pediatrics 2002110 972-84 gastroesophageal reflux and cow milk allergy

REVIEW ARTICLE

Gastroesophageal Reflux and Cow Milk Allergy: Is There a Link?

Silvia Salvatore, MD*, and Yvan Vandenplas, MD, PhD‡

ABSTRACT. Gastroesophageal reflux (GER) and cowmilk allergy (CMA) occur frequently in infants youngerthan 1 year. In recent years, the relation between these 2entities has been investigated and some important con-clusions have been reached: in up to half of the cases ofGER in infants younger than 1 year, there may be anassociation with CMA. In a high proportion of cases,GER is not only CMA associated but also CMA induced.The frequency of this association should induce pedia-tricians to screen for possible concomitant CMA in allinfants who have GER and are younger than 1 year. Withthe exception of some patients with mild typical CMAmanifestations (diarrhea, dermatitis, or rhinitis), thesymptoms of GER associated with CMA are the same asthose observed in primary GER. Immunologic tests andesophageal pH monitoring (with a typical pH patterncharacterized by a progressive, slow decrease in esopha-geal pH between feedings) may be helpful if an associ-ation between GER and CMA is suspected, although theclinical response to an elimination diet and challenge isthe only clue to the diagnosis. This article reviews themain features of GER and CMA, focusing on the aspectsin common and the discrepancies between bothconditions. Pediatrics 2002;110:972–984; cow milk allergy,gastroesophageal reflux, vomiting, (esophageal) pH moni-toring.

ABBREVIATIONS. GER, gastroesophageal reflux; GERD, gastro-esophageal reflux disease; CMA, cow milk allergy; CMI, cow milkintolerance; CM, cow milk; Ig, immunoglobulin; CMP, cow milkprotein; CMFD, cow milk–free diet; AAF, amino acid–based for-mula; eHF, extensive hydrolysate formula; LES, lower esophagealsphincter; HPF, high-power field; PPI, proton pump inhibitor; IL,interleukin.

Gastroesophageal reflux (GER) is defined asthe involuntary passage of gastric contentsinto the esophagus. GER is present in virtu-

ally all infants and has a wide spectrum of symp-toms: from occasional physiologic reflux to the infantwith severe esophageal and extra-esophageal com-plications and even sudden infant death syndrome.Reflux is best classified as primary physiologic orpathologic (with typical or atypical presentation) andsecondary reflux. Reflux is considered physiologicwhen the infant thrives well and experiences no com-

plications. Regurgitation, the effortless return of gas-tric contents into the mouth, is the most commonpresentation of infantile GER, occasionally with pro-jectile vomiting.1,2 Regurgitation of at least 1 episodea day occurs in half of 0- to 3-month-old infants,increases to two thirds of infants at 4 months, anddecreases to 5% at 10 to 12 months of age but causesconcern in at least 25% of parents.1–4 The prevalenceof an increased quantity of GER, documented byesophageal pH monitoring, in a population of uns-elected infants is estimated to be 10%.5 The naturalhistory of GER is improvement with age with disap-pearance of symptoms in 55% infants by 10 months,in 81% by 18 months, and in 98% by 2 years of life.6

Pathologic GER, or GER disease (GERD), is refluxassociated with other manifestations, such as, failureto thrive or weight loss, feeding or sleeping prob-lems, chronic respiratory disorders, esophagitis, he-matemesis, stricture, sideropenic anemia, apnea, ap-parent life-threatening episodes or sudden infantdeath syndrome, and Sandifer’s syndrome. Atypicalpresentations of GER often occurs in the absence ofregurgitation and vomiting and are mainly related torecurring respiratory symptoms.

Secondary GER is considered a different entity andcan be caused by infections, metabolic and neuro-logic disorders, and food allergy. Secondary GER isalways GERD. However, even in secondary GERD,vomiting or other symptoms of primary GERD mayfrequently manifest and therefore a clear-cut distinc-tion between primary and secondary GERD is fre-quently difficult to make. Most review and positionreports on GER mention secondary GERD only brief-ly.7–9 This article specifically focuses on the relationbetween GER, primary or secondary, and cow milkallergy (CMA).

