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 cow milk allergy (CMA) occur frequently in infants younger than 1 year. In recent years, the relation between these 2 entities has been investigated and some important conclusions have been reached: in up to half of the cases of GER in infants younger than 1 year, there may be an association 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 pediatricians to screen for possible concomitant CMA in all infants who have GER and are younger than 1 year. With the exception of some patients with mild typical CMA manifestations (diarrhea, dermatitis, or rhinitis), the symptoms of GER associated with CMA are the same as those observed in primary GER. Immunologic tests and esophageal pH monitoring (with a typical pH pattern characterized by a progressive, slow decrease in esophageal pH between feedings) may be helpful if an association between GER and CMA is suspected, although the clinical response to an elimination diet and challenge is the only clue to the diagnosis. This article reviews the main features of GER and CMA, focusing on the aspects in common and the discrepancies between both conditions. Pediatrics 2002;110:972984; cow milk allergy, gastroesophageal reflux, vomiting, (esophageal) pH monitoring.
ABBREVIATIONS. GER, gastroesophageal reflux; GERD, gastroesophageal reflux disease; CMA, cow milk allergy; CMI, cow milk intolerance; CM, cow milk; Ig, immunoglobulin; CMP, cow milk protein; CMFD, cow milkfree diet; AAF, amino acid based formula; eHF, extensive hydrolysate formula; LES, lower esophageal sphincter; HPF, high-power field; PPI, proton pump inhibitor; IL, interleukin.

astroesophageal reflux (GER) is defined as the involuntary passage of gastric contents into the esophagus. GER is present in virtually all infants and has a wide spectrum of symptoms: from occasional physiologic reflux to the infant with severe esophageal and extra-esophageal complications and even sudden infant death syndrome. Reflux is best classified as primary physiologic or pathologic (with typical or atypical presentation) and secondary reflux. Reflux is considered physiologic when the infant thrives well and experiences no com-

plications. Regurgitation, the effortless return of gastric contents into the mouth, is the most common presentation of infantile GER, occasionally with projectile vomiting.1,2 Regurgitation of at least 1 episode a day occurs in half of 0- to 3-month-old infants, increases to two thirds of infants at 4 months, and decreases to 5% at 10 to 12 months of age but causes concern in at least 25% of parents.1 4 The prevalence of an increased quantity of GER, documented by esophageal pH monitoring, in a population of unselected infants is estimated to be 10%.5 The natural history of GER is improvement with age with disappearance 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 reflux associated with other manifestations, such as, failure to thrive or weight loss, feeding or sleeping problems, chronic respiratory disorders, esophagitis, hematemesis, stricture, sideropenic anemia, apnea, apparent life-threatening episodes or sudden infant death syndrome, and Sandifers syndrome. Atypical presentations of GER often occurs in the absence of regurgitation and vomiting and are mainly related to recurring respiratory symptoms. Secondary GER is considered a different entity and can be caused by infections, metabolic and neurologic disorders, and food allergy. Secondary GER is always GERD. However, even in secondary GERD, vomiting or other symptoms of primary GERD may frequently manifest and therefore a clear-cut distinction between primary and secondary GERD is frequently difficult to make. Most review and position reports on GER mention secondary GERD only briefly.79 This article specifically focuses on the relation between GER, primary or secondary, and cow milk allergy (CMA).
COW MILK INTOLERANCE AND COW MILK ALLERGY

From the *Pediatrics, Clinica Pediatrica di Varese, Universita dellInsubria, ` Brussels, Belgium; and Pediatrics, Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussels, Belgium. Received for publication Sep 24, 2001; accepted Mar 25, 2002. Reprint requests to (Y.V.) Academic Hospital, VUB, Laarbeeklaan 101, 1090 Brussels, Belgium. E-mail: yvan.vandenplas@az.vub.ac.be PEDIATRICS (ISSN 0031 4005). Copyright 2002 by the American Academy of Pediatrics.

Cow milk intolerance (CMI) defines any reproducible clinical adverse reaction to cow milk (CM). Immune-mediated CM-related adverse reactions is defined as CMA. These classic definitions are accepted worldwide, but CMA and CMI are, in many studies, used interchangeably because the immunologic basis of the mechanisms involved are frequently undetermined. Increased total or specific blood immunoglobulin (Ig) E or positive skin-prick test suggest type 1, or quick-onset, food allergy.10 No reliable routine tests for type 2, 3, and 4 cellular mediated CMA are currently available. Increased circulating, fecal, or nasal eosinophil populations or IgG anti- -

972

PEDIATRICS Vol. 110 No. 5 November 2002

lactoglobulin have not been accepted as proof of definitive diagnosis but may reinforce a clinical suspicion.11 Therefore, to simplify this review, we use CMA for true and suspected CMA. Conversely, CMI related to lactase deficiency is excluded. CMA is reported in 0.3% to 7.5% of infants (with 82% of symptoms reported within the first 4 months of life).10 14 On the basis of strict diagnostic criteria, the prevalence of confirmed CMA in developed countries during infancy is approximately 2% to 5%. Reproducible reactions to cow milk protein (CMP) in breastfed 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 atopic parent, 20% when there is 1 atopic parent, 32% when there is 1 atopic sibling, 43% when both parents are atopic, and as high as 72% when both parents have the identical type of atopic disease.16 Approximately 30% to 70% of infants with CMA manifest dermatological symptoms, 50% to 60% manifest gastrointestinal symptoms, and 20% to 30% manifest respiratory symptoms.15,17 This means that the majority of patients with CMA manifest symptoms involving more than 1 system, whereas patients with primary GERD mostly have only 1 system involved. Gastrointestinal symptoms of CMA include recurrent vomiting, food refusal, irritability, diarrhea, rectal bleeding, and malabsorption. Systemic manifestations may include failure to thrive and anaphylaxis. Only a small proportion of gastrointestinal allergy is IgE-mediated.10 Clinical response to an elimination diet and a challenge is the diagnostic principle of food allergy.10,18 Diagnosis of specifically CM protein enteropathy ideally necessitates the proof of small bowel damage with patchy partial villous atrophy and increased intraepithelial lymphocytes.10,11,19 Natural tolerance for CM in infants who are affected by CMA is frequently achieved within the first years of life. Remission of CMA was reported in 15% of the affected children by 1 year, in 22% to 28% by 2 years, in 51% by 3 years, in 55% to 67% by 4 years, and reaching 78% by 6 years.13,20 More recent, in a different 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 of age.15 From the evidence listed above, results show that GER and CMA both are generally self-limited symptoms, possibly interrelated, with only a small proportion of patients ( 10%) who will continue to have the disease-related symptoms after early infancy.
CMA AND GER

The age-dependent and similar clinical presentation (Fig 1) suggests a relation between GER and CMA.21 From the above reported prevalence of GER and 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 who experience pathologic reflux and CMA to 0.2% to 4.9% of infants who present with physiologic regurgitation and CMA. More than 20 years ago, Buisseret22 reported the presence of vomiting, colic, difficult infant feeding, growth retardation, psychological disturbance, and diarrhea in 79 children with CMA. Later, enteropathy (with IgE plasmacytes) was found in 3 (20%) of 15 infants who presented with recurrent vomiting.23 More recent, a CM-free diet (CMFD) was evaluated in 10 of 14 infants who had GER and did not respond to pharmacological reflux treatment: 2 (20%) of 10 improved.24 Kelly et al25 reported on 10 patients who had long-standing symptoms attributed to GERD (vomiting, abdominal pain, poor growth, and poor appetite) and did not respond to standard treatment (including a Nissen fundoplication in 6 children) and had persistent eosinophilic esophagitis; a dramatic clinical and histologic improvement was found in all patients after an amino acid based formula (AAF) was started. In accordance with a diagnosis of primary CMA, there was not only the obvious clinical response to the elimination diet with disappearance of all symptoms but also the clinical relapse in 7 of the 10 infants during an open challenge with CM proteins. In 5 Italian studies (some of them may have repetitive inclusion of patients), the association of

Fig 1. Symptoms attributed to GER and to CMA.

