Best Practice & Research Clinical Gastroenterology
Istituto Allergologico Lombardo, Piazza Monsignor Moneta 1, 20090 Cesano Boscone, Milan, Italy
S.C. Allergology and Clinical Immunology, Niguarda ‘Ca’ Granda’ Hospital, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy
Adverse reactions to foods, aside from those considered toxic, are caused by a particularindividual intolerance towards commonly tolerated foods. Intolerance derived from animmunological mechanism is referred to as Food Allergy, the non-immunological form is calledFood Intolerance. IgE-mediated food allergy is the most common and dangerous type of adversefood reaction. It is initiated by an impairment of normal Oral Tolerance to food in predisposedindividuals (atopic). Food allergy produces respiratory, gastrointestinal, cutaneous andcardiovascular symptoms but often generalized, life-threatening symptoms manifest at a rapidrate—anaphylactic shock. Diagnosis is made using medical history and cutaneous and serologicaltests but to obtain final confirmation a Double Blind Controlled Food Challenge must beperformed. Food intolerances are principally caused by enzymatic defects in the digestive system,as is the case with lactose intolerance, but may also result from pharmalogical effects of vasoactiveamines present in foods (e.g. Histamine). Prevention and treatment are based on the avoidance ofthe culprit food.
Key words: adverse reactions to foods; food allergy; food intolerance; oral tolerance; doubleblind placebo controlled food challenge (DBPCFC); histamine; immunoglobulin E (IgE); mast cells;oral allergy syndrome (OAS); skin prick test (SPT); food patch test (FPT); probiotics;breastfeeding; humanized anti-IgE serum.
BASIC MECHANISMS OF FOOD ALLERGY AND FOOD INTOLERANCE
Oral tolerance (OT) is the state of immunological non-response that is established afterthe first contact with the food antigens in the gut. It is evident that this is an active
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E-mail addresses: [email protected] (C. Ortolani), [email protected] (E.A. Pastorello).
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process which is linked to specific T cells since it is possible to transfer the tolerance inmice using spleen cells.Animal studies have highlighted certain mechanisms which leadto the lack of development of OT which could also be operating in man. These consistof:
i. Apoptosis of antigen-specific T cells, with consequent loss of their specific
immunological function. This mechanism was observed following contact withhigh doses of
ii. Paralysis of the T cells which can occur if the antigen presentation from the
epithelial intestinal cells (which function as Antigen presenting cells) is incompletedue to the lack of co-stimulatory mol
iii. Defect in the production of the regulatory T cells. The development of these cells
is stimulated by external factors such as the intestinal homing of normal bacterialflora after birth. In fact ‘germ free’ mice are not able to develop normal OT
The third mechanism is important in man. In the GALT of adult men the IFNg type
cytokine pattern prevails.During foetal life the cytokine pattern of Th2 cells prevails. This profile would limit damage to the placenta by Th1 cells and guarantee the successof pregnancy itself. If the Th2 profile persists after birth it could contribute to the lack ofdevelopment of OT.Microbial homing in the gut immediately after birth, producinginflammatory factors, is a strong stimulus to switch on a Th1 cell-response.
The so-called ‘hygiene’ hypothesis assumes that a great antibacterial prophylaxis
would favour an increase in allergies.Some epidemiological studies have providedevidence that allergic children have a major intestinal colonisation of lactobacillum andbifidobacterium, whilst in non-allergic children coliform bacteria and Staphyloccocus aureusprevaSome studies have shown that the bifidobacterium homing in the gut of allergicchildren is delayed.Nevertheless, not everything can be explained by the ‘hygiene’hypothesis and the exact role carried out by the intestinal flora in the development ofthe allergy remains unexplained.
