergie alveolitis secondary to
carmine'. Lancet, 1991, 338, pp. 460.
96 Sarkany I., Meara R.H., Everall J. 'Cheilitis due to carmine in lip salve'. Trans. Ann. Rep. St.
John's Hosp. Dermatol. Soc, 1961, 46, pp. 39.
97 Quirce S., Cuevas M., Olaguibel J.M., Tabar A.I. Occupational asthma and immunologic
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100 Wüthrich B., Fabro L. 'Acetylsalicylic acid and food additive intolerance in urticaria, bronchial
asthma and rhinopathy'. Schweiz Med. Wochenschr., 1981, 39, pp. 144550.
101 Doeglas H.M.G. 'Reactions to aspirin and food additives in patients with chronic urticaria,
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103 Settipane G.A., Pudupakkam R.K. 'Aspirin intolerance. III. Subtypes, familial occurrence, and
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patients with asthma'. Clin. Allergy, 1976, 6, pp. 11929.
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adverse response in chronic childhood asthma'. J. Allergy Clin. Immunol. 1977, 60, pp. 813.
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Immunol., 1987, 80, pp. 5307.
108 Kwok R.H.M. 'Chinese restaurant syndrome'. N. Engl. J. Med., 1968, 278, p. 796.
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10.4. Hidden allergens
The food industry has a tendency toward the production of more and more sophisticated foods which contain a lot of ingredients from different source materials, not always labelled. This implies for food allergic individuals, especially for children, the risk of ingestion of 'hidden' allergens.
Common food allergens such as milk, eggs, soya and wheat are constituents of a wide variety of prepared foods. In some cases food labels are dangerously incomplete, obscure or misleading. Another possibility for hidden allergens arises from unintended contamination in food processing
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and preparation. Food allergy patients need to know exactly what they eat, since they risk an anaphylactic shock when they innocently ingest a food containing an ingredient to which they are highly sensitive.
Yunginger et al.1 report seven cases of fatal food-induced anaphylaxis. All the patients had a history of prior anaphylactic episodes after the ingestion of the incriminated food (peanut, four; pecan, one; fish, one; crab, one). All but one (the patient allergic to crab) of the victims unknowingly ate the food allergen.
Sampson et al.2 identified six patients who died of anaphylactic reactions to food and seven others who nearly died. All the patients had known food allergy but had unknowingly ingested the incriminated foods (peanuts, four; nuts, six; eggs, one; milk, two), all of which were contained in foods such as candy, cookies, and pastry.
The Swedish National Food Administration analysed food proteins for verification of contamination or mislabelling. Over a three-year-period, 18 situations occurred where discrepancies between content and label were confirmed.3 In 13 cases the investigation was initiated because of reactions observed by patients with known disease. A meal of sausage containing the amount of cow's milk equivalent to about 60 mg of casein resulted in fatal anaphylaxis. A soya protein preparation in a hamburger caused fatal anaphylaxis in a child with known peanut allergy, due to a cross reactivity between the two legumes. Table 1 depicts the 18 situations of adverse reactions to unexpected allergens in food products. The reason varied: contamination in the process, substitution of ingredients, undeclared ingredients, food products falsely declared as allergen free, unclear labels (declared but not recognized as risk by consumers).
Germ et al.4 described six children allergic to milk, who had adverse reactions occurring minutes after they ate products presumed to be milk-free. In every case the authors found traces of milk protein in the non-dairy foods that were implicated. These foods were frozen desserts labelled 'non-dairy' or 'pareve' (containing neither meat or milk products) or processed meats with no milk products listed on their labels. The analysis of the samples revealed marked variations in the milk protein content from lot to lot. Three reactions occurred after the patients consumed hot dog or bologna from the same manufacturer. The recipes of these two products had recently been changed to include sodium caseinate, but the product labels had not reflected this change. Contamination in the food processing was the reason for the presence of milk proteins in the frozen desserts: although no specific errors in processing were found, the dairy-free products had been manufactured in dairy-processing facilities.
Jones et al.5 reported a case of a two-year-old boy with history of multiple anaphylactic episodes after ingestion of cow's milk, who experienced an identical anaphylactic reaction shortly after ingestion of very small amounts (less than one tablespoonful) of 'pareve' labelled raspberry sorbet. A second container of the same product that had been purchased at the same time as the original one, was analysed for the presence of milk proteins. Using an inhibition immunoassay, the milk allergen level in the sorbet was found to be 11% of the level found in non-fat dry milk.5
The milk allergen level in three independently purchased sorbets of the same product ranged from 2% to undetectable. The presence of milk in three of four of the sorbets was confirmed by immunoblotting studies. The contamination with milk depended on the use of common equipment
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to package both pareve and dairy foods, with inadequate cleaning procedure to prevent contamination.
Kaegi and Wuthrich6 described three cases of falafel burger anaphylaxis due to sesame seed allergy. Falafel burger is a vegetable burger consumed as an alternative to beefburgers by vegetarians. Falafel is an oriental speciality served with a white sauce containing sesame seed paste, prepared with raw uncooked and unroasted sesame seeds. The authors underline the potential hazards of a vegetarian diet in allergic individuals. As previously mentioned, products developed from standard foods, like Simplesse®, may not be recognized in its modified form by food-allergic patients. Sodium caseinate, a milk protein, is another example. It is added to processed meats as an emulsifier. The term 'caseinate' may not be recognized as a milk product. In fact several reports describe adverse reactions in known milk-allergic individuals, after ingestion of caseinate-containing foods. A child with a cow's milk allergy had a near fatal anaphylaxis after ingestion of a caseinate containing chicken soup served in a hospital;7 the hospital staff had not recognized caseinate as a milk protein.
Similarly R.N. Hamburger describes a child highly sensitive to cow's milk proteins, who experienced an allergic episode immediately after ingestion of a oleomargarine 'butter substitute' which contained sodium caseinate.8 Spelt-containing foods may be labelled as a 'wheat alternative' for those with wheat sensitivity,9 although spelt is wheat.10
Milk, egg, wheat and other cereals, soya and peanut are the food allergens most frequently found as unexpected ingredients of food products. Individuals highly sensitive to milk should be instructed to avoid delicatessen meats, luncheon meats, sausages and all processed meats. Moreover dairy-free products are at risk of contamination with milk during processing of food products, like ice cream, frozen dessert, sauces, etc.
Eggs are used in a wide variety of products (custard bases, baked goods, other bakery products) because of their excellent physical properties in food processing. Food which may contain egg include salad dressing, meringues, marshmallows, ice cream and sorbet, mayonnaise-containing foods, coatings and breading for fried foods, sauces, sausages.
Peanuts may be present in many foods especially when peanut butter is employed in food processing and preparation: marzipan rolls, soups, candy, baked goods, etc.
Avoidance of soya products is difficult because soya bean is a major ingredient of processed food products. Foods which may contain soya are cereals, hamburger, infant formulas, baked goods and bakery products, crackers, canned fish, soups, sauces, ice cream and frozen dessert.
Elimination of wheat from the diet is a very difficult problem, because wheat is a predominant food product contained in: cereals, pastas and breads and many other bakery products, sauces, snack foods, candy, sauces and luncheon meats.
In conclusion changes of food allergen properties during food processing and preparation and 'hidden' allergens are the main problem for food-allergic persons. Food-allergic children are particularly at risk, because they are more prone to eat processed foods like snacks, ice creams
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and candies. Moreover, a strict avoidance of the food allergen is very difficult especially by the youngest children since they often do not consume meals and snacks at home, where the food content would be carefully checked by parents.
As mentioned above, individuals highly allergic to food may experience fatal anaphylaxis even after ingestion of very little amounts of the offending food. Therefore it is imperative that all processed foods sold in the European Community countries are clearly labelled with the list of the ingredients and of the starting materials.
REFERENCES 1 Yunginger J.W., Sweeny K.G., Stumer W.Q., Giannandrea L.A. Teigland J.D., Bray M.,
Benson P., York J.A., Biedrzycki L., Squillace D.L. Helm R.M. 'Fatal food-induced anaphylaxis'. JAMA, 1988, 260, pp. 1450-1452.
2 Sampson H.A., Mendelson L., Rosen J.P. 'Fatal and near-fatal food anaphylaxis reactions to food in children and adolescents'. N. Engl. J. Med. 1992, 327, pp. 380-384.
3 Malmheden Yman I., Eriksson Α., Karlsson T., Yman L. 'Adverse reactions to food. Analysis of food proteins for verification of contamination or mislabelling'. J. Allergy Clin. Immunol. 1993, 91 (lpt2), p. 345.
4 Gem J.E., Yang E., Evrard H.M., Sampson H.A. 'Allergic reactions to milk-contamined "non-dairy" products'. N. Engl. J. Med. 1991, 324, pp. 976-979.
5 Jones R.T., Squillace B.A., Yunginger J.W. 'Anaphylaxis in a milk-allergic child after ingestion of milk-contaminated kosher-pareve-labelled "dairy-free" dessert'. Ann. Allergy, 1992, 68, pp. 223-227.
6 Kagi M.K., Wutrich B. 'Falafel burger anaphylaxis due to sesame seed allergy'. Ann. Allergy, 1993, 71, pp. 127-129.
7 Schwartz Rh. 'Near-fatal anaphylaxis to chicken soup and near-anaphylaxis events to cow's milk occuring in the hospital'. J. Allergy Clin. Immunol., 1993, 91 (1 pt 2), p. 152
8 Hamburger R.N. 'Misleading hazardous food labels'. Ann. Allergy, 1992, 68, pp. 200-201.
9 Yunginger J.W. 'Food ingredient labelling: How many ways can wheat be spelt?' Allergy Proc, 1994, 15, pp. 219-220.
10 Friedman H.M., Tortolani Re., Glick J., Burtis R.T. 'Spelt is wheat'. Allergy Proc, 1994, 15, pp. 217-218.
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1 1 . D I A G N O S I S OF FOOD ALLERGY
SYNOPSIS
The diagnosis of food allergy should be based on clinical history and results of in vivo and in vitro tests, but a number of factors make their value questionable. In fact, clinical history is biased by the high 'self-perception' of food allergy, and skin tests and in vitro tests have the drawback of unsatisfactory sensitivity and specificity due to the lack of standardized food allergen extracts. Thus, the 'gold standard' of diagnosis is the double-blind placebo-controlled food challenge (DBPCFC), the only test assessing the patient's reactivity to a suspected food in conditions free from patient's and physician's subjective influences.
11.1. Introduction
As for allergy in general, the diagnosis of food allergy has to be based on clinical history and on in vivo or in vitro tests. However, a number of factors, which will be discussed for each diagnostic tool, makes questionable their value when compared to the test generally considered the 'gold standard' of diagnosis of food allergy, that is the double-blind placebo-controlled food challenge (DBPCFC) which assesses in strictly controlled conditions, free from patient's and physician's subjective biases, the appearance of allergic symptoms following the administration of the suspected food.
11.2. Clinical history
The data from history, besides those commonly obtained regarding the presence of other already diagnosed allergic diseases or of a familiar background of atopy, should be addressed to show the cause-effect relationship between eating a given food and occurrence of allergic symptoms. This often proves very difficult because of a series of confounding factors. Firstly, the so-called self-perception of food allergy is very high,1 especially when compared to the true prevalence of this disease in the general population, which a recent well-conducted study estimated to be about 1 % . 2 This is mainly due to the fact that most patients attribute to food allergy any kind of symptom, whereas only some symptoms can be soundly correlated to hypersensitivity to foods. In particular, we have ample evidence that allergic symptoms may arise from direct contact of the culprit food with the oropharyngeal mucosa, as the oral allergy syndrome,3·4 characterized by itching and tingling, papulae/blisters and swelling of the lips resulting from eating especially fresh fruits and vegetables but also milk, egg, seafood and others, and with the gastrointestinal tract,5
symptoms being vomiting, diarrhoea and abdominal pain. Symptoms can also be generalized, presenting as anaphylaxis with involvement of cardiovascular and respiratory systems.6 This is due to the effects of mediators released by mast cells and basophils during the IgE-mediated reaction, resulting in pathophysiological events such as vasodilation and smooth muscle constriction which underlie potentially life-threatening symptoms such as collapse with loss of consciousness, laryngeal edema or severe bronchoconstriction. In individuals with paroxystic sensitivity, anaphylaxis may arise even if allergenic molecules of the culprit food are inhaled.7
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The IgE-mediated reaction may also lead, for unknown reasons, to a selective involvement of a target organ distant from the site of contact, being thus possible to develop skin symptoms such as atopic dermatitis8 and, even rarely, urticaria/angioedema,9 or respiratory symptoms such as rhinoconjunctivitis10 and asthma,11·12. Only exceptionally, hypersensitivity to foods may trigger sinusitis,13 or otitis.14
Despite a number of anectodal reports, there is as yet no evidence that joints and muscles, as well as the brain, are really involved in food allergy. For instance, most patients with arthritis from suspected food allergy failed to reproduce their symptoms when submitted to DBPCFCand, also in case of positive response, did not demonstrate specific IgE to the food-eliciting symptoms.15
Similarly, no demonstration by DBPCFC provided evidence that food allergy may involve the nervous system and cause symptoms such as headache, hyperactivity or behavioural problems.16
It has to be noted that just nervous and joint symptoms are those most commonly complained of by patients in their self-perception of food allergy.2
Another factor hampering a diagnosis of food allergy by clinical history is the lack, in chronic symptoms, of any cause-effect relationship between eating the food and appearance of symptoms. In acute symptoms, the patient generally recognizes the offending food if it is relatively uncommon to his dietary habit. However, the patients can be unaware of eating a given food because it is contained in apparently unrelated food preparations. This is the case of peanut, which in the United States is used in a number of products such as butter, oil, sweets, and many others, changing its taste to mimic other foods, and has been reported as responsible for fatal anaphylaxis from unaware ingestion.17
In evaluating the food suspected by the patients to cause food allergy the physician has to bear in mind the food items most commonly involved in hypersensitivity reactions, which are (not considering oral allergy syndrome) for children, milk, egg, soya, peanut, nuts, wheat, and fish, and for adults peanut, nuts, and seafood. Thus, it is clear that a high number of food products suspected by patients such as coffee, wine, various beverages, and many others, are unreliable as offending foods, since only exceptionally have they been reported as responsible for true allergy.18·19
However, considering all the factors discussed above and thus limiting the number of patients suspected as having food allergy, no more than 50% of allergic reactions to foods are confirmed by DBPCFC20·21
By contrast, the cause-effect relationship is evident in oral allergy syndrome, where the symptoms develop immediately upon eating the offending food,4 thus allowing the patient to recognize its responsibility. The reliability of patient's identification is confirmed by the high rate of positivity of challenge with the fresh food under medical control.22
7 7 . 3 . Elimination diets
Identification of the offending foods should be suggested by disappearance of symptoms following the elimination of the suspected food(s) from patient's diet. However, this diagnostic element
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is also confounded by factors such as the fact that the foods really responsible for symptoms have: (1) been left out; (2) the compliance of patients to strictly maintain the elimination diet; (3) the possibility that some symptoms, such as urticaria, may disappear regardless of the elimination of food(s). In fact, food items identified by elimination diet were confirmed as responsible by DBPCFC in less than 50% of cases.23
7 7 . 4 . Skin tests
Skin tests are commonly performed in Europe by the technique of skin-prick test (SPT), whereas in USA intradermal tests are still used. In the latter, a small amount (0.02-003 ml) is introduced into the dermis by a syringe with a 25-27 gauge needle. This technique provides a higher sensitivity than SPT, which nevertheless is counterbalanced by a much lower specificity, as demonstrated by the results of DBPCFC, which was negative in patients with positive intradermal test but negative SPT.24
By SPT, a drop of the allergen extract is placed on the skin and then pricked by a blood lancet or a 25-27 gauge needle. To avoid bleeding, lancets with a 1 mm tip unable to go deeply in the skin can be used.25 This also reduces the differences of results caused by the single operator technique regarding pressure, duration of pressure and, consequently, depth of penetration of the allergen. When a standardized technique is used, SPT show a good reproducibility.26 The optimal site on which SPT can be performed is the volar surface of the forearm, the back being an alternative when the forearm is not available (for example because of eczema). Appropriate positive control substances, such as histamine or codeine, and negative control substances, such as normal saline solution, have to be tested in concomitance with allergen extracts.25
A skin response to the negative control or a negligible response to the positive control strongly limit the value of the results of SPT. A positive response is provided by the appearance of a weal and flare reaction reaching its peak in 15-25 minutes and disappearing in 1-2 hours. Late skin reactions, occurring after 4-8 hours and lasting about 24 hours, characterized by infiltration of the tested site, are quite rare with SPT. The minimum criterion of positivity is fulfilled by a weal of 3 mm diameter, but commonly a comparison with the positive control, and particularly a weal diameter of at least the half than that elicited by the positive control, is preferred.