COW MILK INTOLERANCE AND COW MILKALLERGY

Cow milk intolerance (CMI) defines any reproduc-ible clinical adverse reaction to cow milk (CM). Im-mune-mediated CM-related adverse reactions is de-fined as CMA. These classic definitions are acceptedworldwide, but CMA and CMI are, in many studies,used interchangeably because the immunologic basisof the mechanisms involved are frequently undeter-mined. Increased total or specific blood immuno-globulin (Ig) E or positive skin-prick test suggesttype 1, or quick-onset, food allergy.10 No reliableroutine tests for type 2, 3, and 4 cellular mediatedCMA are currently available. Increased circulating,fecal, or nasal eosinophil populations or IgG anti-�-

From the *Pediatrics, Clinica Pediatrica di Varese, Universita dell’Insubria,Brussels, Belgium; and ‡Pediatrics, Academisch Ziekenhuis, Vrije Univer-siteit Brussel, Brussels, Belgium.Received for publication Sep 24, 2001; accepted Mar 25, 2002.Reprint requests to (Y.V.) Academic Hospital, VUB, Laarbeeklaan 101, 1090Brussels, Belgium. E-mail: [email protected] (ISSN 0031 4005). Copyright © 2002 by the American Acad-emy of Pediatrics.

972 PEDIATRICS Vol. 110 No. 5 November 2002

lactoglobulin have not been accepted as proof ofdefinitive diagnosis but may reinforce a clinical sus-picion.11 Therefore, to simplify this review, we useCMA for “true” and “suspected” CMA. Conversely,CMI related to lactase deficiency is excluded.

CMA is reported in 0.3% to 7.5% of infants (with82% of symptoms reported within the first 4 monthsof life).10–14 On the basis of strict diagnostic criteria,the prevalence of confirmed CMA in developedcountries during infancy is approximately 2% to 5%.Reproducible reactions to cow milk protein (CMP) inbreastfed infants occur in approximately 0.5%15

Family history of atopy is a predictor for allergy.The incidence of CMA is 12% when there is no atopicparent, 20% when there is 1 atopic parent, 32% whenthere is 1 atopic sibling, 43% when both parents areatopic, and as high as 72% when both parents havethe identical type of atopic disease.16 Approximately30% to 70% of infants with CMA manifest dermato-logical symptoms, 50% to 60% manifest gastrointes-tinal symptoms, and 20% to 30% manifest respiratorysymptoms.15,17 This means that the majority of pa-tients with CMA manifest symptoms involving morethan 1 system, whereas patients with primary GERDmostly have only 1 system involved. Gastrointestinalsymptoms of CMA include recurrent vomiting, foodrefusal, irritability, diarrhea, rectal bleeding, andmalabsorption. Systemic manifestations may includefailure to thrive and anaphylaxis. Only a small pro-portion of gastrointestinal allergy is IgE-mediated.10

Clinical response to an elimination diet and a chal-lenge is the diagnostic principle of food allergy.10,18

Diagnosis of specifically CM protein enteropathyideally necessitates the proof of small bowel damagewith patchy partial villous atrophy and increasedintraepithelial lymphocytes.10,11,19

Natural tolerance for CM in infants who are af-fected by CMA is frequently achieved within the firstyears of life. Remission of CMA was reported in 15%of the affected children by 1 year, in 22% to 28% by2 years, in 51% by 3 years, in 55% to 67% by 4 years,and reaching 78% by 6 years.13,20 More recent, in adifferent population, CM tolerance in infants with

CMA was achieved in 45% to 50% at 1 year, in 60%to 75% at 2 years, and in 85% to 90% at 3 years ofage.15

From the evidence listed above, results show thatGER and CMA both are generally self-limited symp-toms, possibly interrelated, with only a small propor-tion of patients (�10%) who will continue to have thedisease-related symptoms after early infancy.

CMA AND GERThe age-dependent and similar clinical presenta-

tion (Fig 1) suggests a relation between GER andCMA.21 From the above reported prevalence of GERand CMA, combined theoretical expected prevalence(if a causal relationship exists between the 2 diseases)results in a figure of 0.03% to 0.7% of infants whoexperience pathologic reflux and CMA to 0.2% to4.9% of infants who present with physiologic regur-gitation and CMA. More than 20 years ago, Buis-seret22 reported the presence of vomiting, colic, dif-ficult infant feeding, growth retardation,psychological disturbance, and diarrhea in 79 chil-dren with CMA. Later, enteropathy (with IgE plas-macytes) was found in 3 (20%) of 15 infants whopresented with recurrent vomiting.23 More recent, aCM-free diet (CMFD) was evaluated in 10 of 14infants who had GER and did not respond to phar-macological reflux treatment: 2 (20%) of 10 im-proved.24 Kelly et al25 reported on 10 patients whohad long-standing symptoms attributed to GERD(vomiting, abdominal pain, poor growth, and poorappetite) and did not respond to standard treatment(including a Nissen fundoplication in 6 children) andhad persistent eosinophilic esophagitis; a dramaticclinical and histologic improvement was found in allpatients after an amino acid–based formula (AAF)was started. In accordance with a diagnosis of pri-mary CMA, there was not only the obvious clinicalresponse to the elimination diet with disappearanceof all symptoms but also the clinical relapse in 7 ofthe 10 infants during an open challenge with CMproteins. In 5 Italian studies (some of them may haverepetitive inclusion of patients), the association of

Fig 1. Symptoms attributed to GER and to CMA.