Another important factor to consider is the individual variability of the IgE-mediated
immunological response. For instance, a polymorphism in the CD14 gene has beenassociated with high levels of IgE and food allergy.Moreover, the molecule (TIM-1)encode by Havcr1 gene has shown to be associated with regulation of Th1 and Th2immune responses. The knowledge of an association in humans of TIM-1 and atopyseems to open a new interpretation of the hygiene hypothe
The digestion and absorption of allergenic proteins, could also have a great impact on
allergic sensitisation. It has been observed that the transport of food allergens throughthe epithelial cells of the pre-sensitised gut favours the induction of allergic sensitisation,while on the other hand if the transport of these peptides occurs via the M cells of thePeyer patches the development of OT is favoured.The characteristics of the allergenicproteins of foods in their natural form and after various types of technological foodprocessing could influence digestion and absorption as observed in peanuts.
In 1995, the EAACI position paper on food allergy established a simple and easy-to-apply classification of adverse reactions to food based on the pathogenetic mechanism(
Figure. 1. Adverse reactions to Food EAACI classification.
The first distinction is made between toxic and non-toxic adverse reactions to
foods. Toxic reactions result from a primary harmful effect that the food has on all theindividuals that eat it. Non-toxic reactions are those that take place in the presence offoods which are not tolerated by a few individuals.
If food toxins are ingested in large quantities or on a frequent basis Toxic food reactions(TFR) can occur but are rather infrequent. In fact modern foods contain small amountsof toxins and dietetic variation does not allow accumulation. Toxins can be naturallypresent in foods, induced by food processing, or incorporated in food as contaminantsor additives. Natural toxins from plants may be both endogenous and exogenous. Someexamples of endogenous natural food toxins are glucosinolates in cabbage which have agoitrogenic effect; saxitoxin in shellfish which may cause dyspnoea, paralysis, orhaemorrhages; and vaso-active amines, which are described in the subchapterPharmacological intolerance. Exogenous toxins may result from food processing andstorage. These include aflatoxins, found in peanuts and grains contaminated with mouldwhich can cause encephalopathy, hallucinations, and hepatic disease; and nitrites whichcome from endogenous nitrates in green vegetables causing headaches, hepatic diseaseand methaemoglobinaemia. Traces of substances used for food production may remainin food, as methionine sulphoximine (bleaching agenttrichloroethylene(used insolvent extraction). TFR symptoms usually involve the Central Nervous System,producing headaches, hallucinations, blood and liver problems.
Non-toxic food reactions can be sub-divided into immunological (food allergy) andnon-immunological (food intolerance); at the present these reactions are referredas: ‘non-allergic food hypersensitivity’.food allergy is subdivided into IgE-mediatedand non-IgE-mediated.
IgE mediated food allergy. IgE-mediated reactions which constitute the majority of foodallergic reactions have been the most well studied. If the OT is not developed there isproduction of specific IgE for some foods. IgE are linked to high affinity specific FC3RIreceptors present on the mast cells, fixed cells present in the mucosa and skin, andbasophils circulating in the blood. These cells have numerous cytoplasmic granules inwhich preformed mediators are stored, principally including histamine. When theallergenic proteins are absorbed in the gut they enter into contact with specific IgEslinked to mast cells/basophils. The conjugation of the IgEs with the allergens triggers astimulus to these cells, which degranulate, release mediators in the surrounding micro-environment and synthesize new mediators (prostaglandins, leukotriens, cytokines). An immediate reaction follows few minutes after contact with the allergen, due mainlyto the histamine. At the base of the reaction there is vasodilation, tissue fluid exudation,smooth muscle contraction and mucous secretion. A late-phase response follows theimmediate reaction which begins 4–6 hours after contact with the allergen andcontinues for several days. This response is caused by chemotactic mediators releasedat the same time as the immediate reaction which promote selective recruitment of
inflammatory cells, mainly eosinophils and neutrophils, which infiltrate the tissueproducing an inflammation lasting a few days.
The two clinical elements required to support an IgE-mediated food allergy are the
presence of IgE specific antibodies to the culprit food and a proven relationshipbetween ingestion of the food and the appearance of the symptoms.
Non-IgE-mediated food allergy. Non-IgE-mediated food allergy could consist of immunereactions depending on:
(a) antibodies, of different isotypes from IgE (i.e. IgG, IgM and IgA); (b) immune
complexes formed by food and food antibodies; (c) cell-mediated immunity.