REVIEW ARTICLE

973

974
Age (Mo) 12 28 9.3 60 7.5 7.8 6 6.3 3.7 116 5 pH-m, EGDS, EB, SBB, DBPC, AT pH-m, open challenge EGDS, PT, DBPCC, AT pH-m,EGDS, EB, SBB, DBPCC, AT 2.8 pH-m,EGDS, EB, SBB, DBPCC, AT 2 3.8 pH-m, EGDS, EB, SBB, DBPCC, PT, AT Esophagitis Esophagitis, abnormal pH-m Esophagitis or ? Esophagitis, abnormal pH-m Esophagitis Esophagitis, abnormal pH-m Abnormal pH-m Esophagitis or ? Esophagitis, abnormal pH-m Investigations Criteria for CMA Criteria for GER Criteria for Starting CMFD Source 23 24 GER PT GER 27 25 31 28 All patients 29 30 26 32 33 EGDS, EB, SBB, RX upper series, AT EGDS, EB, SBB, pH-m, AT Response to CMFD, SBB at enrollment Response to CMFD Esophagiti, RX upper series Abnormal pH-m GER SBB GER Response to CMFD, challenge , PT or SBB at enrollment Response to CMFD, challenge Nonresponders to treatment with Nonresponders to treatment Nonresponders to treatment with or SBB Nonresponders to pH-m, EGDS, EB, SBB, RX upper series, open challenge, AT EGDS, EB, SBB, DBPCC, AT pH-m, EGDS, EB, SBB, DBPCC, AT Persisting symptoms of CMA All patients Response to CMFD, challenge Response to CMFD, challenge , SBB after challenge Response to CMFD, challenge , SBB after challenge Response to CMFD, challenge , SBB after challenge NR Response to CMFD, challenge Response to CMFD, challenge 1 laboratory allergic test or symptoms of CMA NR Persisting symptoms of CMA All patients

TABLE 1.

Reported Studies on CMA in GER: Inclusion and Diagnostic Criteria

Patients Included

Total No.

Persistent vomit

15

GER

14

Persistent vomit

25

Resistant GER

12

18

CMA resistant to eHF and GER treatment GER and/or CMA symptoms*

96

GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY

GER and/or CMA symptoms*

140

GER

204

112 16

GER CMA resistant to eHF and GER treatment Persistent vomit and irritability

19

EGDS indicates esophagogastroduodenoscopy; EB, esophageal biopsy; SBB, small bowel biopsy; DBPCC, double-blind, placebo-controlled challenge; PT, permeability test; AT, allergic tests (for details of each study, see Table 2); NR, not reported. * Presence of 1 of vomiting, regurgitation, retarded growth, persistent crying, repeated bronchospasm, sideropenic anemia, apneic episodes. As these 3 studies come from the same group, some patients may be re-included

TABLE 2. CMFD N 2/3 66 ND NR NR 2 66 NR 2 66 NR /N % % % % % % % % ND ND Challenge* SBB FH CMAs CMAH PRICK IgE EOS -Lacto Ab %

Reported Studies on CMA in GER: Clinical and Laboratory Results Phasic pHm % ND ND 1 4 4 ND ND PT % 23 24 27 25 31 28 25? 4 27 38? 27 85 9 90 29 30 26 14 0 0 0 0 3 16 NR NR ND ND ND 87 32 33 4 13 12 93 Source

Total No.

Subgroup Diseases

% GER

15 14

20

14

25

20

20 0 50 0 50 50 0 7 5 NR NR NR NR 2 20 NR NR 1 25 NR NR 0 0 11 61 NR NR NR NR 2 20 11 61

12

83

18 ND 31/ 39 ND 60/ 68 ND 85 ND ND ND 5/17 29 NR 100 88 79

3 12 2 16 4 4 2 10 18 ND 4/4 100 4/4 100 ND 7/9 78 12 66

20 86 14 64 16 16 17 83 100

3 8 2 4 4 2 10 18

3 0 2 4 4 2 10 18

3/15 0/12 1/2 0/16 2/3 2/3 NR NR 0/2

ND 0 0 1 50 NR NR NR NR 6 60 7 39

ND 0 0 0 0 NR NR NR NR NR 11 61

ND 0 0 0 0 NR NR NR NR 0 0 NR

ND ND ND ND ND ND

ND ND ND ND ND ND

6 100 100 ND ND ND

96

30

140

42

204

42

5 14 25 42 30 38 27 85

112

27 19 19 12 63

ND ND ND ND ND ND ND ND ND ND 23 100 ND ND ND

16

33 14 25 42 30 38 119 85 67 18 16

34 15 16 30 21 27 58 42 60 16 100

0 14 25 6 30 38 27 85 NR 18 18 16 13

0/5 0 14 100 25 100 0/6 0 30 100 38 100 0/27 0 85 100 ND 18 100 13 81

21 36 NR 9 21 10 33 NR 31 26 36 42 NR NR NR

NR 3 21 NR 0 0 4 13 NR 1 1 19 22 NR NR 12 75

0 0 3 21 NR 0 0 4 13 NR NR 19 22 NR NR 12 75

1 3 7 50 NR 2 5 13 43 NR 0 0 51 60 NR NR 14 87

0 0 6 43 NR 0 0 10 33 NR NR NR NR NR 2 12

0 0 6 43 NR 0 0 10 33 NR 0 0 31 36 NR NR NR

0 0 12 86 24 96 0 0 26 87 34 90 NR NR 3 4 1 5 ND

19

CMA GER GER only CMA GER GER only CMA GER CMA only GER only CMA GER eHF CMA GER GER only CMA GER CMA GER only CMA GER CMA GER only CMA GER GER only CMA GER eHF CMA GER CMA GER

19

100

FH indicates family history of atopy; CMAs, symptoms of CMA (eczema, respiratory symptoms, diarrhea); CMAH, medical history of atopy; EOS, eosinophils; ND, not done. * Challenge was performed 4 8 weeks after starting CMFD in all studies except in 3:2 done after 27 months31,30 and the other one after 214 months after starting CMFD.33 In these studies, the efficacy of CMFD refers to AAF and the challenge to eHF or soy.31 As these 3 studies come from the same group, some patients may be reincluded.

REVIEW ARTICLE

975

GER and CMA has been reported in 15% to 21% of infants with symptoms suggesting GER or CMA and in 16% to 42% of infants who had previously received a diagnosis of GERD.26 30 Reflux symptoms disappeared within 2 weeks of AAF in 13 consecutive infants who presented with persisting vomiting and were unresponsive to medical reflux treatment; 3 had documented esophagitis, and 7 had multiple food allergy unresponsive to extensive hydrolysate formula (eHF).31 Similarly, AAF was effective in 13 (81%) of 16 infants with symptoms that were suggestive CMA (9 of 16 with persistent vomiting and documented esophagitis in 7) and resistant to eHF and GER treatment. The 3 nonresponders did not react during a challenge with eHF, making the CMA diagnosis questionable.32 Last, in 19 infants with irritability and vomiting (with esophagitis in 9) resistant to eHF and antireflux medications, symptoms disappeared in all patients within 2 weeks after starting AAF. After a period of 2 to 12 months, a doubleblind, placebo-controlled challenge was performed: 12 infants were still intolerant of other formula (3 patients of soy and 9 of eHF).33 Details of the studies are shown in Tables 1 and 2. Intestinal permeability tests were positive in 85% of infants who had GER-CMA that was resistant to eHF32 and were 95% accurate in identifying CMA in 25 infants who presented with chronic vomiting.27 Intestinal permeability tests, based on differential sugar absorption tests with determination of urinary excretion of large molecules such as lactulose or cellobiose compared with small molecules such as mannitol, revealed an abnormal cellobiose/mannitol ratio (2 standard deviations over the mean from normal subjects) in infants with CMA.27 However, intestinal permeability studies are not easily performed in all hospitals, are aspecific for CMA, and have a limited sensitivity in infants without enteropathy.21,34 In 3 studies (from the same group) on infants with GER-CMA, increased -lactoglobulin antibodies were shown to have a sensitivity of 90% to 100% and a specificity of 78% to 90% as a predictive factor of efficacy of a CMFD.28 30 However, the absence of difference between the level of -lactoglobulin antibodies in control infants versus infants with CMA35 has as well been reported. Even the absence of any diagnostic help of IgG -lactoglobulin antibodies for allergic manifestations was suggested.36