REVIEW ARTICLE 973

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974 GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY

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REVIEW ARTICLE 975

GER and CMA has been reported in 15% to 21% ofinfants with symptoms suggesting GER or CMA andin 16% to 42% of infants who had previously re-ceived a diagnosis of GERD.26–30 Reflux symptomsdisappeared within 2 weeks of AAF in 13 consecu-tive infants who presented with persisting vomitingand were unresponsive to medical reflux treatment;3 had documented esophagitis, and 7 had multiplefood allergy unresponsive to extensive hydrolysateformula (eHF).31 Similarly, AAF was effective in 13(81%) of 16 infants with symptoms that were sugges-tive CMA (9 of 16 with persistent vomiting anddocumented esophagitis in 7) and resistant to eHFand GER treatment. The 3 nonresponders did notreact during a challenge with eHF, making the CMAdiagnosis questionable.32 Last, in 19 infants with ir-ritability and vomiting (with esophagitis in 9) resis-tant to eHF and antireflux medications, symptomsdisappeared in all patients within 2 weeks after start-ing AAF. After a period of 2 to 12 months, a double-blind, placebo-controlled challenge was performed:12 infants were still intolerant of other formula (3patients of soy and 9 of eHF).33 Details of the studiesare shown in Tables 1 and 2.

Intestinal permeability tests were positive in 85%of infants who had GER-CMA that was resistant toeHF32 and were �95% accurate in identifying CMAin 25 infants who presented with chronic vomiting.27

Intestinal permeability tests, based on differentialsugar absorption tests with determination of urinaryexcretion of large molecules such as lactulose or cel-lobiose compared with small molecules such as man-nitol, revealed an abnormal cellobiose/mannitol ra-tio (2 standard deviations over the mean fromnormal subjects) in infants with CMA.27 However,intestinal permeability studies are not easily per-formed in all hospitals, are aspecific for CMA, andhave a limited sensitivity in infants without enterop-athy.21,34

In 3 studies (from the same group) on infants withGER-CMA, increased �-lactoglobulin antibodieswere shown to have a sensitivity of 90% to 100% anda specificity of 78% to 90% as a predictive factor ofefficacy of a CMFD.28–30 However, the absence ofdifference between the level of �-lactoglobulin anti-bodies in control infants versus infants with CMA35

has as well been reported. Even the absence of anydiagnostic help of IgG–�-lactoglobulin antibodies forallergic manifestations was suggested.36

An Italian group identified a typical pH tracing(“phasic” pattern, a progressive and slow decrease inesophageal pH between 2 feedings) in 12 (86%) of 14infants with GER-CMA, in 24 (96%) of 25 infantswith only CMA, and in 0 of 47 infants with primaryGER or 0 of 49 control infants.28 The probe waspositioned at 87% of the nose � lower esophagealsphincter (LES) distance, calculated using Strobel’sformula. The authors speculated that a low basalresting tone of the LES, more than inappropriaterelaxations of the LES, may be implicated. Thesefindings were confirmed by the same center in alarger group of infants (phasic pH-metry in 87% ofinfants with GER-CMA and not in patients with GERor in control subjects).29 However, others have con-tradicted these findings, reporting a phasic pH trac-ing in 5% of infants with CMA and in 4% of patientswith GER.26 Selection of patients, diagnosis of CMAand/or GER, and challenge tests were not standard-ized, making comparisons among all of the afore-mentioned reports hazardous. Besides, for provingobjective phasic results, a double-entry analytical ta-ble (constituted by the number of recordings of eachpH value during each 30-minute fraction after feed-ing) of pH-monitoring data is needed.29

From the above studies, symptoms disappeared inall,23,25,27,33 part,26,30–32 or a minority (2 of 10)24 ofinfants who had GERD symptoms resistant to classicGER therapy and were on a CMFD and relapsedduring challenge. Routine immunologic allergic testsand family or patient’s medical history of allergywere not consistently positive or always predictivefor the response to the CMFD (Tables 2 and 3). Nev-ertheless, CMA-related GER seems age-related andlimited to young infants; as in older children, CMAsymptoms evolve to cutaneous symptoms (atopicdermatitis), respiratory symptoms (wheezing,asthma, rhinitis), or lower gastrointestinal motilitydisturbance (constipation), especially when there is apositive family history of allergy.37