It is important to remember that there is no evidence to support the relationship
between the culprit food and a reaction to non-IgE antibodies in any allergic disease. However, in normal individuals there is an increase in IgG food antibodies afteringestion of the Likewise, there is no hard evidence that cell-mediated immunityis responsible for any allergic disease.
The cause of intolerance could be an enzymatic defect or the effect of vaso-activepharmacological substances present in food (enzymatic and pharmacologicalintolerance). The reactions non-classifiable in any known mechanism are referred toas undefined food intolerance.
Enzymatic food intolerance. This is an adverse food reaction resulting from enzymaticdefects of the gastrointestinal tract.
The symptoms manifest in the gastrointestinal tract after ingestion of certain foods.
The most common one is lactose intolerance. This comes from a b-galactosidasedeficiency common in adult populations. It can affect 6–12% of caucasians, but in someethnic groups the prevalence can exceed Lactose is a disaccharide composed ofglucose and galactose. In the small intestine b-galactosidase facilitates the hydrolysis oflactose in the two monosaccharides which are then absorbed. In b-galactosidasedeficiency lactose cannot be completely hydrolysed and the molecules reach the colonwhere they are degraded by bacteria in H2O, CO2 and H2. The fermentation in thecolon causes disturbances such as bloating, abdominal pain and sometimes diarrhoea.
Pharmacological food intolerance. Pharmacological food intolerance is caused byvasoactive amines and other substances present in foods, all of which manifestpharmacological activity. In most cases, there is a dose-effect relationship. Vasoactiveamines include dopamine, histamine, norepinephrine, phenylethylamine, serotonin andtyramine.
Histamine is a diamine and it is the chemical mediator of allergies. It is commonly
thought that foods which contain high quantities of histamine may provoke symptomssimilar to those of an allergic reaction. The histamine in the foods comes fromdegradation of the histidine by microrganisms and can be found in high quantities incheese, alcoholic beverages, and fermented foods. Furthermore, intestinal bacteria canalso decay histidine in histamine. Histamine is rapidly inactivated by the di-aminoxidase(DAO), largely produced in the gastroenteric tract. Therefore, the ingestion of largequantities of histamine does not produce disturbances in normal subjects. Never-theless, some drugs or ingestion of other diamines can impair the DAO activity thusproducing typical histaminic intoxication symptoms.
Table 1. Vasoactive monoamines which may produce pharmacological effects in intolerant patients.
Such an example is the scombroid syndrome resulting from the ingestion of spoiled
fish. Fish contains a lot of histidine which is transformed into histamine in the gut bybacteria. Additionally, two diamines produced in spoiled fish, putrescein and cadaverin,block the DAO. A histaminic effect then follows in the form of erythema, vasodilation,tachycardia, hypertension, migraine, vomiting and diarrhoeaThe symptoms generallyresolve within a few hours. Mortality is very rare and generally depends on comorbidity,e.g. patients with coronary artery diseases may risk myocardial infarction.
A similar result can occur from taking DAO-inhibitor drugs. These include
isoniazide, aminoguanidine, chloroquine, pentamidine, clavulanic acid, dobutamine,pancuronium, imipenem, and others. Another claim is that some foods have ahistamine-releasing effect thus provoking symptoms. However, there is no evidencethat histamine releaser foods can provoke any symptom in man.
A monoamine, tyramine is a protein derivative of tyrosine which is inactivated by the
enzyme, monoaminoxidase (MAO). In absence of anti-MAO treatment (some anti-depressants), the ingestion of tyramine does not produce any symptoms. However, ifingestion of tyramine, or of other monoamines—()—occurs during anti-MAOtreatment symptoms such as tachycardia, hypertensive crisis, migraine, fever and hotflushes may be manifested.
Undefined intolerance. Intolerance resulting from non-identified mechanisms, such asfood additive reactions, come under this name. The additives employed in foodproduction, at the allowed doses, are Generally Recognised as Safe products (GRAS). However, some predisposed individuals may show intolerance reactions principally tosulphites, nitrites, nitrates, monosodium glutamate and some colourings. Possiblesymptoms are asthma, rhinitis, urticaria, itchiness, and migraines. The mechanisms ofthese intolerances are yet to be defined.
