VIEWPOINT ARTICLE

Gastrointestinal manifestations of cow’s milk protein allergy andgastrointestinal motilityYvan Vandenplas (yvan.vandenplas@uzbrussel.be)1, Frederic Gottrand2, Gigi Veereman-Wauters1, Elisabeth De Greef1, Thierry Devreker1,Bruno Hauser1, Marc Benninga3, Hugo SA Heymans3

1.UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium2.Department of Paediatrics, Jeanne de Flandre, University Hospital, Faculty of Medicine, University Lille2, Lille, France3.Department of Paediatrics, Academic Medical Centre ⁄ Emma Children’s Hospital, Amsterdam, The Netherlands

KeywordsConstipation, Cow milk protein hydrolysate, Cow’smilk protein allergy, Extensive hydrolysate,Functional gastrointestinal symptoms,(Gastrointestinal) motility, Gastro-oesophagealreflux, Intolerance, Prevention of cow’s milk allergy,Regurgitation, Treatment of cow’s milk allergy

CorrespondenceYvan Vandenplas, UZ Brussel, Laarbeeklaan 101,1090 Brussels, Belgium.Tel: +3224775780 |Fax: +3224775783 |Email: yvan.vandenplas@uzbrussel.be

Received10 April 2012; revised: 19 July 2012;accepted 1 August 2012.

DOI:10.1111/j.1651-2227.2012.02808.x

ABSTRACTCow’s milk protein allergy (CMPA) may cause gastrointestinal motility disorders. Symptoms

of both conditions overlap and diagnostic tests do not reliably differentiate between both. A

decrease of symptoms with an extensive hydrolysate and relapse during challenge is not a

proof of allergy, because hydrolysates enhance gastric emptying, a pathophysiologic mech-

anism of gastro-oesophageal reflux (GER). Thickened formula reduces regurgitation, and

failure to do so suggests CMPA. A thickened extensive hydrolysate may induce more rapid

improvement, but does not always differentiate between CMPA and GER. Different hypoth-

eses are discussed: is the overlap between CMPA and functional disorders coincidence, or

do both entities present with identical symptoms, or does the fact that symptoms are iden-

tical indicates that there is only one entity involved? Studies on the prevention of CMPA

focused on ‘at-risk families’, and resulted in a decrease of CMPA and atopic dermatitis, but

did not provide data on the incidence of GER.Conclusion: As long as there are no objective diagnostic tools to separate GER from

CMPA, the physician has two options: first treat the most likely diagnosis, and switch if after

2–4 weeks there is no improvement, or treat both conditions with one intervention, what

will not result in a diagnosis.

INTRODUCTIONThe overlap between gastrointestinal (GI) manifestations ofcow’s milk protein allergy (CMPA) and frequent (func-tional) GI complaints such as gastro-oesophageal reflux(disease) [GER(D)] and constipation is a topic of debatesince many years. The debate is the logic consequence ofthe fact that objective diagnostic criteria for each of the enti-ties are missing. Because not one sign or symptom is specificfor CMPA, and because the same is valid for GER(D) andconstipation, and because all conditions are relatively fre-quent, it is a given fact that some of the allergic infants willpresent with GER(D) and ⁄ or constipation and that some ofthe infants with GERD or constipation will have CMPA.Many infants with CMPA present symptoms in differentorgan systems (1). Because GI manifestations are only partof the spectrum of symptoms caused by CMPA, this paperdoes not discuss CMPA in general. If more than one organsystem is involved (mainly GI and cutaneous symptoms, orGI and more general symptoms or more rare GI and respi-ratory tract symptoms), a systemic or (auto-)immune orallergic reaction is very likely (1).

The debate is focused on cow’s milk as this is themajor food allergen in infants. While regurgitationdecreases strongly between 6 and 12 months of age (2),tolerance to cow’s milk protein (CMP) does only develop

after the age of 1 year (1). There is also a pathophysio-logic overlap: an allergic reaction causes inflammationand secretion of substances such as histamine and seroto-nin. The GI tract reacts to the inflammation by alteringmotility. As a result, the question raises if there is ‘coinci-dence’ or if ‘one is the logic consequence of the other’.From the point of view of the gastroenterologist lookingto the GI tract as an organ responsible for transport offood from mouth to anus, regurgitation and constipationare mainly regarded as ‘functional disorders’, becauseanatomic malformations are infrequent. Definitions havebeen proposed in the Rome III criteria (3).

