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Review article S W I S S M E D W K L Y 2 0 0 9 ; 1 3 9 ( 2 1 – 2 2 ) : 3 0 0 – 3 0 7 · w w w . s m w . c h

Peer reviewed article

300

An overview of cow’s milk allergy in children

Avigael.H. Benhamou, Michela. G. Schäppi Tempia, Dominique. C. Belli, Philippe A. Eigenmann

Department of Paediatrics, Geneva University Hospital, Switzerland

Food allergies have increased over the past decade and are an important problem in daily clinical practice. They affect 6% of children and3 to 4% of adults. Furthermore, around 20% of the population falsely believe that they are aller-

gic to some foods and follow unnecessarily re-strictive diets. For infants, the problem is evenmore acute as they need appropriate feeding inorder to achieve normal growth and avoid boneand metabolic problems.

Although any food can cause a reaction, few foods are responsible for the large majority of thesymptoms: i.e., milk, eggs, wheat, peanuts, nuts,sh, shellsh. Of these, cow’s milk allergy is fre-

quently suspected in small children. It can be re-sponsible of a variety of symptoms and can becaused by IgE-mediated or non-IgE-mediated re-actions. The diagnosis relies on a detailed history,skin tests, laboratory tests, an elimination diet and

food challenges. The overall natural evolution of the disease is favourable with most patientsachieving tolerance to milk by the age of ve

years, but some patients will remain allergic forlife.

Key words: cow’s milk; milk; food allergy;eosinophilic oesophagitis; food protein-induced entero-colitis; children

Summary

Adverse reactions to foods or “food hypersen-sitivity” are dened by reactions triggered by in-gestion of food proteins. They can be divided intoallergic reactions and food intolerance [1]. Intol-erance to foods can be caused by a specic com-ponent of the food, such as pharmacologicalagents like monosodium glutamate or histaminefound in scombroid sh, non-specic mast cellactivation by irritating foods such as strawberriesor additives, or may be due to host factors, like inlactase deciency [2, 3].

The term food allergy refers to an immunereaction to the proteins in foods and can be fur-ther split into IgE and non-IgE (mostly cellular)-mediated reactions (g. 1). While IgE-mediatedreactions are well recognised with validated diag-nostic tests, the non IgE-mediated immune reac-tions that can arise in the gastro-intestinal tract are not so well dened and more difcult torecognise. Some of the reactions can also involveboth types of mechanism or evolve secondarily towards an IgE mediated allergy. Table 1 sum-marises the different forms of food allergy.

Cow’s milk proteins are among the major al-lergens involved into both types of allergy andprecise diagnosis is crucial for proper manage-ment. Children are the age group most frequently affected by this disease and should be followedcarefully as severe complications of a restrictive

diet have been described such as severe growthretardation, kwashiorkor, hypocalcaemia and rick-ets [4]. The term “bovine proteins intolerance” isfrequently used in cases of non specic symptomsattributed to milk, but should not be used in caseof milk allergy, whether they are IgE or non-IgE-mediated, these pathologies being caused by animmune reaction to milk proteins. Symptoms sug-gestive of cow’s milk allergy may be encounteredin about 5–15% of infants but when strict diagno-sis criteria are used, the incidence of milk allergy

seems to be about 2–5% [5, 6]. Most patientsdevelop symptoms before twelve months of age,

Introduction

No financial

support or benefits

have been re-

ceived by any

co-author fromany source that

is related directly

or indirectly to the

scientific work

reported in this

article.

Food hypersensitivity

Food allergy Non allergic

food intolerance

IgE-mediated

food allergy

Non-IgE-mediated

food allergy

Figure 1

Classification of food hypersensitivity.

Adapted from Johansson SG [52].

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301S W I S S M E D W K L Y 2 0 0 9 ; 1 3 9 ( 2 1 – 2 2 ) : 3 0 0 – 3 0 7 · w w w . s m w . c h

Pathophysiology IgE-mediated allergy presents when the or-

ganism fails to achieve normal tolerance to foodallergens. The major food allergens involved inchildren’s allergies are heat, acid, and protease sta-ble, water-soluble glycoproteins 10 to 70 kd insize. They include e.g., proteins in milk (caseins),peanut (vicillins), and egg (ovomucoid) and non-specic lipid transfer proteins found in apple (Mald 3). Heating or the method of cooking of foodsmight reduce (egg) or enhance (roasted peanut)allergenicity by modifying conformational epi-topes [8].