Drugs interfering with the skin response, such as antihistamines or topical steroids, must be withdrawn from a time interval depending on the half-life of each drug prior to performing SPT.25
The diagnostic value of a test is expressed by statistical parameters such as sensitivity, specificity, positive and negative predictive value. SPT with food extracts, provided good quality extracts were used, showed to have excellent negative predictive value, corresponding to more than 95% as assessed by the results of DBPCFC with the food eliciting the skin response, but a positive predictive value under 50%. 10,21,27-29 Thus, negative SPT with food extracts almost exclude the possibility that the patient is allergic to that food(s), whereas positive SPT are unsatisfactory in predicting the presence of clinical allergy. However, contrasting results were reported in populations of children and adults, as in the former a good sensitivity was found,27·30 while in the latter the sensitivity was poor.31
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For aeroallergens, diagnostic accuracy was significantly improved by the availability of standardized extracts with known composition and potency and, in some cases, with purified allergens measured in mass units.32 So far, no standardized food allergen extracts are available. An attempt to use individual milk protein fractions for skin testing in children allergic to cow's milk did not lead to better results than those obtained with whole cow's milk.33 By contrast, the approach to practically standardize the extracts by mixing large amounts of the foods obtained encouraging results. In fact, comparing commercial extracts of cow's milk and hen's egg to fresh extracts respectively yielded by 40-70 tons of milk and 40 000-50 000 eggs (thus eliminating the differences among the various source materials) allowed to increase the sensitivity from 50 to. 100% for milk and from 80 to 100% for egg as assessed by DBPCFC34 Despite the small groups of patients investigated, these findings stress the importance of using fresh material, and particularly the same material administered in DBPCFC, to perform skin tests, as already observed for foods such as shrimp, whose extract freshy prepared and used for both skin tests and DBPCFC gave a sensitivity of 100%.35
It is likely that the superiority of fresh extracts on commercial extracts depends upon the presence in foods of labile allergens, unable to resist the common procedures of allergen extraction. This is particularly evident in allergy to fruits and vegetables, for which it has long been known that commercial extracts give unreliable skin test results.36 Since the late 1970s various techniques were proposed for using fresh fruits and vegetables instead of commercial extracts. Among these, a scratch chamber test,37 which however was not feasible for routine use because of it being time-consuming, a direct skin-prick test applying on the skin the peel of the fruits/vegetables38 and, finally, the so-called prick + prick technique, performed pricking with the same lancet first the fruit/vegetable and then the skin.39 This method was found to be simple and reliable, and showed a good reproducibility also using different botanical varieties of fruits, such as apples, and different parts of the fruit such as the peel or the pulp39. A study investigated the diagnostic accuracy of prick + prick with fresh fruits/vegetables compared to prick tests with commercial extracts in patients with oral allergy syndrome from a number of fruits and vegetables.40 The prick + prick showed a much higher sensitivity for apple, peach, cherry, orange, carrot, celery and tomato, whereas prick tests with commercial extracts had a better sensitivity for peanut, nut and pea. In the latter the presence of stable allergens not readily released for the high contents of fats is likely to account for such a result. As regards the specificity, a wide variation was observed, ranging from a minimum of 42% for carrot to a maximum of 93% for peanut for prick + prick, and from 40% for pea to 100% for apple for prick tests with commercial extracts. The overall specificity seemed unsatisfactory, but the apparently false positive results can often be related to cross-reactivity of specific IgE antibodies recognizing identical allergens present in vegetable foods and in pollens, to which subjects with oral allergy syndrome are frequently sensitized.41
This was confirmed by the complete negativity of prick+prick with fresh material in a control group of healthy subjects.40
A recent study reported that the prick+prick technique was more sensitive than prick with commercial extracts also for foods such as milk, egg, various nuts, and seafood.42 It is interesting to note that a patient in this study, showing a cause-effect relationship between occurrence of symptoms and ingestion of shrimp, had a negative prick test with raw shrimp but a positive prick test with cooked shrimp, thus suggesting the possibility that new allergenic epitopes can be produced by cooking.
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7 7 . 5 . In vitro tests
These tests are aimed at detecting food-specific IgE antibodies or at measuring histamine release from basophils or mast cells challenged with the suspected food.
IgE antibodies are commonly detected by the technique of RAST or similar assays, which in general are believed to be less sensitive than in vivo tests.43 By considering as positive only a RAST class of 2-3, a study reported sensitivity and specificity comparable to skin tests, as assessed by the results of DBPCFC,27 but in another study the increase of sensitivity obtained in this way resulted in a decrease of specificity.44 Good results were obtained with the common positivity of class 1 for foods such as codfish, since a sensitivity of 100% was accompanied by a specificity of 90%.45 This seems clearly related to the high content of the major allergen of codfish, i.e. allergen M/Gad c /, in the preparation used for coupling RAST-discs, as settled by Aas.46
When unstable allergens are involved, the problem of loss of allergenicity during the procedure of allergen extraction, which makes the results of skin tests doubtful, also affects RAST, especially with fruits and vegetables. The use of fresh material for coating the RAST disc (or other solid phases) can provide, as for skin tests, more reliable results. In fact, fresh fruits/vegetables as coating material achieved an overall 67% concordance with clinical history and a concordance with skin tests ranging from 58% for apple to 78% for carrot in subjects with oral allergy syndrome.47 In another study, the poor results obtained with a commercial RAST for celery were greatly improved by coating the RAST disc with fresh celery, and especially with the roots rather than the leaves.48 In the already cited study on accuracy of diagnostic tests in oral allergy syndrome40 commercial RAST demonstrated a good sensitivity only for apple and a specificity ranging from 61 % for peanut to 87% for carrot.
As regards test of histamine release from basophils, though it gives results comparable more to skin tests than to in vitro detection of specific IgE, its results are commonly better concordant with RAST results.49 In two studies respectively investigating the value of diagnostic tests in allergy to milk and egg34 and to codfish45 basophil histamine release had a sensitivity lower than skin tests and RAST. Another possibility is provided by measuring histamine release from intestinal mast cells obtained from biopsies in patients with gastrointestinal symptoms from suspected food allergy. In one study this test gave better results, as demonstrated by intragastric challenge with foods, compared not only to basophil histamine release but also to skin tests and RAST.50
However such a procedure requires confirmation and is undoubtedly not feasible for routine clinical use.
7 7 . 6 . Double-blind placebo-controlled food challenge (DBPCFC)
Challenge testing is commonly considered the ultimate diagnostic procedure to demonstrate an allergic reaction to an offending agent. However, in opposition with other allergies such as Hymenoptera venom hypersensitivity, challenge tests for food allergy require a control with placebo. Open challenge with foods are unreliable because of the particular importance of psychological factors involved in adverse reactions to foods, as already underlined in clinical history. The only exceptions to this are represented by small children, in which psychological bias
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is negligible, and by subjects with oral allergy syndrome, in which the clear cause-and-effect relationship between eating the culprit fruit or vegetable and occurrence of oropharyngeal symptoms makes reliable the open challenge, as demonstrated by the concordance with both clinical history and skin tests.22
Single-blind challenge, during which only the physician knows the food being administered, is not an adequate choice because the patient can understand from the physician's care when the suspected food is given.51
Thus, the physician must also be unaware of whether a food or a placebo is tested and, in the first case, of which food is evaluated. This is fulfilled by the technique of double-blind, placebo-controlled food challenge (DBPCFC). By this technique, an equal number of increasing doses (commonly starting from 500 mg and reaching 10 g) or placebo are administered at regular intervals.52 Food(s) and placebo are masked by opaque capsules or by a strongly flavoured liquid. The challenge is stopped when objective symptoms or laboratory changes, such as the decrease of FEV1 in asthmatic patients, occur. When only subjective symptoms occur, the challenge has to be repeated two or more times. The patient is then kept under observation for an adequate period of time depending on his symptoms duration and severity as established by history. However, in patients with life-threatening reactions to foods DBPCFC is not advisable.
Provided all these precautions are taken, DBPCFC may also have its flaws, mainly represented by the possibility that patients recognize the food despite the double-blindness, by the stability of the clinical conditions of the allergic disorders, and by the fact that other factors besides the food(s) are involved in determining the clinical reactivity. In the first case, recognizing the food is favoured by the use of liquid preparations, which mask the flavour of food, but not its consistency and texture as well. The use of opaque capsule, which bypass the oropharyngeal tract, prevents this possibility, but the taste of food can be however perceived if eructation, spontaneous or provoked by the patient, occurs once the capsule has dissolved in the stomach.
As regards the clinical conditions at the moment of challenge, the patients should be free from the assumption of both suspected food(s) and drugs for control of the allergic symptoms. However, as discussed above, patients may be unaware of eating a given food, different from that of the challenge, in an unsuspected preparation, and thus the symptoms observed during the challenge can be not elicited by the food under evaluation. Moreover, only subjective symptoms may occur regardless of food administration, as demonstrated by the fact that only 20% of a number of healthy volunteers had no such symptoms during three days of observation by physicians.53
Finally, other factors can be necessary to cause symptoms besides eating a given food. This is the case of food-dependent exercise-induced anaphylaxis in which both eating the food(s) and physical exercise are required to elicit symptoms.54 This clinical association is generally noted by patients, however cases of allergic reactions caused by food assumption and exercise following a DBPCFC ruling out the responsibility of the suspected food are reported.55
Therefore, DBPCFC as a 'gold standard' is not perfect, but its diagnostic accuracy, as determined by a sensitivity of 95-98% and a specificity of 99%56 is by far higher than any other diagnostic procedure as yet available.
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3 Amlot P.L., Kemeny D.M., Zachary C , Parks P., Lessof M.H. 'Oral allergy syndrome (OAS): Symptoms of IgE-mediated hypersensitivity to foods'. Clin. Allergy, 1987, 17, pp. 33-38.
4 Ortolani C , Ispano M., Pastorello E.A., Bigi Α., Ansaloni R. 'The oral allergy syndrome'. Ann. Allergy, 1988, 61, pp. 47-52.
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6 Bochner B., Lichtenstein L.M. 'Anaphylaxis'. Ν. Engl. J. Med., 1991, 324, pp. 1785-1789.
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8 Burks A.W., Mallory S.B., Williams L.W. 'Atopic dermatitis: Clinical relevance of food hypersensitivity reactions'. J. Pediatr., 1988, 113, pp. 447-451.
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10 Bock S.A., Atkins F.M. 'Patterns of food hypersensitivity during sixteen years of double-blind placebo-controlled food challenges'. J. Pediatr., 1990, 117, pp. 561-567.
11 Onorato J., Merland Ν., Terral C.B., Michel F.B., Bousquet J. 'Placebo-controlled double-blind food challenge in asthma'. J. Allergy Clin. Immunol., 1986, 78, pp. 1139-1146.
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13 Shapiro G.G. 'Role of allergy in sinusitis'. Pediatr. Infect. Dis., 1985, 4, pp. 55-58.
14 Bernstein J.M. 'The role of IgE-mediated hypersensitivity in the development of otitis media with effusion'. Otolaryngol Clin. North. Am., 1992, 25, pp. 197-211.
15 Panush R.S. 'Food induced ('allergic') arthritis: Clinical and serological studies'. J. Rheumatol., 1990, 17, pp. 291-294.
16 Terr A.L. 'Unconventional theories and unproven methods in allergy'. In Middleton E., Reed CE., Ellis E.F., Adkinson N.F., Yunginger J.W., Busse W.W. (Eds): 'Allergy. Principles and practice'. Mosby Year Book, St Louis, 1993, pp. 1767-1793.
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17 Yunginger J.W., Sweeney K.G., Sturner W.Q. 'Fatal food induced anaphylaxis'. JAMA, 1988, 260, pp. 1450-1452.
18 Simon R.A. 'Sulfite sensitivity'. Ann. Allergy, 1986, 56, pp. 281-288.
19 Kagy M.K., Wuthrich Β., Johansson S.G.O. 'Campari-orange anaphylaxis due to carmine allergy'. Lancet, 1994, 344, pp. 60-61.
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21 Sampson H.A. 'Role of immediate food hypersensitivity in the pathogenesis of atopic dermatitis'. J. Allergy Clin. Immunol., 1983, 71, pp. 473-480.
22 Pastorello E.A., Ortolani C , Farioli L., Pravettoni V., Ispano M., Borga Α., Bengtsson Α., Incorvaia C , Berti C , Zanussi C. 'Allergenic cross-reactivity among peach, apricot, plum and cherry in patients with oral allergy syndrome: An in vivo and in vitro study'. J. Allergy Clin. Immunol., 1994, 94, pp. 699-707.
23 Pastorello E.A., Stocchi L., Pravettoni V., Bigi Α., Schilke M.L., Incorvaia C , Zanussi C. 'Role of the elimination diet in adults with food allergy'. J. Allergy Clin. Immunol., 1989, 84, pp. 475-483.
24 Bock S.A., Buckley J., Hoist Α., May CD. 'Proper use of skin tests with food extracts in diagnosis of food hypersensitivity'. Clin. Allergy, 1978, 8, pp. 559-564.
25 Dreborg S. (ed). 'Skin tests used in Type I allergy testing. Position paper of the European Academy of Allergology and Clinical Immunology'. Allergy, 1989, p. 44 (Suppl 10).
26 Taudorf E., Mailing H.J., Lauren L.C. 'Reproducibility of histamine skin-prick test'. Allergy, 1985, 40, pp. 344-349.
27 Sampson H.A., Albergo R. 'Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis'. J. Allergy Clin. Immunol., 1984, 74, pp. 26-33.
28 Atkins F.M., Steinberg S.S., Metcalfe D.D. 'Evaluation of immediate adverse reactions to foods in adults patients. I. Correlation of demographic, laboratory, and prick-skin test data with response to controlled oral food challenge'. J. Allergy Clin. Immunol. 1985, 75, pp. 348-355.
29 Sampson H.A. 'Comparative study of commercial food antigen extracts for diagnosis of food hypersensitivity'. J. Allergy Clin. Immunol., 1988, 82, pp. 718-726.
30 Bock S.A., Lee W.Y., Remigio L., Hoist Α., May CD. 'Appraisal of skin tests with food extracts for diagnosis of food hypersensitivity'. Clin. Allergy, 1978, 8, pp. 559-564.
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31 Bernstein M., Day J.H., Welsh A. 'Double-blind food challenge in the diagnosis of food sensitivity of the adult'. J. Allergy Clin. Immunol., 1982, 70, pp. 205-210.
32 Ipsen H., Klysner S.S., Nedergaard Larsen J., Lowenstein H., Matthiesen F., Schou C , Hauschildt Sparholt S. 'Allergenic extracts'. In Middleton E., Reed CE., Ellis E.F., Adkinson N.F., Yunginger J.W., Busse W.W. (Eds): 'Allergy. Principles and practice'. Mosby Year Book, St Louis, 1993, pp. 529-553.
33 Bahna S.L. 'New aspects of diagnosis of milk allergy in children'. Allergy Proc, 1991, 12, pp. 217-220.
34 Norgaard Α., Skov P.S., Bindslev-Jensen C. 'Egg and milk allergy in adults: comparison between fresh foods and commercial allergen extracts in skin-prick test and histamine release from basophils'. Clin. Exp. Allergy, 1992, 22, pp. 940-947.
35 Daul C.B., Morgan J.E., Hughes J., Lehrer S.B. Provocation-challenge studies in shrimp-sensitive individuals'. J. Allergy Clin. Immunol., 1988, 81, pp. 1180-1186.
36 Hannuksela M., Lahti A. 'Immediate reactions to fruits and vegetables'. Contact Dermat, 1977, 3, pp. 79-84.
37 Lahti Α., Hannuksela M. 'Hypersensitivity to apple and carrot can be reliably detected with fresh material'. Allergy, 1978, 33, pp. 143-146.
38 Andersen K.E., Lowenstein H. 'An investigation of the possible immunological relationship between allergen extracts from birch pollen, hazelnut, potato and apple'. Contact Dermat, 1978, 4, pp. 73-79.
39 Dreborg S., Foucard T. 'Allergy to apple, carrot and potato in children with birch pollen allergy'. Allergy, 1983, 38, pp. 167-172.
40 Ortolani C , Ispano M., Pastorello E.A., Ansaloni R., Magri A. 'Comparison of results of skin-prick tests (with fresh foods and commercial extracts) and RAST in 100 patients with oral allergy syndrome'. J. Allergy Clin. Immunol., 1989, 83, pp. 683-690.
41 Ortolani C , Pastorello E.A., Farioli L., Ispano M., Pravettoni V., Berti C , Incorvaia C , Zanussi C. 'IgE-mediated allergy from vegetable allergens'. Ann. Allergy 1993, 71, pp. 470-476.
42 Rosen J.P., Selcow J.E., Mendelson L.M., Grodovsky M.P., Factor J.M., Sampson H.A. 'Skin testing with natural foods in patients suspected of having food allergies: Is it a necessity?'. J. Allergy Clin. Immunol., 1994, 93, pp. 1068-1070.
43 Homburger H.A., Katzman J.A. 'Methods in laboratory immunology. Principles and interpretation of of laboratory tests for allergy'. In Middleton E., Reed CE., Ellis E.F., Adkinson N.F., Yunginger J.W., Busse W.W. (Eds): 'Allergy. Principles and practice'. Mosby Year Book, St Louis, 1993, pp. 554-572.
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44 Wraith D.G., Merret J., Roth A. 'Recognition of food-allergic patients and their allergens by the RAST technique and clinical investigation'. Clin. Allergy, 1979, 9, pp. 25-36.
45 Hansen T.K., Bindslev-Jensen C. 'Codfish allergy in adults. Identification and diagnosis'. Allergy, 1992, 47, pp. 610-617.
46 Aas K., Lundkvist U. 'The radioallergosorbent test with a purified allergen from codfish'. Clin. Allergy 1973, 3, pp. 255-261.
47 Halmepuro L., Wountela K., Kalimo K. 'Cross-reactivity of IgE antibodies with allergens in birch pollen, fruits and vegetables'. Int. Arch. Allergy Appi. Immunol., 1984, 74, pp. 235-20.
48 Pauli G., Bessot J.C, Dietemann-Molard Α., Braun PA. 'Celery sensitivity: Clinical and immunological correlations with pollen allergy'. Clin. Allergy, 1985, 15, pp. 273-279.
49 Nolte Η., Schiotz P.O., Kruse Α., Skov S. 'Comparison of intestinal mast cell and basophil histamine release in children with food allergic reactions'. Allergy, 1989, 44, pp. 554-565.
50 Selbekk B.H. 'A comparison between in vitro jejunal MAST cells degranulation and intragastric challenge in patients with suspected food intolerance'. Scand. J. Gastroenterol, 1985, 20, pp. 299-303.
51 Sampson H.A. 'Immunologically mediated food allergy: the importance of food challenge procedures'. Ann. Allergy, 1988, 60, pp. 262-269.
52 Bock S.A., Sampson H.A., Atkins F.M., Metcalfe D.D., May CD. 'Double-blind placebo-controlled food challenge as an office procedure: A manual'. J. Allergy Clin. Immunol., 1988, 82, pp. 986-997.