An Italian group identified a typical pH tracing (phasic pattern, a progressive and slow decrease in esophageal pH between 2 feedings) in 12 (86%) of 14 infants with GER-CMA, in 24 (96%) of 25 infants with only CMA, and in 0 of 47 infants with primary GER or 0 of 49 control infants.28 The probe was positioned at 87% of the nose lower esophageal sphincter (LES) distance, calculated using Strobels formula. The authors speculated that a low basal resting tone of the LES, more than inappropriate relaxations of the LES, may be implicated. These findings were confirmed by the same center in a larger group of infants (phasic pH-metry in 87% of infants with GER-CMA and not in patients with GER or in control subjects).29 However, others have contradicted these findings, reporting a phasic pH tracing in 5% of infants with CMA and in 4% of patients with GER.26 Selection of patients, diagnosis of CMA and/or GER, and challenge tests were not standardized, making comparisons among all of the aforementioned reports hazardous. Besides, for proving objective phasic results, a double-entry analytical table (constituted by the number of recordings of each pH value during each 30-minute fraction after feeding) of pH-monitoring data is needed.29 From the above studies, symptoms disappeared in all,23,25,27,33 part,26,30 32 or a minority (2 of 10)24 of infants who had GERD symptoms resistant to classic GER therapy and were on a CMFD and relapsed during challenge. Routine immunologic allergic tests and family or patients medical history of allergy were not consistently positive or always predictive for the response to the CMFD (Tables 2 and 3). Nevertheless, CMA-related GER seems age-related and limited to young infants; as in older children, CMA symptoms evolve to cutaneous symptoms (atopic dermatitis), respiratory symptoms (wheezing, asthma, rhinitis), or lower gastrointestinal motility disturbance (constipation), especially when there is a positive family history of allergy.37
ESOPHAGITIS

Endoscopy and esophageal biopsies are recommended when esophagitis is suspected. Basal cell hyperplasia, papillary elongation, and intraepithelial or lamina propria inflammatory cell infiltration are histologic criteria for esophagitis.38,39 Eosinophilic infiltration is still a poorly characterized entity and should be interpreted with caution as it is not a

TABLE 3. Disease

Summary of the Results of CMA-GER Studies Total No. of Points 219 291 Total No. of Points 219 291 CMFD /N 216/219 35/84 PRICK /N 102/194 3/87 % 53 3 % 99 42 Challenge /N 197/209 0/38 Total IgE /N 29/80 0/87 % 36 0 % 94 0 SBB /N 96/124* 0/28 EOS /N 47/141 0/206 % 33 0 % 77 0 FH /N 53/139 47/194 % 38 24 CMAs /N 52/199 1/161 % 26 1 CMAH /N 54/199 0/75 PT /N 18/20 1/16 % 90 6 % 27 0

CMA GER GER only Disease

-Lacto Ab /N 125/129 35/194 % 97 18

Phasic pHm /N 39/62 3/142 % 63 2

CMA GER GER only

* 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.

976

GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY

specific marker for primary GER or for CMA. Eosinophilic esophagitis was initially attributed to GER39,40 but has now been related to a spectrum of disorders, including reflux, food allergy, primary eosinophilic esophagitis, and eosinophilic gastroenteropathy.41,42 In mice, eosinophilic esophagitis has even been related to inhalant allergens.43 The role of food protein is debated, and patients with eosinophilic esophagitis ( 5 eosinophils per high-power field [HPF]) may respond to dietary elimination, cromolyn sodium, or steroids.42 A specific endoscopic finding has been proposed for primary eosinophilic esophagitis, consisting of a granular, furrowed, and occasionally ringed appearance of the esophageal mucosa.42 Quantification of the eosinophilic infiltrate, on distal biopsy specimens, may provide criteria for a different entity causing eosinophilic infiltration. A small number of esophageal eosinophils (2.3 1.2/HPF) are suggestive of reflux esophagitis, whereas a high number ( 20/HPF) suggests primary eosinophilic esophagitis or eosinophilic gastroenteritis.41,42 The latter is confirmed by the observation that 7 eosinophils/HPF was related to an 85% positive predictive value of successful GER treatment.44 An eosinophilic density between 5 and 20/ HPF results in a gray zone, showing, perhaps, an overlap between reflux and eosinophilic esophagitis.42 The more the eosinophilic infiltration is limited to the distal esophagus, the more it is likely to be reflux related. Orenstein et al42 suggested that esophageal acidification as well as IgE allergic response induces mast cell degranulation with release of mediators that increase mucosal blood flow and attract and activate eosinophils. Activated eosinophils close to lymphocytes were present in an electron microscopic study in children with esophagitis.45 Eotaxin, an eosinophil-specific chemokine and activation markers of T-cells, is increasingly detected in CMPassociated esophagitis.46 This inflammatory response elicited by food protein seems to involve the entire gastrointestinal tract.33 It was suggested recently that esophageal mucosal homing of intestinal CM-sensitized T-cells may be responsible for CM-related esophagitis, in a way distinct from luminally mediated primary reflux esophagitis.47 In a murine model, oral antigen (ovalbumin) induced diffuse eosinophilic gastrointestinal inflammation (including the esophagus, stomach, and small intestine) mediated by eotaxin and related gastric dysmotility. Dysmotility may have promoted GER with antigendriven eosinophilic inflammation of the esophagus.48
GASTRIC EMPTYING

Multiple dietary factors, including volume,49 osmolality,50 caloric density,51 and protein content,52,53 influence gastric motility. In healthy infants, the type of milk regulates the gastric emptying rate: the gastric residual content, 2 hours after feeding, was the smallest with whey-hydrolysate formula and breast milk (16% and 18%, respectively) and progressively higher with acidified, whey-predominant, casein, follow-up, and CM formula (25%, 26%, 39%, 47%, and 55%, respectively).52 Casein empties the stomach slower than soy (39.7% vs 44.6%, respectively) or

whey-hydrolyzed isocaloric formula (48.5%). The incidence of GER seems to be inversely related to the gastric emptying rate (20.4%, 17.7%, and 16.3%, respectively).53 Low-fat high-carbohydrate formula improves gastric emptying, but its benefit in infants with GER has not been validated.9 Delayed gastric emptying is reported in GERD and may be involved in causing inappropriate relaxations of the LES.54 Cucchiara et al55 performed electrogastrography and antral ultrasonography in 42 patients with histologic esophagitis: dysrhythmic episodes and delayed gastric emptying were significantly more frequent in reflux patients than in control subjects. High-volume and high-osmolality meals increase the incidence of reflux episodes through significant changes in LES pressure.56 More than 60 years ago, in 12 children with food allergy, a test meal containing the food allergen was shown, using fluoroscopy, to cause gastric hypotonia, pylorospasm, and alteration of intestinal peristalsis.57 In 30 adult patients with proven food allergy, gastric biopsies taken during food challenge (also causing symptoms) showed a significant decrease in stained mast cells and tissue histamine.58 Recently, gastric emptying was shown to be delayed in patients with CMA in comparison with control subjects and infants with GER. In 7 patients with CMA, CM challenge caused a significant decrease of normogastria with an increase in bradygastria and tachygastria compared with infants with GERD or control subjects.59 In a murine model of experimental antigeninduced eosinophilic gastrointestinal inflammation mediated by eotaxin, marked gastric dysmotility (defined by fluorescent microsphere bead particle retention), gastromegaly and failure to thrive were reported. Electron microscopy analysis of small bowel biopsies revealed that eosinophils were in close proximity to damaged enteric nerves (containing swollen, enlarged axonal chambers with variable loss of internal organelles, indicative of axonal necrosis). Eosinophils, through the release of the major basic protein, may induce muscarinic receptor dysfunction, with alteration of smooth muscle contraction, gastric motility, and emptying.48 In a recent abstract, mast cell degranulation occurring proximal to the gastric nerve fibers and concomitant electrogastrography disturbances were demonstrated in patients with a positive food challenge, showing a link among cellular immune involvement, nervous system, and electrical gastric activity.60 Formula selection and meal size hence may be involved in infants with GER as the formula composition and volume may influence reflux by different mechanisms: increase in intragastric pressure (in case of bolus feeding), delay in gastric emptying,61 or trigger of immune response.
CONSTIPATION

