Abstract
Gastro-esophageal reflux disease (GERD) and cow’s milk allergy protein (CMPA) and are both common disorders in childhood, mainly infancy, and several studies have hypothesised a causal relationship between them, suggesting that at least in a subgroup of infants GERD is attributable to CMA. In children with CMPA, a neuroimmune interactions provoked by cow’s milk challenge might induce gastric motor abnormalities and in turn increase the number of reflux episodes. Studies assessing the relationship between the two conditions have shown an association ranging between 16 and 55%, which is far beyond from that expected from pure coexistence. Therefore, a possible concomitant CMPA, mainly in those infants and children with GERD unresponsive to medical treatment data, should be highly considered. Current ESPGHAN-NASPGHAN guidelines already suggest a short trial cow’s milk free diet in those infants with chronic regurgitation unresponsive to medical therapy, vomiting and failure to thrive.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
Keywords
Introduction
Allergy is an immune-mediated disorder involving all tissues and organs where immune cells might dwell. Historically, immune-mediated reactions have been distinguished in four major types according to the first classification provided by Coombs and Gell [1]. For the purpose of our chapter, it is only important to mention that allergic reactions can either be immediate, implying an IgE-mediated reaction, or delayed, which are not IgE mediated.
Gastrointestinal (GI) allergies are almost generally mentioned and simplified as “food allergies”, since food antigens are the culprits in deranging the physiologic gut immune response in genetically susceptible individuals. However, it is worth mentioning that some foods might cause adverse reaction for immunological, chemical and pseudo-pharmacodynamic interactions, such as in coeliac disease, non-coeliac wheat sensitivity and scombroid fish poisoning.
Allergy-related clinical conditions such as food allergy, rhinitis and eczema have witnessed a constant rise over the last decades, and this trend has not changed [2, 3].
Food allergy prevalence is estimated to be roughly 6–8% in paediatric group. The prevalence is highest in infants and toddlers, with 2.5% of infants suffering from milk allergy and up to 10% of children older than1 year suffering from food allergies, such as cow’s milk, egg, nuts, soya, wheat and fish/shellfish [4]. It should be noted that prevalence data are often derived from studies in western populations, which focus on a relatively limited number of foods [5]. Districting patterns of food consumption and allergic sensitization might bias the relevance of specific foods to the public health in different countries [6].
Cow’s milk protein allergy (CMPA) is the most common food allergy in infants with prevalence in early childhood of approximately 2–3% in developed countries [7]. CMPA has been identified as a worldwide health problem with high costs and burden for little patients and their families [8, 9]. CMPA has been frequently identified as the underlying cause in common gastrointestinal motility disorders of the childhood such as gastro-oesophageal reflux disease (GORD), recurrent abdominal pain, diarrhoea and constipation. The definitive diagnosis of allergy in these conditions, however, is difficult since CMPA could be non-IgE mediated and thus confirmed only by means of exclusion diet trial and subsequent re-challenge.
This chapter aims to review the putative mechanisms for allergy in GORD and to provide a comprehensive snapshot of available evidence on the topic.
Pathophysiology
In the eighties a clinical study showed that an enteropathy with abundant IgE plasmocytes as well as a rise of intraepithelial lymphocytes could be found in children with GORD attributable to CMPA [10]. The mechanisms by which food allergy causes gastrointestinal motor abnormalities are still a matter of debate. However, it is widely shown that allergic reactions to food proteins, either due to non-IgE or IgE-mediated mechanisms, induce mucosal infiltration and activation of different type of inflammatory cells, such as eosinophils, mast cells (MCs) and B and T lymphocytes, throughout the gastrointestinal tract [11]. Eosinophils and MCs are considered the key effector cells of both immediate and delayed-type hypersensitivity reactions, and upon activation they release a variety of pro-inflammatory, nociceptive and vasoactive mediators as well as significant number of neurotransmitters. Within the gastrointestinal tract, MCs are in close apposition to nerve endings, and therefore their activation and degranulation are able to evoke different neuromuscular responses, such as activation of muscle contractility and neural reflexes, which might ultimately result in change gastrointestinal motor functions [12, 13].