53 Reidenberg N.M., Lowenthal D.T. 'Adverse non-drug reactions'. N. Engl. J. Med., 1968, 27, pp. 678-681.
54 Kidd J.M., Cohen S.H., Sosman A.J., Fink J.N. 'Food-dependent exercise-induced anaphylaxis'. J. Allergy Clin. Immunol., 1983, 71, pp. 407-411.
55 Kaplan M.S. 'The importance of appropriate challenges in diagnosing food sensitivity'. Clin. Exp. Allergy, 1994, 24, pp. 291-293.
56 Sampson H.A. 'Adverse reactions to foods'. In Middleton E., Reed CE., Ellis E.F., Adkinson N.F., Yunginger J.W., Busse W.W. (Eds): 'Allergy. Principles and practice'. Mosby Year Book, St Louis, 1993, pp. 1661-1686.
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12. C O N T R O V E R S Y ON A D V E R S E R E A C T I O N S TO FOOD
SYNOPSIS
Methods that are not shown to be effective and safe by proper clinical trials should be considered 'unproven methods' or 'non-validated methods'. Non-validated methods are not recommended in clinical practice, because the literature does not provide convincing data on the reliability of these methods and, in some cases, well-conducted studies do not show any difference between the investigated method and the placebo. The most commonly employed non-validated methods are discussed in Chapter 12.
Symptoms typical of food allergy are discussed in Chapter 3. It is controversial whether clinical manifestations different from those listed above, could be due to one food allergy. Medical knowledge and clinical studies provided by the literature do not justify the emphasis of some investigators and of the media in claiming the link between food allergy and unusual symptoms. Among atypical complaints migraine is the most suitable for a relationship with food intake. However the basic mechanism of the presumed food-adverse reaction is unknown and a true food allergy is unlikely.
In the last decade an agreement on the main concepts in the area of ARF has been obtained in the medical scientific community. The clinical symptoms of food allergy and intolerance and the procedures for the diagnosis of ARF have been clearly defined. The progress in our knowledge of ARF has clarified some of the long-standing debates in the area of unconventional and controversial method and theories in this field.
Methods that are not shown to be effective and safe by proper clinical trials should be considered 'unproven methods' or 'non-validated methods'.
Methods which may be effective and appropriate for the diagnosis of certain disease, but not for ARF, should be referred as 'inappropriate'.
12. 1 Non-validated methods
Non-validated methods are not recommended in clinical practice, because the literature does not provide convincing data on the reliability of these methods and, in some cases, well-conducted studies do not show any difference between the investigated method and the placebo.
1 2 . 1 . 1 . C i t o t o x i c i t y t e s t
In this In vitro test a food allergen is added to whole blood or to leucocyte suspensions. The reduction in number or the change in the appeareance of the cells would indicate a sensitivity to a specific food.1·2·3
However no controlled studies4·5·6 have shown efficacy of the test in diagnosing food allergy or intolerance. Several studies demonstrated that this test cannot discriminate between offending and tolerated foods and between active and placebo.6·7
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Moreover test results were not reproducible when repeated several times in the same patient with the same food allergen.
A Position Statement from the American Academy of Allergy and Immunology on controversial methods states that no proofs are available for the efficacy of the test in diagnosing food allergy and that several controlled studies indicate that the test is ineffective.9 In conclusion citotoxicity testing is not recommended for clinical practice and should be reserved only for experimental well-designed trials.
1 2 . 1 . 2 . Subcutaneous and subl ingual provocat ion and neutra l izat ion
This method consists of the sublingual, subcutaneous, or intradermal administration of food extracts of sufficient quantity to elicit objective or subjective symptoms. Symptom provocation is then followed by the immediate administration of a weaker or stronger dilution of the provoking material that is said to be capable of neutralizing the allergic reaction and relieve symptoms.
There are great variations in protocols proposed by different authors and there is no standardization of the method.
The test has been proposed not only for the diagnosis of food allergy but also for the diagnosis of a wide variety of illness in different medical fields: thombophlebitis,10 vasculitis,11 arythmias,12
psychological symptoms,13 gynecologic disorders,14 miscellanea.15 Eight placebo-controlled studies have been performed for evaluating this technique. Five studies show that test results are consistent with a placebo effect.16·17·18·19·20 Of the other three, one is a case report of a milk allergic patient.21 In the second study psychological symptoms after administration of food extracts are more pronounced than after placebo; however, blinding procedure was inadequate, because some patients recognize taste and colour of the active material.13 The third study was flawed by the large number of drop-outs and incomplete blinding of the investigator.15
The most rigorous and valuable is the study of Jewett et al.17 The investigators performed a double-blind placebo-controlled study of the intradermal provocation-neutralization method. Eighteen patients were tested in the offices of seven physicians who were proponents of this technique and experienced in its use, using the same extracts as those previously thought to provoke symptoms during unblinded testing. At each session three injections of extract and nine of diluent were given in random sequence. Patients could not distinguish the placebo (24% positive responses) from the active extracts (27% positive responses). Neutralizing doses given to seven patients were equally efficacious whether the injection contained the suspected allergen or a placebo.
A similar study with equal results were performed by Kailin and Collier22 in evaluating the efficacy of the sublingual and of the subcutaneous provocation-neutralization testing. There was no distinction of reactions between active food extracts and placebo. Neutralizing doses were judged to be effective in 70.6% of the active treatment and in 70% of the placebo administration, showing no difference in the results between food extracts and placebo.
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In conclusion there are no reports showing definitely that provocation-neutralization testing can be useful for the diagnosis of food allergy. On the contrary, there is clear evidence that test results are random and not related to the administered substance.
The American Academy of Allergy and Immunology Position Statement concludes that the provocation neutralization method has been shown to be ineffective and without rationale on immunologic basis. The conclusion of the National Centre for Health Care Technology23 was similar. Moreover the Health Care Financing Administration concluded that sublingual provocation testing and neutralization therapy for food allergy are widely used but lack scientific evidence of effectiveness.24 These procedures have been excluded from Medicare coverage.25
1 2 . 1 . 3 . DRIA test
The DRIA test, available in Italy, is based on the sublingual provocation and neutralization. The patient sits on a chair and the quadriceps muscle of thigh is connected to a device suitable for recording the muscle strength. A positive result is a drop in strength within four seconds after the sublingual contact with the test material. The drop should indicate allergy or intolerance to the tested food. Scientific bases of the DRIA testing are unknown. Information on the test have been obtained only from media and from the report that accompanies the test results to the patients submitted to DRIA testing.26 Proponents of the method claim that it is more advantageous than classical diagnostic techniques, because the test is quicker and practical, but they do not show a better diagnostic efficacy than other in vivo and in vitro procedures. No double-blind placebo-controlled clinical trials have been performed with DRIA test to show its efficacy in diagnosing food allergy; and there are no publications in the scientific medical literature. The paper delivered by proponents contains many assertions that are not demonstrated, for example: 'If the test is positive, it means that every time that the food has a contact with the body, the immune system became engaged for a defense from the food and therefore weakens'; 'these toxic substances, through the white blood cells, go around the body causing inflammations and irritations even far away', 'food intolerance is a certain concomitant cause of many autoimmune, metabolic, eno-crine, and circulatory diseases'. The test is proposed as highly sensitive and highly specific for diagnosing food allergy and intolerance; however, in the same paper, the final interpretation of the test results is given to the practitioner, because a positive result may indicate a 'specific food intolerance' or 'simply a transient overcharge' and a negative result may be not completely negative because 'some food may give a constant alteration of the layout recorded without a drop in the muscle strength'; 'therefore sometimes even a formally negative test may nevertheless permit the practitioner to identify possible individuals at risk for a particular food category'. Given this background, lacking a validation of the method and considering the negative evaluation of sublingual provocation and neutralization testing, from which the DRIA test derive, this technique should not be employed for diagnostic purposes.
1 2 . 1 . 4 . Electroacupuncture
The electroacupuncture or electrodermal testing is performed with a device, which measures the electrical activity of the skin in points considered suitable for detecting food allergy. The patient holds a positive and negative electrode in each hand. An alluminium plate within the circuit is the
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support for the tested food; a drop in electrical current when the probe touches the skin allows the diagnosis of allergy to that food.27
There is no scientific or clinical proof that this method can diagnose food allergy.
12 .1 .5 Applied k ines io logy
This method for diagnosing food allergy is based on the subjective manual measuring of the muscle strength.28 The patient holds a food contained in a glass bottle in one hand while the technician estimates muscle strength in the other hand. A decrease in muscle strength should indicate a positive test result.
Alternatively, the bottles may be rested against the chest or even near the patient, but without contact with the body. Scientific ground and diagnostic efficacy of applied kinesiology are not documented.
12.2. Inappropriate diagnostic tests
Methods effective and proper for diagnosis of other disease, but not food allergy, are considered inappropriate for that purpose.
Measurement of circulating IgE antibodies specific to food and food-immune complex assay is an inappropriate diagnostic test proposed by someone for diagnosis of food allergy.
1 2 . 2 . 1 . Serum IgG ant ibodies
Circulating IgG antibodies to food are frequently found in patients with ARF,29 but they are also seen in normal subjects and the pathogenetic role has not been demonstrated. The presence may be the consequence of prolonged exposure to ubiquitous antigens resulting in an lgG4-restricted response.30 This measurement of specific IgE antibodies to foods is not useful in the diagnosis of food allergy.
1 2 . 2 . 2 . Food immune complex assay
Circulating IgG and IgE immune complexes containing food antigens may be found in patients suffering from asthma and eczema.29·31
One case of arthritis provoked by ingestion of milk was accompanied by circulating immune complexes, but the level of these complexes did not relate to clinical symptoms after milk challenge.32
Food immune complexes are normal phenomena33 and may be detected in normal individuals.34·35 Moreover patients with ARF have not yet been shown to differ in the quantity or quality of these complexes when compared with controls.
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In agreement with the American Acadamy of Allergy and Immunology Position Statement on circulating IgG and IgE food immune complexes, we conclude that the efficacy of the method for the diagnosis of food allergy is unproven and that the method does not have a place in current clinical practice.36
12.3. Clinical manifestations non-typical of food allergy
Symptoms typical of food allergy are: oral allergy syndrome, anaphylaxis, urticaria-angioedema, eczema, asthma, rhinoconjunctivitis, laryngeal oedema, vomiting and diarrhoea. (See Chapter 10). It is controversial If clinical manifestations different from those listed above, could depend on food allergy.
The clinical evaluation of patients with atypical complaints which are mainly chronic, subjective, and late in onset, is very difficult, because of the problem of objectively measuring the clinical reaction to a food. For this reason the scientific medical authorities require a trial of three DBPCFC for confirming a ARF when symptoms are only subjective.37
The relationship between food and symptoms is confirmed when adverse reactions develop only during active challenges.
Very few cases of atypical food-related complaints are demonstrated by such a diagnostic procedure.
1 2 . 3 . 1 . H e a d a c h e
Headache is a very common complaint, difficult to attribute to a single cause. Some foods and food additives are known as precipitating factors of vascular headache, elicited by pharmacologic agents present in foods: tyramine, phenylethylamine, histamine, ethyl alcohol, nitrites, monoso-dium glutamate.38
Much more controversial is the attribution of headaches to food allergy. Egger et al.39 studied 88 children with severe migraine. Ninety-three percent of the patients placed on oligoantigenic diet experienced relief and of the 40 children challenged in the double-blind study, 26 subjects (70%) had positive food-provoked migraine challenges. The mean reactions time was two days (until a maximun of seven days). Egger et al. found neither allergy history nor allergy testing of value in predicting which subjects would respond to which foods. Fifty-five foods were responsible for 331 migraine attacks. The high number of implicated foods has been considered by authors as evidence for a specific reaction and therefore for an allergic reaction. However the type of allergic reaction is unknown, given that SPT results were not related to food triggers and no other immunologic types of reactions were investigated nor hypothezed. Double-blind placebo-controlled studies on food allergy indicate that the history of ARF is confirmed in less than 50% of patients with typical manifestations of allergic diseases and that suspected foods are confirmed in less than 30% of cases.40 Therefore it is surprising the high percentage of positive food challenge results in Egger et al. patients, who had late reactions and atypical symptoms.
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Pearson and Rix41 investigated 23 patients who reported various complaints suspected for food allergy. Only four patients with manifestations typical for allergic disease (urticaria) had clinical suspicion confirmed by a positive DBPCFC. Of the 19 patients with negative DBPCFC, 13 were afflicted with headaches and all had definite psychological problems. The conflicting results of the two studies may depend on the more strict diagnostic protocol adopted by Pearson and Rix who submitted the patients to a series of three DBPCFC with each suspected food, as recommended for studies of food allergy patients who report only subjective symptoms.37.
Atkins et al. and coworkers investigated 36 children with migraine. Sixteen children felt that a specific food would precipitate migraine. However, when DBPCFC were performed using these foods, no migraine headaches were observed.42
Mansfied et al.43 evaluated adult patients with migraine. SPT, elimination diets, DBPCFC and plasma histamine were performed. Of the 16 SPT positive 11 patients responded to diet, while only two of 27 SPT negative responded, with a significant difference between the two group of patients. Seven patients with 66% or greater reduction in headache frequency during a diet trial were submitted to DBPCFC. In five of seven, at least one food provoked migraine. In three subjects plasma histamine rose during migraine provoking-challenges and did not after placebo. All the five DBPCFC positive patients were SPT positive for the migraine-provoking food. The authors conclude that tests for IgE-specific food allergy appear helpful in selecting patients likely to benefit from diet manipulation. This result is in contrast with the study of Egger et al.39 who did not find any correlation between migraine-provoking foods and SPT results.
In conclusion, it is possible that in a patient a food allergic reaction may induce headache attacks, however it is unlikely that food allergy has an important role in the disease.
1 2 . 3 . 2 . Chi ldren's hyperact iv i ty
Typical symptoms of this behavioural disorder are: hyperactivity, distractability, impulsivity and excitability. This syndrome has been also called 'attention deficit disorder', to describe a child hyperkinetic, difficult to discipline and with learning disabilities. Hyperactivity is essentially a description of the child's personality and the threshold for recognizing such behavior as pathological is strictly dependent on the opinion of the observers (physicians, parents, teachers).44 In one study of teacher opinions, older teachers considered more children hyperkinetic than did younger teachers.45
The relationship between food and attention deficit disorder received noticable publicity in 1975, since Feingold wrote a popular best-selling book stating that additives and colouring were responsible for the hyperkinetic syndrome in most of the patients.46 The Feingold hypothesis found some support, especially by media, and several studies have since been performed to evaluate the theory. A review of the topic indicates that most properly conducted studies performed with blind challenges, refute the relationship between behaviour and food additive ingestion.47
In 1982 the National Institute of Health organized a consensus development conference on defined diets and childhood hyperactivity.48 The conclusion was that existing data indicate that
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diet manipulation may be helpful in a small number of hyperkinetic children, and not in more than 50% as claimed by Feingold. Anyway, possible effects of the diet on behaviour does not have an allergic mechanism.48 It has been also shown that drugs are considerably more effective than diet manipulation in controlling children's hyperkinesis.49 Subsequently Egger et al.50 found beneficial effects of oligoantigenic diets in 82% of 76 hyperkinetic children. The result is highly surprising considering the multifactorial nature of the syndrome, as mentioned by the same authors. During the subsequent reintroduction, the substances that most commonly induced worsening of the behaviour were tartrazine and benzoic acid (79% of tested children), but no child reacted to these alone: 46 other provocative foods were identified and most patients reacted to several of these. Although not reported in the study mentioned,50 description of their own study in a different paper51 reports that 'the interval between eating an allergy-provoking food and reaction was usually two to three days, but it varied from a few minutes to more than seven days'. On this basis 28 children entered a double-blind crossover, placebo-controlled trial in which food identified in the open phase was reintroduced: symptoms returned or were exacerbated much more often when patients were on active material than on placebo. However the list of the offending foods and food additives reported by authors is the list of substances identified during the open phase; therefore we do not know the offending foods and food additives identified on the basis of the results of the double-blind placebo-controlled study. The authors report that tartrazine and benzoates, unlike salicylates, have no established pharmacological activity and can be antigenic; they support a food allergic basis for the syndrome. However, no grounds are given for that hypothesis. Thus a critical estimation of the study leads to scepticism on their general significance. The need for a triplicate confirmation of positive DBPCFC result with each offending food is unavoidable in demonstrating food allergy or intolerance as the cause of atypical symptoms elicited by late reactions to multiple foods and food additives in the picture of a multifactorial disease, like hyperkinesis.
Recently a DBPCFC study suggested the role of dietary factors in hyperkinetic children.52
DBPCFC gave a positive result in 100% of the 16 children tested. These data are surprising because in well-controlled studies DBPCFC confirmed the history in less than 50% of selected patients.53 The interval between active and placebo challenge and the interval between eating an offending food and reaction are not reported. The study protocol made provision for a seven-day challenge period, where the child would randomly receive a placebo or a challenge item at home. In Egger's et al. study the time of reaction was usually two to three days.51 Therefore it would be interesting to know how a reaction has been attributed to active material or to a placebo in the study of Boris and Mandel.52 Finally, in this study the evalutation of children's behaviour was left to the impressions of parents and although the study was blinded and the parents completed a symptom-score card, the choice of the parents as judges is at least questionable.
In conclusion, hyperkinesis is a multifactorial syndrome and it is possible that some children show a worsening of the disease induced by ingested substances. However no consistent data suggests a relevant part of foods and food additives in triggering behavioural changes and learning disturbances.
1 2 . 3 . 3 . Schizophrenia
A relationship between coeliac disease and schizophrenia have been claimed by Donan.54·55·56
However, two large studies have failed to find evidence of coeliac disease in schizophrenics.57·58
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A number of dietary studies have been performed to test the Dohan's hypothesis with conflicting results. Some studies, criticizable for different reasons, suggested the idea, whereas other studies have provided no foundation for Dohan's theory.59
Differences in antibodies to wheat and gluten between schizophrenics and controls have been shown by some studies, but not confirmed by others.
For the time being there is no direct evidence to indicate a role for allergic mechanisms in the generation of mental symptoms or psychosis.