CM-dependent colic and constipation have been reported and may support the idea of overall motility disturbance as part of the pathogenetic link between CMA and GER. Cytokines and the ongoing inflammatory process of the neurologic and motor system may mediate this effect. Lymphocyte and
REVIEW ARTICLE 977

eosinophil infiltration of the lamina propria and increased intraepithelial eosinophils with crypt infiltration were significantly detected in children with CMA-related constipation.62 Some chronically constipated children recover on a CMFD and relapse during challenge. A cellular immune mechanism seems to be involved, but common allergic tests, family history, or manifestations of atopy are predictive of a positive response to CMFD only in a subgroup of patients.13,62 67 Motility disturbance of the lower gastrointestinal tract is beyond the topic of this review and will not be discussed further.
DIETETIC CONSIDERATIONS

Before the commercialization of antiregurgitation formulas in the United States, formula change and thickened feedings were reported, respectively, in 8% and 2% of patients.4 However, today, antiregurgitation formulas are widely used and decrease the number and severity of regurgitation.9,61,68,69 Recent recommendations of dietary treatment of regurgitation68 do not consider avoidance of CMP as secondary GERD was excluded a priori. Dietary approach is based on elimination of CMP. CMFD options include soy formula, eHF, or AAF.
Soy

lecular weight above 1200 daltons,79 but eHF contains small amounts of peptides of 1200 to 1500 daltons80 and anaphylactic reaction to eHF has been reported.81 85 Intolerance to eHF has been reported in CMA with gastrointestinal or extraintestinal symptoms and in infants with either delayed or immediate type of hypersensitivity.31,32,86 93 -Lactoglobulin can be detected in whey-based eHF in an amount equivalent to that in breast milk.94 Therefore, it can be considered that breastfed infants who react to the minute amounts of CMP in breast milk could also react to eHF.32 eHF intolerance often occurs in multiple food allergy and persistent food intolerance, and in this situation, AAFs are needed for months or years.31,89,91,95 Unfortunately, there are no criteria for predicting which infants with CM- or soy-induced intestinal hypersensitivity will and will not respond to eHF. Diagnosis of eHF intolerance requires elimination diet first with AAF, which allows symptoms to disappear, and then a positive response to an oral challenge.32
AAF

Soy protein based formula is not recommended in the initial treatment of CMA,18 although most infants with IgE-mediated CMA may do well on soy formula, particularly after the age of 6 months.70 In a prospective study, healthy infants who were fed breast milk, CM, or soy formula showed proven allergic response to soy in 0.5% and to CM in 1.8% of the population.71 A survey reported allergy to CM to occur in 3.4% and to soy in 1.1% of all infants.72 In prevention, soy is not effective and the atopic manifestations are comparable in the CM and soy groups.73 The rate of clinical adverse reaction to soy in patients with proven CMA ranges from 10% to 67% (particularly high when 2 atopic parents or gastrointestinal involvement is present),13,74 76 but a double-blind, placebo-controlled challenge documented that soy allergy was demonstrated in only 4% to 5% of patients.77,78 Soy-induced enteropathy and enterocolitis are mostly not IgE mediated. Infants with documented CM-induced enteropathy or enterocolitis share the same non-IgE mechanism and are frequently equally sensitive to soy protein. Therefore, the American Academy of Pediatrics recommended that in patients with gastrointestinal symptoms caused by a nonIgE-mediated CMA, soy formula should be avoided and eHF or AAF should be administered.79
Hydrolysates

Recommended dietary products for the treatment of CMA in infants are limited to eHF and AAF, which are the only feedings that meet the standards for hypoallergenicity.18,70 Partially hydrolyzed formula is not recommended in the treatment of CMA.18 An eHF should, by definition, be tolerated by at least 90% of infants with CMA.18 Nonantigenic hydrolysates should not contain peptides with a mo978

Pure AAF is a nonallergenic food.18 AAF is effective to treat all CMA manifestations, even in multiple food allergy.25,31,32,89,91,93 Symptoms may reappear during challenge (even with eHF) after a period of 3 months.31 Failure to respond to AAF was reported in 6 of 44 infants with gastrointestinal symptoms reportedly attributable to CMA,32,93 but at least 3 of these patients did not have a positive challenge to eHF, which makes the diagnosis of CMA hazardous. It is still unclear whether the effect of AAF in GERD is the consequence of an immune or a gastrointestinal phenomenon.25,33 The AAF may exert nonimmune effects on gastrointestinal tract function such as gastrointestinal motility, gastric emptying, acid output, esophageal sphincter function, or gastrointestinal microflora. Furthermore, as the response to AAF may be a combination of a real response to amino acids, a placebo effect, and spontaneous improvement, a CM challenge remains mandatory to confirm the diagnosis of CMA. A challenge should be validated with an objective scoring system to document symptoms during a period as long as 7 days. This prolonged observation is particularly important to detect late-onset reactions.31 In CMA, eHF and AAF allow children to experience normal weight gain.31,32,89,91,93,96,97 A biochemical nutritional evaluation of infants on an eHF (Nutrilon Pepti) for 3 months showed overall normal results.98 Comparing eHF to AAF, biochemical indices (hemoglobin, albumin, prealbumin, transferrin, alkaline phosphatase, sodium, and potassium) were similar and remained within normal ranges after 6 to 8 months.96,99 Albumin was reported to be significantly improved on eHF but not on AAF,99 whereas the levels of plasma essential amino acids were smaller in eHF but higher in AAF compared with breast milk.96 Plasmatic branched-chain amino acids, especially valine, differed in breastfed and eHF- or AAF-fed infants, reflecting differences in the amino acid profiles of these formulas.96 All of the above reports support the nutritional adequacy of eHF and

GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY

AAF. Although safe,100 unnecessary use of CMFD and AAF must be avoided as it may also be detrimental to children.101 However, concerns about long-term lactose deprivation, possible alteration of intestinal microflora, taste, and, principally, cost of AAF still exist. Lactose is not present in many eHF and is present in AAF mainly to avoid contamination with residual CMP, but diets without lactose may have disadvantages for the composition of colonic flora and calcium absorption.18 AAF is approximately 25% more expensive than eHF, which costs significantly more than standard formula.70,97 Tolerance to CMP may be acquired after months or years of CMFD. Therefore, controlled rechallenges should be performed at regular intervals to avoid unnecessarily prolonged restricted diets.18 In patients with a history of severe hypersensitive reaction, the CM challenge should be performed rigorously in a hospital setting (because of possible anaphylactic reactions) and postponed to at least 9 to 12 months later.
Breast Milk

CMA in exclusively breastfed infants has a prevalence of 0.37% in a population in which CMA occurs at 1.9%.102 More recent, reactions to CMP in breastfed infants were reported in approximately 0.5%15 and an increasing number of exclusively breastfed infants become sensitized to multiple antigens very early in life.103106 No difference in incidence of regurgitation was reported in relation to breastfeeding or formula-feeding.105107 Comparing 37 breastfed to formula-fed healthy neonates, breast milk was associated with less and shorter reflux episodes 3 and 4 hours after feeding, although there was no significant difference in episodes per hour between the 2 groups. These results are possibly related to more quiet sleep (associated with rare reflux episodes), improved clearance rate, and enhanced gastric emptying, maybe related to differences in macronutrient content such as lipids and other components such as growth factor (not analyzed in this study).108 When CMA-related GERD is suspected, a dietetic trial with complete avoidance of CMP (with calcium supplementation when required) in the maternal diet is suggested for 3 to 4 weeks. When helpful, CMP should be reintroduced in the maternal diet to prove any causal relationship.
PROPOSED DIAGNOSTIC AND THERAPEUTIC APPROACH