ESOPHAGITISEndoscopy and esophageal biopsies are recom-

mended when esophagitis is suspected. Basal cellhyperplasia, papillary elongation, and intraepithelialor lamina propria inflammatory cell infiltration arehistologic criteria for esophagitis.38,39 Eosinophilicinfiltration is still a poorly characterized entity andshould be interpreted with caution as it is not a

TABLE 3. Summary of the Results of CMA-GER Studies

Disease Total No.of Points

CMFD Challenge SBB FH CMAs CMAH

�/N % �/N % �/N % �/N % �/N % �/N %

CMA�GER 219† 216/219 99 197/209 94 96/124* 77 53/139 38 52/199 26 54/199 27GER only 291 35/84 42 0/38 0 0/28 0 47/194 24 1/161 1 0/75 0

Disease Total No.of Points

PRICK Total IgE EOS �-Lacto Ab Phasic pHm PT

�/N % �/N % �/N % �/N % �/N % �/N %

CMA�GER 219† 102/194 53 29/80 36 47/141 33 125/129 97 39/62 63 18/20 90GER only 291 3/87 3 0/87 0 0/206 0 35/194 18 3/142 2 1/16 6

* For SBB, the data of 2 studies28,29 were not included as the results of CMA-GER and CMA-only were not reported separately.† As 3 studies come from the same group, some patients may be reincluded.


specific marker for primary GER or for CMA. Eosin-ophilic esophagitis was initially attributed toGER39,40 but has now been related to a spectrum ofdisorders, including reflux, food allergy, primary eo-sinophilic esophagitis, and eosinophilic gastroenter-opathy.41,42 In mice, eosinophilic esophagitis haseven been related to inhalant allergens.43 The role offood protein is debated, and patients with eosino-philic esophagitis (�5 eosinophils per high-powerfield [HPF]) may respond to dietary elimination, cro-molyn sodium, or steroids.42 A specific endoscopicfinding has been proposed for primary eosinophilicesophagitis, consisting of a granular, furrowed, andoccasionally ringed appearance of the esophagealmucosa.42 Quantification of the eosinophilic infil-trate, on distal biopsy specimens, may provide crite-ria for a different entity causing eosinophilic infiltra-tion. A small number of esophageal eosinophils(2.3 � 1.2/HPF) are suggestive of reflux esophagitis,whereas a high number (�20/HPF) suggests pri-mary eosinophilic esophagitis or eosinophilic gastro-enteritis.41,42 The latter is confirmed by the observa-tion that �7 eosinophils/HPF was related to an 85%positive predictive value of successful GER treat-ment.44 An eosinophilic density between 5 and 20/HPF results in a “gray zone,” showing, perhaps, anoverlap between reflux and eosinophilic esophagi-tis.42 The more the eosinophilic infiltration is limitedto the distal esophagus, the more it is likely to bereflux related. Orenstein et al42 suggested that esoph-ageal acidification as well as IgE allergic responseinduces mast cell degranulation with release of me-diators that increase mucosal blood flow and attractand activate eosinophils. Activated eosinophils closeto lymphocytes were present in an electron micro-scopic study in children with esophagitis.45 Eotaxin,an eosinophil-specific chemokine and activationmarkers of T-cells, is increasingly detected in CMP-associated esophagitis.46 This inflammatory responseelicited by food protein seems to involve the entiregastrointestinal tract.33 It was suggested recently thatesophageal mucosal homing of intestinal CM-sensi-tized T-cells may be responsible for CM-relatedesophagitis, in a way distinct from luminally medi-ated primary reflux esophagitis.47 In a murinemodel, oral antigen (ovalbumin) induced diffuse eo-sinophilic gastrointestinal inflammation (includingthe esophagus, stomach, and small intestine) medi-ated by eotaxin and related gastric dysmotility. Dys-motility may have promoted GER with antigen-driven eosinophilic inflammation of the esophagus.48

GASTRIC EMPTYINGMultiple dietary factors, including volume,49 os-

molality,50 caloric density,51 and protein content,52,53

influence gastric motility. In healthy infants, the typeof milk regulates the gastric emptying rate: the gas-tric residual content, 2 hours after feeding, was thesmallest with whey-hydrolysate formula and breastmilk (16% and 18%, respectively) and progressivelyhigher with acidified, whey-predominant, casein,follow-up, and CM formula (25%, 26%, 39%, 47%,and 55%, respectively).52 Casein empties the stomachslower than soy (39.7% vs 44.6%, respectively) or

whey-hydrolyzed isocaloric formula (48.5%). The in-cidence of GER seems to be inversely related to thegastric emptying rate (20.4%, 17.7%, and 16.3%, re-spectively).53 Low-fat high-carbohydrate formulaimproves gastric emptying, but its benefit in infantswith GER has not been validated.9

