Abstract
Background/Aims
Gastroesophageal reflux disease (GERD) and cow's milk allergy (CMA) are two common conditions that occur in infancy. This study was performed to investigate the frequency of CMA in a group of patients with GERD.
Methods
Eighty-one children with signs and symptoms of GERD were enrolled in this study. All subjects received omeprazole for 4 weeks after the initial evaluation. Empirical elimination of cow's milk from the diet was started for the patients who did not respond to the omeprazole treatment.
Results
Seventy-two cases presented with gastrointestinal signs and symptoms, whereas the remaining nine cases presented with respiratory complaints. After the initial treatment with omeprazole, two thirds of the cases (54 patients, 66.7%) responded well, and all of their symptoms were resolved. Cow's milk was eliminated from the diets of the remaining 27 patients. All signs and symptoms of GERD were resolved in this group after a 4 week elimination of cow's milk from the diet.
Conclusions
A diagnosis of CMA was considered in one third of the pediatric cases with signs and symptoms of GERD. This finding shows that CMA can mimic or aggravate all signs and symptoms of severe GERD during infancy.
Keywords: Cow's milk allergy, Food hypersensitivity, Gastroesophageal reflux disease
INTRODUCTION
Gastroesophageal reflux disease (GERD) and food hypersensitivity are two common disorders of infancy and childhood.1,2 Gastroesophageal reflux is an effortless retrograde movement of gastric contents into the esophagus, which could be considered as a normal physiologic process when lasting less than 3 minutes, occurring in the postprandial period, and causing few or no symptoms. However, when the reflux of gastric contents causes troublesome symptoms and/or complications, the diagnosis of GERD is made. The most common manifestations of GERD is distal esophagitis, followed by failure to thrive, esophageal peptic strictures, Barrett's esophagus, and pulmonary disease.3,4
GERD is a multifactorial disease that frequently manifests during early infancy, and has a great tendency for spontaneous improvement during the first years of life, which might be as a result of feeding habits alteration as well as improved function of the lower esophageal sphincter (LES).1,5,6 Increased frequency of reflux in infants younger than age 4 months could suggest developmental immaturity of the LES,7,8 which seem to be the most common cause of gastroesophageal reflux in children.9-12
Association between GERD and cow's milk allergy (CMA) has been first described in infants and toddlers.13 Consequently, several studies were performed with controversial results on prevalence of CMA in infants with GERD,13-16 which could be due to different diagnostic criteria for either GERD or CMA among these studies.17,18
This study was performed for the first time in our region to investigate the frequency of CMA in a group of infants with GERD.
MATERIALS AND METHODS
Eighty one patients who had been referred to the Children's Medical Center (Pediatrics Center of Excellence in Tehran, Iran) with signs and symptoms of GERD during 2006-2007, were enrolled in this study. There was no history of any previous underlying disease for the participants. Patients with associated diseases such as neurodevelopmental disorders, esophageal atresia and anatomical malformations were excluded from the study. The diagnosis of GERD was made based on clinical symptoms considering the medical history of patients and physical examination. Several questions regarding vomiting or regurgitation, crying, weight gain, respiration problems, cyanosis, apnea, pneumonia, bronchitis, chronic coughing, hiccups, and diarrhea were asked from the parents of patients.19 Barium swallow was also performed in some patients with intractable vomiting to evaluate esophageal stricture, hiatal hernia and/or intestinal obstruction.
All patients were treated with omeprazole 2 mg/kg/day divided in two doses for 4 weeks. The effect of omeprazole on GERD was assessed 4 weeks after treatment. For the patients who did not respond to this treatment, a trial of cow's milk elimination diet was considered for either infant or the mothers whom their child was breast fed for 4 weeks. The effect of cow's milk elimination was assessed after this 4-week period. Patients who respond to this elimination diet (including omitting cow's milk protein from diet) in addition to GERD treatment were assumed as CMA.