1 2 . 3 . 4 . Other neurologic and psychic disorders
Some authors suggest that food allergy is responsible for a series of neurological and psychic disorders like tension-fatigue syndrome (alternating periods of anxiety and apathy), epilepsy, neurosis, and depression, disorders defined as 'cerebral allergy'.59
Even cases of young offenders have been attributed to food allergy, with the authors' suggestion to test prisoners with an oligoantigenic diet.60
The idea that allergic mechanisms adversly affect the nervous system has been encouraged by media, which popularized such a claim. Popular books claim that nobody can be considered neurotic, until allergy has been excluded. One of these books is dedicated to all patients considered neurotic, hypochondriac, hysteric and are instead affected with an environmental illness.59
Certainly, neurological and psychological symptoms may be associated to allergic reactions, both as a response to the suffering condition provoked by allergy (it is not surprising that a child's behaviour is abnormal after a night spent scratching his eczematous skin) and as symptoms arising during systemic allergic manifestations. There are several reports of neurological signs with or without psychological symptoms, in the course of angioedema and anaphylaxis.59 It is equally true that psychological factors may exacerbate bronchial asthma and urticaria. It is however unlikely that neurological and psychological symptoms are the only clinical manifestation of a food allergy. There are some rare case reports, well-documented with repeatedly positive DBPCFC, suggesting an adverse reaction to food: examples are one case of EEG changes following ingestion of beef,61 and one case of episodes of hysteria and crying induced by milk ingestion and prevented by sodium cromoglycate.62 Some studies, criticizable for various reasons (i.e. lack of DBPCFC, no reactions to placebo, employment of non-validated methods) claim the link between neurologic and psychic disorders and food allergy. On the contrary, considering well-designed and properly conducted studies, this relationship has been rejected.
Pearson et al.41 performed DBPCFC in 23 adults who attributed their symptoms to food allergy. Only four patients with clinical manifestations typical of food allergy (urticaria) had the suspicion confirmed by a positive DBPCFC with the causative food; none of the four food allergic patients experienced neurologic or psychological symptoms in the course of DBPCFC. None of the 19 patients who reported a wide variety of atypical complaints had a positive DBPCFC and 18/19 had a psychiatric disorder.
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Some patients clearly had psychogenic reactions, because symptoms repeatedly appeared in the course of open challenges, whereas DBPCFC repeatedly gave negative results. Patients, who accepted the negative results of the DBPCFC and reintroduced in the diet the foods previously suspected, had a remission or major improvement in the symptoms. On the contrary, symptoms tended to persist in patients who refused to accept that they did not have food allergies.59 In another study, food allergy or intolerance were not confirmed by DBPCFC in 23 patients with atypical complaints.23
In conclusion, social or neuropsychic disorders may be secondary to well known somatic effects of toxic or pharmacologic or typical allergic reactions to food; however there are no convincing data in the medical literature to support the belief that multiple atypical symptoms are commonly related to food allergy or intolerance.
1 2 . 3 . 5 . A r t h r i t i s
Panush63 investigated the role of food in rheumatoid-like arthritis. Thirty percent of the selected patients with rheumatoid arthritis reported food related 'allergic' arthritis. Sixteen of these patients completed double-blind food challenges and three patients had positive challenge results: milk, shrimp, and nitrates were the incriminated foods and food additives. All three were seronegative with palindromic symptoms and nonerosive disease. Specific lgG4, IgA, IgM and IgE to food, lg-food immune complexes, and in vitro cellular reactivity to food were not distinctively abnormal in these patients. The milk-sensitive patient had increased IgG anti-alpha lactoalbu-mine, IgG-milk complexes, and delayed skin and cellular reactivity to milk; however no relationship was found between these immunologic parameters and clinical symptoms. Thus the me· chanism(s) for food-related arthritis is unknown.
In conclusion, most patients who believe that their arthritis is provoked by food, cannot confirm this belief in blind controlled studies. Occasional patients with rheumatic diseases may have food-related symptoms of unknown pathogenesis. Further double-blind placebo-controlled studies are required to clarify the role of food and food allergy in rheumatic diseases. At present, diet or nutritional therapy for rheumatic diseases should be considered experimental.
1 2 . 3 . 6 . V a s c u l i t i s
Some anecdotal cases of food-induced vasculitis have been reported. Milk, fish crustácea, egg, wheat, bean and chocolate are the suspected foods. Unfortunately the diagnosis was not confirmed by a biopsy after DBPCFC with the causative food.44
Therefore well-documented studies are needed to clarify the significance of these reports.
Recently Wuthrich described a case of urticarial vasculitis due to sulfite sensitivity, documented by a positive skin biopsy after positive DBPCFC with 50 mg of sodium disulfite.64
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1 2 . 3 . 7 . Irritable bowel syndrome
The irritable bowel syndrome (IBS) consists of abdominal pain or distension, diarrhoea and constipation. Food allergy and intolerance as a cause of IBS have been investigated by several studies. In five studies DBPCFC were done to check the role of food in determining the syndrome.65·66·67·68·69 In one study none of the patients had evidence for adverse reactions to food in causing IBS.68 Only one study confirmed a food allergy as cause of their syndrome in three of the 27 investigated patients. All the three patients had evidence of associated atopic disease and positive SPT to common inhalant allergens.66 In the three remaining studies food intolerance was found to provoke symptoms of IBS, respectively in three of 49,67 in one of 2369
and in six of 2765 patients. Lactase deficiency was the mechanism of the intolerance in the food intolerant patient of Gallo's et al. study.69 Alun Jones et al. found an increase of rectal prostaglandins in the food intolerant patients.65 Interestingly in one study, nine of the 10 patients with negative DBPCFC were found strong 'placebo reactors'.67 Moreover, the Bentley's study revealed minor psychiatric disorders in 12 of 14 patients examined by an independent psychiatrist.66
In conclusion food intolerance may be the cause of IBS only in a small minority of patients with that syndrome. Rarely, atopic individuals may experience gastrointestinal symptoms, consistent with IBS, after ingestion of a specific food to which they are sensitized.
1 2 . 3 . 8 . Otit is media with e f fus ion
Otitis media with effusion (OME) is associated with allergic rhinitis in 1/3 of the cases.70
Eustachian tube dysfunction induced by allergic reactions in the nasal mucosa is probably the underlying mechanism of OME associated with allergic rhinitis against inhalant allergens.71 Only in a very small minority of patients may OME be associated with allergic rhinitis caused by food allergy, especially in cow's milk allergic children, below the age of two years.70 A recent study suggests a high prevalence of food allergy in serous otitis media. However no blind challenges were performed.72
1 2 . 3 . 9 . Allergy to twentieth century
This diagnosis has been proposed by clinical ecologists for individuals whom they labelled allergic to a wide variety of substances, including foods and food additives.
Seiner and Condemi73 report a case of a 31 year-old woman, admitted to the hospital for severe malnutrition, leukopenia, and monilia sepsis. She had a history of polysomatic symptoms, diagnosed as severe psychiatric disease at the age of 20. At the age of 25, she was admitted to an ecologie clinic and discharged with a diagnosis of 'universal responder', that is, adverse reactions to everything. The patient was then confined to a porcelainized room in her home and parenterally fed because of alleged food intolerance. Due to severe wasting, she was admitted to hospital where immediately food was gradually reintroduced, in spite of the patient's resistance, who had phobic reactions to whatever food. Once proper nutrition was restored with a general diet, all haematologic and immunologic parameters were found to be normal.
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Some reports have shown that misdiagnosis of food allergy made by 'alternative' practitioners can lead to a delay of diagnosis and treatment of serious underlying organic diseases.74·75 Terr76
investigated 50 patients with diagnosis of environmental illness formulated by clinical ecologists. Histories were extremely heterogenous. No physical findings or laboratory abnormalities patterns were found, including immunologic parameters. Patients had characteristic symptoms of psychosomatic illness, with chronic multisystem complaints. In these patients provocation and neutralization testing, and diet and environmental limitations had caused further new symptoms and fear of environmental and food contaminants, without evidence that symptoms arose from sensitization to foods and chemicals induced by a toxic environmental factor on the immune system.
Clinical ecologists claim the existence of a candida hypersensitivity syndrome also known as yeast hypersensitivity. The syndrome is an undefined clinical entity, with a wide variety of subjective symptoms, but without pathologic changes on physical examination and without laboratory test abnormalities. The diagnosis is based entirely on the history, clinical symptoms, previous exposure to presumed risk factors such as antibiotics, corticosteroids, pregnancy, excess in the diet of sugar yeast and foods believed to have a high mould content. The cause of the syndrome should be an unknown toxin produced by Candida albicans, a fungus that is part of the normal flora, against which some individuals develop hypersensitivity. The presumed toxin is believed to have a suppressive effect on the immune system. The American Acadamy of Allergy and Immunology Position Statement defines the syndrome as unproven and some of the proposed treatments as potentially dangerous.77
7 2 . 4 . Conclusions
At present the data provided by the scientific literature and the medical knowledge do not allow to use unproven methods in clinical practice.
Medical knowledge and clinical studies provided by the literature do not justify the emphasis of some investigators and of the media in claiming the link between food allergy and unusual symptoms. Among atypical complaints migraine is the most suitable for a relationship with food intake. However a basic mechanism for the presumed food adverse reaction is unknown and a true food allergy is unlikely.
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48 Consensus conference. 'Defined diets and childhood hyperactivity'. JAMA, 248, p. 290, 1982.
49 Williams J.I., Cram D.M., Tausing F.T., Webster E. 'Relative effects of drugs and diet on hyperactive behaviours - An experimental study'. Pediatrics, 61, p. 811, 1978.
50 Egger J., Graham P.J., Carter CM., Gumley D., Soothill J.F. 'Controlled trial of oligoantigenic treatment in the hyperkinetic syndrome'. Lancet, pp. 540-545, 1985.
51 Egger J. Food allergy and the central nervous system. Food Allergy, ed. Eberhardt Schmidt. Nestle Nutrition Workshop Series, Vol. 17 Nestec Ltd. Vevey/Raven Press, Ltd. New York, 1988.
163
52 Boris M., Mandel F.S. 'Food and additives are common cause of the attention deficit hyperactive disorder in children'. Ann. Allergy, 72, p. 462, 1994.
53 Sampson H.A. 'Adverse reactions to food'. In Middleton E., Reed CE., Ellis E.F., Adkinson F.N., Younginger J.W., Busse W.W. editors. 'Allergy principles and practice', ed. IV., Mosby, St Louis, 1993, pp. 1661-1686.
54 Dohan F.C. 'Wartime changes in hospital admission for schizophrenia'. Acta. Psychiat. Scand., 42, p. 1, 1966.
55 Dohan F.C 'The possible pathogenic effect of cereal grains in schizophrenia. Coeliac disease as a model'. Acta Neurol., Napoli, 31, p. 195, 1976.
56 Dohan F.C. 'Schizophrenia and neuroactive peptides from (letter)'. Lancet /', p. 1031, 1979.
57 Dean G., Hannify L., Stevens F., Temperly I., O'Broid J.D., Scott J., Cahalane S.F. 'Schizophrenia and coeliac disease'. J. Ir. Med Ass., 68, p. 545, 1975.
58 Stevens F.M., Lloyd R.S., Gerachty S.M.J., Reynolds M.T.G., Sarsfield M.J., McNicholl B., Fottrell P.F., Wright R., MaCarthy CF. 'Schizophrenia and coeliac disease - the nature of the relationship'. Psychol. Med., 7, p. 259, 1977.
59 Pearson D.J., Rix K.J.B. 'Allergomimetic reactions to food and pseudo-food-allergy'. In PAR. Pseudo-allergic reactions. Involvement of drug and chemicals, Vol 4, pp. 59-105, Karger, Basel, 1985.
60 Bennett S.P., McEwen L., McEwen H., Fell P.J., Brostoff J. 'Response to diet in chronic young offenders. Fifth International Symposium on immunological and clinical problems on food allergy'. Milano, 17-19.5.1992, pp. 67.
61 Crayton J.W., Stone T., Stein G. 'Epilepsy precipitated by food sensitivity: Report of a case with double-blind placebo-controlled assessment'. Clin. Electroencephalogr., 4, pp. 192-198, 1981.
62 Denman A.M. 'The relevance of immunopathology to research into schizophrenia'. In Hem-mings, Biochemistry of schizophrenia and addiction, MTP Press, Lancaster, 1980, pp. 97-109.
63 Panush S.R. 'Food induced (allergic) arthritis: Clinical and serologic studies'. J. Rheumatol., 17, p. 291, 1990.
64 Wuthrich B., Kagi M.K., Hafner J. 'Disulfite-induced acute intermittent urticaria with vasculitis'. Dermatology, 187, pp. 290-292, 1993.
65 Jones V.A., Shorthouse M., Mac Loughlan P. 'Food intolerance: A major factor in irritable bowel syndrome'. Lancet ii, pp. 1115-1117, 1982.
164
66 Bentley S.J., Pearson D.J., Rix K.J.B. 'Food hypersensitivity in irritable bowel syndrome'. Lancet ii, pp. 295-297, 1983.
67 Farah D.A., Calder I., Benson L. 'Specific food intolerance: Its place as a cause of gastrointestinal symptoms'. Gut., 26, pp. 164-168, 1985.
68 Zwetckenbaum J.F., Burakof R. 'Food allergy and the irritable bowel syndrome'. Am. J. Gastroenterol., 83, pp. 901-904, 1988.
69 Gallo C , Vighi G., Ortolani C. 'Food allergy: A minor factor in irritable bowel syndrome'. J. Allergy Clin. Immunol., 85, p. 272, 1990.
70 Bernstein J.M. The role of IgE-mediated hypersensitivity in the development of otitis media with effusion. Otoryngol Clin North Am 25: pp. 197-211, 1992.
71 Friedman R.A., Doyle W.J., Casselbrant M.L., Bluestone C , Fireman P. 'Immunologic-mediat-ed eustachian tube obstruction: A double-blind crossover study'. J. Allergy Clin. Immunol., 71, pp. 442-447, 1983.
72 Nsouli T.M., Nsouli S.M., Linde R.E., O'Mara F., Scanion R.T., Bellanti J.A. 'Role of food allergy in serous otitis media'. Ann. Allergy, 73, pp. 215-219, 1994.
73 Seiner J.C, Condemi J. 'Unproven diagnostic and therapeutic techniques for allergy'. In Middleton E., Reed CE., Ellis E.F., Adkinson N.F., Yunginger J.W. 'Allergy principles and practice', ed. 3, The CV. Mosby Company, St Louis, 1988, pp. 1571-1597.
74 Robertson D.A., Ayres R.C., Smith CL., Wright R. 'Adverse consequences arising from misdiagnosis of food allergy'. Br. Med. J. 297, pp. 719-720, 1988.
75 Labib M., Gama R., Whright J., Marks V., Robins D. 'Dietary maladvice as a cause of hypothyroidism and short stature'. Br. Med. J., 298, pp. 232-233, 1989.
76 Terr A.I. 'Environmental illness. A clinical review of 50 cases'. Arch. Intern. Med., 146., pp. 145-149, 1986.
77 Americam Academy of Allergy and Immunology. Position statement: 'Candidiasis hypersensitivity syndrome'. J. Allergy Clin. Immunol., 78, pp. 271-273, 1986.
165
1 3 , P O S I T I V E A P P R O A C H E S
13.1. Hypoallergenic formulas
S Y N O P S I S
Hypoallergenic formulas (HF) may be used to treat allergic symptoms Induced by cow's milk in sensitized children or to prevent food allergies in infants at high risk for the development of allergic disease. The important role that HF may play in the treatment of cow's milk allergy has been defined. In vitro and in vivo studies show that extensive casein hydrolysates are the less allergenic formulas in cow's milk allergic children. An elemental formula (Neocat) seems to be a good alternative as well. However it should be underlined that these formulas are hypoallergenic and not non-allergenic, because some highly sensitive milk-allergic infants may react adversely to being fed such formulas.
The role of HF in the prevention of allergic diseases is still controversial. Although some studies indicate a protective role of some HF in preventing allergic diseases in high-risk babies, further studies are needed to elucidate this point. In vitro and animal studies should select new formulas suitable for milk substitutes in cow's milk allergic children. Preclinical screening of these hydrolysates should demonstrate the absence of intact proteins and more than 99% of the peptides with molecular weight < 1.5 KD, and non anaphylaxis in animals challenged with the formula under investigation.19
Hydrolysates selected by preclinical studies should then be screened by DBPCFC and open consumption, showing to be tolerated in cow's milk allergic Infants, in which the diagnosis of allergy to milk has been documented by positive DBPCFC.
Hypoallergenic formulas (HF) may be used to treat allergic symptoms induced by cow's milk in sensitized children or to prevent food allergies in infants at high risk for the development of allergic disease. The important role that HF may play in the treatment of CMA has been defined whereas their role in the prevention of allergic diseases is still controversial. The first point is to establish what does 'hypoallergenic' mean. It is a qualitative term, which does not allow the physician or the parents to understand the entity of the risk to an infant being fed that HF. HF should mean that fewer cow's milk allergic infants will experience adverse reactions to HF than to an intact cow's milk protein-based formula. Although a not quantitatively defined reduction in the allergenicity of infant formulas may be sufficient for some adverse reactions, such as colic, it could be insufficient to prevent anaphylactic reactions in highly sensitized infants.