When food antigens are ingested, they areprocessed in the gut where the gastrointestinalmucosal barrier displays complex physical(mucus, epithelial cell tight junctions, acid, andenzymes) and immunological protective mecha-nisms. Abrogation of the barrier through stomach

pH neutralisation might promote food allergy [9].Similarly, developmental immaturity of compo-nents of the gut barrier (enzymatic activity andIgA production) might account for the increasedprevalence of food allergy in infancy.

Antigen-presenting cells, especially intestinalepithelial cells and dendritic cells, and regulatory

T cells play a central role in oral tolerancethrough expression of IL-10 and IL-4. Commen-sal gut ora might also inuence the mucosal im-mune response. Toleranc is largely established inthe rst 24 hours after birth and produces im-

munomodulatory molecules that have a benecialinuence on the development of certain immuneresponses. Recent studies have shown that imbal-ances in the composition of the bacterial micro-biota might be a major factor in allergy, asthma orinammatory bowel disease [10].

IgE-mediated allergy begins with sensitisa-tion. The allergens are ingested, internalised andexpressed at the surface of antigen presentingcells (APC). The APC interact with T-lympho-cytes and promote the transformation of B-lym-phocytes to antibody secretors cells. Once formedand released into the circulation, IgE binds,through their Fc portion, to high afnity recep-tors on mast cells, leaving their allergen specicreceptor site available for future interaction withallergen.

The process by which a non-IgE-mediatedallergy develops is less well understood but theinitial antigen recognition phase is probably simi-lar, and drives an inammatory reaction primarily mediated through T cells and eosinophils, involv-ing activation by different cytokines such as IL-5.

For an allergic reaction to occur, re-exposureis needed with, in case of IgE-mediated allergy,

binding of the allergen to allergen-specic IgEantibodies. Cross-linking of a sufcient numberof mast cell/basophil-bound IgE antibodies by al-lergen initiates a process of intra-cellular sig-nalling; this leads to degranulation of cells, withthe release of histamine and other mediators of inammation.

Clinical syndromes The most severe manifestation of IgE medi-

ated milk allergy is anaphylaxis. After mast celldegranulation, released inammatory mediators

affect multiple organs systems. Symptoms includepruritus, urticaria, angio-oedema, vomiting, diar-rhoea, abdominal cramps, respiratory difculty,

wheezing, hypotension, syncope, and shock. Cu-taneous symptoms are the most common, how-ever, up to 20% of anaphylaxis can present with-

often within one week after introduction of cow’smilk based formula but cases of development of amilk allergy at any age have been described.

Concerning meat, only around 10% of IgE-mediated milk allergic patients are also sensitised

to bovine serum albumin [7]. This protein is de-graded by heat and well cooked beef or veal meatsare usually perfectly tolerated.

IgE-mediated milk allergy

IgE-mediated Mixed IgE and cell mediated Cell mediated

Gastrointestinal Oral allergy syndrome Eosinophilic oesophagitis Food protein-induced enterocolitisGastrointestinal anaphylaxis Eosinophilic gastroenteritis Food protein-induced proctocolitis

Food protein-induced enteropathy

Cutaneous Angio-oedema, urticaria Atopic dermatitis Contact dermatitis

Morbiliform rashes Dermatitis herpetiformis

Flushing

Respiratory Acute rhinoconjunctivitis Food induced pulmonary haemosiderosis(Heiner syndrome)

Acute bronchospasm

Generalized Anaphylaxis

Table 1

Food Allergies.

Adapted from

Sampson HA [11].

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302Cow’s milk allergy

out involvement of the skin, particularly in chil-dren. The onset of symptoms from food-inducedanaphylaxis is variable but the majority of reac-tions manifest themselves within seconds to therst hour after exposure.

Among symptoms attributed to food allergy,atopic dermatitis is often cited. Indeed, it has been

well established that approximately 30% of chil-

dren suffering from moderate to severe atopicdermatitis present an associated food allergy that

worsens eczema. The most frequently involvedfood is cow’s milk and milk-specic IgE can befound in most patients. However some of themsuffer from non-IgE-mediated allergy and addi-tional tests such as epicutaneous tests or oralprovocation test can be essential to conrm thediagnosis.