Psychosomatic reactions to foods depend on a primitive mental disturbance in theindividual affected. For this reason they have not been included in the EAACI
classification. In fact, many patients believe that they are allergic or intolerant to certainfoods, solely on the basis of self persuasion.
Diseases of uncertain attribution to food allergy
The ascription to food allergy of certain diseases is controversial. In order to clarify thedivergent opinions an EAACI PP has been issued arrives at the followingconclusions:
There is not sufficient evidence to attribute chronic fatigue syndrome, neuropathy,mental disturbances, vasculitis, or arthritis to food allergy/intolerance;There is some evidence that irritable bowel syndrome, serous otitis media, andmigraines are rarely due to food allergy/intolerance.
Pseudoallergic reactions are non-immunological reactions that reproduce symptoms ofallergic diseases. Only some of the many manifestations that are identified by this termdepend on the release of histamine, other manifestations can be due to the release ofother mediators.
They are not listed in the EAACI classification which refers to mechanisms.
Ultimately, the term does not help in orienting the diagnostic procedure and treatment.
The clinical manifestations recognised by the scientific community as being attributableto food allergy are basically those demonstrated in IgE-mediated sensitised patients bystandardised challenge tests, DBPCFC.IgE-mediated reactions involve the skin, therespiratory apparatus, the gastro-intestinal tract and the cardiovascular system. A verydistinctive pattern of food allergy involves the unpredictability of the severity as well asthe variability of the reactions. Consequently, a food usually causing a mild reaction canprovoke a severe one if consumed after an aspirin, alcohol intake, ACE-inhibitors, orbeta blockers or immediately before exercise
Acute urticaria/angioedema is one of the most frequent manifestations of food allergy.
In a recent review, it was reported that a total of 710 out of 5622 patients with apositive food challenge reacted to the culprit food with acute urticaria; the foodsmostly commonly involved being milk, egg, peanut, additives, mustard and cod.Urticaria is usually linked to other symptoms involving the gastrointestinal or therespiratory apChronic urticaria is usually not associated with food allergy. Contact urticaria due to foods may be elicited by mucosal or skin exposure.
In Atopic Eczema Dermatitis Syndrome food allergy play an important role. The IgE
antibodies bound to Langerhans cells play an important role as receptors, thus it isalways important to look for the correlation with any form of sensitisation.DBPCFC performed on affected patients demonstrated that food allergy play apathogenic role in about 35–80% of children with moderate to severe atopic dermatitis. In half of the cases, the cutaneous symptoms were associated with gastrointestinal and
respiratory ones.Milk, eggs, wheat and soy were demonstrated to be the mostinvolved foods.
Gastrointestinal anaphylaxis arises in a sensitised person immediately after ingestion of
the culprit food, producing nausea, abdominal pain, cramps, vomiting and diarrhoea. This is the most frequent syndrome of food allergy.The same symptoms, whilst beingchronic and possessing a progressive course, are the manifestations of eosinophilicoesophagytis and gastroenteritis, characterized by the infiltration of the oesophageal,gastric and/or intestinal wall with eosinophils. These diseases can be associated withfood allergy, and in this case an elemental diet seems capable of reducing the infiltrationand symptoms.
The oral allergy syndrome (OAS) is a very common manifestation of food allergy
especially in adultallergic to tree pollen. This syndrome involves oral itching, lipswelling and laryngeal angioedema of the mouth and the pharynx upon contact with anallergenic food. Symptoms can also involve other organs and become more severe. There are four levels of increasing severity: 1, oral mucosal symptoms only; 2, oralmucosal plus gastrointestinal symptoms; 3, oral mucosal plus systemic symptoms(urticaria, rhino-conjunctivitis, or asthma); and 4, oral mucosal symptoms plus life-threatening problems (glottis edema, anaphylactic shock).
Taking into account the symptoms reported in DBPCFC studies, level 1 occurred
most commonly (80%), followed by level 3 (16%) and 2 (5%).