The reduction of antigenicity and allergenicity of native proteins derived from milk, soya or other sources, is usually achieved by heating or by enzymatic hydrolysis. As a general rule, the more extensive the hydrolysis, the lower the molecular weight of a protein hydrolysate and the lower the likelihood of residual antigenicity and of potential allergenicity.1
Several in vitro and in vivo studies investigated the allergenicity of HF. The allergenicity of several alternative formulas was investigated using RAST and RAST inhibition on serum of 16 cow's milk allergic patients.2 All the patients had a RAST grade of > 3 for cow's milk. The following foods
166
were investigated: goat's milk, sheep's milk, human milk, cow's milk infant formula, goat's milk infant formula, casein hydrolysate (Pregestemil and Nutramigen), non-hydrolyzed casein formula, whey hydrolysate (Pepti-Junior, Almiron-Pepti, Altaré), soya milk (Wysoy), soya beef hydrolysate (Prejormin), elemental feed (Neocat). Modified cow's milk formula, goat's infant formula, sheep and goat's milk produced RAST results similar to cow's milk. RAST score > 3 was found in two patients for soya milk, in three patients for soya/beef hydrolysate, in two for Pregestemil, in one for Nutramigen, in seven with Pepti Junior, in five for Almiron-Pepti, in six for human milk, in 12 for non-hydrolyzed casein formula, in none for Neocat. RAST results for Altare were not reliable for technical reasons. The inhibition curves showed the least inhibition with Neocat and a very low inhibition with caseine hydrolysate, while soya formula showed a certain degree of inhibition, which were still more evident with soya/beef hydrolysate and with Pepti-Junior. Although the clinical implications of this in vitro study should be established by in vivo study, elemental food and casein hydrolysates seem to be the less allergenic milk substitutes.
Wahn et al.3 investigated the residual allergenicity of protein hydrolysate in 20 cow's milk allergic children by in vivo test (skin prick test and oral challenge) and in vitro method (RAST, RAST inhibition, crossed radioimmunoelectrophoresis, basophil histamine release). All tested hydrolysates induced significantly smaller mean wheal reactions compared with those induced by whole cow's milk. Casein hydrolysates and extensively hydrolyzed whey hydrolysates showed little IgE-binding activity. Oral challenges performed with eight children gave positive results in five with partial whey hydrolysate, in two with extensive whey hydrolysates and in one with soya-challenge hydrolysate. None reacted to oral challenge with casein hydrolysates. Thus, extensive casein hydrolysates showed the least residual allergenic activity. Among whey hydrolysates, more extensively hydrolysated formulas showed a lesser reactivity than the partial whey hydrolysates, confirming the importance of peptide lengths in determining the allergenicity of the hydrolysate: peptides of more than 1 500 daltons molecular weight have considerable allergenic activity.
Bindels and Boerme4 determined the molecular weight of HF: casein hydrolysates (Alimentum, Nutramigen and Pregestemil) compared with whey hydrolysates (NAN-HA Nutrilon Pepti, Pepti Junior, Profylac) contain a higher proportion of small peptides (96.5-95% versus 54-88%) and lower proportion of petides with molecular weight > 6 000 (0.5% versus 2-18%).
Animal studies confirm that the immunogenicity of HF depend on the degree of hydrolysis: rabbits hyperimmunized with formulas containing extensively hydrolyzed proteins (Alimentum, Nutramigen, and Pregestermil) generated very weak immune responses (> 100 fold antibody increase), whereas products containing intact or partially hydrolyzed proteins (Similac, Enfamil, Good Start, Beba HA, and Nidina HA) elicited high level (> 10 000 fold increase) immune response.5
Oldaeus et al6 performed SPT with blinded extracts of various hydrolyzed formulas in children with a history of cow's milk allergy, as the first step in the clinical evaluation of the residual allergenicity of HF: 0/15 children demonstrated positive SPT to Nutramigen, 1/15 to Aliare, 7/15 to Beba HA (whey hydrolysate), 7/15 to formula A and 5/15 to formula B.
The low allergenicity of extensively hydrolyzed casein formulas (Pregestemil and Nutramigen) was demostrated also by Gjesing et al7 by using crossed radioimmunoelectrophoresis (CRIE) to study the presence of serum IgE against cow's milk allergens in 21 milk allergic patients. It was
167
found that the two casein hydrolysates consisted of such small molecules that the rabbit antiserum could not precipitate the hydrolyzed proteins in the gels on the CRIE plates. Although this does not imply a complete lack of allergenicity, the probability of having IgE-binding epitopes is reduced.
The safety of a casein hydrolysate formula (Alimentum) has been investigated by Sampsom et al.8
DBPCFCs with 10 gm of powdered cow's milk and Alimentum were performed in 25 children with cow's milk allergy. Some 23/25 had positive DBPCFC with cow's milk, whereas all children tolerated the challenge to casein hydrolysate and were fed the hydrolysate formula without experiencing adverse reactions.
Allergic reactions to partial whey hydrolysate9 and to extensive whey hydrolysate10 formulas have been described. In some cases sensitization to these formulas seems to have occurred in the first days of life in the maternity hospital where the same formula was given to babies for prophylaxis of cow's milk allergy.
Some cases of allergic reactions to extensively hydrolyzed casein-based formulas have been reported too.11·12·13 Sampson et al11 evaluated the safety of an aminoacid-derived infant formula (Neocate) in children allergic to cow's milk. DBPCFC were performed in 28 children; one child reacted to an extensive casein hydrolysate (Nutramigen) but none reacted to Neocate, although three of 16 showed a positive SPT to this formula. Unfortunately Neocate has an unpleasant taste and most children refused to drink it.
Soya milks have been widely used as an alternative to cow's milk formulas. However soya allergy occurs as frequently as cow's milk allergy when introduced as initial formula.14. Moreover a consistent number of infants with cow's milk allergy and cow's milk-induced enterocolitis will develop soya allergy when fed on a soya formula.1516 Although some investigators argue that soya formulas should be the preferred choice for children with IgE-mediated allergy to cow's milk,17 the Nutrition Committee of the American Academy of Pediatrics advises that unhydrolyzed soya formulas are not used for cow's milk protein allergy.18
Several studies compared casein and whey hydrolysates and soya formulas to cow's milk feeding in the prevention of allergic diseases in infants at high risk for atopy. Feeding soya formulas did not show any advantage over cow's milk in such infants.19 In particular a randomized prospective clinical investigation carried out by Kjellman and Johansson, in infants born from bilateral allergic parents, failed to demonstrate any protective effect of soya feedings on the development of allergic diseases in the first three years of life.14 On the contrary extensive casein hydrolysate feeding led to a lower prevalence of allergic disease than cow's milk feeding in infants at risk for atopy at one year of age.19·20
Another study demonstrated a lower incidence of eczema by 18 months in infants fed on casein hydrolysates when compared to either cow's milk or soya milk feedings.21 Recently a double-blind study of high-atopic risk neonates showed that partial whey hydrolysate, when compared to cow's milk and soya formula feedings, reduced the prevalence of eczema at six months of age.22
However further studies are needed to confirm the protective role of HF in the prevention of allergic manifestations in infants at high risk for atopy.
168
In conclusion in vitro and in vivo studies show extensively that casein hydrolysates are the less allergenic formulas in cow's milk allergic children. An elemental formula (Neocat) seems to be a good alternative as well. However it should be underlined that these formulas are hypoallergenic and not non-allergenic, because some highly sensitive milk-allergic infants may adversely react to feeding such formulas.
In vitro and animal studies should select new formulas suitable for milk substitutes in cow's milk allergic children. Preclinical screening of these hydrolysates should demonstrate the absence of intact proteins and more than 99% of the peptides with molecular weight < 1.5 KDA, and non-anaphylaxis in animals challenged with the formula under investigation.19
Hydrolysates selected by preclinical studies should then be screened by DBPCFC and open consumption, showing to be tolerated in cow's milk allergic infants, in which the diagnosis of allergy to milk has been documented by positive DBPCFC.
The American Academy of Pediatrics states that a formula can be designated as hypoallergenic when at least 90% of milk-allergic children can consume it without adverse reactions. Although some studies indicate a protective role of some hypoallergenic formulas in preventing allergic disease in high-risk babies, further studies are needed to elucidate this point
Finally, studies are required to investigate the type of feeding given to new-borns during the first few hours after birth, before starting breast-feeding, because these feedings could have a sensitizing effect and in some ways influence the development of allergy to cow's milk.
REFERENCES
1 Kleinman R. E. 'Cow milk allergy in infancy and hypoallergenic formulas'. J. Pediatr., 121, pp. S116-S21, 1992.
2 Dean T.P., Adler B.R., Ruge F., Warner J.O. 'In vitro allergenicity of cow's milk substitutes'. Clin. Exp. Allergy, 23, pp. 205-210, 1993.
3 Wahn U., Wahl R., Rugo E. 'Comparison of the residual allergenic activity of six different hydrolyzed protein formulas'. J. Pediatr., 121, pp. S80-S84, 1992.
4 Letter to the editor. 'Hydrolyzed cow's milk formulae'. Pediatric Allergy and Immunol., 5, pp. 189-190, 1994.
5 Cordle CT., Duska McEwen G., Janas L.M., Malone W.T., Hirsch M.A. 'Evaluation of the immunogenicity of protein hydrolysate formulas using laboratory animal hyperimmunization'. Pediatric Allergy and Immunol., 5, pp. 14-19, 1994.
6 Oldaeus G., Bradley CK., Björksten B., Kjellman M. 'Allergenicity screening of "hypoallergenic" milk-based formulas'.
169
7 Gjesing Β., Osterballe O., Schwartz Β., Wahn U., Lowenstein H. 'Allergenspecific IgE antibo
dies against antigenic components in cow milk and milk substitutes'. Allergy, 41, pp. 5156,
1986.
8 Sampson H.A., BernhiselBroadbent J., Yang E., Scanion S.M. 'Safety of casein hydrolysate
formula in children with cow milk allergy'. Pediatr., 118, pp. 520525, 1991.
9 Businco L., Lucenti P., Árcese G., Ziruolo G., Cantani A. 'Immunogenicity of a socalled
hypoallergenic formula in atrisk babies: Two case report'. Clin. Exp. Allergy., 24, pp. 4245,
1994.
10 Businco L., Cantani Α., Longhi Α., Giampietro P.G. 'Anaphylactic reactions to a cow's milk
whey protein hydrolysate (AlfaRè, Nestle) in infants with cow's milk allergy'. Ann. Allergy, 62,
pp. 333335, 1989.
11 Sampson H.A., James J.M., BernhiselBroadbent J. 'Safety of an amino acid derived infant
formula in children allergic to cow milk'. Pediatrics, pp. 463464, 1992.
12 Bock S.A. 'Probable allergic reaction to caseine hydrolysate formula'. J. Allergy Clin. Immunol.,
84, p. 272, 1990.
13 Schwatz R.H., Amonette M.S. 'Cow milk protein hydrolysate infant formulas not always
hypoallergenic'. J. Pediatr., 119, p. 839, 1991.
14 Kjellman Μ.Ν., Johansson S.G.A. 'Soya versus cow's milk in infants with biparental history of
atopic disease: Development of atopic disease and immunoglobulins from birth to four years of
age'. Clin. Allergy, 9, pp. 347358, 1979.
15 Hide Q.W., Gant C. 'Hypoallergenic formulae have they a therapeutic role?'. Clin. Exp. Allergy,
24, pp. 35, 1994.
16 Burks A.W., Casteel H.B., Fiedorek S.C, Williams L.W., Pumphrey CL. 'Prospective oral food
challenge study of two soyabean protein isolates in patients with possible milk or soya protein
enterocolitis'. Pediatr. Allergy Immunol., 5, pp. 4045, 1994.
17 Businco L., Bruno G., Giampietro P.G., Cantani A. 'Allergenicity and nutritional adequacy of
soya protein formulas'. J. Pediatr., 121, pp. S21S28, 1992.
18 American Academy of Pediatrics Committeee on Nutrition. 'Soyprotein formulas: Recommen
dation for use in infant feeding'. Pediatrics, 72, pp. 359363, 1983.
19 Zeiger R.S. 'Development and prevention of allergic disease in childhood'. In Middleton E.,
Reed CE., Ellis E.F., Adkinson F.N., Youginger J.W., Busse W.W. editors. 'Allergy principles
and practice'. Ed IV Mosby, St Louis, pp. 11371171, 1993.
20 Zeiger R.S., Heller S., Mellon M.H. et al. 'Effect of combined maternal and infant foodallergen
avoidance on development of atopy in early infancy: A randomized study'. J. Allergy Clin.
Immunol., 84, p. 72, 1989.
170
21 Chandra R.K., Shakuntla P., Hamed A. 'Influence of material diet during lactation and use of formula feeds on development of atopic eczema in high risk infants'. Br. Med. J., 299, p. 228, 1989.
22 Chandra R.K., Singh G., Shridhara B. 'Effect of feeding whey hydrolysate soya and conventional cow milk formulas on incidence of atopic disease in high risk infants'. Ann. Allergy, 63, p. 102, 1989.
13.2. Non-allergenic food
A new idea of prevention in food allergy must take into account the production of hypo- or non-allergenic food. Current means used to induce hypoallergenicity are heating, enzymatic hydrolysis and selection of vegetable stocks which synthesises little or no major allergenic protein (e.g. wheat deficient in gliadins). This last goal could be obtained by biogenetic engineering with the production of transgenic plants.
The unique current therapy of food allergy is the avoidance of the culprit food, since the elimination of the specific food allergen from the diet will achieve resolution of the symptoms. In many instances, however, the elimination of one food implies the elimination of an entire class of foodstuffs thus making it very difficult to follow an acceptable diet. The complete knowledge of the molecular structure and chemical properties of the allergens involved in any single case could allow the setup of methodologies able to degrade them directly to a non-allergenic configuration. An even more substantial procedure would be based on the modification at a molecular level of the allergenic proteins by acting on their synthesis.
Thus a new approach in the prevention of food allergy can be advanced and must take into account the concept of hypoallergenicity or non-allergenicity obtainable by modifying food proteins by different techniques. The predictable commercial importance of this new approach, as the development of hypoallergenic milk already shows, will be another considerable incentive to rapidly improve this field of research.
The allergenicity of a foodstuff mainly depends on the number of major allergens and their stability during bleaching, pulverization, roasting and cooking processes.1 Current means which can be used to induce hypoallergenicity are heating and enzymatic hydrolysis.2
A crude, global approach is heating, which denatures the conformational epitopes of proteins (tertiary structure).3 Thermolabile allergens are often observed among fruits and vegetables, which can be tolerated after cooking by allergic subjects.4 However, sometimes heating increases the allergenicity of some foods.5"6 So we must know the characteristics of every allergenic protein in food in order to choose the appropriate technique. In milk, for example, we know that casein withstands heat7 and obviously we need an alternative method, that is enzymatic digestion by pepsin and trypsin.89 In fact heating reduces, but does not eliminate whey protein allergenicity.10"11
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A hypoallergenic rice has been obtained by hydrolysis of the globulinic fraction of grains by a
protease associated with a surfactant.12
The destruction of the major allergen (globulin, w.16kda),
is shown by the sodium dodecyl sulphatepolyacrylamide gel electrophoresis study and the
negative radioallergosorbent test with this new extract. Most children sensitized to rice have no
recurring problems when they are fed with this rice.
Agronomically, a possibility is represented by the selection of vegetable stocks which synthesises
little or no major allergenic protein. An example is wheat deficient in gliadins.13
·14
Glutenfree diet
is mandatory in celiac disease,1518
but the compliance of the patients to the diet is often difficult
and sometimes gluten is ingested inadvertently.1924
Gliadins are a heterogeneous group of
proteins with a wellknown genetic map. Loci encoding gliadins are located at the end of the short
arm of the chromosomes of groups 1 and 6 of wheat, and are designated as GNA1, GNB1, GND1
(Gli1 loci), GNA2. GMB2, GND2 (Gli2 loci)25
. Gli1 loci encode for γ and ω gliadin; Gli2 loci
encode for α and β gliadin. Genotypes lacking a whole cluster of gliadin components, controlled
by genes at a given complex locus, exists in durum and bread wheat.26
Crosses between these
lines have also resulted in production of lines lacking gliadin components controlled by two or
more complex loci. Using an in vitro model of celiac disease Corazza28
(1995) tested the toxicity
of lines of bread wheats lacking all the GIÌA2 encoded gliadin components and a line lacking at
once GND1 and GMA2 controlled gliadin component. Using a peptictryptic digest of these
wheats in an in vitro organ culture system, a significantly lower toxicity was found in respect to
bread wheat containing all gliadin fractions. Even if it cannot be excluded that daily exposure to
flour obtained from the gliadin deficient wheats tested in the mentioned study, may cause in vivo
mucosal damage in celiac patients it suggests a new perspective in the treatment of celiac
disease and seems particularly promising since further generations of wheat lines, more and
more deficient in toxic gliadins, have been already breeding.
Technologically the manufacture of protein isolates could be deliberately oriented towards a
decrease in major allergens. Certain soybean proteins isolated have a lower Kunitz inhibitor
content than others, for example, and are less sensitizing for animals.29
Other techniques for modifying allergenicity have been explored, such as disulphide bond
reduction for the tryptic inhibitor of soybean and bond breaking with sialic acid for milk
proteins;30
·31
but the most promising aid in the production of hypo or nonallergenic food, in the
last few years, has derived from the recent advances in biotechnology. Immunoblotting technique
associated to RAST inhibition, monoclonal antibodies and ricombinant DNA techniques have
allowed the identification of the amino acid sequence of many allergens and sometimes of their
different epitopes, as well as the determination of the nucleotide sequence of the genes coding
for these epitopes and allergens.3·3238
This background, joined with the biogenetic engineering
that can transfer a specific gene from one source to a target plant, has provided the possibility of
producing nonallergenic food. The first transgenic plant was obtained in 1984.39
Since then
many economically important crops have been genetically engineered in order to obtain plants
with high efficiency.40
The most transgenic plants produced so far have been obtained using two
general methods which are Acrobacfer/i/mmediated41
and direct DNA uptake, with the latter
including such specific method as particle bombardment, electroporation and polyethylene glycol
permeabilization.42
·45
The main properties obtained in transgenic plants are: insect protection,
delayed ripening, virus resistance, herbicide tolerance, disease resistance, modified starch,
172
modified oils and male sterility.46 Most of the qualities introduced in transgenic crops result from the expression of one or more new proteins, which usually are expressed at low levels and represent a minor percentage of the total plant proteins.