Diagnosis testsSkin Prick Tests (SPTs)

SPT is a rapid and inexpensive means of de-tecting sensitization in IgE-mediated disordersand can be done in infants as well [11]. The nega-tive predictive value is excellent (>95%) and canconrm the absence of IgE-mediated allergic re-activity. However, a positive test response doesnot necessarily prove that the food is causal (poorspecicity), and only establishes sensitivity to thefood (atopy, in absence of symptoms of allergy).

Serum IgE antibody dosage The quantitative measurement of food-spe-

cic IgE antibodies is often the next step. The al-lergen of interest is bound to a solid matrix andexposed to the patient’s serum. IgE antibodiesspecic for the allergen bind to the protein-ma-trix and are detected by use of a secondarily la-belled antibody specic for the Fc portion of human IgE. Similar to skin tests, sensitisation canexist without clinical reactions and the tests can-not be used to diagnose food allergy without con-sideration of the clinical history. However, in-creasingly high concentrations of food-specicIgE correlate with an increasing likelihood of aclinical reaction. Different predictive values are

being generated from emerging studies, whichmight represent nuances of diet, age, disease, andchallenge protocols [12].

Despite an excellent sensitivity, a small subset of patients can still occasionally suffer from clini-cal reaction while serum food-specic IgE is un-detectable. Consequently, if there is a strong sus-picion of allergic reactivity, even with negativeIgE tests, an oral food challenge is necessary toconrm the absence of clinical allergy.

Oral food challenge (open or double blind)

When the diagnosis remains uncertain, theoral food challenge is the gold standard. A welldescribed protocol was published by SA Bock in1988 [13] and a standardised protocol has beenproposed by the European Academy of Allergy and Clinical Immunology in 2004 [14]. The pa-

tient ingests, over two hours, progressively in-creasing quantities of the suspected food. Theprocedure is interrupted when clinical symptomsappear (positive test) or after a substantial quan-tity has been ingested without reaction (negativetest). Because of the risk of anaphylactic reaction,this test must be performed under close medicalsupervision, with a trained team and an adequate

setting for resuscitation. This protocol is lengthy,costly and can cause anxiety and/or unpleasant clinical reactions, but is undoubtedly indicated inpatients with an unclear diagnosis [15].

Treatment Elimination diet

The cornerstone of food allergy treatment isthe elimination diet. Patients and their familiesmust be taught to read food labelling, which is es-pecially crucial for milk and eggs, both containedin many different preparations under various

names (for example butter, casein, cream, lactal-bumin, lactoglobulin or lactose for milk).

Booklets and educational materials are avail-able online in French [16] (http://allergoped.hug-ge.ch) or in English [17] (http://www.foodal-lergy.org).

For small children, elimination diets must beconsidered with the greatest caution and requireregular medical follow up, as they can seriously impair the quality of life and involve potentially severe side effects. When a cow’s milk allergy isdiagnosed in an infant, the practitioner must rec-ommend to the parents the use of a substitutionpreparation based on extensively hydrolysed cow’smilk and must follow the patient to decide thebest timing for the potential reintroduction.

Most parents wish to substitute cow’s milk foranother mammalian’s milk or a soy-based prepa-ration. However, virtually all cow’s milk allergicpatients suffer from a cross-reactivity to ewe andgoat’s milk and in addition, these milk varietieshave an inadequate nutritional composition tosuit the infant’s needs and might cause for exam-ple megaloblastic anaemia through folic acid de-ciency [18]. Some studies suggest that camel and

donkey’s milk might be immunologically bettertolerated but their composition is very different from human milk and may not be used [19].

Soy preparations, although historically therst prescribed, are not perfectly suited to the nu-tritional needs of children. Furthermore, despitethe absence of protein homology and cross-al-lergy, around 10% of IgE-mediated and 60% of non IgE-mediated allergic children are also aller-gic to soy [20, 21].

Extensively hydrolysed formulas are com-posed of a mixture of peptides and amino acids

produced from predigested bovine casein or whey and are tolerated by 95% of milk allergic chil-dren. In case of persistent symptoms, an amino-acids based formula can be used, especially inchildren with multiple food allergies or growthimpairment. In Switzerland, 3 extensively hydro-

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lysed formulas (Althéra, Damira or PregominPepti) and 2 amino acids formulas (Pregomin ASand Neocate) [22] are available.