Several studies in experimental animal models of food hypersensitivity have shown that antigen challenge in vivo is able to induce panenteric motor abnormalities, such as delayed gastric emptying, altered gastric secretion and disruption of both preprandial and postprandial small intestine motor activity with small intestine disappearance of cyclic MMC during fasting period and inability in activating the fed motor activity [14,15,16]. Moreover, the motor abnormalities induced by antigen challenge parallel the histological evidence of mast cell degranulation in the gastric mucosa as well as the increase in both specific markers for mucosal MC degranulation and intraluminal release of histamine and persist long after the initial challenge [17].
In children, early-onset neuroimmune interactions induced by cow’s milk challenge in the gastric mucosa of atopic children could cause prompt imbalance of gastric myoelectrical activity. Ravelli et al. showed that in infants with vomiting induced by CMPA, milk challenge induces delayed gastric emptying and gastric myoelectrical dysrhythmias [18]. Few years later, Schaeppi and coworkers confirm the previous data showing that early-onset neuroimmune interactions induced by cow’s milk challenge in the gastric mucosa of atopic children parallel the rapid derangement of gastric myoelectrical activity [19]. Notably, cow’s milk exposure of the gastric mucosa induced a rapid degranulation of MCs and eosinophils. Activated MCs migrated in proximity of mucosal nerve fibres; moreover tryptase released from MCs was colocalized with proteinase-activated receptors 2 (PAR-2) on the same fibres. In the interim, there was a swift induction of electrogastrographic myoelectrical abnormalities. Intriguingly in the stomach of animal models, PAR-2 induces neurally mediated motor and secretory response, more specifically a fundic biphasic contractile response which implies relaxation followed by contraction [20]; in addition, a suppression of acid production follows this activity mediated by PAR-2 [21].
Furthermore, it has been identified that episodes of dysrhythmia are possible causes of antral hypo-contractility, which in turn promotes a delay of stomach emptying [22]. A delay in gastric emptying might increase gastro-oesophageal reflux by increasing the availability of material to reflux or by inducing prolonged gastric distention and by increasing the frequency of transient lower oesophageal sphincter relaxations (TLOSRs), which are the main underlying mechanism of gastro-oesophageal reflux [23]. It could be speculated that in a subgroup of infants and children with CMPA neuroimmune activation evoked during milk challenge might derange the gastric motor activity and hence delay the gastric emptying and increase the rate of TLOSRs, resulting in an increase in the number of reflux episodes.
Clinical Picture and Diagnostic Strategies
It is clear that allergy to cow’s milk protein may cause symptoms such as irritability, distress and vomiting indistinguishable from GORD, thus complicating the diagnostic pathway in the clinical practice.
Although most studies report a comparable incidence of regurgitation in unselected populations of formula versus breastfed infants, Hegar et al. reported a higher incidence of regurgitation in formula-fed infants [24]. Alongside this consideration, it should be stressed that the prevalence of CMPA is five to ten times higher in formula fed than in breastfed infants [25], thus fashioning the possible epidemiological scenario for two overlapping conditions.
However, studies assessing the relationship between food allergy and GORD show an overall association between 16 and 55% [26], thus far beyond what can be expected from pure coexistence of the two entities. In the mid-1990s, Iacono et al. described that 42% of infants with GORD symptoms and histologic oesophagitis clinically improved on a cow’s milk-free diet and then worsened following antigen challenge [27]. Subsequently, Nielsen et al. showed that 56% of children with severe GORD were found to have CMA on double-bind or open challenge [28]. Recently, Yukselen et al. identified food allergy in 65 of 151 children with GORD refractory to medical therapy, of which 89% reacted to cow’s milk, whilst a minority (11%) did so towards egg [29]. Notably, only half of those patients with GORD and food allergy had positive oral challenge and skin prick test and/or specific IgE; on the contrary, the other half could merely confirm the diagnosis by means of oral challenge.