The recent changes in formula composition, such as addi-tion of nucleotides, long-chain poly-unsaturated fatty acids(LcPUFAs), prebiotic oligosaccharides and ⁄ or probiotics,are likely to interfere in this debate. All these novelties claimto induce a better immune response and to decrease allergy.They also potentially change GI tract motility. It is, forexample, claimed that stools are softer with the added pre-and probiotics. Most of the epidemiologic data on CMPA ⁄ Idate from before these additions. Epidemiologic data col-lected after the formula changes listed above in unselectedpopulations are missing. If the claimed theoretical benefitresults in a clinical benefit, the incidence of frequent GIcomplaints should have decreased.

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COW’S MILK PROTEIN ALLERGY OR FUNCTIONAL GI SYMPTOMS?Cow’s milk protein allergy is a reproducible clinicallyabnormal reaction to cow’s milk protein (CMP) owing tothe interaction between one or more milk proteins and oneor more immune mechanisms. About 90% of the patientsdevelop symptoms before the age of 3 months dependingon the moment of CMP introduction or within 2 monthsafter introduction. CMPA rarely develops after the age of12 months. Improvement or disappearance of symptoms ona CMP-free diet adds substantial evidence to the diagnosis.A factor that often is not considered is the time needed forimprovement of symptoms; the sooner, the more likely thatallergy may be involved. If the reintroduction of CMPcauses relapse of symptoms, the diagnosis seems estab-lished, because a challenge test is considered as the goldenstandard diagnostic test.

Although false-positive diagnostic testing (specific IgE,skin prick test, patch test) does occur, the diagnosis ofCMPA is ‘likely’ if patients present with suggestive symp-toms and (one of) these tests show(s) positive results. But,CMP can also lead to non-IgE-dependent reactions. Somesymptoms are more frequently linked to non-IgE-mediatedallergy. In daily routine, there is no diagnostic testing fornon-IgE-mediated allergic reactions. But, immunoglobulinfree light chain (Ig-fLC)-dependent allergic hypersensitivityresponses have been demonstrated to occur (in mice) (4).Also, in children affected with IgE-mediated and non-IgE-mediated CMPA or atopic dermatitis (AD), serum Ig-fLCconcentrations were increased, implying the relevance ofIg-fLC measurements in the diagnosis of human allergic dis-ease (4,5). These findings suggest that in the future, parame-ters may become available to contribute to the diagnosis ofCMPA, although the overlap between ‘allergic’ and ‘nonal-lergic’ children is important (4). The relationship betweenIg-fLC and GI symptoms has not been investigated.

The old term ‘intolerance’ gives rise to confusion. Toavoid this, ‘intolerance’ is proposed to be restricted to theincapacity to fully digest carbohydrates, mainly disaccha-rides, of which lactose is the most important one. Primarylactose intolerance is an almost nonexisting disease at thisage. Thus, if lactose intolerance occurs in infants, it is almostalways secondary to another disease and the consequenceof atrophy or damage of the villi. Low lactase activity mayalso be the consequence of a transitory slow maturation inwhich case the undigested lactose acts as a prebiotic. As aconsequence, the term ‘adverse reaction’ would be prefera-ble to ‘intolerance’. The question arises how to make the dif-ference between an ‘allergic reaction of which theimmunologic mechanism involved cannot be shown in rou-tine’ (non-IgE-mediated allergy) and a ‘functional’ symp-tom? Bearing this in mind, the term ‘non-IgE-mediatedCMPA’ will be used to designate this group of infants withadverse reactions to CMP and no increase of specific IgE orno clear positive dermatological contact tests such as skinprick or patch tests.