Some rare diseases resulting from gastrointestinal food allergy are probably
Food protein-induced proctocolitis; is a colitis with emission of numerous diarrhoeal
discharges containing blood and thus entailing anaemia and loss of body weight;generally caused by allergy to cow’s milk.
Food protein-induced enteropathy; it is very common during infancy, it occurs in the
form of intestinal inflammation with loss of integrity of the villi and leads tomalabsorption syndrome; when triggered by cow’s milk it is generally defined as‘intolerance to cow’s milk’.
Food protein-induced enterocolitis syndrome; provoking vomiting, diarrhoea, serious
dehydration until cardiogenic shock, noted for allergy to soy and cereals.
Heiner’s syndrome has been described as a disease which depends on IgG-mediated
immunity to cow’s milk proteins causing occult gut bleeding, anaemia and pulmonaryhemosiderosis.
Asthma, especially poorly controlled asthma, is a risk factor for more severe and fatal
food induced anaphylactic reactions.Moreover, airway hyper-reactivity may beinduced by food allergy in sensitised subjects. In one study, stable asthma was worsenedwhen small amounts of food allergens were ingested by sensitised subjecFoodallergy was a major risk factor for severe life-threatening asthma, in children,approximately 50% of asthmatic children that required intubation for severe asthma hadfood allergy compared with about 10% of asthmatics not requiring intubation.
Anaphylaxis is a systemic IgE mediated reaction induced by the massive release of
mast cell mediators targeting organs of the cutaneous, respiratory, gastrointestinal andcardiovascular systems. In the 1990’s, food allergy was recognized as the mostimportant cause of anaphylaxis outside the hospiCurrently, there is noagreement on the definition of anaphylaxis. Consequently, the actual prevalence of thissevere reaction is unknown even though many epidemiological studies have beenconducted. Epinephrine is the medication of choice for treating anaphylaxis yet studiesindicate that it is under-utilized.
Diagnosis of IgE-mediated food allergy is based on history, objective examination,allergy tests, elimination diets and challenge tests.
Medical history is useful for dealing with reactions which are manifested immediatelyafter the ingestion of a food; but less than 50% of clinical suspects are confirmed byDBPCFC. The following factors must be ascertained from medical history:
† The latency between the ingestion of the food and the appearance of the symptoms.
The shorter the latency period the more reliable the assumptions made based onmedical history.
† The type of symptoms. Symptoms of food allergy are OAS, conjunctivitis, rhinitis,
asthma, glottis oedema, rash, urticaria/angioedema, vomiting, diarrhoea, anaphylac-tic shock. Eczema is a delayed symptom. There are contact reactions in skin or eyesand by inhalation. Some reactions appear only after physical exercise (exercise-induced food anaphylaxis).
† The suspect food. We can only suspect a culprit food if the reaction occurs a few
minutes after ingestion. It is important to know previous food reactions.
† The duration of the symptoms. It is improbable that a reaction continuing many
hours or days is due to a food allergy.
† The reoccurrence of the symptoms after ingestion of a food.
The diagnostic accuracy of Skin Prick tests (SPT) with commercial extracts is extremelyvariable. In some cases, SPT using the food in its natural form (prickCprick) are morereliable, especially for plant food allergyThe diagnostic accuracy of specific IgE issimilar to that of SPT and varies according to the extract used.In general, SPTremains the test of first choice since it provides immediate results which allow a directclinical evaluation and it is cheaper than in vitro methods. Both methods can providefalse positive results due to cross-reactivity. For example, subjects allergic to grassescommonly have IgE specifics to cereal flours, but without symptoms.There have beensome attempts to correlate IgE antibody levels to DBPCFC outcomes. Childrensuffering from atopic dermatitis in two studies provided diagnostic decision points (95%PPV) for some allergenic foods. Some confirming studies do not exist for atopicdermatitis whilst no studies exist for other allergic populations and other clinicalsituations. Additionally, DBPCFC is still the gold standard for diagnosis of certainty forIgE-mediated food allergy
Elimination diets can be useful in patients with persistent symptoms. Foods testingpositive to SPT/RAST and those suspected from history are excluded. Three weeks areusually sufficient to confirm the suspect of a food allergy. The result is considered
positive if a consistent improvement of the symptoms results. If the symptoms reappearwhen foods are reintroduced a DBPCFC must be performed.