Therefore, the use of soy preparation shouldbe discouraged and reserved, after an extended al-lergy work-up, to infants suffering from galac-tosaemia and to children older than six months

whose parents refuse hydrolysed milk for nan-

cial or ethical (vegan) reasons [23]. Thus, an extensively hydrolysed formula is

the recommended substitute in cases of milk allergy of infants and small children.

Emergency treatment The physician must prescribe and explain the

use of an emergency treatment in case of acciden-tal exposure. This treatment includes oral antihis-tamine for mild cutaneous or digestive reactionsand self-injectable adrenaline (Epipen® or

Anapen®) for systemic or respiratory reactions. A

self-injectable adrenaline prescription is indicatedfor patients at risk of a severe reaction, as shownin table 2. Steroids can also be prescribed to pre-

vent rebound and late phase symptoms but thepatient must be clearly informed of their delayedeffect and that their use should not delay adrena-line therapy.

Promising treatments Treatments directed at curing food allergy are

currently under development. Several studieshave shown that oral immunotherapy is a promis-ing approach, especially in patients with severe

and persistent food allergy and recent studieshave described successful trials with hen’s egg andcow’s milk [24]. Immunomodulatory approachessuch as anti IgE or anti IL-5 have also shown in-teresting results in recent clinical studies but needto be validated in larger trials.

Food allergy prevention

Maternal diet modulation such as dietary antigen avoidance during pregnancy or lactationhave failed to show efcacy in atopic diseases pre-

vention (atopic dermatitis, food sensitisation orasthma) [25, 26].

For infants, actual European and Americanrecommendations rely on exclusive breast feedingfor 4–6 months, followed by the delayed intro-duction of solid foods in children with atopic risk (atopic parents or siblings, or children with atopicdermatitis) [26]. However, recent studies suggest that infants who are exposed to food allergens

early in life through the oral route are less likely to have food allergies than infants without suchexposure. Such prevention strategies may evolvein the next few years [27]. Conversely, it has beendemonstrated that a precocious cutaneous expo-sure to food allergens could promote sensitisationand development of food allergy, at least forpeanuts [28, 29].

Currently, there is no evidence for a benecialeffect of early introduction of specic foods toprevent food allergy.

Supplementation with pre and probiotics hasshown contradictory results and further studiesare therefore necessary to determine their possi-ble utility in allergy prevention[30].

Evolution IgE-mediated milk allergy in children has

been shown to resolve in most patients before theage of three years. Therefore, infants should beregularly evaluated by a specialist (paediatricallergologist or gastro-enterologist), who willdecide the best timing for milk reintroduction.

However, around 20% of patients will remainallergic for a longer time period. Prognostic fac-

tors for oral tolerance development depend onmilk-specic IgE levels and their decrease overtime. Even adult milk allergic patients can de-

velop tolerance at a later time and regular follow-up should be proposed.

Absolute indications:

– Previous cardiovascular or respiratory reaction to a food,insect sting or latex

– Exercise induced anaphylaxis

– Idiopathic anaphylaxis

– Child with IgE-mediated food allergy and co-existent persistent asthma

Relative indications:

– Any reaction to small amounts of a food(e.g., airborne food allergen or contact only via skin)

– History of only a previous mild reaction to peanut or a treenut

– Remoteness of home from medical facilities

– Food allergic reaction in a teenager

Table 2

Indications for

prescribing self-in-

jectable epinephrine .

Adapted from

Muraro A [14].

Gastrointestinal cow’s milk allergy

Pathophysiology

The basic mechanism leading to a breach of tolerance leading to allergy is yet not well estab-lished. Various factors, related to the patient (genetic factors, gut ora) and unrelated (timing,dosage, frequency of allergen exposure) interact inthe pathogenesis of this disease. In gastrointesti-

nal allergies, most patients suffer probably from a

type IV reaction with an abnormal responsivenessof TH2 lymphocytes. These produce increasedquantities of inammatory mediators, such asIL-4 and IL-5, as well as chemokines, leading toeosinophil activation and recruitment. In somepatient, a mixed IgE and non IgE-mediated al-

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lergy can develop and diagnostic tests shouldaddress both mechanisms [31].