In the past, some attempts had been made in order to elucidate the relationship between CMPA and GORD in the clinical setting by means of pH monitoring. However, these pH-only studies have led to conflicting results [25,26,27,28,29,30,31,32]. A particular phasic pH pattern characterized by a slow and progressive decrease in oesophageal pH between two feeds had been previously suggested as an effective tool for identifying patients with CMA-induced GORD by an Italian group [29, 30]. Nielsen et al. performed 48-h pH monitoring in 10 children with a severe GORD and CMA, with CM elimination diet at day 1 and CM challenge at day 2 [31]. Interestingly, they failed to find any difference in the reflux parameters between the two recording days. On the contrary, a Polish study confirmed the findings of the Italian groups showing that amongst the children with CMPA and GORD, pH-metric records showed a pattern of rapid increase of pH value after a meal with its subsequent gradual decrease [33].
However, only the introduction of combined impedance and pH monitoring could shed further light on this topic. Forty-eight-hour multichannel intraluminal impedance-pH monitoring in children with CMPA and suspected GORD has shown a significant increase in weakly acid reflux episodes during cow’s milk challenge compared to elemental formula feeding [34]. Nevertheless, it was not possible to ascertain whether the decrease in reflux episodes was attributable to the enhanced gastric emptying because of the elemental formula or to the suppression of an underlining immune mechanism towards cow’s milk antigens. This clinical finding, however, relies on the mechanisms addressed in a previous study showing how cow's milk induces severe gastric dysrhythmia and delayed gastric emptying in sensitized infants, thus triggering GORD and inducing reflex vomiting [18].
Albeit oesophageal manometry has no diagnostic yield in this clinical framework, a research study has found that both lower oesophageal sphincter (LOS) resting pressure and LOS length did not differ between children with primary GORD and CMPA-related GORD [35].
Conclusion
In conclusion, CMPA and GORD show an association between 16 and 55% in children. These data should induce paediatricians to screen for possible concomitant CMPA mainly in those infants and children with GORD unresponsive to medical treatment. Current ESPGHAN-NASPGHAN guidelines clearly advice a 2–4 week trial of protein hydrolysate or amino acid–based formula in infants with chronic regurgitation unresponsive to medical therapy, vomiting and failure to thrive [36].
References
Rajan TV. The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation. Trends Immunol. 2003;24:376–9.
Savage J, et al. Food allergy: epidemiology and natural history. Immunol Allergy Clin N Am. 2015;35:45–59.
Kattan I. The prevalence and natural history of food allergy. Curr Allergy Asthma Rep. 2016;16:47.
Hill DA, et al. The epidemiologic characteristics of healthcare provider-diagnosed eczema, asthma, allergic rhinitis, and food allergy in children: a retrospective cohort study. BMC Pediatr. 2016;16:133.
Burks AW, et al. ICON: food allergy. J Allergy Clin Immunol. 2012;129:906–20.
Bjorksten B, et al. Criteria for identifying allergenic foods of public health importance. Regul Toxicol Pharmacol. 2008;51:42–52.
Warren CM, et al. The epidemiology of milk allergy in US children. Ann Allergy Asthma Immunol. 2013;110:370–4.
Sackesen C, et al. Cow's milk allergy as a global challenge. Curr Opin Allergy Clin Immunol. 2011;11:243–8.
Gupta R, et al. The economic impact of childhood food allergy in the United States. JAMA Pediatr. 2013;167:1026–31.
Forget P, et al. Cow’s milk protein allergy and gastro-oesophageal reflux. Eur J Pediatr. 1985;144:298–300.
Bischoff S, Crowe SE. Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology. 2005;128:1089–113.
Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology. 1996;111:1683–99.
Barbara G, Stanghellini V, De Giorgio R, et al. Functional gastrointestinal disorders and mast cells: implications for therapy. Neurogastroenterol Motil. 2006;8:6–17.