The Double Blind Placebo Controlled Food Challenge (DBPCFC) is the only validatedtest for the diagnosis of food allergy.The rules of standardization of the correctprocedure for the DBPCFC are described in an EAACI Position Paper.Given that themethod is complex and time consuming it is only applied in candidate patients forpermanent avoidance of foods essential to diet such as milk, eggs, etc. It iscontraindicated in patients with previous severe reactions to food in order to avoidlife-threatening reactions. The food to be tested is administered dried or lyophilised inopaque capsules, or alternatively in its natural form masked by an inert base. Theplacebo consists of a capsule of the same appearance containing dextrose or an inertbase consisting of foods, which are certain to be tolerated by the patient and allow anadequate masking of the food to be administered.
Food patch tests (FPT) have been recently introduced for diagnosis of food allergieswith delayed symptoms. In children suffering from atopic dermatitis with delayedreactions FPT does improve diagnostic accuracy, but not in the milk allergy ofimmediate type.The method has not yet been validated or standardised for thepurpose of routine diagnosis. Even though many studies have been conducted in orderto evaluate the usefulness of lymphocytes proliferation and the cytokines increase afterexposure in vitro to food allergens, there is no confirmation of their value in the routinediagnostic approach.
The diagnosis of lactose intolerance is based on the increase of H2 in the breath afteringestion of lactose which is determined using a H2 breath test analyser.
Many unproven methods (cytotoxicity tests, provocation and neutralization sublingualor subcutaneous, bioresonance, applied kinesiology, etc.) have been proposed and areused for diagnostic and sometimes therapeutic purposes in food allergy andintolerance. There is no scientific evidence to support the efficacy of any of thesemethods and in many cases it has been documented that their results do not differ fromthose obtained using placebo.
Allergen cross-reactivity is the phenomenon that occurs when IgE antibodies originallydirected at the epitopes of one allergenic source recognize similar structures in anotherallergenic source. Cross-reactivity may be only in vitro, serological evidence, but it canalso be clinically expressed. Up to now no diagnostic tests have been available to
determine whether an in vitro cross-reactivity will cause a reaction in vivo. Tropomyosin is the main allergenic protein in crustaceans (shrimps, lobster, crab,etc.) and molluscs and it is the principal cause of the wide cross-reactivity betweenthese species.
It has been recently observed that more than 65% of plant food allergens belong
to only four structural families, the cereal prolamin superfamily, the cupins, the Betv 1 homologues and the prThis could lead to extensive IgE cross-reactivityeven among allergens belonging to taxonomically unrelated plants. Additionally,cross-reactive IgE binding can be retained by up to 35–40% of the amino acidsequence if the conformational structure is preserved. However, the in vitro IgEcross-reactivity is not always clinically expressed and can give rise to many falsepositive results with diagnostic tests; this implies that the elimination diet shouldnever be based only on allergological tests, but always on the revision of clinicalhistory supported in selected cases by appropriate challenge tests. It is thereforeimportant to avoid predefined lists of foods which are cross-reactive with a givepollen or, even worse, foods containing one of the so-called ‘panallergens’. Moreover, it is important not to forget that the majority of allergenic proteins inplants are widespread defensive molecules. To be allergenic a food must presentsome characteristics that are not related to its protein composition: the frequencyof consumption by a given population, the thermal stability upon food preparation,the digestibility in relation to gastric or intestinal fluids.
