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Adverse reactions to cows’ milk
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Adverse reactions to cows’ milk
introduced. The first of these formulas was introduced by Baron Justus von Liebig in 1867 and contained wheat flour, cows’ milk, malt flour and potassium bicarbonate. This soon had many competitors, and the first infant milk powder appeared in 1915. Later innovations focused on humanising the formulations to mimic breast milk as closely as possible. As the safety of cows’ milk preparations has improved with modern production methods, and hence the prevalence of their ingestion has increased, there has been an increase in adverse reactions to cow’s milk. Before considering these adverse reactions, it is worth clarifying the terminology used to describe them. Terms such as ‘food allergy’, ‘food intolerance’ and ‘food hypersensitivity’ are often used interchangeably even within the same publication, yet they may represent a disparate group of conditions. Even with the help of formal classifications, the use of different systems in the USA and Europe has added to the confusion. Modern classifications have divided adverse reactions to food into those that are immune mediated (food allergy) and those that are also reproducible but are not immune mediated (food intolerance).1 By requiring the reaction to be reproducible, food aversion (a psychological phenomenon that is not reproducible under blinded conditions) is thus excluded. Up to 30% of adults report adverse food reactions when surveyed, yet most of these are not reproduced on double-blind placebo-controlled food challenge,2 illustrating the high prevalence of food aversion. The European classification divides adverse food reactions into those that are due to toxins and would affect any exposed individual if ingested in sufficient quantities (toxic reactions) and those that affect susceptible individuals only (non-toxic).3 The latter group can be divided into reactions that are mediated by the immune system (food allergy) and those that are not (food intolerance). Revision of this latter classification has replaced the term ‘food intolerance’ with ‘non-allergic food hypersensitivity’.4 Despite clear classification systems, the term ‘food intolerance’ still represents, to many practitioners and public alike, the group of allergic reactions to food that are non-IgE mediated. The common use of the term ‘cows’ milk intolerance’ to describe nonIgE-mediated immunological reactions to cow’s milk illustrates this point well.5 Non-immunological reactions to food can be further subdivided into those that are due to enzymatic deficiencies or pharmacological reactions, and those that do not fit into either of these two. This review considers the spectrum of adverse reactions to milk, both allergy and intolerance (non-allergic hypersensitivity). There is also a brief review of some of the more controversial areas where symptoms may be inappropriately linked causally with milk consumption.
Adam T Fox Mike Thomson
Abstract Cows’ milk has been drunk by humans for almost 9000 years. It is of particular importance as a substitute for human breast milk. Milk ingestion can cause a spectrum of adverse reactions in children, including both immune-mediated (food allergy) and non-immunemediated (food intolerance) reactions. Immune-mediated responses include immediate, potentially life-threatening IgE-mediated milk allergy as well as non-IgE and mixed IgE/non-IgE manifestations of disease. This review examines the different types of response that cows’ milk ingestion may elicit and considers the different underlying mechanisms. New manifestations of adverse reactions, previously considered unrelated to dietary intake, are also considered.
Keywords allergy; eczema; food allergy; gastrointestinal allergy; lactose intolerance; milk
Introduction The use of cows’ milk as a beverage probably began around 9000 years ago with the domestication of cattle. The method for making cheese from milk was known to the ancient Greeks and Romans, and the use of milk and milk products spread throughout Europe in the following centuries. Current UK consumption is around 230 kg/person/year (Food and Agriculture Organisation of the United Nations), which includes the milk used in infant formulas. Human milk substitutes existed before the modern age of formulas. When infants could not be fed by their mothers, humans adopted two methods for substitute feeding. The first was a surrogate mother (e.g. wet nurse), who would feed the child human milk. The alternative was to feed the child milk obtained from another mammal. Until the end of the 19th century, the use of a wet nurse was by far the safest of these two methods. As general sanitation measures improved during the latter part of the 19th century, and as differences in composition between human milk and that of other mammals were defined, feeding animal milk became more successful. However, few infants survived until infant formulas based on cows’ milk, with added water and carbohydrate, were
Non-immune-mediated reactions to cows’ milk: lactose intolerance
Adam T Fox MA (Hons) MSc MRCPCH is Consultant in Paediatric Allergy at the Children’s Allergy Service, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, UK.