A careful history, observation of feeding, and physical examination of the infant are always mandatory to detect signs of pathologic or secondary GER. In view of the reported considerations of CMrelated GER, current recommendations8,9,68,69 of diagnostic and therapeutic approaches to reflux in infants may be modified as shown in Figs 2 to 4. A few details are discussed further herein. Parental reassurance should always be the firstline approach associated with restriction of volume in overfed infants. The 30 reverse Trendelenburg position (not prone in the first 6 months of life) remains a valid adjunctive measure in patients with

GERD.69 As reported before, thickened formula may reduce regurgitation in formula-fed infants, but in breastfed infants, this recommendation is obviously not possible. The efficacy of thickened formula in GERD is questionable because its impact on GER parameters is unpredictable.9 A trial with CMFD (AAF if formula-fed and maternal avoidance of CMP if breastfed) could be tried in patients with positive atopic history or laboratory allergic test results, before drug treatment. AAF (compared with eHF) is preferred as it clearly and definitively excludes CMA in nonresponders. In infants with persisting symptoms, anti-GER medication can be given a trial. A recent systematic review found no evidence that cisapride significantly reduced GERD symptoms. However, only 7 studies (286 children in total) were considered eligible. Moreover, cisapride was associated with a significant reduction in the reflux index109 and when symptoms were redefined, a significant clinical effect appeared. Today, as a consequence of reported cardiac adverse reactions mainly when given in association with azoles or macrolides, cisapride is not available or is highly restricted in many countries.69 Data for other prokinetics (domperidone or metoclopramide) are even less convincing.9,69 The efficacy of domperidone in pediatric GERD is better when used in combination with other antireflux agents (antacids, thickened formula, or Gaviscon).9 Gaviscon (a sodium alginate-antacid preparation) acts as a mechanical barrier against reflux. It lasts longer than other antacids, and contraindications are limited to preterm or renal affected patients, because of its high content of sodium. Gaviscon showed significant efficacy in reducing vomiting and regurgitation and a 42% success rate in healing esophagitis.110 115 In 1 study, the combination of Gaviscon plus Carobel was superior to cisapride to relieve symptoms of reflux.112 In a randomized, multicenter comparison of sodium alginate and cisapride in 353 adults with uncomplicated GER, Gaviscon was reported to have overall superior symptom relief.116 A large pediatric randomized controlled study is expected to confirm its efficacy. In patients who do not respond to this medical therapeutic approach, upper endoscopy is needed. However, in situations in which endoscopy is not easily 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 beneficial drug treatment, a stopping challenge is recommended to exclude placebo effect and to avoid unnecessary long-term medication. In suspected esophagitis, endoscopy (with esophageal and, if possible, small bowel biopsy to rule out enteropathy) is recommended. Upper gastrointestinal radiologic series are essential to exclude anatomic malformations. Treatment of esophagitis is based on PPIs or H2-receptor antagonists.9 PPIs are more effective than H2 antagonists, well tolerated, and safe.9,117127 Limited side effects are reported in 1% to 6% of patients.9 The long-term safety of PPIs in children is still a matter of concern despite that large and long follow-up (up to 11 years) studies in adults
REVIEW ARTICLE 979

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

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

showed neither serious adverse events128 nor gastric dysplasia, neoplasia, inflammation, atrophy, or argyrophil cell hyperplasia in Helicobacter pylorinegative patients.129 The step-down or step-up therapeutic
980

approach to GERD is still debated.130 However, PPIs high efficacy of for healing, low number of relapses, and absence of serious adverse events make it the treatment of choice for esophagitis and severe

GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY

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

GERD128 131 and to maintain remission in patients with esophagitis.132 Patients with resistant GERD can benefit from a CMFD regimen or from steroids if significant eosinophilic esophagitis is present. Surgery, after full investigation (upper gastrointestinal series and endoscopy, pH monitoring, manometry, and gastric emptying studies), is reserved for life-threatening conditions that do not respond to a full GERD therapeutic approach or for patients who are dependent on medication. A possible food-related response should be investigated before the decision to perform a surgical antireflux procedure is made.25
Atypical Reflux

linkage of the atopy locus was found at D13S161136; a significant association between atopic dermatitis and D13S218 was observed on chromosome 13q12 14137 and linkage between markers on 13q21.3-qter (containing markers D13S285 and D13S293) and asthma, in the white population, was suggested.138 Although a complex interaction of genes and environmental factors are likely involved in allergic manifestations, it may be considered that even genetic and immunologic mechanisms are involved in CMA and GER.
Hyperreactive Esophagus

In atypical reflux (ie, chronic respiratory symptoms), as GERD is frequently occult and vomiting and regurgitation are mostly lacking, pH monitoring is the investigation of choice. If pathologic, treatment with PPI, H2 antagonists, or prokinetics is indicated and often required for a longer period of time. In nonresponders, endoscopy is recommended. Even in this group, CMA should be considered as a possible underlying condition.
SPECULATION POINTS Gene Relationship

It is intriguing to speculate on a possible relation between persistent reflux and esophageal hyperreactivity. As respiratory inflammation (respiratory syncytial virus bronchiolitis) during the first year of life seems to predispose, possibly via IL-13mediated mechanisms,139 to bronchial hyperreactivity in later childhood,140 untreated infantile GERD with persistent inflammation of esophageal mucosa could be related to hypersensitive or acid-sensitive esophagus or non esophagitis-related disease in adults.
Probiotic Approach

A genome-wide scan of 5 families that were affected by severe pediatric GER demonstrated that severe GER may follow an autosomal dominant hereditary pattern with high penetrance. The gene was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263.133 Chromosome 13 also contains several candidate genes for asthma and atopy, such as RANTES (a chemokine that attracts monocytes, T-cells, and eosinophils), STAT5a (a signal transducer of interleukin (IL)-5, so particularly important in IL-5 mediated eosinophil responses), endothelin receptor type B, chemokine receptor 7,134 and IgE-dependent histamine-releasing factor.135 Other reports suggested an important role of chromosome 13 in the development of allergic manifestations. The peak of

A recent study showed a significant beneficial effect of perinatal administration of Lactobacillus GG in preventing atopic dermatitis in high-risk infants.141 In that study, the treated and placebo groups did not differ in circulating IgE and skin-prick responses, suggesting that the clinical effects of this probiotic may be limited to IgE-independent mechanisms.142 It would be interesting to evaluate whether the rate of gastrointestinal allergic symptoms (mostly nonIgEmediated) could also be lowered by this therapeutic measure. Furthermore, patients on omeprazole may present bacterial overgrowth (more significant than on H2-receptor antagonists),143 and, therefore, probiotics may be useful to reestablish balanced flora and even influence tolerance in patients with GER-CMA. In terms of safety, sporadic rare side effects, such as septicemia and liver abscess, were reported, although not 1 side effect was reported when milk was
REVIEW ARTICLE 981

used as the vehicle.144 However, it is probably too early to suggest a widespread use of probiotics in all patients with CMA-GERD. More reports are attended.
CONCLUSION