Delayed gastric emptying is reported in GERD andmay be involved in causing inappropriate relax-ations of the LES.54 Cucchiara et al55 performed elec-trogastrography and antral ultrasonography in 42patients with histologic esophagitis: dysrhythmic ep-isodes and delayed gastric emptying were signifi-cantly more frequent in reflux patients than in con-trol subjects. High-volume and high-osmolalitymeals increase the incidence of reflux episodesthrough significant changes in LES pressure.56 Morethan 60 years ago, in 12 children with food allergy, atest meal containing the food allergen was shown,using fluoroscopy, to cause gastric hypotonia, pylo-rospasm, and alteration of intestinal peristalsis.57 In30 adult patients with proven food allergy, gastricbiopsies taken during food challenge (also causingsymptoms) showed a significant decrease in stainedmast cells and tissue histamine.58 Recently, gastricemptying was shown to be delayed in patients withCMA in comparison with control subjects and in-fants with GER. In 7 patients with CMA, CM chal-lenge caused a significant decrease of normogastriawith an increase in bradygastria and tachygastriacompared with infants with GERD or control sub-jects.59 In a murine model of experimental antigen-induced eosinophilic gastrointestinal inflammationmediated by eotaxin, marked gastric dysmotility (de-fined by fluorescent microsphere bead particle reten-tion), gastromegaly and failure to thrive were re-ported. Electron microscopy analysis of small bowelbiopsies revealed that eosinophils were in close prox-imity to damaged enteric nerves (containing swollen,enlarged axonal chambers with variable loss of in-ternal organelles, indicative of axonal necrosis). Eo-sinophils, through the release of the major basic pro-tein, may induce muscarinic receptor dysfunction,with alteration of smooth muscle contraction, gastricmotility, and emptying.48 In a recent abstract, mastcell degranulation occurring proximal to the gastricnerve fibers and concomitant electrogastrographydisturbances were demonstrated in patients with apositive food challenge, showing a link among cel-lular immune involvement, nervous system, andelectrical gastric activity.60

Formula selection and meal size hence may beinvolved in infants with GER as the formula compo-sition and volume may influence reflux by differentmechanisms: increase in intragastric pressure (incase of bolus feeding), delay in gastric emptying,61 ortrigger of immune response.

CONSTIPATIONCM-dependent colic and constipation have been

reported and may support the idea of overall motil-ity disturbance as part of the pathogenetic link be-tween CMA and GER. Cytokines and the ongoinginflammatory process of the neurologic and motorsystem may mediate this effect. Lymphocyte and

REVIEW ARTICLE 977

eosinophil infiltration of the lamina propria and in-creased intraepithelial eosinophils with crypt infil-tration were significantly detected in children withCMA-related constipation.62 Some chronically con-stipated children recover on a CMFD and relapseduring challenge. A cellular immune mechanismseems to be involved, but common allergic tests,family history, or manifestations of atopy are predic-tive of a positive response to CMFD only in a sub-group of patients.13,62–67 Motility disturbance of thelower gastrointestinal tract is beyond the topic of thisreview and will not be discussed further.

DIETETIC CONSIDERATIONSBefore the commercialization of antiregurgitation

formulas in the United States, formula change andthickened feedings were reported, respectively, in8% and 2% of patients.4 However, today, antiregur-gitation formulas are widely used and decrease thenumber and severity of regurgitation.9,61,68,69 Recentrecommendations of dietary treatment of regurgita-tion68 do not consider avoidance of CMP as second-ary GERD was excluded a priori. Dietary approach isbased on elimination of CMP. CMFD options includesoy formula, eHF, or AAF.

SoySoy protein–based formula is not recommended in

the initial treatment of CMA,18 although most infantswith IgE-mediated CMA may do well on soy for-mula, particularly after the age of 6 months.70 In aprospective study, healthy infants who were fedbreast milk, CM, or soy formula showed provenallergic response to soy in 0.5% and to CM in 1.8% ofthe population.71 A survey reported allergy to CM tooccur in 3.4% and to soy in 1.1% of all infants.72 Inprevention, soy is not effective and the atopic man-ifestations are comparable in the CM and soygroups.73 The rate of clinical adverse reaction to soyin patients with proven CMA ranges from 10% to67% (particularly high when 2 atopic parents or gas-trointestinal involvement is present),13,74–76 but adouble-blind, placebo-controlled challenge docu-mented that soy allergy was demonstrated in only4% to 5% of patients.77,78 Soy-induced enteropathyand enterocolitis are mostly not IgE mediated. In-fants with documented CM-induced enteropathy orenterocolitis share the same non-IgE mechanism andare frequently equally sensitive to soy protein. There-fore, the American Academy of Pediatrics recom-mended that in patients with gastrointestinal symp-toms caused by a non–IgE-mediated CMA, soyformula should be avoided and eHF or AAF shouldbe administered.79