Gastro-oesophageal reflux (D) has always been men-tioned as one of the presenting manifestations of CMPA.Buisseret mentioned ‘vomiting’ as a typical presenting

symptom of CMPA in a Lancet paper in 1978 (5). Forgetreported in 1985 a small series of 15 children presentingwith recurrent vomiting, not responding to GER therapy,that became symptom free on a CMP-free diet (6). Difficul-ties to demonstrate the relation between CMPA and GERare illustrated in the study by Nielsen et al. (7). The authorsperformed a 48-h pH monitoring in infants presenting withGERD and cow milk hypersensitivity; they could demon-strate that the pH monitoring was more abnormal in infantswith ‘GERD and allergy’ than in the other groups, but achallenge test did not increase reflux (7). Ravelli et al. (8)used electrogastrography to show that gastric motilityreacted different to a CMP challenge in control infants,infants with GERD and infants with CMPA. This abnormalmotility could be related to a delayed gastric emptying (8).A cow’s milk challenge increases weakly acidic reflux(pH > 4 and <7) in children with CMPA and GER (9).Impedance-pH monitoring may therefore be useful in iden-tifying a subgroup of infants with cow’s milk protein-induced GERD (9).

Unfortunately, only rough estimates can be made on theprevalence or incidence of GI manifestations of CMPA. Theconsequence of the definition that not every allergic reac-tion is IgE mediated in combination with the fact that todayonly IgE reactivity can be measured in daily routine is thatnon-IgE-mediated allergy has become a synonym for intol-erance or adverse reaction. Studies using a stringent scien-tific approach focus mainly on IgE-mediated allergy and ⁄ ora positive challenge test and report 2–5% as the incidenceof CMPA. However, up to 10% or even 15% of the infantsseem to develop ‘some adverse’ reactions to cow’s milk.

There is a quite broad consensus that in infants a chal-lenge test can be performed ‘open’, mainly because of thecomplexity of a double-blind challenge (1). If no symptomsare elicited within 2 weeks of regular cow’s milk feeding,CMPA can be excluded. Challenge tests can be performedin an inpatient or outpatient setting to document signs andsymptoms, the milk volume that provokes the symptomsand to give symptomatic treatment if needed (10). The start-ing dose during milk challenge should be lower than a dosethat can induce a reaction and increase stepwise to 100 mL(1,10). More details on the practical aspects of a challengetest are discussed elsewhere (1). To rule out a false-positivetest result owing to lactose intolerance, the challenge proce-dure should be performed with a lactose-free CMP-contain-ing milk (10). Challenges should be carried out in a hospitalsetting in the following circumstances: a previous history ofimmediate type allergic reactions, unpredictable reactionsuch as in infants with positive IgE sensitivity who has neverbeen given cow’s milk or has not been given cow’s milk fora long time, and severe atopic eczema (owing to difficulty inassessment) (10).

It is known that a double-blind challenge reduces thenumber of infants considered ‘allergic’ after a positive openchallenge with about one-third (11). Infants that react 24 hor even later to a challenge or react only to large volumesmay not be picked up by a double-blind challenge. Althoughsymptoms during the challenge are most of the time the

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same as the original presenting symptoms, this is not adogma. During challenge, presenting symptoms may differfrom the original. As said before, infants with non-IgE-med-iated CMPA tend to become tolerant to CMP more rapidlythan those with IgE-mediated CMPA. The higher the IgElevel, the more likely the allergy is going to persist (12). Thismeans that if a challenge is performed some months afterthe initial suspected diagnosis and turns out negative, it can-not be concluded that the original diagnosis of CMPA waserroneous. A negative challenge only means that at themoment of the challenge the food is tolerated. And a posi-tive challenge does not confirm that the immune system isinvolved.