This review reveals a link between GER and CMA. The molecular basis of their combined pathogenicity involves immune, neurologic, and motor mechanisms but still needs more research. A personal clinical history of allergy or positive allergic tests may help to select patients for a first-line approach with a CMFD, before conventional antireflux drug treatment. In patients without presumptive signs of CMA, CMFD should be reserved to nonresponders to drug treatment.
REFERENCES
1. Orenstein SR, Cohn JF, Shalaby T, et al. Reliability and validity of an infant gastroesophageal questionnaire. Clin Pediatr. 1993;32:472 484 2. Orenstein SR, Shalaby TM, Cohn J. Reflux symptoms in 100 normal infants: diagnostic validity of the Infant Gastroesophageal Reflux Questionnaire. Clin Pediatr. 1996;35:607 614 3. Chouhou D, Rossignol C, Bernard F, et al. Le reflux gastrooesophagien dans le centres de bilan de sante de lenfant de moins de 4 ans. Arch Fr Pediatr. 1992;49:843 845 4. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux in infancy. Arch Pediatr Adolesc Med. 1997;151: 569 572 5. Vandenplas Y, Goyvaerts H, Helven R, et al. Gastroesophageal reflux, as measured by 24-hour pH-monitoring, in 509 healthy infants screened for risk of sudden infants death syndrome. Pediatrics. 1991;88:834 840 6. Shepherd R, Wren J, Evans S, et al. Gastroesophageal reflux in children. Clinical profile, course and outcome with active therapy in 126 cases. Clin Pediatr. 1987;26:55 60 7. Vandenplas Y, Ashkenazi A, Belli D, et al. A proposition for the diagnosis and treatment of gastro-esophageal reflux disease in children: a report from a working group on gastro-esophageal reflux disease. Eur J Pediatr. 1993;152:704 711 8. Vandenplas Y, Belli D, Benhamou PH, et al. Current concepts and issues in the management of regurgitation of infants: a reappraisal. Acta Paediatr. 1996;85:531534 9. Vandenplas Y, Belli D, Benhamou P, et al. A critical reappraisal of current management practices for infant regurgitation: recommendation of a working party. Eur J Pediatr. 1997;156:343357 10. ESPGAN Working group. Diagnostic criteria for food allergy with predominantly intestinal symptoms. J Pediatr Gastroenterol Nutr. 1992; 14:108 112 11. Thomson M. Disorders of the esophagus and stomach in infants. Baillieres Clin Gastroenterol. 1997;11:547557 ` 12. Bock SA. Prospective appraisal of complaints of adverse reaction to foods in children during the first 3 years of life. Pediatrics. 1987;79: 683 688 13. Bishop JM, Hill DJ, Hosking CS. Natural history of cow milk allergy: clinical outcome. J Pediatr. 1990;116:862 867 14. Gerrard JW, McKenzie J, Golubott N, et al. Cows milk allergy: prevalence and manifestations in an unselected series of newborns. Acta Paediatr Scand. 1973;234:1 15. Host A. Cows milk protein allergy and intolerance in infancy. Some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol. 1994;5(suppl 5):136 16. Kjellman NI. Atopic disease in seven-year-old children. Incidence in relation to family history. Acta Paediatr Scand. 1977;66:465 471 17. Schrander JJ, van den Bogart JP, Forget PP, et al. Cows milk protein intolerance in infants under 1 year of age: a prospective epidemiological study. Eur J Pediatr. 1993;152:640 644 18. Host A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80 84 19. Walker-Smith JA. Diagnostic criteria for gastrointestinal food allergy in childhood. Clin Exp Allergy. 1995;25(suppl 1):S20 S22

20. Schrander JJ, Oudsen S, Forget PP. Follow up study of cows milk protein intolerant infants. Eur J Pediatr. 1992;151:783785 21. Cavataio F, Carroccio A, Iacono G. Milk-induced reflux in infants less than one year of age. J Pediatr Gastroenterol Nutr. 2000;30:S36 S44 22. Buisseret PD. Common manifestations of cows milk allergy in children. Lancet. 1978;8059:304 305 23. Forget P, Arends JW. Cows milk protein allergy and gastrooesophageal reflux. Eur J Pediatr. 1985;144:298 300 24. McLain BI, Cameron DJ, Barnes GL. Is cows milk protein intolerance a cause of gastro-oesophageal reflux in infancy? J Paediatr Child Health. 1994;30:316 318 25. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acidbased formula. Gastroenterology. 1995;109:15031512 26. Milocco C, Torre G, Ventura A. Gastro-oesophageal reflux and cows milk protein allergy. Arch Dis Child. 1997;77:183184 27. Staiano A, Troncone R, Simeone D, et al. Differentiation of cows milk intolerance and gastro-oesophageal reflux. Arch Dis Child. 1995;73: 439 442 28. Cavataio F, Iacono G, Montalto G, et al. Clinical and pH-metric characteristics of gastro-esophageal reflux secondary to cows milk protein allergy. Arch Dis Child. 1996;75:5156 29. Cavataio F, Iacono G, Montalto G, et al. Gastroesophageal reflux associated with cows milk allergy in infants: which diagnostic examinations are useful? Am J Gastroenterol. 1996;91:12151220 30. Iacono G, Carroccio A, Cavataio F, et al. Gastroesophageal reflux and cows milk allergy in infants: a prospective study. J Allergy Clin Immunol. 1996;97:822 827 31. Hill DJ, Cameron DJS, Francis DEM, et al. Challenge confirmation of late-onset reactions to extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Allergy Clin Immunol. 1995;96: 386 394 32. de Boissieu D, Matarazzo P, Dupont C. Allergy to extensively hydrolyzed cow milk protein in infants: identification and treatment with an amino acid based formula. J Pediatr. 1997;131:744 747 33. Hill DJ, Heine RG, Cameron DJS, et al. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr. 2000;136:641 647 34. van Elburg RM, Uil JJ, de Monchy JG, et al. Intestinal permeability in pediatric gastroenterology. Scand J Gastroenterol Suppl. 1992;194:19 24 35. Host A, Husby S, Gjesing B, et al. Prospective estimation of IgG, IgG subclass and IgE antibodies to dietary proteins in infants with cow milk allergy. Levels of antibodies to whole milk protein, BLG and ovalbumin in relation to repeated milk challenge and clinical course of cow milk allergy. Allergy. 1992;47:218 229 36. Keller KM, Burgin-Wolff A, Lippold R, et al. The diagnostic significance of IgG cows milk protein antibodies re-evaluated. Eur J Pediatr. 1996; 155:331337 37. Iacono G, Cavataio F, Montalto G. Persistent cows milk protein intolerance in infants: the changing faces of the same disease. Clin Exp Allergy. 1998;28:817 823 38. Vandenplas Y. Reflux esophagitis in infants and children. A report from the Working Group of the European Society of Pediatric Gastroenterology and Nutrition on Gastro-oesophageal Reflux Disease. J Pediatr Gastroenterol Nutr. 1994;18:413 422 39. Black DD, Haggitt RC, Orenstein SR. Esophagitis in infants. Morphometric histological diagnosis and correlation with measures of gastroesophageal reflux. Gastroenterology. 1990;98:1408 1414 40. Winter HS, Madara JL, Stafford RJ. Intraepithelial eosinophils: a new diagnostic criteria for reflux esophagitis. Gastroenterology. 1982;83: 818 823 41. Liacouras CA, Wenner WJ, Brown K, et al. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr. 1998;26:380 385 42. Orenstein SR, Shalaby TM, Di Lorenzo C, et al. The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children. Am J Gastroenterol. 2000;95:14221430 43. Mishra A, Hogan SP, Brandt EB, et al. An etiological role for aeroallergens and eosinophils in experimental esophagitis. J Clin Invest. 2001; 107:8390 44. Ruchelli E, Wenner W, Voytek T, et al. Severity of esophageal eosinophilia predicts response to conventional gastroesophageal reflux therapy. Pediatr Dev Pathol. 1999;2:1518 45. Justinich CJ, Ricci A Jr, Kalafus DA. Activated eosinophils in esophagitis in children: a transmission electron microscopic study. J Pediatr Gastroenterol Nutr. 1997;25:194 198 46. Garcia-Zepeda EA, Rothenberg ME, Ownbey RT, et al. Human eotaxin

982

GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY

47. 48.

49. 50. 51. 52.

53.

54. 55.

56.

57. 58. 59.

60.

61. 62. 63. 64. 65. 66. 67. 68.

69.

70. 71.

72.

73.

74.

75.