HydrolysatesRecommended dietary products for the treatment

of CMA in infants are limited to eHF and AAF,which are the only feedings that meet the standardsfor hypoallergenicity.18,70 Partially hydrolyzed for-mula is not recommended in the treatment ofCMA.18 An eHF should, by definition, be toleratedby at least 90% of infants with CMA.18 Nonantigenichydrolysates should not contain peptides with a mo-

lecular weight above 1200 daltons,79 but eHF con-tains small amounts of peptides of �1200 to 1500daltons80 and anaphylactic reaction to eHF has beenreported.81–85 Intolerance to eHF has been reportedin CMA with gastrointestinal or extraintestinalsymptoms and in infants with either delayed or im-mediate type of hypersensitivity.31,32,86–93 �-Lacto-globulin can be detected in whey-based eHF in anamount equivalent to that in breast milk.94 Therefore,it can be considered that breastfed infants who reactto the minute amounts of CMP in breast milk couldalso react to eHF.32 eHF intolerance often occurs inmultiple food allergy and persistent food intoler-ance, and in this situation, AAFs are needed formonths or years.31,89,91,95 Unfortunately, there are nocriteria for predicting which infants with CM- orsoy-induced intestinal hypersensitivity will and willnot respond to eHF. Diagnosis of eHF intolerancerequires elimination diet first with AAF, which al-lows symptoms to disappear, and then a positiveresponse to an oral challenge.32

AAFPure AAF is a nonallergenic food.18 AAF is effec-

tive to treat all CMA manifestations, even in multiplefood allergy.25,31,32,89,91,93 Symptoms may reappearduring challenge (even with eHF) after a period of 3months.31 Failure to respond to AAF was reported in6 of 44 infants with gastrointestinal symptoms re-portedly attributable to CMA,32,93 but at least 3 ofthese patients did not have a positive challenge toeHF, which makes the diagnosis of CMA hazardous.

It is still unclear whether the effect of AAF inGERD is the consequence of an immune or a gastro-intestinal phenomenon.25,33 The AAF may exert non-immune effects on gastrointestinal tract functionsuch as gastrointestinal motility, gastric emptying,acid output, esophageal sphincter function, or gas-trointestinal microflora. Furthermore, as the re-sponse to AAF may be a combination of a real re-sponse to amino acids, a placebo effect, andspontaneous improvement, a CM challenge remainsmandatory to confirm the diagnosis of CMA. A chal-lenge should be validated with an objective scoringsystem to document symptoms during a period aslong as 7 days. This prolonged observation is partic-ularly important to detect late-onset reactions.31

In CMA, eHF and AAF allow children to experi-ence normal weight gain.31,32,89,91,93,96,97 A biochem-ical nutritional evaluation of infants on an eHF (Nu-trilon Pepti) for 3 months showed overall normalresults.98 Comparing eHF to AAF, biochemical indi-ces (hemoglobin, albumin, prealbumin, transferrin,alkaline phosphatase, sodium, and potassium) weresimilar and remained within normal ranges after 6 to8 months.96,99 Albumin was reported to be signifi-cantly improved on eHF but not on AAF,99 whereasthe levels of plasma essential amino acids weresmaller in eHF but higher in AAF compared withbreast milk.96 Plasmatic branched-chain amino acids,especially valine, differed in breastfed and eHF- orAAF-fed infants, reflecting differences in the aminoacid profiles of these formulas.96 All of the abovereports support the nutritional adequacy of eHF and


AAF. Although safe,100 unnecessary use of CMFDand AAF must be avoided as it may also be detri-mental to children.101 However, concerns aboutlong-term lactose deprivation, possible alteration ofintestinal microflora, taste, and, principally, cost ofAAF still exist. Lactose is not present in many eHFand is present in AAF mainly to avoid contaminationwith residual CMP, but diets without lactose mayhave disadvantages for the composition of colonicflora and calcium absorption.18 AAF is approxi-mately 25% more expensive than eHF, which costssignificantly more than standard formula.70,97 Toler-ance to CMP may be acquired after months or yearsof CMFD. Therefore, controlled rechallenges shouldbe performed at regular intervals to avoid unneces-sarily prolonged restricted diets.18 In patients with ahistory of severe hypersensitive reaction, the CMchallenge should be performed rigorously in a hos-pital setting (because of possible anaphylactic reac-tions) and postponed to at least 9 to 12 months later.