RESULTS
Forty two male and 39 female infants, with age range of 1 month to 2 years (median age of 12.5 months), were included in this study. Seventy two cases (88.89%) suffered from gastrointestinal signs and symptoms (such as nausea, vomiting, and irritability), whilst the remaining 9 cases (11.11%) presented with respiratory complaints (such as frequent cough, wheezing, asthma, and recurrent aspiration). Other less frequent symptoms were chocking which was seen in 3 patients and apnea (less than 10 seconds) which were reported in 2 patients. The age distribution of all patients, participating in this study, is presented in Fig. 1.
Fig. 1.
Age distribution of the study patients with cow's milk allergy (CMA) and gastroesophageal reflux disease (GERD).
After initial treatment with omeprazole, 54 out of 81 patient (66.67%) responded well to this treatment; all of their symptoms were resolved. These patients were diagnosed as GERD.
The remaining 27 patients (33.33%) underwent an elimination diet of cow's milk and reassessed for their symptoms after 4 weeks of this diet. All the signs and symptoms of these patients were resolved in this group after 4 weeks period of elimination of cow's milk from diet; thus the diagnosis of CMA was considered for these patients.
Among these 27 patients (15 male and 12 female) with CMA, 21 cases (77.78%) had gastrointestinal signs and symptoms, whereas 6 (22.22%) had respiratory symptoms. There was positive family history of allergy in at least one parent of 12 individuals (44.44%). The age distribution of patients with CMA in this study is summarized in Fig. 1.
DISCUSSION
GERD is a disease that commonly occurs during the first year of life; some forms of severe GERD have been shown to be associated with CMA.20,21 The pathogenesis of GERD is multifactorial and complex, involving the frequency of reflux, gastric acidity, gastric emptying, esophageal clearing mechanisms, the esophageal mucosal barrier, visceral hypersensitivity, and airway responsiveness.
In the present study, the CMA was diagnosed in one third of patients with sign and symptoms of GERD. A substantial part of these patients had family history of allergy or atopy. Although respiratory symptoms are expected to be seen in severe GERD, 6 out of 9 cases with respiratory symptoms were diagnosed as CMA. This finding shows that CMA can mimic all signs and symptoms of severe GERD.
The prevalence of food hypersensitivities in childhood and infancy is estimated about 7-8%.22 CMA is the most common one with prevalence of 2-3% in the infants.23,24 CMA can involve several organs, particularly skin and gastrointestinal tract. All parts of gastrointestinal lumen, including the esophagus, stomach, small intestine, colon and rectum, may be involved in CMA.20,21 It should be noted that in this study the trial of cow's milk elimination diet was not done in the infants who responded to omeprazole. So, the prevalence of CMA among GERD might be estimated to be lower than it really was.
Many questions about the causative relationship and the optimal diagnostic modalities of the GERD-CMA association have been remained unsolved until now.21 A trial of empiric elimination of cow's milk protein either in formula fed infants or breast fed infants mother has been considered as an diagnostic strategy for infants suspected to having food allergy, followed by either an open challenge or a double-blind, placebo-controlled food challenge (DBPCFC) to confirm or exclude a food allergy. However, DBPCFC should be conducted in adults and in children older than 3 years.20,21,23
It should be noted that there are some differences between primary GERD or secondary GERD due to CMA. Although it is not expected that the patients with CMA respond to omeprazole and diet elimination is necessary for treatment, a 24-hour esophageal pH monitoring could be recommended to determine the etiology of disease.24
Although the gold standard therapy of GERD is proton pump inhibitors and H2 receptor blockers, the diagnostic strategy in infants who are suspected of having food allergy should involve 2-4 weeks elimination diet. It should be noted that adherence to a diet without proper guidance may have a negative effect on growth and development.25-27 It is important to diagnose CMA to avoid unnecessary elimination diets. The treatment of gastrointestinal manifestations of CMA relies on avoidance of cow's milk protein and dietary measures depending on the age of the child. Supportive treatment may also be included. Appropriate formula substitutes such as those containing extensively hydrolysed protein or, if not tolerated, amino acid-based formulas, should be used to secure appropriate energy and micronutrient needs.