Bearing all the above in mind, it seems reasonable to esti-mate that between 5% and 10% of the formula-fed infantswill develop some adverse reaction to CMP. Unfortunately,there are insufficient data on the number of supposed aller-gic infants that present ‘only’ with GI manifestations. About20% of all 3- to 4-month-old infants regurgitate more thanfour times a day, and this seems to be a threshold for moth-ers to seek medical help (13). It is probably reasonable toestimate the (recent) prevalence of infant constipationbelow 5%. Prebiotic-supplemented formula is well toleratedby full-term infants. It increases stool colony counts of bifi-dobacteria and lactobacilli and results in stools similar tothose of breastfed neonates without affecting weight gain(14,15). The administration of Lactobacillus reuteri (DSM17938) in infants with chronic constipation had a positiveeffect on bowel frequency, even when there was noimprovement in stool consistency and episodes of inconsol-able crying episodes (16).

In the light of the difficulties to distinguish betweenallergy and adverse reactions and functional disorder, thequestion arises if ‘the overall prevalence of GI complaints’could not be considered as an equivalent for ‘IgE- and non-IgE-mediated’ allergy? To obtain more accurate data onprevalence and incidence, proactive data collection viaquestionnaires in representative population samples is man-datory to minimize the impact of parental coping with thesefrequent symptoms.

In daily primary health care, it is not easy and possiblyeven not clinically relevant to separate functional disordersfrom non-IgE-mediated allergy if therapeutic options tack-ling both conditions can be offered. Efficacy of certain ther-apeutic interventions does not help to separate non-IgE-mediated allergy from functional GI manifestations. Therecommended treatment of CMPA is elimination of CMPfrom the mother’s diet in breastfed infants, amino acid-based formula (AAF) in formula-fed infants with ‘severe’manifestations of CMPA (life-threatening symptoms, failureto thrive) or extensive hydrolysates for the majority ofinfants (1,10). Published evidence with the new rice hydro-lysates is too recent and limited to include them in guide-lines (10). The NASPGHAN-ESPGHAN guidelines on themanagement of regurgitation and reflux recommend in dis-tressed and regurgitating infants a therapeutic approachwith either thickened formula or an extensive hydrolysate(13). If a thickened ‘regular infant formula’ results in a

significant reduction of episodes of regurgitation, allergyseems unlikely because protein structure did not change.But what if an extensive hydrolysate results in a significantreduction of regurgitation? As hydrolysates have a muchfaster gastric emptying than native protein, and as delayedgastric emptying is a pathophysiologic mechanism causingGER, improvement of regurgitation with a hydrolysate can-not be considered as a proof of allergy. Partial hydrolysatesare not indicated in the treatment of CMPA (1,10). Partialhydrolysates may be tolerated in about half of the infantswith IgE-mediated CMPA (17). Partial hydrolysates are alsoconsidered to be more ‘easily digested’, although scientificevidence for this statement is missing. Several infant for-mula companies commercialized thickened partial hydroly-sates. As a consequence, a thickened extensive hydrolysatemay be considered as a treatment option in infants present-ing with troublesome regurgitation and in whom ‘allergy’would be a plausible diagnosis on clinical grounds. This atti-tude would mean that a number of nonallergic infants aregiven an extensive hydrolysate for no reason and that anumber of allergic infants are given a thickened formula forno reason. But, up to now there is no convincing literatureregarding nutritional adverse events of a thickened formulaor an extensive hydrolysate, if cost is not considered. In dif-ficult cases, AAF may contribute to separate infants withCMPA from those with reflux. Indeed, about 5% of theCMPA infants may still react to an extensive hydrolysate(1). If that is the case, the infant will improve with AAF.Mainly because AAF is very expensive, and because reim-bursement systems differ from country to country, there isstill debate whether AAF should be used ‘first line’ (in allinfants) or ‘second line’ (only in infants not improving oneHF). A long-term elimination diet and feeding restrictionsmay lead to intake problems during diversification. In‘clear-cut’ CMPA, the CM-free diet is recommended at leastduring 6–9 months and up to the age of 1 year (1).