Catto-Smith AG, Patrick MK, Scott RB, et al. Gastric response to mucosal IgE-mediated reactions. Am J Phys. 1989;257:G704–8.
Diamant S, Gall D, Scott R. The effect of intestinal anaphylaxis on postprandial motility in the rat. Can J Physiol Pharmacol. 1989;67:1326–30.
Scott RB, Diamant SC, Gall DG. Motility effects of intestinal anaphylaxis in the rat. Am J Phys. 1998;255:G505–11.
Saavedra Y, Vergara P. Hypersensitivity to ovalbumin induces chronic intestinal dysmotility and increases the number of intestinal mast cells. Neurogastroenterol Motil. 2005;17:112–22.
Ravelli AM, Tobanelli P, Volpi S, Ugazio AG. Vomiting and gastric motility in infants with cow’s milk allergy. J Pediatr Gastroenterol Nutr. 2001;32:59–64.
Schäppi MG, et al. Mast cell-nerve interactions in children with functional dyspepsia. J Pediatr Gastroenterol Nutr. 2008;47:472–80.
Cocks TM, et al. Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle. Gastroenterology. 1999;116:586–92.
Nishikawa H, et al. Suppression by protease activated receptor-2 activation of gastric acid secretion in rats. Eur J Pharmacol. 2002;447:87–90.
Chen JZ, et al. Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis. Dig Dis Sci. 1996;8:1538–45.
Emerenziani S, et al. Gastroesophageal reflux and gastric emptying, revisited. Curr Gastroenterol Rep. 2005;7:190–5.
Hegar B, et al. Natural evolution of regurgitation in healthy infants. Acta Paediatr. 2009;98:1189–93.
Vandenplas Y, et al. Guidelines for the diagnosis and management of cows’ milk protein allergy in infants. Arch Dis Child. 2007;92:902–8.
Salvatore S, et al. Gastroesophageal reflux and cow’s milk allergy: is there a link? Pediatrics. 2002;110:972–98.
Iacono G, et al. Gastroesophageal reflux and cow’s milk allergy in infants: a prospective study. J Allergy Clin Immunol. 1996;97:822–7.
Yukselen A, et al. Food allergy in children with refractory gastroesophageal reflux disease. Pediatr Int. 2016;58:254–8.
Cavataio F, et al. Clinical and pH-metric characteristics of gastro-oesophageal reflux secondary to cows’ milk protein allergy. Arch Dis Child. 1996;75:51–6.
Cavataio F, et al. Gastroesophageal reflux associated with cow’s milk allergy in infants: which diagnostic examinations are useful? Am J Gastroenterol. 1996;91:1215–20.
Milocco C, et al. Gastro-oesophageal reflux and cows’ milk protein allergy. Arch Dis Child. 1997;77:183–8.
Nielsen RG, et al. 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;39:383–91.
Kamer B, et al. Gastroesophageal reflux in infants with food allergy. Med Sci Monit. 2000;6:348–52.
Borrelli O, et al. Cow’s milk challenge increases weakly acidic reflux in children with cow’s milk allergy and gastroesophageal reflux disease. J Pediatr. 2012;161:476–81.
Semeniuk J, et al. Manometric study of lower esophageal sphincter in children with primary acid gastroesophageal reflux and acid gastroesophageal reflux secondary to food allergy. Adv Med Sci. 2008;53:283–92.
Vandenplas Y, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009;49:498–547.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Valitutti, F., Rybak, A., Borrelli, O. (2017). Gastro-oesophageal Reflux and Cow’s Milk Allergy. In: Vandenplas, Y. (eds) Gastroesophageal Reflux in Children. Springer, Cham. https://doi.org/10.1007/978-3-319-60678-1_14
Download citation
DOI: https://doi.org/10.1007/978-3-319-60678-1_14
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-60677-4
Online ISBN: 978-3-319-60678-1
eBook Packages: MedicineMedicine (R0)