Breast MilkCMA in exclusively breastfed infants has a preva-

lence of 0.37% in a population in which CMA occursat 1.9%.102 More recent, reactions to CMP in breast-fed infants were reported in approximately 0.5%15

and an increasing number of exclusively breastfedinfants become sensitized to multiple antigens veryearly in life.103–106

No difference in incidence of regurgitation wasreported in relation to breastfeeding or formula-feed-ing.105–107 Comparing 37 breastfed to formula-fedhealthy neonates, breast milk was associated withless and shorter reflux episodes 3 and 4 hours afterfeeding, although there was no significant differencein episodes per hour between the 2 groups. Theseresults are possibly related to more quiet sleep (as-sociated with rare reflux episodes), improved clear-ance rate, and enhanced gastric emptying, mayberelated to differences in macronutrient content suchas lipids and other components such as growth factor(not analyzed in this study).108

When CMA-related GERD is suspected, a dietetictrial with complete avoidance of CMP (with calciumsupplementation when required) in the maternal dietis suggested for 3 to 4 weeks. When helpful, CMPshould be reintroduced in the maternal diet to proveany causal relationship.

PROPOSED DIAGNOSTIC AND THERAPEUTICAPPROACH

A careful history, observation of feeding, andphysical examination of the infant are always man-datory to detect signs of pathologic or secondaryGER. In view of the reported considerations of CM-related GER, current recommendations8,9,68,69 of di-agnostic and therapeutic approaches to reflux in in-fants may be modified as shown in Figs 2 to 4. A fewdetails are discussed further herein.

Parental reassurance should always be the first-line approach associated with restriction of volumein overfed infants. The 30° reverse Trendelenburgposition (not prone in the first 6 months of life)remains a valid adjunctive measure in patients with

GERD.69 As reported before, thickened formula mayreduce regurgitation in formula-fed infants, but inbreastfed infants, this recommendation is obviouslynot possible. The efficacy of thickened formula inGERD is questionable because its impact on GERparameters is unpredictable.9 A trial with CMFD(AAF if formula-fed and maternal avoidance of CMPif breastfed) could be tried in patients with positiveatopic history or laboratory allergic test results, be-fore drug treatment. AAF (compared with eHF) ispreferred as it clearly and definitively excludes CMAin nonresponders.

In infants with persisting symptoms, anti-GERmedication can be given a trial. A recent systematicreview found no evidence that cisapride significantlyreduced GERD symptoms. However, only 7 studies(286 children in total) were considered eligible.Moreover, cisapride was associated with a signifi-cant reduction in the reflux index109 and when symp-toms were redefined, a significant clinical effect ap-peared. Today, as a consequence of reported cardiacadverse reactions mainly when given in associationwith azoles or macrolides, cisapride is not availableor is highly restricted in many countries.69 Data forother prokinetics (domperidone or metoclopramide)are even less convincing.9,69 The efficacy of domperi-done in pediatric GERD is better when used in com-bination with other antireflux agents (antacids, thick-ened formula, or Gaviscon).9 Gaviscon (a sodiumalginate-antacid preparation) acts as a mechanicalbarrier against reflux. It lasts longer than other ant-acids, and contraindications are limited to preterm orrenal affected patients, because of its high content ofsodium. Gaviscon showed significant efficacy in re-ducing vomiting and regurgitation and a 42% suc-cess rate in healing esophagitis.110–115 In 1 study, thecombination of Gaviscon plus Carobel was superiorto cisapride to relieve symptoms of reflux.112 In arandomized, multicenter comparison of sodium al-ginate and cisapride in 353 adults with uncompli-cated GER, Gaviscon was reported to have overallsuperior symptom relief.116 A large pediatric ran-domized controlled study is expected to confirm itsefficacy.

In patients who do not respond to this medicaltherapeutic approach, upper endoscopy is needed.However, in situations in which endoscopy is noteasily available, a trial proton pump inhibitor (PPI)or H2 antagonists for 2 weeks would be reasonable.As for an elimination diet, after 1 month of beneficialdrug treatment, a “stopping challenge” is recom-mended to exclude placebo effect and to avoid un-necessary long-term medication.

In suspected esophagitis, endoscopy (with esoph-ageal and, if possible, small bowel biopsy to rule outenteropathy) is recommended. Upper gastrointesti-nal radiologic series are essential to exclude ana-tomic malformations. Treatment of esophagitis isbased on PPIs or H2-receptor antagonists.9 PPIs aremore effective than H2 antagonists, well tolerated,and safe.9,117–127 Limited side effects are reported in1% to 6% of patients.9 The long-term safety of PPIs inchildren is still a matter of concern despite that largeand long follow-up (up to 11 years) studies in adults

REVIEW ARTICLE 979

showed neither serious adverse events128 nor gastricdysplasia, neoplasia, inflammation, atrophy, or argy-rophil cell hyperplasia in Helicobacter pylori–negativepatients.129 The step-down or step-up therapeutic

approach to GERD is still debated.130 However, PPI’shigh efficacy of for healing, low number of relapses,and absence of serious adverse events make it thetreatment of choice for esophagitis and severe

Fig 2. Proposed approach in infants presenting with persisting vomiting/regurgitation.