76.

is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med. 1996;2:449 456 Thomson M. Esophagitis. In: Pediatric Gastrointestinal Disease. 3rd ed. Hamilton, Ontario, Canada: BC Decker; 2000:297316 Hogan SP, Mishra A, Brandt EB, et al. A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation. Nat Immunol. 2001;2:353360 Sutphen JL, Dillard VL. Effect of feeding volume on gastroesophageal reflux in infants. J Pediatr Gastroenterol Nutr. 1988;7:185188 Sutphen JL, Dillard VL. Dietary caloric density and osmolarity influence gastroesophageal reflux in infants. Gastroenterology. 1989;97:601 604 Calbet JA. Role of caloric content on gastric emptying in humans. J Physiol. 1997;498:553559 Billeaud C, Guillet J, Sandler B. Gastric emptying in infants with or without gastroesophageal reflux according to the type of milk. Eur J Clin Nutr. 1990;44:577583 Tolia V, Lin S, Kuhns LR. Gastric emptying using three different formulas in infants with gastroesophageal reflux. J Pediatr Gastroenterol Nutr. 1992;15:297301 Coben RM, Weintraub A, Di Marino AJ Jr, et al. Gastroesophageal reflux during gastrostomy feeding. Gastroenterology. 1994;106:1318 Cucchiara S, Salvia G, Borrelli O, et al. Gastric electrical dysrhythmias and delayed gastric emptying in gastroesophageal reflux disease. Am J Gastroenterol. 1997;92:11031108 Salvia G, De Vizia B, Manguso F, et al. Effect of intragastric volume and osmolality on mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease. Am J Gastroenterol. 2001;96:17251732 Fries JH, Zizmor J. Roentgen studies of children with alimentary disturbances due to food allergy. Am J Dis Child. 1937;54:1239 1251 Reimann HJ, Lewin J. Gastric mucosal reactions in patients with food allergy. Am J Gastroenterol. 1988;83:12121219 Ravelli AM, Tobanelli P, Volpi S, et al. Vomiting and gastric motility in infants with cows milk allergy. J Pediatr Gastroenterol Nutr. 2001;32: 59 64 Borrelli O, Schappi MG, Knafelz D, et al. Mast Cell-Nerve Interaction Is Critical for Food Allergic Intestinal Dysmotility. Presented at the 34th Annual Meeting of ESPGHAN; May 9 12, 2001; Geneva, Switzerland (abstr 04) Vandenplas Y, Lifshitz JZ, Orenstein S, et al. Nutritional management of regurgitation in infants. J Am Coll Nutr. 1998;17:308 316 Iacono G, Cavataio F, Montalto G, et al. Intolerance of cows milk and chronic constipation in children. N Engl J Med. 1998;339:1100 1104 Bloom DA. Allergic colitis: a mimic of Hirschsprung disease. Pediatr Radiol. 1999;29:37 41 Chin KC, Tarlow MJ, Allfree AJ. Allergy to cows milk presenting as chronic constipation. BMJ. 1983;287:1593 Daher S, Sole D, de Morais MB. Cows milk and chronic constipation in children. N Engl J Med. 1999;340:891 Iacono G, Carroccio A, Cavataio F, et al. Chronic constipation as a symptom of cow milk allergy. J Pediatr. 1995;126:34 39 Shah N, Lindley K, Milla P. Cows milk and chronic constipation in children. N Engl J Med. 1999;340:891 892 Vandenplas Y, Belli D, Cadranel S, et al. Dietary treatment for regurgitation: recommendations from a working party. Acta Paediatr. 1998;87:462 468 Vandenplas Y, Hegar B. Diagnosis and treatment of gastro-esophageal reflux disease in infants and children. J Gastroenterol Hepatol. 2000;15: 593 603 American Academy of Pediatrics, Committee on Nutrition. Hypoallergenic infants formulas. Pediatrics. 2000;106:346 349 Halpern SR, Sellers WA, Johnson RB, et al. Development of childhood allergy in infants fed breast, soy or cows milk. Allergy Clin Immunol. 1973;51:139 151 Johnstone DE, Roghmann KJ. Recommendation for soy infant formula: a review of the literature and a survey of pediatric allergists. Pediatr Asthma Allergy Immunol. 1993;7:77 88 Chandra RK. Five-year follow-up of high-risk infants with family history of allergy who were exclusively breast-fed or fed partial whey hydrolysate, soy, and conventional cows milk formulas. J Pediatr Gastroenterol Nutr. 1997;24:380 388 Kjellman NI, Johansson SG. Soy versus cows milk in infants with a biparental history of atopic disease: development of atopic disease and immunoglobulins from birth to 4 years of age. Clin Allergy. 1979;9: 347358 Bock SA, Atkins FM. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges. J Pediatr. 1990;117:561567 Zeiger RS, Sampson HA, Bock SA. Soy allergy in infants and children

with IgE-associated cows milk allergy. J Pediatr. 1999;134:614 622 77. Sampson HA. The role of food allergy and mediator release in atopic dermatitis. J Allergy Clin Immunol. 1988;81:635 645 78. Businco L, Bruno G, Giampietro PG, et al. Allergenicity and nutritional adequacy of soy protein formulas. J Pediatr. 1992;121:S21S28 79. American Academy of Pediatrics, Committee on Nutrition. Soy proteinbased formulas: recommendations for use in infant feeding. Pediatrics. 1989;83:1068 1069 80. Gern JE, Yang E, Errard HM, et al. Allergic reactions to milkcontaminated nondairy products. N Engl J Med. 1991;324:976 979 81. Lifschitz CH, Hawkins HK, Guerra C, et al. Anaphylactic shock due to cows milk protein hypersensitivity in a breast-fed infant. J Pediatr Gastroenterol Nutr. 1988;7:141144 82. Businco L, Cantani A, Longhi AL, et al. Anaphylactic reactions to cows milk whey hydrolysate (Alpha-Re, Nestle) in infants with cows milk allergy. Ann Allergy. 1989;62:333 83. Ellis MH, Short JA, Heiner DC. Anaphylaxis after ingestion of a recently introduced hydrolyzed whey protein formula. J Pediatr. 1991;118:74 77 84. Schwartz RH, Amonette MS. Cow milk protein hydrolysate infant formula not always hypoallergenic. J Pediatr. 1991;119:839 85. Saylor JD, Bahna SL. Anaphylaxis to casein hydrolysate formula. J Pediatr. 1991;118:7174 86. Harrison CJ, Puntic WL, Durbin GM, et al. Case report: atypical allergic colitis in preterm infants. Acta Paediatr Scand. 1991;80:11131116 87. Kelso JM, Sampson HA. Food protein-induced enterocolitis to casein hydrolysate formulas. J Allergy Clin Immunol. 1993;92:909 910 88. Rosenthal E, Schlesinger Y, Birnhaum Y, et al. Intolerance to casein hydrolysate formula. Acta Paediatr Scand. 1991;80:958 960 89. Ammar F, de Boissieu D, Dupont C. Allergy to protein hydrolysates. Report of 30 cases. Arch Pediatr. 1999;6:837 843 90. Giampietro PG, Kjellman NIM, Oldaeus G, et al. Hypoallergenicity of an extensively hydrolyzed whey formula. Pediatr Allergy Immunol. 2001; 12:83 86 91. Sicherer SH, Noone SA, Koerner CB, et al. Hypoallergenicity and efficacy of an amino acid-based formula in children with cows milk and multiple food allergy. J Pediatr. 2001;138:688 693 92. Lake AM. Beyond hydrolysates: use of L-amino acid formula in resistant dietary protein-induced intestinal disease in infants. J Pediatr. 1997; 131:658 660 93. Vanderhoof JA, Murray ND, Kaufman SS, et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants. J Pediatr. 1997;131:741744 94. Makinen-Kiljunen S, Palosuo T. A sensitive enzyme-linked immunosorbent assay for determination of bovine -lactoglobulin in infant feeding formulas and in human milk. Allergy. 1992;47:347352 95. Carroccio A, Cavataio F, Montalto D, et al. Intolerance to hydrolysed cows milk proteins in infants: clinical characteristics and dietary treatment. Clin Exp Allergy. 2000;30:1598 1603 96. Isolauri E, Sutas Y, Makinen-Kiljunen S, et al. Efficacy and safety of hydrolyzed cow milk and amino acid-derived formulas in infants with cow milk allergy. J Pediatr. 1995;127:550 557 97. Niggemann B, Binder C, Dupont C, et al. Prospective, controlled, multicenter study on the effect of an amino-acid-based formula in infants with cows milk allergy/intolerance and atopic dermatitis. Pediatr Allergy Immunol. 2001;12:78 82 98. Vandenplas Y, Hauser B, Blecker U, et al. The nutritional value of a whey hydrolysate formula compared with a whey-predominant formula in healthy infants. J Pediatr Gastroenterol Nutr. 1993;17:9296 99. McLeish CM, MacDonald A, Booth IW. Comparison of an elemental with a hydrolysed whey formula in intolerance to cows milk. Arch Dis Child. 1995;73:211215 100. Sampson HA, James JM, Bernheisel-Broadbent J. Safety of an amino acid-derived infant formula in children allergic to cow milk. Pediatrics. 1992;90:463 465 101. Isolauri E, Sutas Y, Salo MK, et al. Elimination diet in cows milk allergy: risk for impaired growth in young children. J Pediatr. 1998;132: 1004 1009 102. Jakobsson J, Lindberg T. A prospective study of cows milk protein intolerance in Swedish infants. Acta Paediatr. 1979;68:853 859 103. de Boissieu D, Matarazzo P, Rocchiccioli F, et al. Multiple food allergy: a possible diagnosis in breastfed infants. Acta Paediatr. 1997;86: 10421046 104. Isolauri E, Tabvanainen A, Peltola T, et al. Breast-feeding of allergic infants. J Pediatr. 1999;134:2732 105. Hill DJ, Heine RG, Cameron DJS, et al. The natural history of intolerance to soy and extensively hydrolyzed formulas in infants with multiple food protein intolerance. J Pediatr. 1999;135:118 121 106. Walker-Smith JA, Murch SH. Gastrointestinal food allergy. In: Diseases

REVIEW ARTICLE

983

107.