Clinical syndromesPatients with gastrointestinal milk allergies

may present with various clinical symptoms, ac-cording to localisation of the inammation(table 3). Heiner’s syndrome is another expression

of non IgE-mediated milk allergy in which pa-tient present with chronic respiratory symptoms,pulmonary inltrates, pulmonary haemosiderosisand serum precipitating antibodies to multiplecows’ milk protein fractions. This rare disease hasbeen well described in a recent article by Mois-sidis and colleagues [32].

Eosinophilic gastroenteropathies These are dened by inltration of the intes-

tinal wall by eosinophils. Historically and ana-tomically, three clinical entities have been des-

cribed: milk-induced colitis, eosinophilic oesoph-agitis and food protein-induced enterocolitis. Those pathologies have an increasing clinical

importance, as their recognition is relatively re-cent, and their prevalence seems to be markedly increasing. The differential diagnosis of digestiveeosinophily is broad and must include inamma-tory bowel disease, parasitic infections, and hy-pereosinophilic syndrome or drug hypersensitiv-ity. No diagnostic test is pathognomonic and thediagnosis of gastrointestinal eosinophilic allergy must rely on the clinical presentation, cuta-neous/epicutaneous tests, biopsy and/or oral foodchallenges.

Food and cow’s milk colitis Rectal bleeding is an alarming symptom but

is generally benign and self-limiting but can beattributed to milk allergy in about 20% of thecases [33]. Affected infants may present with iso-lated rectal bleeding with mucus emission fromthe rst hours of life, probably through in uterosensitisation, or before the rst 3 to 6 months

of life but usually remain in excellent generalcondition. Rectal biopsy demonstrates a typicaleosinophilic inammation with occasionally ero-sion of the epithelium, microabscess or brosis.Symptoms are induced by cow’s milk proteinscontained in formula milk or breast milk, half of the patients being diagnosed while exclusively breast-fed. Most of those infants are only allergicto milk but approximately 20% can also react toeggs and less frequently to other food proteins.Clinical evolution is usually excellent with resolu-tion of symptoms within ve days after a cow’s milk

free diet for the mother or the change to a hydro-lysed preparation for the baby. In case of failure of maternal diet, an additional removal of eggs fromthe diet may be considered. Occasionally, the affec-tation is more severe and a fully hydrolysed oramino-acid diet is required. This allergy usually re-solves in a few months, allowing milk reintroduc-tion between 6 and 12 months of age.

Eosinophilic oesophagitis This disease has only been identied as a

proper entity in the last 15 years and studies show a rising prevalence. It affects mainly men in theirsecond or third decade of life, but it is increas-ingly reported in the paediatric literature [34]. It is dened by an inltration of the oesophagus by eosinophils, and associated with symptoms of re-ux resistant to proton pump inhibitor therapy.

Digestive allergies Symptoms Complications Diagnosis Tests Evolution Treatment Non IgE-mediatedor mixed

Food and milk colitis Rectal bleeding with Anaemia (seldom) Elimination diet Resolution in Elimination diet followedmucus emission on for the mother or 6–12 months 6 month later

an infant extensively hydrolysed milk by a reintroduction test (non breast fed infant ormaternal diet failure),colonic biopsy if resistant totreatment stool culture

Eosinophilic Regurgitations, reux, Failure to thrive, Endoscopy, biopsy, Long lasting Elimination diet,oesophagitis anorexia, dysphagia weight loss, cutaneous and epicutaneous topical (swallowed)

or food refusal, oesophageal stricture tests, or systemic steroids vomiting, gastric pain amino-acid diet and oral

provocation tests

Food Protein- Intractable vomiting Leucocytosis, Suggestive history, Children: Elimination diet followedInduced and/or diarrhoea hypovolemic shock, possibly resolution in by reintroduction test Enterocolitis 2–4 h after the ingestion metabolic acidosis, epicutaneous and/or 2–5 yearsSyndrome (FPIES) hypotension oral provocation test Adults:

resolution orpersistent

Food protein- Insidious symptoms, Hypereosinophilia, Endoscopy, biopsy, Milk : resolution Elimination diet and doubleinduced enteropathy abdominal discomfort, haematemesis/rectal skin prick and in 1–2 years blind placebo controlled

dysphagia, weight loss, bleeding, iron deciency epicutaneous tests, Solid foods: provocation tests vomiting, diarrhoea anaemia, hypoalbumin- oral provocation tests slow resolution

emia, failure to thrive or persistent

Table 3

Non-IgE-mediated food allergies.