In the present study, it has been shown that elimination of cow's milk product in the patients with diagnosis of refractory GERD resolved the problems. It seems that cow's milk product can either aggravate GERD symptoms (via dysmotility of gastrointestinal tract) or explain nonresponsive GERD to appropriate pharmacologic treatment.28
Footnotes
No potential conflict of interest relevant to this article was reported.
References
- 1.Nelson SP, Chen EH, Syniar GM, Christoffel KK Pediatric Practice Research Group. Prevalence of symptoms of gastroesophageal reflux during infancy: a pediatric practice-based survey. Arch Pediatr Adolesc Med. 1997;151:569–572. doi: 10.1001/archpedi.1997.02170430035007. [DOI] [PubMed] [Google Scholar]
- 2.Høst A. Cow's milk protein allergy and intolerance in infancy: some clinical, epidemiological and immunological aspects. Pediatr Allergy Immunol. 1994;5(5 Suppl):1–36. [PubMed] [Google Scholar]
- 3.Shay S, Tutuian R, Sifrim D, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol. 2004;99:1037–1043. doi: 10.1111/j.1572-0241.2004.04172.x. [DOI] [PubMed] [Google Scholar]
- 4.Sherman PM, Hassall E, Fagundes-Neto U, et al. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am J Gastroenterol. 2009;104:1278–1295. doi: 10.1038/ajg.2009.129. [DOI] [PubMed] [Google Scholar]
- 5.Nelson SP, Chen EH, Syniar GM, Christoffel KK Pediatric Practice Research Group. One-year follow-up of symptoms of gastroesophageal reflux during infancy. Pediatrics. 1998;102:E67. doi: 10.1542/peds.102.6.e67. [DOI] [PubMed] [Google Scholar]
- 6.Miyazawa R, Tomomasa T, Kaneko H, Tachibana A, Ogawa T, Morikawa A. Prevalence of gastro-esophageal reflux-related symptoms in Japanese infants. Pediatr Int. 2002;44:513–516. doi: 10.1046/j.1442-200x.2002.01609.x. [DOI] [PubMed] [Google Scholar]
- 7.Fonkalsrud EW, Ament ME. Gastroesophageal reflux in childhood. Curr Probl Surg. 1996;33:1–70. [PubMed] [Google Scholar]
- 8.Mittal RK, Balaban DH. The esophagogastric junction. N Engl J Med. 1997;336:924–932. doi: 10.1056/NEJM199703273361306. [DOI] [PubMed] [Google Scholar]
- 9.Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J. Transient lower esophageal sphincter relaxation. Gastroenterology. 1995;109:601–610. doi: 10.1016/0016-5085(95)90351-8. [DOI] [PubMed] [Google Scholar]
- 10.Cucchiara S, Minella R, Campanozzi A, et al. Effects of omeprazole on mechanisms of gastroesophageal reflux in childhood. Dig Dis Sci. 1997;42:293–299. doi: 10.1023/a:1018853516206. [DOI] [PubMed] [Google Scholar]
- 11.Di Lorenzo C, Piepsz A, Ham H, Cadranel S. Gastric emptying with gastro-oesophageal reflux. Arch Dis Child. 1987;62:449–453. doi: 10.1136/adc.62.5.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Holloway RH, Wyman JB, Dent J. Failure of transient lower oesophageal sphincter relaxation in response to gastric distension in patients with achalasia: evidence for neural mediation of transient lower oesophageal sphincter relaxations. Gut. 1989;30:762–767. doi: 10.1136/gut.30.6.762. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Iacono G, Carroccio A, Cavataio F, et al. Gastroesophageal reflux and cow's milk allergy in infants: a prospective study. J Allergy Clin Immunol. 1996;97:822–827. doi: 10.1016/s0091-6749(96)80160-6. [DOI] [PubMed] [Google Scholar]
- 14.Cavataio F, Carroccio A, Iacono G. Milk-induced reflux in infants less than one year of age. J Pediatr Gastroenterol Nutr. 2000;30(Suppl):S36–S44. doi: 10.1097/00005176-200001001-00006. [DOI] [PubMed] [Google Scholar]