The difficulties to diagnose CMPA strengthen the impor-tance of prevention. Infant formula is derived from cow’smilk for the simple reason that there are many cows andbecause cows provide more milk. There is broad consensusthat almost every constituent of cow’s milk needs to beadapted according to better fulfil the nutritional needs ofinfants: the total amount and proportion of protein, theamount of minerals, the addition of nucleotides, LcPUFAs,etc. So, why not accept that it would also be preferable tochange the structure of the proteins and feed every infant a(partial) hydrolysate? Unfortunately, data showing benefitof doing so are limited to at-risk populations. There are verylimited data showing a reduction of CMPA in the generalpopulation. This is merely the consequence of methodologi-cal problems regarding the size of the needed study popula-tions. There are in absolute numbers more allergic childrenin the non-at-risk group than in the at-risk group, for thesimple reason that the non-at-risk group is much larger.

Regarding constipation, a similar criticism can be hypoth-esized. Several studies mentioned constipation as a (fre-quent) symptom of CMPA. But milk, especially casein, isknown to constipate. Hydrolysates are known to cause soft,

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greenish stools. One of the studies on CMPA and refluxused soy formula as treatment, thus avoiding the stool-soft-ening effect of hydrolysates (18). However, this study can becriticized because it was reported that soy formula waseffective in 100% of the CMPA allergic infants, while thereis consensus that at least some (around 10%) CMPA infantsdevelop also allergy to soy. Moreover, paediatric gastroente-rologists ‘know’ (although epidemiologic data are missing)that constipation as a ‘functional disorder’ on soy formulaexists, probably with the same frequency as functional con-stipation with regular infant formula. Again, whether this is‘functional’ or ‘non-IgE-mediated allergy’ can be debated. Isconstipation really a symptom of CMPA? According to datafrom Italy, the incidence of constipation is not different inatopic and nonatopic children (19). Therefore, constipationas single manifestation of CMPA seems to be relatively rare.‘Anti-constipation formulas’ have been commercialized.Although some of these formulas have been evaluated insmall trials (20,21), scientific evidence is very limited. Asextensive hydrolysates are known to cause greenish semi-solid stools, their use could be considered, although thereare no data on the efficacy of extensive hydrolysate in infantconstipation. An interaction between GER ⁄ regurgitationand constipation has been advocated as well. Frequentregurgitation will result in an excessive loss of water, andmay therefore be considered as a risk factor for constipa-tion.

SUMMARYIt is extremely difficult, virtually still impossible today, toseparate ‘non-IgE-mediated allergy’ from ‘functional disor-ders’ in infants presenting with GI adverse reactions tocow’s milk-based formula.

If more than one organ system is involved, the diagnosisof ‘allergy’ is much more likely than ‘functional disorder’.

In distressed infants presenting with troublesome regurgi-tation and ⁄ or vomiting, two options for dietetic treatmentseem reasonable. If the goal is symptom relief as soon aspossible, a thickened extensive hydrolysate is an option. Ifsymptom relief is obtained, it will not allow to distinguishallergy from functional disorders. If the goal is to separatefunctional symptoms from allergy, again two choices arepossible. If a ‘functional disorder’ is the most likely diagno-sis (regurgitation and vomiting as single manifestation, neg-ative family history of atopic disease), a thickened formulawith unmodified protein should be the choice. If ‘allergy’ isthe more likely diagnosis (different organ systems involved,positive family history of atopic disease), an extensivehydrolysate should be the preferred option. A re-evaluationafter 2 weeks is recommended and other diagnostic optionsshould be considered according to the clinical evolution. Asin many cases the diagnosis is not clearly established, dura-tion of treatment should be limited.

Regarding constipation, the situation is even more nebu-lous. First, true constipation in formula-fed infants below6 months seems rare, both as ‘functional disorder’ and as‘single manifestation of CMPA’. As a consequence,

treatment of ‘functional constipation’ in infants youngerthan 6 months is difficult to recommend because of the pov-erty of data. The efficacy of ‘anti-constipation formula’ isnot documented, but neither is the efficacy of extensive hy-drolysates.

CONFLICT OF INTERESTYVDP is the speaker for Abbott and Mead Johnson Nutri-tionals, and he is a consultant and speaker of Biocodex, Da-none (Nutricia, SHS), Nestle Nutrition and UnitedPharmaceuticals. FG is a consultant and speaker of Nutri-cia, Danone, Nestle, Movetis and Astra Zeneca.

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