From a practical point of view, we recognise three main cross-reactivity
syndromes: the birch-fruit syndrome (sensitisation to birch pollen and foods suchas apple, carrot, hazelnuts etc.), the latex-fruit syndrome (sensitisation to latex andfoods such as chestnuts, avocado, banana) and the LTP syndrome (sensitisation topeach and other Prunoideae fruits, walnut, maize). The main elements defining across-reactivity syndrome are the presence of different symptoms related to theingestion of several foods (such as respiratory symptoms to pollen inhalation orcutaneous symptoms due to contact with another substance) and the identificationof a molecule that acts as a cross-reactive allergen. The allergens at the base of thesymptoms in the three syndromes mentioned above are Bet v 1, Hev b 6.02, andlipid transfer proteins, respectively. In other clinical pictures of reactivity to multipleallergens the lack of identification of a specific cross-reactive allergen does notallow a proper definition of a nosological entity. The definition of a cross-reactivitysyndrome also implies an epidemiological criterion as the symptoms due to cross-reactions must be clearly demonstrated in a considerable number of subjects, andnot only in single case reports.
Treatment of food allergy consists of the complete elimination of the allergen from thediet. This may create a problem of nutritional deficiency which can be avoided by usingvitamin and mineral supplements. Another problem is the possibility of not detectingthe allergen to be avoided in commercial foods. It is therefore important that thepatient pay attention to the labels of foods. Recently, the EC approved the Directive2003/89/ EC with respect to labelling which amends the previous Directive and statesthat the presence of the 13 allergenic ingredients, listed in the Annex IIIa, in foods mustbe declared ().
Table 2. Ingredients referred to in the Directive 2003/89/EC which have to be declared in the labelling offood products.
Directive 2003/89/EC of The European Parliament and of The Council Annex IIIaIngredients Referred To In Article 6(3a), (10) And (11)Cereals containing gluten (i.e. wheat, rye, barley, oats, spelt, kamut or their hybridised strains) andproducts thereofCrustaceans and products thereofEggs and products thereofFish and products thereofPeanuts and products thereofSoybeans and products thereofMilk and products thereof (including lactose)Nuts, i.e. Almonds (Amygdalus communis L.), Hazelnuts (Corylus avellana), Walnuts (Juglans regia), Cashews(Anacardium occidentale), Pecan nuts (Carya illinoiesis (Wangenh.) K. Koch), Brazil nuts (Bertholletia excelsa),Pistachio nuts (Pistacia vera), Macadamia nuts and Queensland nuts (Macadamia ternifolia) and productsthereofCelery and products thereofMustard and products thereofSesame seeds and products thereofSulphur dioxide and sulphites at concentrations of more than 10 mg/kg or 10 mg/litre expressed as SO2.
Specific immune therapy (SIT) for food allergens is not available. An experimental
study of SITusing peanuts was suspended due to the level of adverse reaction being too
New promising immunological approaches are being applied in the study of mice,
one of these is based on the use of recombinant allergens engineered with modificationof the epitopes, another employs the allergen mixed with heat killed listeria (HKL) as anadjuv
An interesting kind of approach to prevent serious food allergic reactions employs
humanized monoclonal anti-IgE antibodies. The antibodies connect to the IgE receptorson the mast cells without inducing cell degranulation and temporarily blocking thereaction. Preliminary reports indicate that anti-IgE therapy is able to significantlyincrease the quantity of peanut protein necessary to provoke allergy symptoms insubjects allergic to peanuts.The use of anti-IgE therapy in conjunction with SIT couldbe a useful treatment in the future.
Acute food reaction therapy is based on anti-histamine drugs (anti H1),
corticosteroids and in the case of life-threatening reactions, I M epinephrine. Thereis not an evident role for sodium chromoglycate.
Various researches have demonstrated that prolonged breastfeeding reduces the
incidence of allergic diseases. In particular, a meta-analysis highlighted the reduction ofatopic dermatitis in children predisposed to atopy who were breastfed for at least 3months compared to children predisposed to atopy who were fed cow’s milkfor thesame period. Another study demonstrated the preventive effect of breastfeeding on thedevelopment of asthma in children.On the base of this evidence both European andAmerican guidelinesrecommend exclusive breastfeeding for allergy-prone infantsfor 4–6 months and 6–12 months, respectively. American guidelines also advisemothers to avoid including peanuts and tree nuts from their diet during lactation.