108.

109.

110. 111.

112.

113.

114.

115.

116.

117. 118.

119. 120.

121.

122.

123. 124. 125.

of the Small Intestine in Childhood. 4th ed. Oxford, United Kingdom: Isis Medical Media; 1999:205234 Osatakul S, Sriplung H, Puetpaiboon A, et al. Prevalence and natural course of gastroesophageal reflux symptoms: a 1-year cohort study in Thai infants. J Pediatr Gastroenterol Nutr. 2002;34:63 67 Heacock HJ, Jeffery HE, Baker JL, et al. Influence of breast versus formula milk on physiological gastroesophageal reflux in healthy, newborn infants. J Pediatr Gastroenterol Nutr. 1992;14:41 46 Gilbert RE, Augood C, MacLennan S, et al. Cisapride treatment for gastro-oesophageal reflux in children: a systematic review of randomized controlled trials. J Pediatr Child Health. 2000;36:524 529 Weldon AP, Robinson MJ. Trial of Gaviscon in the treatment of gastrooesophageal reflux in infancy. Aust Paediatr J. 1972;8:279 281 Buts JP, Barudi C, Otte JB. Double-blind controlled study on the efficacy of sodium alginate (Gaviscon) in reducing gastroesophageal reflux assessed by 24-h continuous pH monitoring in infants and children. Eur J Pediatr. 1987;146:156 158 Greally P, Hampton FJ, MacFayden UM, et al. Gaviscon and Carobel compared with cisapride in gastro-oesophageal reflux. Arch Dis Child. 1992;67:618 621 LeLuyer B, Mougenot JF, Mashako L, et al. Multicenter study of sodium alginate in the treatment of regurgitation in infants. Ann Pediatr. 1992;39:635 640 Oderda G, DellOlio D, Forni M, et al. Treatment of childhood peptic esophagitis with famotidine or alginate-antacid. Ital J Gastroenterol. 1990;22:346 349 Miller S. Comparison of the efficacy and safety of a new aluminiumfree paediatric alginate preparation and placebo in infants with recurrent gastro-oesophageal reflux. Curr Med Res Opin. 1999;15:160 168 Poynard T, Vernisse B, Agostini H. Randomized, multicentre comparison of sodium alginate and cisapride in the symptomatic treatment of uncomplicated gastroesophageal reflux. Aliment Pharmacol Ther. 1998; 12:159 165 Dalzell AM, Searle JW, Patrick MK. Treatment of refractory ulcerative oesophagitis with omeprazole. Arch Dis Child. 1992;67:641 642 Cucchiara S, Minella R, Iervolino C, et al. Omeprazole and high dose ranitidine in the treatment of refractory reflux oesophagitis. Arch Dis Child. 1993;69:655 659 Martin PB, Imong SM, Krischer J, et al. The use of omeprazole for resistant oesophagitis in children. Eur J Pediatr Surg. 1996;6:195197 Kato S, Ebina K, Fujii K, et al. Effect of omeprazole in the treatment of refractory acid-related diseases in childhood: endoscopic healing and twenty-four hour intragastric acidity. J Pediatr. 1996;128:415 421 De Giacomo C, Bawa P, Franceschi M, et al. Omeprazole for severe reflux esophagitis in children. J Pediatr Gastroenterol Nutr. 1997;24: 528 532 Cucchiara S, Minella R, Campanozzi A, et al. Effects of omeprazole on mechanisms of gastroesophageal reflux in childhood. Dig Dis Sci. 1997;42:293299 Walters JK, Zimmermann AE, Souney PF, et al. The use of omeprazole in the pediatric population. Ann Pharmacother. 1998;32:478 481 Alliet P, Raes M, Bruneel E, et al. Omeprazole in infants with cimetidine-resistant peptic esophagitis. J Pediatr. 1998;132:352354 Israel DM, Hassall E. Omerprazole and other proton pump inhibitors: pharmacology, efficacy, and safety, with special reference to use in

children. J Pediatr Gastroenterol Nutr. 1998;27:568 579 126. Strauss RS, Calenda KA, Dayal Y, et al. Histological esophagitis: clinical and histological response to omeprazole in children. Dig Dis Sci. 1999;44:134 139 127. Hassal E, Israel D, Shepherd R, et al. Omeprazole for treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and dose requirements. International Pediatric Omeprazole Study Group. J Pediatr. 2000;137:800 807 128. Kuipers EJ, Meuwissen SGM. The efficacy and safety of long-term omeprazole treatment for gastroesophageal reflux disease. Gastroenterology. 2000;118:795798 129. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and influence on gastric mucosa. Gastroenterology. 2000;118:661 669 130. McGuigan JE. Treatment of gastroesophageal reflux disease: to step or not to step. Am J Gastroenterol. 2001;96:1679 1681 131. Tytgat GN. Medical therapy of gastroesophageal reflux disease in secondary and tertiary care settings. Yale J Biol Med. 1999;72:181194 132. Annibale B, Franceschi M, Fusillo M, et al. Omeprazole in patients with mild or moderate reflux esophagitis induces lower relapse rates than ranitidine during maintenance treatment. Hepatogastroenterology. 1998; 45:742751 133. Hu FZ, Preston RA, Post JC, et al. Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14. JAMA. 2000; 284:325334 134. Deloukas P, Schuler GD, Gyapay G, et al. A physical map of 30,000 human genes. Science. 1998;282:744 746 135. MacDonald SM, Pazebas WA, Jabs EW. Chromosomal localization of tumor protein, translationally-controlled 1 (TPT 1) encoding the human histamine releasing factor (HRF) to 13q12 q14. Cytogenet Cell Genet. 1999;84:128 129 136. Bhattacharyya S, Leaves NI, Witshire S, et al. A high-density genetic map of the chromosome 13q14 atopy locus. Genomics. 2000;70:286 291 137. Beyer K, Nickel R, Freidhoff L, et al. Association and linkage of atopic dermatitis with chromosome 13q1214 and 5q3133 markers. J Invest Dermatol. 2000;115:906 908 138. The Collaborative Study of Genetics of Asthma. A genome-wide search for asthma susceptibility loci in ethnically diverse populations. Nat Genet. 1997;15:389 392 139. Lukacs NW, Tekkanat KK, Berlin A, et al. Respiratory syncytial virus predispose to augmented allergic airway responses via il-13-mediated mechanisms. J Immunol. 2001;167:1060 1065 140. McBride JT. Pulmonary function changes in children after respiratory syncytial virus infection in infancy. J Pediatr. 1999;135(2, pt 2):28 32 141. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet. 2001;357:1076 1079 142. Murch S. Toll of allergy reduced by probiotics. Lancet. 2001;357: 10571059 143. Thorens J, Froehlich F, Schwizer W, et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective, randomised double blind study. Gut. 1996;39:54 59 144. Salminen S, von Wright A, Morelli L, et al. Demonstration of safety of probiotics: a review. Int J Food Microbiol. 1998;44:93106

984

GASTROESOPHAGEAL REFLUX AND COW MILK ALLERGY