- 15.Kamer B, Chilarski A, Lange A, Piaseczna-Piotrowska A. Gastroesophageal reflux in infants with food allergy. Med Sci Monit. 2000;6:348–352. [PubMed] [Google Scholar]
- 16.Milocco C, Torre G, Ventura A. Gastro-oesophageal reflux and cow's milk protein allergy. Arch Dis Child. 1997;77:183–184. doi: 10.1136/adc.77.2.183a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Heine RG, Cameron DJ, Chow CW, Hill DJ, Catto-Smith AG. Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings. J Pediatr. 2002;140:14–19. doi: 10.1067/mpd.2002.120695. [DOI] [PubMed] [Google Scholar]
- 18.Hassall E. Macroscopic versus microscopic diagnosis of reflux esophagitis: erosions or eosinophils? J Pediatr Gastroenterol Nutr. 1996;22:321–325. doi: 10.1097/00005176-199604000-00017. [DOI] [PubMed] [Google Scholar]
- 19.Salvatore S, Hauser B, Vandemaele K, Novario R, Vandenplas Y. Gastroesophageal reflux disease in infants: how much is predictable with questionnaires, pH-metry, endoscopy and histology? J Pediatr Gastroenterol Nutr. 2005;40:210–215. doi: 10.1097/00005176-200502000-00024. [DOI] [PubMed] [Google Scholar]
- 20.Husby S. Food allergy as seen by a paediatric gastroenterologist. J Pediatr Gastroenterol Nutr. 2008;47(Suppl 2):S49–S52. doi: 10.1097/01.mpg.0000338813.97803.16. [DOI] [PubMed] [Google Scholar]
- 21.Nielsen RG, Bindslev-Jensen C, Kruse-Andersen S, Husby S. Severe gastroesophageal reflux disease and cow milk hypersensitivity in infants and children: disease association and evaluation of a new challenge procedure. J Pediatr Gastroenterol Nutr. 2004;39:383–391. doi: 10.1097/00005176-200410000-00015. [DOI] [PubMed] [Google Scholar]
- 22.Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics. 1987;79:683–688. [PubMed] [Google Scholar]
- 23.Høst A, Husby S, Osterballe O. A prospective study of cow's milk allergy in exclusively breast-fed infants: incidence, pathogenetic role of early inadvertent exposure to cow's milk formula, and characterization of bovine milk protein in human milk. Acta Paediatr Scand. 1988;77:663–670. doi: 10.1111/j.1651-2227.1988.tb10727.x. [DOI] [PubMed] [Google Scholar]
- 24.Semeniuk J, Kaczmarski M. Acid gastroesophageal reflux and intensity of symptoms in children with gastroesophageal reflux disease: comparison of primary gastroesophageal reflux and gastroesophageal reflux secondary to food allergy. Adv Med Sci. 2008;53:293–299. doi: 10.2478/v10039-008-0053-5. [DOI] [PubMed] [Google Scholar]
- 25.Fox VL, Nurko S, Teitelbaum JE, Badizadegan K, Furuta GT. High-resolution EUS in children with eosinophilic "allergic" esophagitis. Gastrointest Endosc. 2003;57:30–36. doi: 10.1067/mge.2003.33. [DOI] [PubMed] [Google Scholar]
- 26.Yu JW, Pekeles G, Legault L, McCusker CT. Milk allergy and vitamin D deficiency rickets: a common disorder associated with an uncommon disease. Ann Allergy Asthma Immunol. 2006;96:615–619. doi: 10.1016/S1081-1206(10)63558-2. [DOI] [PubMed] [Google Scholar]
- 27.Henriksen C, Eggesbø M, Halvorsen R, Botten G. Nutrient intake among two-year-old children on cows' milk-restricted diets. Acta Paediatr. 2000;89:272–278. [PubMed] [Google Scholar]
- 28.Hill DJ, Heine RG, Cameron DJ, et al. Role of food protein intolerance in infants with persistent distress attributed to reflux esophagitis. J Pediatr. 2000;136:641–647. doi: 10.1067/mpd.2000.104774. [DOI] [PubMed] [Google Scholar]