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Patients usually complain of ill-dened symp-toms of discomfort, dysphagia and tend to avoideating brous or dry foods. Children present as-pecic symptoms such as abdominal pain, vomit-ing or regurgitation and anorexia, or isolatedgrowth failure. Endoscopy can show various fea-tures from normal to patchy white or red areas

with occasionally oesophageal strictures, with a

typical tracheiform aspect. Biopsies reveal denseinltration of the wall by eosinophils (>15–20

/eld). This oesophagitis can be complicated by oesophageal stenosis and food impaction [34, 35].Eosinophilic oesophagitis is usually caused by afood allergy with a mixed IgE and non IgE-medi-ated mechanism, in particular in children andteenagers. In adult patients, the prevalence of atopy is also very high, but in addition to foods,sufferers may also react to inhaled allergens.Non-allergic immune reactions also seem to co-exist.

Allergen identication must be coordinatedby a specialist as it can be very troublesome as various antigens might be involved. An adaptedelimination diet with elemental (amino acids) orsemi-elemental formulas can lead to symptomresolution in 30–70% of affected patients [36, 37].Nevertheless, the use of topical or systemic steroidsis frequently required, especially if the causal foodcan not be clearly identified or if the inflammationlasts for a long time.

Food protein-induced enterocolitis This allergy can present with spectacular

symptoms of intractable vomiting and/or bloody-mucous diarrhoea that can lead to lethargy andhypovolaemic shock. The symptoms appear aftera free interval, mostly two hours after ingestion of the allergen. Children presenting with thesesymptoms are frequently worked-up for suspicionof sepsis. The blood count during the acuteepisode exhibits a marked leukocyte reaction withhigh levels of immature forms (non-segmentedneutrophils). The mechanism is non-IgE-mediated and food specic IgE remains unde-tectable. Colonic biopsies reveal cryptic abscess

with diffuse inammatory inltration. This al-lergy can also be caused by food proteins otherthan milk, as reactions to soy, sh, rice, potato andchicken have been described [38].

The natural history of milk-induced entero-colitis is usually good after a 2–3 year eliminationdiet whereas the evolution might be more pro-longed in patients with solid food protein-in-duced enterocolitis. Patients with unclear clinicalpictures should have a thorough diagnostic work-up with endoscopy and biopsies in order to ex-clude an eosinophilic disease.

Food protein-induced enteropathy This insidious form of allergy is slowly evolv-

ing within several days or weeks. Patients sufferfrom chronic diarrhoea, bloating, vomiting and

weight loss or failure to thrive in children, similar

to that appearing in coeliac disease. The diagnosisis most often made on the basis of clinical experi-ence and elimination/challenge tests. However,depending on the clinical presentation, gastroin-testinal biopsies are helpful to adequately identify the disorder at the tissue level and exclude otherdisorders. On small bowel biopsy, a picture simi-lar to coeliac disease, though usually less pro-

nounced, such as patchy partial villous atrophy and crypt hyperplasia may be found with in-creased numbers of intraepithelial lymphocytes.

Intestinal protein and blood loss leading to thehypoalbuminaemia and anaemia arefrequentlyob-served in this syndrome.It usually affects infants inthe rst months of life and responds to cow’s milk elimination. In older children, soy must also beconsidered and a case report of reactions to eggshas also been published [39].

Diagnosis

Skin Prick Tests (SPT) They are much less useful in food-sensitive

digestive allergy than in IgE-mediated allergies.In non-IgE-mediated allergies, such as food- pro-tein induced enterocolitis or milk colitis, the test is negative. However, the SPTs can be useful torule out an IgE-mediated allergy or in patholo-gies involving combined mechanisms, especially in eosinophilic oesophagitis where they can helpthe identication of the causal allergen [40].