Lactic acid bacteria (LAB) present in the human gut play a beneficial or probiotic role
including the improvement of the local immune system. Scientists have attempted to
select strains of LAB with immunostimulatory properties to use against gut diseases(bacterial, cancer) or to improve gastrointestinal mucosal immunity and OT. Somebeneficial effects on the prophylaxis of atopic dermatitis and other allergic diseases havebeen reporteThe role played by LAB on enhancement of gut and systemicimmunity is supported by extensive evidence but the development of an effective andsafe mucosal vaccine of LAB requires more basic knowledge on the gut antibodyresponse and on the pharmacokinetic of LAB vaccines.In conclusion, more studiesneed to be done before considering routine use of probotics in the prevention andtherapy of allergic disease.
† embracing the EAACI classification based on pathogenesis has improved the
comprehension of Adverse Reactions to food
† an adverse food reaction can only be confirmed when the relationship between
food ingestion and symptoms has been proven. A confirmed AFR can only beclassified as food allergy if SPT/RAST to the culprit food is positive
† ingestion of food rich in histamine generally does not produce disturbances† gastrointestinal anaphylaxis and oral allergy syndrome are the most common
† epinephrine is the medication of choice for anaphylaxis† the DBPCFC remains the only test which has been validated for diagnosis of
† the only treatment of food allergy consists of the complete elimination of the
† prolonged breast feeding reduces the incidence of allergic diseases
† the role carried out by intestinal flora and regulatory T cells in the
development of allergy must be further studied
† an agreement on the definition of anaphylaxis must be reached† controlled studies need to be done in order to validate an in vitro test which
† epidemiological and clinical studies are necessary for identification of the
threshold dose of anaphylaxis (Non-Observed Adverse Effects Level) indifferent enhancing conditions in order to improve the safety of food labelling
† new models of SIT, possibly combined with anti-IgE treatment, must be
The EAACI classification of adverse reactions to food based on pathogenesis allowsa clear understanding of these diseases. There is sufficient evidence to support
IgE-mediated food allergy based on many controlled studies, some randomised, thathave applied DBPCFC.
Symptoms can be clearly defined for every disease classified as IgE-mediated food
allergy from the results of studies based on DBPCFC.
Food intolerance is less clearly defined with the exception of lactose intolerance
which can be precisely diagnosed using the Breath Test.
The diagnosis of both food allergy and food intolerance must be based on the
demonstration that they are real harmful effects of the suspected food. Thisdemonstration can only be obtained by submitting the patient to DBPCFC. Skin andsierological tests can only confirm that the allergy is IgE-mediated. Studies have beendone to establish the cut-off values of specific IgE which may render DBPCFCunnecessary but they have not yet been confirmed.
The only efficient treatment for IgE-mediated food allergy (and intolerance) is the
absolute exclusion of the culprit food from the diet, even in ingredient form. Thecorrect application of the new European Directive for labelling will prevent the risk dueto hidden allergenic ingredients in commercial foods. The SIT is not currently available. An important norm of primary prevention for newborns prone to allergy is exclusivebreastfeeding for at least the first 6 months. There are interesting results regarding therole of probiotics in the promotion of a normal immunological state of the GALT but avalidation of these vaccines does not yet exist.
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JAVIER ERNESTO SHEFFER TUÑÓN (Resumen ejecutivo) Licenciado en Derecho y Ciencias Políticas egresado de la Universidad de Panamá, con Postgrado en Negociación y Métodos Alternativos para la Solución de Controversias, cursado en la Universidad Tecnológica de Panamá. Posee máster en estas disciplinas alternas al sistema tradicional de justicia ordinaria. Designado por el Mini
Schede tecniche PRESSIONI DI ESERCIZIO MAX AMMISSIBILI sezione: Schede Tecniche catalogo tecnico PRESSIONI DI ESERCIZIO MAX AMMISSIBILI Pressioni di esercizio max ammissibili in funzione della temperatura e del materiali (rating) secondo norme DIN 2401 Valvole flangiate max pressione d'esercizio ammissibile in Kg/Cm2 alla temperatura di °C Pressione acciaio fuso (1