Fig 3. Proposed approach in infants presenting with suspected esophagitis.


GERD128–131 and to maintain remission in patientswith esophagitis.132 Patients with resistant GERD canbenefit from a CMFD regimen or from steroids ifsignificant eosinophilic esophagitis is present.

Surgery, after full investigation (upper gastrointes-tinal series and endoscopy, pH monitoring, manom-etry, and gastric emptying studies), is reserved forlife-threatening conditions that do not respond to afull GERD therapeutic approach or for patients whoare dependent on medication. A possible food-re-lated response should be investigated before the de-cision to perform a surgical antireflux procedure ismade.25

Atypical RefluxIn atypical reflux (ie, chronic respiratory symp-

toms), as GERD is frequently occult and vomitingand regurgitation are mostly lacking, pH monitoringis the investigation of choice. If pathologic, treatmentwith PPI, H2 antagonists, or prokinetics is indicatedand often required for a longer period of time. Innonresponders, endoscopy is recommended. Even inthis group, CMA should be considered as a possibleunderlying condition.

SPECULATION POINTS

Gene RelationshipA genome-wide scan of 5 families that were af-

fected by severe pediatric GER demonstrated thatsevere GER may follow an autosomal dominant he-reditary pattern with high penetrance. The gene wasmapped to a 13-cM region on chromosome 13q be-tween microsatellite markers D13S171 andD13S263.133 Chromosome 13 also contains severalcandidate genes for asthma and atopy, such as RAN-TES (a chemokine that attracts monocytes, T-cells,and eosinophils), STAT5a (a signal transducer of in-terleukin (IL)-5, so particularly important in IL-5–mediated eosinophil responses), endothelin receptortype B, chemokine receptor 7,134 and IgE-dependenthistamine-releasing factor.135 Other reports sug-gested an important role of chromosome 13 in thedevelopment of allergic manifestations. The peak of

linkage of the atopy locus was found at D13S161136;a significant association between atopic dermatitisand D13S218 was observed on chromosome 13q12–14137 and linkage between markers on 13q21.3-qter(containing markers D13S285 and D13S293) andasthma, in the white population, was suggested.138

Although a complex interaction of genes and envi-ronmental factors are likely involved in allergic man-ifestations, it may be considered that even geneticand immunologic mechanisms are involved in CMAand GER.

Hyperreactive EsophagusIt is intriguing to speculate on a possible relation

between persistent reflux and esophageal hyperreac-tivity. As respiratory inflammation (respiratory syn-cytial virus bronchiolitis) during the first year of lifeseems to predispose, possibly via IL-13–mediatedmechanisms,139 to bronchial hyperreactivity in laterchildhood,140 untreated infantile GERD with persis-tent inflammation of esophageal mucosa could berelated to hypersensitive or acid-sensitive esophagusor non–esophagitis-related disease in adults.

Probiotic ApproachA recent study showed a significant beneficial ef-

fect of perinatal administration of Lactobacillus GG inpreventing atopic dermatitis in high-risk infants.141

In that study, the treated and placebo groups did notdiffer in circulating IgE and skin-prick responses,suggesting that the clinical effects of this probioticmay be limited to IgE-independent mechanisms.142 Itwould be interesting to evaluate whether the rate ofgastrointestinal allergic symptoms (mostly non–IgE-mediated) could also be lowered by this therapeuticmeasure. Furthermore, patients on omeprazole maypresent bacterial overgrowth (more significant thanon H2-receptor antagonists),143 and, therefore, probi-otics may be useful to reestablish balanced flora andeven influence tolerance in patients with GER-CMA.In terms of safety, sporadic rare side effects, such assepticemia and liver abscess, were reported, al-though not 1 side effect was reported when milk was

Fig 4. Proposed approach in infants presenting with atypical symptoms of reflux.

REVIEW ARTICLE 981

used as the vehicle.144 However, it is probably tooearly to suggest a widespread use of probiotics in allpatients with CMA-GERD. More reports are at-tended.

CONCLUSIONThis review reveals a link between GER and CMA.

The molecular basis of their combined pathogenicityinvolves immune, neurologic, and motor mecha-nisms but still needs more research. A personal clin-ical history of allergy or positive allergic tests mayhelp to select patients for a first-line approach with aCMFD, before conventional antireflux drug treat-ment. In patients without presumptive signs ofCMA, CMFD should be reserved to nonrespondersto drug treatment.

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