Atopy patch test In this test, the food is applied for 48 hours

against the skin in a sealed patch. The test is posi-tive if erythema, induration and/or vesiculous le-sions appear 24 to 48 hours later at the site of thepatch. It reproduces theoretically a T-cell mecha-nism similar to the possible mechanism of an en-teropathy. However, T-cells from different sitesexpress different homing markers, such as CLA (Cutaneous Lymphocyte Antigen) for the skinand α4β7-integrin for the gut, which may alterthe sensitivity and specicity of the test [41]. Thistest has been better studied in severe atopic der-matitis where its sensitivity is around 65%. It has

been shown to be helpful in identifying the causalfood in eosinophilic oesophagitis in children [40]but is frequently negative in adult patients.

Elimination diet and oral food challenges The cornerstone of diagnosis of food-induced

gastrointestinal allergy is a response to an elimi-nation diet, with recurrence of the symptomsupon challenge. As allergic reactions are usually delayed, the elimination diet must be performedfor at least one month before the food challenge.In obvious cases where a single food is implicated

and the patient improves dramatically during theelimination period, the food challenge may beomitted. However, the identication of the causalfood(s) is often strenuous and the specialist might sometimes have to prescribe an extremely restric-tive “oligo-antigenic” diet. When symptoms are

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well controlled, the diet is then progressively di- versied to determine the patient’s tolerance. This type of investigation should be reserved forparticularly complicated cases [42, 43]

In some allergic syndromes such as food pro-tein-induced enterocolitis, the challenge cancause a very serious clinical reaction leading tohypovolaemic shock. Therefore, it is mandatory

to insert an intravenous line and have medical su-pervision with resuscitation facilities and appro-priate treatment available. For late reactions, thecumulative intake must also be sufcient as somepatients can tolerate a small quantity of the aller-genic proteins without demonstrating overt symptoms. The food challenge is used as a diag-nosis test but should also be envisaged for the fol-low up when it is reasonably likely that tolerancehas been regained [44].

In vitro tests

In vitro tests such as ECP (EosinophilicCationic Protein), basophil activation tests orlymphocyte proliferation tests have not demon-strated an acceptable sensitivity and/or specicity in the diagnosis of food allergies [45, 46].

Endoscopic examination and biopsies Endoscopic examination demonstrates and

characterises inammation of the gut mucosa andenables verication of the absence of other aeti-ologies such as inammatory bowel disease, neo-

plasia or infectious disease. Histological charac-teristics may vary according to the clinical syn-dromes and are detailed earlier.

Treatment Elimination diet

Similarly to IgE-mediated allergies, elimina-tion is the only effective measure. After diagnosis,

patients must be reassessed regularly to decide onthe best timing of reintroduction, especially in

young children in whom a diet must be as limitedas possible to avoid possible deciency and whomallergies tend to spontaneous rapid resolution.

Steroids and other medical treatments In cases of multiple food allergy or when the

causative antigen cannot be clearly identied, inparticular for long lasting eosinophilic oesophagi-tis, steroids might be necessary to achieve diseasecontrol. Initially, steroids where used systemically,

mostly orally, but recent studies have demon-strated good results with swallowed uticasone,administrated via an inhaler without spacer [47].

Anecdotalreportsofsuccessfuluseofcromogly-cate [48, 49] or montelukast [50] have been pub-lished. Novel therapies, such as humanised anti-IL-5 (mepolizumab) may be a useful adjunct inthe treatment of severe refractory eosinophilicgastroenteropathies and other hypereosinophilicdisorders [51].

Conclusion

Cow’s milk allergies are frequently suspectedby patients and the general population incriminat-ing milk in many symptoms, often without any medical justication. The various clinical syn-dromes related to milk are indeed quite diversebut are nevertheless well dened. Furthermore,elimination diets are cumbersome, impair quality of life, and can lead to serious detrimental effects,

especially in children and should only be pre-scribed after a proper allergy workup. An elimina-tion diet must be clearly explained to the patient,

with the help of a dietician if needed, and the pa-tient should be adequately substituted, especially

with calcium, in order to avoid any nutritional de-ciency. Regular medical evaluation usually allowsmilk to be reintroduced after a few months or

years.

Correspondence: P. A. Eigenmann, Department of Pediatrics

Geneva University Hospital 6 rue Willy-Donzé CH-1211 Genève 14Switzerland

E-Mail: [email protected]

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