Current technology is limited to the introduction of genes to ectopic (away from the normal locus of a gene) position in the genoma.47 Ideally, gene expression would be modified by gene 'replacement' at the normal locus of a gene, but such technology is still in its infancy and is not available in any practical sense. Until gene replacement does become practical, the scientist is faced with the necessity of manipulating gene expression via the expression of extra copies of the gene engineered to interfere with, or amplify the expression of the homologous, endogenous gene. Antisense RNA is one popular approach to interference with endogenous gene expression.48 Potentially this technology can also be used to suppress target gene expression in a cell-type-specific manner, by the appropriate use of a cell-type-specific promoter.49 Another approach to modifying gene expression is over-expression by the introduction of additional copies of an endogenous gene.40 This can be successfully used to increase the endogenous level of expression of a gene.40 However, as it turns out, this is not the only possible result.40 The attempted over-expression of endogenous genes by the introduction of additional copies of a gene can also result in the co-suppression of the expression of both the endogenous gene and the transgene, resulting in loss of expression just as in the case of antisense transgenes.47 This phenomenon appears to be quite common, and even extends to interaction between two unlinked transgenes. All these characteristics can be potentially useful in inhibiting the expression of a gene coding for an allergenic protein.
Genetic engineering provides a unique opportunity to eliminate or, at least to reduce, the amount of a specific allergen in a food. By introducing genes in the antisense orientation (the opposite orientation required to produce a protein), the levels of protein produced by the 'sense' orientation can be dramatically reduced. This technique has been used to reduce significantly the major allergen in rice.50·51 Matsuda et äl. cloned the gene encoding the 16 kDa allergenic protein from rice and introduced the gene encoding this protein in the antisense orientation into rice. The levels of the 16 kDa protein were significantly reduced in rice seed from 312 mg per seed to 60 mg per seed. Further studies are underway to achieve greater reductions in this allergenic protein. The antisense technique could be applied to other food crops such as peanuts and soybeans to selectively reduce the amounts of the specific allergens, although the presence of multiple allergens and multigene families makes this solution more difficult.
Dealing with the problem of non-allergenic food a particular consideration must be reserved to food allergens hidden in 'theoretically non-allergenic foodstuff'. The past decade has witnessed a number of advances in food technology and the novel use of many food products (e.g., partially hydrolyzed proteins for flavouring, binders, protein enrichment, etc.) to improve the taste, quality and desirability of many foods while keeping the price down. These advances have clearly had a favourable impact for the average consumer and the food industry, but have made it increasingly difficult for the patient with true food allergies to avoid accidental ingestion of food allergens. The wellbeing of these subjects depends on complete and accurate disclosure of all ingredients on the labels of all foods. All ingredients present in foodstuff must be on the product's label since there is no threshold below which all patients may tolerate a food. Food-allergic individuals can react to a mere trace of the offending food allergens.52·53 Indeed allergic reactions, sometimes life-threatening or fatal, have been reported even after only utilizing the utensils (e.g. spoon, fork, etc.),
173
cleaned but previously used with the culprit food, as well as after fortuitous inhalation of the offending food or kissing the lips of a person who has recently eaten the offending food.38 On the other hand total avoidance can be extremely difficult. A few foods are responsible for the majority (90%) of allergic reactions, including egg, milk, peanuts, soybean, and wheat in children, and peanuts, tree nuts, fish and shellfish in adults.54 Unfortunately most of them are used to ameliorate the qualities of other foods by the food industry, restaurants and other food-service settings. Yunginger et al.55 (1983) reported several adverse reactions due to a contamination with allergenic offending food following an inadequate cleaning of the equipment used. Moreover several deaths of food allergic patients have been reported following inadvertent ingestion of food allergens and most of these incidents occurred in restaurants or food services.56 Sampson (1991)57 reported similar life-threatening or fatal reactions among young children accidentally exposed to the offending food. Gern (1991)58 reported several cases of allergic reactions to foods due to unlabelled use of milk-based ingredients in foods.
Thus food processors should attempt to avoid the processing errors and oversights that cause the inadvertent contamination of one food with another and result in such allergic reactions, sometimes with devastating consequences. At the same time they must improve the labelling of their food products by an exhaustive list of all the ingredients, also those in very small amounts, and, if feasible they have to avoid the use of the prevalent allergenic foods. In other words they have to produce 'non-allergenic' foods.
Biotechnology, and in particular genetic engineering, represent a new challenge in the field of the allergenicity of foods. Indeed it has been demonstrated that food derived from transgenic plants can be more allergenic than the natural one. It depends on the allergenicity of the protein encoded by the new gene transferred into a food crop from a source that can be allergenic. An actual example was the demonstration that a gene encoding a Brazil nut 2S albumin storage protein which has been engineered into soybean59 and canola60 encodes a major allergen.61 The Brazil nut 2S albumin storage protein was selected as an ideal candidate gene to enhance the nutritional seed quality because it contains 18.8% of the essential amino acid methionine.62
However, since anaphylaxis due to Brazil nut are known,63·64 the transferred gene should be surveyed as an allergic source. The Brazil nut 2S protein expression in soybean represented a significant fraction of total soybean proteins. Eight of nine patients allergic to Brazil nut reacted with transgenic soybean containing Brazil nut gene when their sera were tested by RAST and immunoblot assays.65·66 This transgenic soybean would have to be labelled as containing Brazil nut, if marketed, to alert Brazil nut allergic subjects. Since a lot of foods from transgenic plant varieties are on the market (e.g. tomato, cucumber, carrot, soybean, apple, kiwi, orange, etc.) and many more are expected, it is mandatory to evaluate the allergenicity of the food derived from these crops. When a gene is obtained from an allergenic food source, it should always be investigated if it encodes for an allergen, and then labelled with the name of the allergen when marketed.
A practicable alternative is to introduce into plants, by genetic engineering, proteins obtained from non-allergenic sources, that do not encode allergens, produced at low doses and extremely labile in model digestive conditions. A combination of these parameters provides assurance that proteins encoded by genes transferred into food crops will not increase the allergenicity of the food supply.
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In all the cases discussed above three steps are needed before labelling a food as hypo- or non-allergenic. The first step in the decision tree employs in vitro tests that are RASTs,67 ELISAs68 or immunoblotting assays69 and uses IgE from pooled serum of patients truly allergic to the food that might be present in the examined foodstuff. A clear positive result from the in vitro test would require the specification on the label that that allergen is present in that food.
The second step is based on in vivo skin-prick testing67 that has to be performed only if the first step is negative for allergy. A positive result of this SPT would raise the same concern as the in vitro tests above.
Only when the second step also is negative for food allergy can the last step be done. It provides for double-blind placebo-controlled food challenges (DBPCFC) performed in sensitive and non-sensitive patients under controlled clinical conditions.
This type of assessment requires some ethical considerations regarding the likelihood of inducing anaphylaxis, the availability of adequate safety precautions, and approval of local institutional review boards. The term hypo-/non-allergenic can be accepted only for those foods that have completed this trial.
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43, pp. 300-306.
2 Jost R., Monti J.C, Pahud J.J. 'Whey protein allergenicity and its reduction by technological means'. Food Technol., 1987, 41, pp. 118-121.
3 Crespo J.F., Pascual C , Martin Esteban M. 'New perspective in food allergens'. In: Anonymous (ed). Proceedings of the XIV European Congress of Allergy and Clinical Immunology ECACI 1995. Madrid (Spain). May 24-25, 1995, pp. 889-895.
4 Ortolani C , Ispano M., Pastorello E.A., Ansaloni R., Magri C. 'Comparison of results of SPT (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome'. J. Allergy Clin. Immnol. 1989, 83, pp. 683-690.
5 Herían A.M., Taylor S.L., Bush R.K. 'Identification of soyabean allergens by immunoblotting with sera from soya-allergic adults'. Int. Arch. Allergy Appi. Immunol., 1990, 92, pp. 193-198.
6 Asselin J., Amiot J., Gauthier S.F., Mourad W., Hebert J. 'Immunogenicity and allergenicity of whey protein hydrolysates'. J. Food Sci., 1988, 53, pp. 1208-1211.
7 Jost R., Fritsche R., Pahud J.J. 'Reduction of milk protein allergenicity through processing'. In Somogyi J.C, Müller H.R., Ockhuizen Th. (eds). 'Food allergy and food intolerance'. Karger, Bazel 1991, pp. 127-137.
8 Asselin J., Hebert J., Amiot J. 'Effects of in vitro proteolysis on the allergenicity of major whey proteins'. J. Food Sci., 1989, 54, pp. 1037-1039.
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9 Guesry P.R., Secretin M.C, Jost R., Pahud J.J., Monti J.C. 'Hypoallergenic formulas'. In Hamburger R.N. (ed). 'Food intolerance in infancy'. New York, Raven Press, 1989, vol. I, pp. 253-265.
10 Kilsjaw P.J., Heppell L.M.J., Ford J.E. 'Effects of heat treatment of cow's milk and whey on the nutritional quality and antigenic properties'. Arch. Dis. Child., 1982, 57, pp. 842-847.
11 Heppell L.M.J., Cant A.J., Kilshaw P.J. 'Reduction in the antigenicity of whey proteins by heat treatment: A possible strategy for producing a hypoallergenic infant milk formula'. Br. J. Nutr., 1984,51, pp. 29-36.
12 Watanabe M., Miyakawa J., Ikezawa Z., Suzuki Y., Hiaro T., Yoshizawa T., Arai S. 'Production of hypoallergenic rice by enzymatic decomposition of constituent proteins'. J. Food Sci., 1990, 55, pp. 781-783.
13 Kasarda D., Qualset CO., Mecham D.K., Goodemberger D.M., Straber W. 'A test of toxicity of bread made from wheat lacking alpha-gliadins coded for by 6A chromosome'. In: McNicholl B., McCarty CF., Fottrell P.F., (eds). Lancaster, MPT Press, 1978, pp. 55-61.
14 Ciclitira P.J., Hunter J.O., Lennox E.S. 'Clinical testing of bread made from nullisomic 6A wheat in coeliac patients'. Lancet, 1980 ii, pp. 234-236.
15 Trier J.S. 'Celiac sprue. N. Engl. J. Med., 1991, 325, pp. 1709-1719.
16 Holmes G.K.T., Prior P., Lane M.R., Pope D., Allan R.N. 'Malignancy in coeliac disease. Effect of a gluten-free diet'. Gut. 1989, 30, pp. 333-338.
17 Trier J.S., Falchuk Z.M., Carey M.C, Schreiber D.S. 'Celiac sprue and refractory sprue'. Gastroenterology, 1978, 75, pp. 307-309.
18 Corazza G.R., Gassbarrini G. 'Defective splenic function and its relation to bowel disease'. Clin. Gastroenterol, 1983, 12, pp. 651-669.
19 Mortimer E., Syewart J.S., Norman A.P., Booth C.C. 'Follow-up study of coeliac disease'. BMJ, 1968, 3, pp. 7-9.
20 Gryboski J. 'False security of a gluten-free diet'. Am. J. Dis. Child., 1981, 60, pp. 672-674.
21 Colaço J., Egan-Mitchell B., Stevens F.M., Fottrell P.F., McCarthy CF., McNicholl B. 'Compliance with gluten-free diet in coeliac disease'. Arch. Dis. Child., 1987, 62, pp. 706-708.
22 Mayer M., Greco L., Troncone R., Auricchio S., Marsh M.N. 'Compliance of adolescents with coeliac disease with a gluten-free diet'. Gut., 1991, 127, pp. 963-965.
23 Mulder C.J.J., Van Bergeijk J.D., Jansen T.L.T., Uil J.J. 'Coeliac disease: Diagnostic and therapeutic pitfalls'. Scand. J. Gastroenterol., 1993, 28 Suppl. 200, pp. 42-47.
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24 Congdom P., Mason M.K., Smith S., Crollik Α., Steel Α., Littlewood J. 'Smallbowel mucosa in
asymptomatic children with celiac disease'. Am. J. Dis. Child., 1981, 135, pp. 118121.
25 Payne P.I. 'Genetics of wheat storage proteins and the effect of allele variation on bread
making quality'. Annual review of plant physiology 1987, 38, pp. 141153.
26 Lafiandra D., Colaprico G., Kasarda D.D., Porceddu E. 'Null alleles for gliadin blocks in bread
and durum wheat cultivars'. Theoretical and applied genetics 1987, 74, pp. 610616.
27 Lafiandra D., Splendido R., Tomassini C , Porceddu E. 'Lack of expression of certain storage
proteins in bread wheats; Distribution and genetic analysis of null forms'. In Lasztity R., Bekes
F. (eds). Proceedings 3rd international workshop on gluten proteins. Singapore: World Scienti
fic Publishing, 1987, pp. 7190.
28 Frisoni M., Corazza G.R., Lafiandra D., De Ambrogio E., Filipponi C , Bonvicini F., Borasio E.,
Porceddu E., Gasbarrini G. 'Wheat deficient in gliadins: Promising tool for treatment of coeliac
disease'. Gut., 1995, 36, pp. 375378.
29 Mazo V.K., Samenkova Ν.F., Gmoshinskii I.V., Pepeliav I.V., Zorin S.N., Krzhechkovskaia V.V.,
Malikova N.A., Marokko I.Ν., Ushakov V.V. 'Complex experimental assessment of potential
allergenicity of various isolates of soya proteins'. Vopr. Pitan. (USSR), 1989, 6, pp. 2227.
30 Brandon D.L., Haque S., Friedman M. 'Antigenicity of native and modified Kunitz soyabean
trypsin inhibitors'. Adv. Exp. Med. Biol. 1986, 199, pp. 449469.
31 Heine W., Wutske K.D., Radke M. 'Zur Verminderung der Immunogenität von Milchproteinen
durch Desialinisierung'. Infusionstherapie, 1989, 16, pp. 264266.
32 King T.P., Hoffman D., Lowenstein Η., Marsh D.G., Plattsmills T.A.E., Thomas W. 'Allergen
nomenclature'. J. Allergy Clin. Immunol., 1995, 96, pp. 514.
33 O'Neil C , Helbling A.A., Lehrer S.B. 'Allergie reactions to fish'. Clin. Rev. Allergy, 1993,11, pp.
183200.
34 Burks A.W., Williams L.W., Helm R.M., Connaughton C , Cockrell G., O'Brien T. 'Identification
of a major peanut allergen, Ara hl, in patients with atopic dermatitis and positive peanuts
challenges'. J. Allergy Clin. Immunol., 1991, 88, pp. 172179.
35 Burks A.W., Williams L.W., Connaughton C , Cockrell G., O'Brien T., Helm R.M. 'Identification
and characterization of a second major peanut allergen; Ara hil, with use of sera of patients
with atopic dermatitis and positive peanut challenge'. J. Allergy Clin. Immunol., 1992, 90, pp.
962969.
36 Burks A.W., Cockrell G., Connaughton C , Karpas Α., Helm R.M. 'Epitope specificity of the
major peanut allergen, Ara hil'. J. Allergy Clin. Immunol., 1995, 95, pp. 607611.
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37 Shimojo N., Katsuki T., Coligan J.E., Nishimura Y., Sasazuki T., Tsunoo H., Sakamaki T., Kohno Y., Miimi H. 'Identification of the disease-related Τ cell epitope of ovalbumin and epitope-targeted Τ cell inactivation in egg allergy'. Int. Arch. Allergy Immunol., 1994, 105, pp. 155-161.
38 Taylor S.L. 'Chemistry and detection of food allergens'. Food Technol., 1992, May, pp. 146-152.
39 Horsch R.B., Fraley R.T., Rogers S.G., Sanders P.R., Lloyd Α., Hoffman N. 'Inheritance of functional foreign genes in plants'. Science, 1984, 223, pp. 496-498.
40 Fisk HJ. , Dandekar A.M. 'Direct gene transfer technology and progress: The introduction and expression of transgenes in plants'. Sei. Hort., 1993, 55, pp. 5-36.
41 Dandekar A.M., McGranaham G.H., James D.J. 'Transgenic woody plants'. In Shaindow and R. Wu (eds), Transgenic plants, 2. Academic Press, San Diego (Calif.), pp. 129-151, 1994.
42 Klein T.M., Wolf E.D., Wu R., Sanford J.C. 'High-velocity microprojectiles for delivering nucleic acids into living cells'. Nature, 1987, 327, pp. 70-73.
43 Fromm M., Callis J., Taylor L.P. Walbot V. 'Electroporation of DNA and RNA into plant protoplasts'. Methods Enzymol, 1987, 153, pp. 351-366.
44 Lindsey K., Jones M.G.K. 'Electroporation of cells'. Physiol. Plant., 1990, 79, pp. 168-172.
45 Shillito R.D., Saul M.W., Paszkowski J., Muller M., Potrykus I. 'High frequency direct gene transfer to plants'. Bio/technology, 1985, 4, pp. 1099-1103.
46 Anonymous. Health aspects of marker genes in genetically modified plants. World Health Organization Food Safety Unit, Geneva 1993.
47 Jorgensen R. 'The modification of horticultural plant phenotypes by direct gene transfer'. Sci. Hort., 1993, 55, pp. 1-4.
48 Van de Krol A.R., Mol J.N.M., Stuitje A.R. 'Antisense genes in plants: An overview'. Gene, 1988, 72, pp. 45-50.
49 Cannon M., Platz J., O'Leary M.O., Soojdeo C, Cannon F. 'Organ-specific modulation of gene expression in transgenic plants using antisense RNA'. Plant. Mol. Biol., 1990, 15, pp. 39-47.
50 Matsuda T., Alvarez Am Tada Y., Adachi T., Nakamura R. 'Gene engineering for hypoallergenic rice: Repression of allergenic protein synthesis in seeds of transgenic rice plants by antisense RNA'. In Anonymous (ed): Proceedings of the international workshop on life science in production and food-consumption of agricultural products, October 24-28, Japan, 1993.
51 Matsuda T., Nakase M., Adachi T., Nakamura R. 'Allergenic proteins in rice: Strategies for reduction and evaluation'. In Anonymous (ed): Food allergies and intolerances'. Bonn, DFG Senate Commission on the evaluation of food safety, 1995.
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52 Taylor S.L., Bush R.K., Busse W.W. 'Avoidance diets — How selective should we be?' New. Eng. Reg. Allergy Proc, 1986, 7, pp. 527-532.
53 Taylor S.L. 'Food allergies and related adverse reactions to foods: A food science perspective'. In Perkin J. (ed), Food allergies and adverse reactions. Gaithersburg: Aspen Publishers Inc., 1990, pp. 189-206.
54 Eigenmann P.A., Sampson H.A. 'An update on food hypersensitivity'. Fund. Clin. Immunol., 1994, 2, pp. 121-133.
55 Yunginger J.W., Gauerke M.B., Jones R.T., Dahlberg M.J.E., Ackerman S.J. 'Use of radioimmunoassay to determine the nature, quantity and source of alergenic contamination of sunflower butter'. J. Food Protect., 1983, 46, pp. 625-628.
56 Yunginger J.W., Sweeney K.G., Stumer W.Q., Giannandrea L.A., Teigland J.D., Bray M., Benson P.A., York J.A., Biedrzycki L., Squillace D.L., Helm R.M. 'Fatal food-induced anaphylaxis'. JAMA, 1988, 260, pp. 1450-1452.
"Sampson H.A., Mendelson L., Rosen J.P. 'Fatal and near-fatal food anaphylaxis reactions in children and adolescents'. N. Engl. J. Med., 1992, 327, pp. 380-384.
58 Gern J.E., Yang E., Evrard H.M., Sampson H.A. 'Allergic reactions to milk-contaminated "non-diary" products'. New. Eng. J. Med., 1991, 324, pp. 976-979.
59 Townsend J.J., Thomas L.A., Kullisek E.S., Daywalt M.J., Winter K.R.K., Altenbach S.B. 'Improving the quality of seed proteins in soyabean'. In Anonymous (ed): Proceedings of the fourth biennial conference of molecular biology of soyabean, Iowa State University, Ames 1992, p. 4.
60 Altenbach S.B., Kuo C-C, Staraci L.C, Pearson K.W., Wainwright C , Georgescu Α., Townsend J. 'Accumulation of Brazil nut albumin in seed of transgenic canola results in enhanced levels of seed protein methionine'. Plant. Mol. Biol., 1992, 18, pp. 235-245.
61 Shewry P.R., Napier J.Α., Tatham A.S. 'Seed storage proteins: Structures and biosynthesis'. Plant. Cell. 1995, 7, pp. 945-956.
62 Sun S.S.M., Altenbach S.Β., Leung F.W. 'Properties, biosynthesis and processing of sulfur-rich protein in Brazil nut (Bertholletia excelsa HBK)'. Eur. J. Biochem., 1987, 158, pp. 597-604.
63 Gillespie D.N., Nakajima S., Gleich G.J. 'Detection of allergy to nuts by the radioallergosorbent tests'. J. Allergy Clin. Immunol., 1976, 57, pp. 302-309.
64 Arshad S.H., Malmberg E., Kraft Κ., Hide D.W. 'Clinical and immunological characteristics of Brazil nut allergy'. Clin. Exp. Allergy, 1991, 21, pp. 373-376.
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65 Nordlee J.A., Taylor S.L., Townsend J.A., Thomas L.A. 'High methionine Brazil nut protein binds human IgE'. J. Allergy Clin. Immunol., 1994, 93, pp. 209.
66 Nordlee J.A., Taylor S.L., Townsend J.A., Thomas L.A., Townsend R. 'Investigations of the allergenicity of Brazil nut 2 storage protein in transgenic soyabean'. In Anonymous (ed). Proceedings from the OECD workshop on food safety evaluation. Paris, OECD Environmental Health and Safety Division, 1995, pp. 121-125.
67 Sampson H.A., Albergo R. 'Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis'. J. Allergy Clin. Immunol., 1984,74, pp. 26-33.
68 Burks A.W., Sampson H.A., Buckley R.H. 'Anaphylactic reactions following gammaglobulin administration in patients with hypogammaglobulinemia: Detection of IgE antibodies to IgA'. N. Engl. J. Med., 1986, 314, pp. 560-564.
69 Burks A.W., Brooks J.R., Sampson H.A. 'Allergenicity of major component proteins of soybean determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting in children with atopic dermatitis and positive soya challenges'. J. Allergy Clin. Immunol., 1988, 81, pp. 1135-1142.
7 3 . 3 . Specific immunotherapy in food allergy
SYNOPSIS
The optimal treatment of food allergy is to avoid the culprit food, but this may be very difficult because masked foods are present in a number of preparations, exposing the allergic subject to unaware consumption of the culprit food. A series of fatal reactions derived from eating apparently unsuspected foods has been reported. In recent years, specific immunotherapy was considered as a treatment of food allergy and a first double-blind placebo-controlled study performed on patients allergic to peanut with a defatted peanut extract demonstrated, by a marked reduction of symptoms scores to DBPCFC and decrease of skin sensitivity to peanut extract in actively treated patients, that this treatment may be effective.
The optimal treatment of food allergy is represented by avoidance of the responsible food identified by the elimination/challenge procedure.1 However, for some foods it is extremely difficult to avoid small amounts hidden in food preparations apparently unrelated to the culprit food. This is the case of milk, contained for example in hot dogs, canned tuna and margarine,2
and of peanut, which is used in USA in a number of food supplies even changing its taste to mimic other foods. The presence of peanut allergens in a large series of food products has been demonstrated by analysing the food by immunoassays.3 Eating even negligible amounts of the culprit allergen in an unsuspected food may expose the allergic patients to life-threatening anaphylactic reactions. A study analysed a series of deaths in USA caused by food anaphylaxis and found that in 54% of cases there was an unaware ingestion of peanut.4 Currently, the only therapeutical measure offered to this kind of patient is represented by immediate administration of epinephrine, especially in pre-loaded automatic devices. Theoretically, in such cases specific
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immunotherapy should have the same value as in patients with anaphylaxis from hymenoptera stings. However, despite encouraging results obtained in some uncontrolled studies in patients allergic to fish,5"7 specific immunotherapy has not been considered as a treatment of food allergy until recently.
In 1992, the first placebo-controlled study of immunotherapy in food allergy8 was published. The food chosen for the study was peanut, because it is, as reported above, a frequent cause of anaphylaxis which cannot be surely avoided and, moreover, allergy to peanut shows no tendency, unlike allergy to most other foods, to be outgrown with time.9 For the study 11 patients were selected aged from 14 to 43 years with history of anaphylactic reactions (involving cardiovascular and respiratory systems) to peanut, and positive skin tests and DBPCFC for peanut. The patients were randomized to receive immunotherapy with either a defatted peanut extract or a placebo by a rush protocol in five days. Four increasing doses with a 60-minute interval were administered in days from one to four starting from a concentration of 1:10 000 wt/vol in the first day and reaching a concentration of 1:100 wt/vol in the fourth day. In the fifth day, two doses respectively of 0.4 and 0.5 ml of the 1:100 wt/vol concentration were administered. Then the patients received weekly maintenance doses for four weeks and underwent another DBPCFC. Respiratory peak flow was monitored during immunotherapy, and treatment was stopped for the day if its value decreased under > 20% of baseline or if systemic reactions occurred.
Unfortunately, the study was not completed because of a fatal incident caused by administration of the peanut extract to a placebo-treated patient. The analysis of results at the time of stopping the study in the four patients who had repeated the DBPCFC showed that in the three actively treated patients there was a marked reduction of symptom score to the challenge, while in the only available placebo-treated patient no difference in symptom score in respect to the basal challenge was found.
Moreover, the three actively treated patients had a marked decrease in skin-test sensitivity to the peanut extract, as opposed to the three placebo-treated patients in whom a slight increase of skin sensitivity occurred.
Apart from the fatal incident, the frequency of systemic reactions to immunotherapy was 13.3% (16 out of 120 injections), urticaria being the most common (10 reactions), followed by conjunctivitis and asthma. No cardiovascular reaction occurred.
These preliminary data, as stated by Sampson in an accompanying editorial, make it conceivable to think of specific immunotherapy as a form of treatment for food-allergic patients at risk from life-threatening reactions to each ingestion of even small amounts of the culprit food. However, other controlled studies have to be performed, analysing various foods and different protocols of administration, before immunotherapy can be proposed as a practical treatment of food allergy.
REFERENCES
1 Kettelhut B.V., Metcalfe D.D. 'Food allergy in adults'. In Lichtenstein L.M., Fauci A.S. (eds): Current therapy in allergy, immunology and rheumatology. B.C. Decker, Philadelphia, 1988, pp. 56-9.
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2 Gern J.E., Yang E.Y., Evard H.M., Sampson H.A. 'Allergie reactions to milk-contaminated "dairy-free" products'. N. Eng. J. Med., 1991, 324, pp. 976-79.
3 Keating M.V., Jones R.T., Worley N.J. 'Immunoassay of peanut allergens in food-processing materials and finished foods'. J. Allergy Clin. Immunol., 1990, 86, pp. 41-44.
4 Yunginger J.W., Sweeney K.G., Stumer W. 'Fatal food-induced anaphylaxis'. JAMA, 1988, 260, pp. 1450-52.
5 Freeman J. '"Rush" inoculation'. Lancet, 1930, 1, p. 744.
6 Aas K. 'Studies of hypersensitivity to fish. A clinical study'. Int. Arch. Allergy, 1966, 29, pp. 346-66.
7 Dannaeus Α., Inganaes M. 'A follow-up study of children with food allergy. Clinical course in relation to serum IgE- and IgG-antibody to milk, egg and fish'. Clin. Allergy, 1981, 11, 533-9.
8 Oppenheimer J.J., Nelson H.S., Bock S.A., Christensen F., Leung D.Y.M. 'Treatment of peanut allergy with rush immunotherapy'. J. Allergy Clin. Immunol., 1992, 90, pp. 256-62.
9 Bock S.A., Atkins F.M. 'The natural history of peanut allergy'. J. Allergy Clin. Immunol., 1989, 83, pp. 900-4.
10 Sampson H.A. 'Food allergy and the role of immunotherapy'. J. Allergy Clin. Immunol., 1992, 90, pp. 151-2.
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1 4 . I M P O R T A N C E O F F O O D H Y P E R S E N S I T I V I T Y IN P U B L I C H E A L T H , E C O N O M I C E F F E C T S , G R O U P S A T R I S K
Public health's role will be to make more effort than in the past to spread correct information on food allergy to the medical profession and to the public so as to provide an authoritative bulwark to the spread of unorthodox practices which are the main source of controversies on this topic. Measures will have to be taken to prevent or deal with serious allergic reactions, instructing those in charge of restaurants, hotels and school canteens on what should be done in cases of severe anaphylactic reactions. Constructive relations must be established with the food industry to make sure the users receive accessible information on food products, and to jointly promote studies to set in motion the farthest-reaching positive approaches.
14.1. The public health role
The importance of food allergy in public health has been affected by the overestimation of this disease. In fact, as mentioned in other chapters of this study, the true prevalence of food allergy is undoubtedly lower than figures quoted in the popular press, for instance in a prospective study on 480 children1 (Bock 1987) it was demonstrated that the prevalence of food allergy was actually 8% as compared to the parents' conviction which was 28%. The 'gold standard' for the diagnosis of food allergy is the DBPCFC2 The only exception are the severe reactions, such as anaphylaxis or laryngeal edema, in which DBPCFC tests are not to be done. Several studies have demonstrated a tremendous discrepancy between subjective perception of food intolerance and the results of DBPCFC1·3·4 Indeed the only two studies that estimate the prevalence of food allergy/intolerance in adults, using DBPCFC, confirm that actual food allergy/intolerance affect about 0.8-1.4-% of the population, in spite of the high percentage (12.4-20.4%) of adults complaining of food allergy/intolerance. More attention needs to be paid to epidemiologic studies in order to determine the actual prevalence of food allergy and disclose this data to the public and scientific community. The general practitioner must be informed by current medical education on the development of scientific protocols and position papers.
EAACI has produced an understandable and pragmatic document that clearly defines the characteristics of food allergy and intolerance.2 The new classification, based on pathogenesis, will aid in avoiding improper definitions of food-adverse reactions. For example the term 'food intolerance' is often used improperly when the pathogenic mechanisms are vague or unknown. The DBPCFC can unravel all doubts in regard to the mechanisms involved in food-adverse reactions; if the DBPCFC is employed, the cases of assured food reactions that do not fall under the heading of IgE-mediated reactions become extremely rare. It is likely that the latter rare cases, for which the DBPCFC is positive are falsely negative for specific IgE, occur because standardized allergen extracts are lacking, hence reducing the sensitivity of tests.
Unfortunately the prevailing opinion is that the DBPCFC should be performed only in particular cases and that the diagnosis of food allergy and intolerance may be reached 'more simply' by the patient history and positive tests for food specific IgE. On the contrary, public health facilities would greatly benefit from promoting the DBPCFC as the only bona fide method for a correct
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clinical diagnosis of food allergy/intolerance. The role of public health facilities must be that of endorsing a correct diagnostic methodology in food allergy. In fact only the correct identification of the actually allergic patients allow us to protect them better against the culprit foods.
The existing confusion and the insufficient clearness of the official medicine concerning food allergy and intolerance favour the delivery and multiplication of so-called 'unorthodox medical practices'. Many practitioners of 'alternative medicine' (clinical ecologists and natural healers) and popular magazines complicate the actual problem of food allergy, facilitating over-diagnosis of 'multiple food allergies'. The consequences of these blunders produces an elevated financial burden for the patient and society, mainly because of costly diagnostic procedures and diet regimens. Furthermore, the danger of disease due to a non-equilibrated diet impinges further on social health cost. It is often believed that implementation of high restrictive elimination diets by 'alternative' practitioners is benign. However there is a report of severe consequences, resulting also in death, arising from misdiagnosis of food allergy by 'alternative' practitioners in patients affected by other organic diseases.5 In all these cases the proper diagnosis was seriously delayed by the misdiagnosis of food allergy.
A correct diagnosis of food allergy justifies the economic effects on health care. The cost is mainly due to the elimination diet that has to be respected throughout all daily activities (work, recreation, school and family), and to the educational programme required to instruct all personnel involved in these activities how to behave correctly in the preparation of food and when a food-allergic reaction occurs. On the other hand, at present, no study has analysed thoroughly the social and financial cost of the food allergy, that is the number of missing workdays, the cost of both chronic and acute treatment (drugs, emergency procedures, etc.), the prevalence of the severe reactions and their rate of mortality.
Recent publications have emphasized the serious, sometimes fatal, consequences of food-induced anaphylaxis.6"8 A retrospective study that encompassed 31/2 years and included 179 patients was conducted at the Mayo Clinic, Rochester, Minnesota, USA, for an assessment of patients who have experienced anaphylaxis, and food was the first cause of anaphylaxis in the current series, the tentative in 33% of patients.9 They used the term 'tentative' because no rechallenge was obviously conducted in each case for the possible dramatic consequences. The authors claim that no international classification of diseases code exists for food anaphylaxis, and many cases go unidentified without labour-intensive individual chart abstraction. Hence further studies on the incidence of food anaphylaxis are needed, its frequency being most likely underestimated. Many physicians do not account for the importance of allergic disease in adults. In particular a history suggestive of food allergy related by adult patients may be dismissed. The study by Yocum and Khan9 points out how serious such an error can be, since up to 37% of the patients had previously experienced severe reactions and 49% were atopic. This failure in communication between the patients and their physicians can and must be avoided because a thorough investigation at the time of an initial allergic reaction will help patients prevent future difficulties.
Several cases of severe allergic reaction due to improperly labelled foods have been reported.10·6
It is therefore anticipated that there will need to be specific laws that require a thorough and detailed labelling of all foods. Indeed in the abovementioned study five patients had previously
184
documented positive prick-skin tests to a specific food and had inadvertently ingested the food as a cause of their current anaphylactic episode.9 These observations highlight the need for all physicians who treat patients with allergies to emphasise education and to urge patients to identify food constituents before they are ingested. At the same time physicians also must educate their patients in self-help, both for questioning the contents of meals in restaurants and for self-administration of epinephrine. Prescribing EpiPen or Ana-Kit as prompt therapy for severe reactions is mandatory because studies have documented that any delay in treating food-induced anaphylaxis increases the possibility of a fatal outcome.6·7 making it imperative to request the consultation of the allergist for all food allergic patients.
Physicians have to know that some factors can affect the quality and the magnitude of the allergic reactions to food. For instance they must know and teach their allergic patients that exercise and non-steroidal antiinflammatory drugs, increasing the intestinal permeability to food protein, could start or worsen a food reaction;11·12 other drugs, such as ß-adrenergic blocking agents or angiotensinogen-converting enzyme (ACE)-inhibitors, can be a problem in patients with anaphylaxis because they may complicate the emergency treatment.13"16 These drugs do not increase the risk of allergic reactions, but predispose the patients to more severe systemic reactions and to be more refractory to therapy. The reason to avoid ß-blockers is generally clear to all physicians, but they have to know that a potential danger also exists with use of ACE inhibitors; as compensation for anaphylaxis-induced loss of plasma volume (up to 50% within 10 minutes), angiotensin II is produced as well as epinephrine and norepinephrine as reactive vasopressors.17
Moreover angiotensin II also inactivates bradykinin. Thus hypothetically the use of ACE inhibitors in patients with a history of anaphylaxis should be evaluated carefully in the future. Physicians who staff the emergency department should be adequately trained to assess and treat anaphylaxis as the majority of the patients with severe food allergic reactions initially seek assistance in this area. These physicians also need to know the importance of determining titres of serum tryptase or urinary histamine in patients suffering from severe allergic reaction since these tests are crucial to document generalized mediator release. In fact the diagnosis of food anaphylaxis is seldom coded correctly and these tests can become a useful tool for the allergists who often are consulted only when the acute reaction is over. The presence of these mediators is the evidence of the involvement of mast cells and basophils and therefore supports the allergic origin of the reaction.
Allergists must actively educate physicians and school nurses to identify patients with anaphylaxis. Emergency treatment of anaphylaxis in schools and in the workplace must be facilitated; fear of legal liability because of the use of epinephrine in such public places must be allayed even if a primary concern of school officials about the use of injectable epinephrine has been the possible side effects rather than its lifesaving benefits. Injectable epinephrine should be available in the classroom, rather than in the school nurse's office, for administration by affected children or their teacher, inasmuch as immediate availability is critical for preventing fatal reactions. Strict avoidance of school snacks and more careful supervision of casual ingestion of food at school parties and on school outings must be stressed by allergists to parents and school officials. Patients allergic to food and persons living with them have to be, of course, educated to avoid every food not appropriately labelled, in which all ingredients are not well identified and recorded. The gravity of anaphylaxis and the need to pursue the culprit food must also be emphasised to the general public.
185
Unfortunately even official medicine proposes often unsatisfactory methods of diagnosis, such as specific IgE determination and skin-prick tests that are useful but not diagnostic by themselves. These tests have a scarce overall accuracy because of the poor standardization of the food allergens used.18 For example Brazil nut, chestnut, milk, walnut, codfish, halibut, chicken, and aniseed, all foods previously reported to cause severe life-threatening reactions, have many false negative at these tests, perhaps because the commercial extracts contain low levels of relevant allergens.19 In some cases diagnostic extracts are difficult to obtain because of the lability of the allergens which cannot stand up to the extraction procedures. This is mainly true for most fruit and vegetables, which give more reliable results when used as fresh material by prick + prick technique and which are very often responsible for OAS in the adult population.20·21 An effort has to be made to spread the knowledge that patients allergic to certain pollens (birch, mugwort, grass, etc.) can often later develop an OAS.21"24 Potent antigens are concentrated in the seed and skin portions of various fruits and vegetables and are usually available using prick + prick method. Recently the use of fresh milk, peanut, egg and seafood have also shown better results than commercial extracts.25 Instead, the presence of specific IgE to a food is not necessarily associated with clinical symptoms and may occur as an effect of a cross-reactivity to allergen shared by foods and different sources.26·27 Inadequate diagnosis often causes useless dietary restrictions causing unjustified sacrifice for the patients and their families.
Moreover the official medicine still wrongly feeds the belief that foods rich in histamine may be responsible of Pseudoallergie reactions with cutaneous and respiratory complaints.29 Unfortunately more and more often patients without food allergy but with other allergic diseases are advised by their physicians to undergo a diet without histamine-rich foods. This method, originated from few non-validated studies, is rapidly spreading as advice for the allergic patients but also to non-allergic patients suffering from cutaneous and/or respiratory symptoms.
The main role of the public health facilities, and particularly of the allergists, is to collaborate with food producers, recording allergenic food and aiding alimentary factories to adopt all the measures needed to prevent allergic reactions. The first basic rule is to label in a correct and exhaustive manner all the foods, even if there are only traces of some ingredients because trace amounts of food can trigger life-threatening allergic reactions. The European Community has to make an effort to provide public health facilities with stringent protocols and position papers on food allergy.
The role of the members of the public health facilities is not limited to labelling and education, but they have to direct their research towards the production of non-allergenic foods. The previous chapter has already dealt with this problem and the enormous effort made in the development of hypoallergenic formula derived by extensively hydrolyzed whey has traced the pathway to be followed. However the rare, allergic reactions to hypoallergenic formula underline the difficuly in obtaining a safe allergen-free food product even after high protein degradation. Of course the control of biochemical, immunologic and clinical parameters to evaluate the food hypoallergenicity is another task of the public health facilities.
Likewise difficult is the endeavour of modifying the specific immune response of the allergic patient towards the food allergen and this attempt requires principally the work of the allergists. Specific immunotherapy (SIT) to certain foods are still experimental and poorly standardized.29·30
186
Moreover SIT will be accepted only when doubleblind placebocontrolled studies have obtained
unequivocal data in its favour; but this kind of study is at high risk for the dangerous life
threatening reactions that can occur. A promising solution, lately suggested and partially applied,
is the use of analogous peptides of epitopes responsible of food allergy which have been isolated
and synthesized by DNArecombinant techniques. These peptides can compete with the aller
genic epitopes at the level of the specific Tcell receptor for the allergen and can switch off the
allergic immune response against the food allergen. Evidence of this potential employment has
been actually documented, for instance, for ovalbumin allergy.31
7 4 . 2 . G r o u p s at risk
Several factors contribute to determine the risk of developing food allergy. First of all we could
divide them into factors that facilitate a general atopic response and factors that affect more
specifically the rise of a food allergy.
Genetic determinants have an important role in atopic diseases. In fact children with nonatopic
parents have a potential risk of being atopic of about 515%.32
The risk increases to 2040% if
one parent or one sibling is atopic32
The risk is higher (4080%) if both parents are atopic with the
highest probability occurring when they suffer from the same atopic disease.32
Other parameters
have been studied and proposed as predictive of the risk of atopic disease.33
·34
They are: (1)
elevated total IgE in the cord blood;35
(2) increased total IgE in infancy and childhood; (3)
significant specific IgE antibody (skin and serum); (4) elevated concentrations of salivary IgAanti
casein in newborns; (5) delayed postnatal maturation of Tcell competence; (6) low in vitro
production of IFNγ and TNFa often present in children born from atopic parents; (7) increased
eosinophils in the cord blood, in blood and/or in the nasal mucosa An infancy; (8) increased
monocyte phosphodiesterase activity; (9) alterations of the ratio of essential fatty acids in
umbilical cord serum; (10) cord blood thrombocytopenia. Some of these assays, such as total IgE
in the cord blood, are easily available and partially reliable, while some others have furnished
controversial and questionable results.34
Concerning the specific risk of developing a food allergy, certain groups have been identified that
are at higher risk than the general population. First of all children, who have an overall prevalence
of true food allergy of 8%,1 present a higher risk than the adult population in which the food
allergy prevalence is estimated to be about 2%.3·
4 Some factors have been claimed to affect the
rise of food allergy in children. These are: (1) brief or nonbreast feeding; (2) premature weaning;
(3) maternal diet introducing food allergens through breast milk; (4) early solid foods; (5) transient
or permanent IgA deficiency;36
·38
(6) maternal drug intake during pregnancy, e.g. ßblocking
agents; (7) maternal smoking during pregnancy. Some of these risk factors have been deeply
analysed but controversial results have often been reported by different authors. For instance Van
Asperen (1984)39
was unable to show a protective effect of either breastfeeding or cow's milk or
solid avoidance on the development of atopic disease in infancy; these results contrast with what
has been reported by several other prospective studies that showed a protective role of breast
feeding and cow's milk avoidance on the development of food allergy.34
Recent immunological
confirmation that dietary allergens such as cow's milk proteins and egg allergens are frequently
present in breast milk,40
combined with the early sensitization of exclusive breastfed infants to
187
egg and milk41, imply that exclusive breast-feeding would be less than optimal in preventing food hypersensitivity without also instituting maternal dietary restrictions of major allergenic foodstuffs. Moreover nowadays we know that small amounts of food allergen, like those present in breast milk, facilitate the pathway of the Th2 response towards a sensitization and specific IgE production.42 Chandra et al.43 documented that a maternal elimination diet avoiding major allergenic foods during lactation may help to prevent atopic dermatitis in their infants. Hattevig40 reported similar beneficial effects in infants of mothers avoiding egg, cow's milk, and fish during the first three months of lactation. Chandra et al.44 noted also that there was an apparent comparability of the breast fed and formula fed groups in decreasing the prevalence of allergic disease by two years when infants with high cord blood IgE levels were studied. Infants exposed directly to multiple diverse solid food allergens early in infancy apparently develop a higher rate of eczema but similar incidence of asthma by two years;45 recommendations to withhold solid food feedings until after six months may therefore be well founded. Two studies have recently examined the effect of contemporary maternal and infant dietary restrictions on the development of atopic diseases. Chandra46 showed that a maternal diet excluding egg, milk, fish, peanut and beef during pregnancy and lactation, coupled with breast-feeding and delaying solid food introduction for six months reduced the incidence of eczema in infants at risk for atopy. Zeiger47 in a similar study on 288 children documented that the prevalence of atopic disorders were reduced at one year due to lower prevalences of food allergy in the prophylactic group. From these two studies it emerges that extensive food avoidance by both mother and infant transiently reduces food allergy without influencing allergic rhinitis and asthma; the prenatal avoidance likely did not contribute to any of the beneficial effects reported in these two studies. Maternal intake of metoprolol, a ß-blocker, during pregnancy significantly increased the appearance of elevated neonatal IgE concentrations and the development of atopic symptoms before 18 months of age.48 Maternal smoking during pregnancy gave a two- to five-fold increased risk for development of eczema, asthma and pneumonia during infancy.49
The role of early aeroallergen exposure is doubtful even if a recent study of 120 children, identified before birth as being at high risk for atopy, shows that a double approach to allergen avoidance, focusing on foods and aeroallergens, appears to be beneficial in preventing sensitization in these high-risk infants, but it does not clarify if food sensitization has been avoided or merely deferred.50 Burr (1993) in a randomized controlled trial involving 453 children with a family history of allergic disease showed that breast-feeding may confer long-term reduction of the incidence of wheeze that persists at seven years of age.51
Another relevant group at risk for food allergy is represented by patients suffering from pollinosis, prevalently adult patients with inhalant allergy to pollen of birch, mugwort, grass and ragweed. Usually these patients are at high risk for developing OAS years after the rise of respiratory allergy.20·21 ·24 Another group at risk for OAS is the group of patients with allergy to latex (Hevea brasiliensis): Pecquet reported that nearly half the patients with latex allergy in his study had an allergic reaction to a fruit, the most frequently mentioned being banana (34%), avocado (25%), and kiwi (20%).52 Allergy to chestnut is also frequent in these patients, while reactions to apricot, grape, passion fruit, and pineapple are less frequently noted.52 Since the prevalence of latex allergy is particularly elevated in three subgroups that are medical and nursing staff, employees working in a plant manufacturing latex products, and subjects with a history of repeated surgical procedures (mainly patients with spina bifida), these three subgroups have to be indirectly considered at risk for developing food allergy towards the abovementioned fruits.
188
Since the magnitude of allergen exposure is generally recognized as a driving factor in determin
ing the prevalence of a certain food allergy, it is obvious that certain populations are at higher risk
for developing allergic reactions to specific foods characteristic of their dietary habits, such as fish
in Scandinavian countries53
and peanut in North American countries.19
A study by Scadding (1988)54
suggests an important role for poor sulphoxidation ability in
facilitating the rise of food allergy. This study analyzed the sulphur and carbon oxidation ability in
a population of welldefined food allergic patients and documented that the portion of poor
sulphoxidizers (58 of 74) was significantly greater than that of a previously determined normal
control population (67 of 200; ρ < 0.005). The proportion of poor carbon oxidizers was not
significantly different from the controls. Hence the metabolic defect of sulphoxidation may play a
role in the pathogenesis of adverse reactions to foods. Since about 35% of the subjects in the
general population present a deficit in sulphoxidation they have to be considered a group at risk
for food allergy compared with the normal population.
In the field of food allergy/intolerance celiac disease holds a peculiar position. Indeed celiac
disease is likely to be an abnormal immune response in individuals susceptible to the ingestion of
certain cereal peptides. It is well known that some populations have a greater risk for developing
celiac disease, such as, for instance, Irish people.55
It is also known that there is a clearly major
prevalence of celiac disease in consanguineoses of patients with celiac disease.56
In the past
years evidence is accumulating that particular HLA antigens are associated with celiac disease.
HLA antigen analysis has determined that groups at elevated risk for celiac disease present
frequently HLA B8, DR3, DR7 and DQw2.
In conclusion, the analysis of the groups at risk from food allergy, besides defining the correct
pathway to quickly foresee which subjects will likely develop a food allergy, allows us to project
the best strategies to prevent the onset of food allergy.
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1 5 . C O N C L U D I N G R E M A R K S
Over the past few years public opinion has been showing increasing interest in food allergies. The lay press — in fact the mass media in general — has fuelled this curiousity. Unfortunately, however, the information published is not always entirely correct.
It is for instance widely believed that food allergy or intolerance can cause a variety of diseases and disorders, ranging from the classical allergic manifestations such as eczema or urticaria to symptoms not normally attributed to allergies, such as arthritis and irritable bowel syndrome. The layman also tends to accept the suggestion that, in addition to true food allergies, diagnosable on the basis of skin reactions and assays for specific IgE for certain foods, much of the pathology arising in connection with foods is caused by food intolerance, although this 'disorder' lacks a precise pathogenic reference except for some rare diseases caused by enzymatic deficits.
In 1995 the Subcommittee of the European Academy of Allergy and Clinical Immunology published a position paper, 'Adverse reactions to food' which set up a new classification and terminology for these reactions. Essentially this position paper gives priority to IgE-mediated reactions; while admitting that theoretically there could be non-lgE-mediated immune reactions, it indicates clearly that there is no real proof that they have any role in causing symptoms.
The position paper is specific that food intolerance may be enzymatic or pharmacological; the first heading includes the rare reactions due to enzymatic deficits and the second heading those where the symptoms depend on the effects of certain amines that are either naturally present or develop in foods. The subheading of undefined food intolerance temporarily includes only celiac disease and adverse reactions to food additives.
The position paper stressed the importance in all clinical situations of applying the appropriate diagnostic procedure which should be based on DBPCFC, the only way of confirming food intolerance or allergy.
The new classification and particularly the general outline of the 'role of food in relation to the different hypotheses', presented in section 2 of this study casts ample light on the real problems of food allergy and intolerance. These are questions of public health relevance to which clinical and basic research must seek answers. Thus EC agro-industrial research projects developed in the future will have to take account of this approach and its related problems.
The main point is that the IgE-mediated pathogenic mechanism is by far the most frequent and is also the most important as regards the severity of symptoms, hence the danger posed by the culprit foods, which may cause harm even only as trace contaminants.
The next most important point is sensitivity to gluten, the main cause of celiac disease.
Enzymatic intolerance can usually be traced to inborn metabolic errors; diseases in this group are extremely rare and precise dietary rules can usually be formulated to avoid problems.
194
Lactose intolerance is an exception, since it is very widespread. However, it is a relatively bland condition and generally raises difficulties only in preparing milk formulas for infants in countries where its prevalence is high.
Pharmacological intolerance is another problem affecting limited numbers of people, and the foods containing the culprit amines have been clearly identified.
Focusing on IgE-mediated allergies, therefore, several important question are still open. First of all we have to improve our knowledge of alimentary allergens. Many allergenic molecules have been identified in recent years, some have been sequenced and some allergenic epitopes have been recognized, but this research field is still in its infancy. Correct methods must be established for identifying the main allergens and intermediates and these require sera from at least 50 individuals, correctly diagnosed on the basis of DBPCFC as being intolerant to the study food. If at last 50 are used the resulting allergogram should meet stringent criteria. It would nevertheless be advisable to select these allergic individuals in different parts of the EU, so as to allow for the possibility of genetic and dietary differences.
Identification of the major and intermediate allergens for the main foods should then be followed by purification of the major allergenic proteins and their immunological study, aimed at identifying the epitopes involved in the immune response.
Immunological research will then provide purified allergenic molecules or allergens produced by recombinant DNA technology, and these can be employed for research into characteristics of their immunogenicity.
From the practical viewpoint it is important if we are to prevent food allergies to reduce the allergenic potential of foods. In the past this has been tackled for cow's milk, the basic food item in infant formulas, and the market now offers a variety of hypoallergenic products. For milk and other animal proteins, egg and fish, the allergens are highly stable even to cooking and digestion, so reducing their allergenicity means breaking the molecule down so vigorously that the organoleptic attractions of the original food may be lost. Many plant allergens, however, are labile to heart and digestion, so methods will probably be found to reduce their allergenicity.
Identification of the major allergenic molecules in specific foods will lead to considerable improvements in the diagnosis of allergies, and in vitro diagnostic tests will then became possible with much better overall accuracy, so that it may eventually no longer be necessary to use the DBPCFC test.
Knowledge and availability of the allergenic molecules for certain foods will also enable us to standardize food allergens used for specific immunotherapy. Right now these methods are not available, and research is still awaiting better standardization of the allergens. Recognition of the Τ epitopes of certain food allergens may open new prospects for modulating the IgE response.
Identification of the allergenic molecules will boost research into the production of transgenic plants containing little or none of the allergens concerned.
195
While awaiting this scientific and technological progress we must draw on our current knowledge of the effects of food processing and preparation. This is particularly important for products prepared by new methods, such as the microparticulate proteins and certain additives; which may constitute a risk for people with allergies. The best policy for the EU is to make certain that the user receives correct and detailed information about each type of food and each ingredient in the final product, and that manufacturers respect these requirements.
Public health's role will be to make more effort than in the past to spread correct information on food allergy to the medical profession and to the public so as to provide an authoritative bulwark to the spread of unorthodox practices which are the main source of controversies on this topic. Measures will have to be taken to prevent or deal with serious allergic reactions, instructing those in charge of restaurants, hotels and school canteens on what should be done in cases of severe anaphylactic reactions. Constructive relations must be established with the food industry to make sure the user receives accessible information on food products, and jointly to promote studies to set in motion the farthest-reaching positive approaches.
196
European Commission
EUR 16893 — Study of nutritional factors in food allergies and food intolerances
C. Ortolani, E. A. Pastorello
Luxembourg: Office for Official Publications of the European Communities
1997 — 196 pp. — 21.0 χ 29.7 cm
ISBN 92-827-9554-3
The present study was launched as an initiative by the Agro-industrial Division E-2 of the European Commission, Directorate-General XII 'Science, Research and Development'. This study forms part of a series of studies launched by the division on important issues pertaining to food and non-food research. Their aim is to present the current state of the art and give recommendations by the authors for future research which could remove obstacles in the way of introduction of new technologies and products from the agro-industrial sector into the marketplace.
It should be stated that this document represents the findings and opinions of the authors and should not be considered as the opinions or recommendations of the Commission services.
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