Most dietary disaccharides are normally hydrolyzed and absorbed in the proximal portion of the small intestine. If there are insufficiencies in the enzymes (disaccharidases) required, the osmotic load of the luminal fluid may exceed critical levels.6–8 This stimulates the right colon to propel fluid onwards and
Mike Thomson MD FRCP FRCPCH Consultant in Paediatric Gastroenterology, Centre for Paediatric Gastroenterology, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK.
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causes the passage of frequent, fluid stools. In addition, some of the unabsorbed sugar is fermented by colonic bacteria, and the gas produced by this process leads to bloating and abdominal discomfort. The symptoms worsen with increasing disaccharide intake.9,10 The most common form of disaccharidase deficiency is primary adult hypolactasia, which is commonly known as lactose intolerance.11,12 In most of the human population (particularly darker-skinned races), lactase expression is genetically programmed to decline after infancy to only 5–10% of original levels.13 This pattern mirrors that seen in other mammals, where dependence on milk occurs only during infancy. Persistence of infant lactase levels is the norm only in Northern and Central European populations and the nomadic, milk-dependent populations of the arid zones of North Africa and Arabia.14 In these populations, only around 15% of individuals show a significant decline in lactase expression. In most Asian populations, low lactase levels are found in more than 90%.15 The age of presentation with symptoms of lactose intolerance varies between ethnic groups, but is dependent on the speed of decline in lactase and the amount of lactose ingested. Classically, the onset is around the beginning of the second decade of life (at approximately 10–14 years). The most common presentation is with diarrhoea, bloating and abdominal discomfort after drinking milk. Culture-containing milks are usually better tolerated due to lower lactose levels after fermentation. Avoidance of lactose-containing products or use of commercially available enzyme supplements before ingesting lactose is an effective treatment.16 Rarely, permanent lactose intolerance results from congenital lactase deficiency, presenting as severe diarrhoea in the neonatal period. This is commonly the label misused to describe gut-related allergic hypersensitivity to cows’ milk protein (CMP) in infancy, even by medical practitioners. Intolerance of lactose may occur transiently. Lactase is commonly expressed only in mature enterocytes at the tips of the villi. Any condition that increases the enterocyte migration rate (e.g. gastroenteritis), often inducing allergy to CMP and consequent villus inflammation, leads to fewer mature enterocytes at the villus tips. These enterocytes contain less lactase and thus lactose tolerance decreases in the post-enteritis period.
Spectrum of immune-mediated reactions to cows’ milk Disorder
IgE-mediated (acute onset) Cell-mediated (delayed onset/chronic)
Immediate allergy/anaphylaxis
Other underlying mechanisms
Cows’ milk protein-induced proctocolitis Cows’ milk protein-induced enteropathy Food protein-induced enterocolitis syndrome Allergic eosinophilic gastroenteropathy Cows’ milk protein -induced refluxassociated oesophagitis Food-sensitive eczema
Table 1
Eosinophilic oesophagitis Cow's milk protein allergy-induced reflux-associated oesophagitis
Eosinophilic gastroenteritis
FPIES
Cow’s milk protein induced enteropathy Eosinophilic gastroenterocolitis
Cow’s milk protein induced proctocolitis
Immune-mediated reactions to cows’ milk CMP allergy is the commonest food allergy in childhood.17 The incidence of CMP allergy in infancy seems to be approximately 2–3% in developed countries. However, symptoms suggestive of CMP allergy may be encountered in 5–15% of infants, emphasizing the importance of controlled elimination/milk challenge procedures.18 Allergy to cows’ milk presents with a broad range of clinical symptoms and syndromes (Table 1) (Figure 1). In addition to the well-recognised immediate-type IgE-mediated allergies, a more diverse range of more delayed presentations such as eczema and gastrointestinal symptoms such as reflux, colic, enteropathy and constipation are increasingly being considered as part of the spectrum of milk allergy.17 The mechanisms underlying such presentations do not appear to be IgE mediated and are poorly understood. They may be IgG mediated or T cell mediated, and in some cases remain
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Mechanism
Figure 1 Site of pathology in milk protein induced gastrointestinal food allergy
controversial. This review outlines briefly the most common presentations of CMP allergy. IgE-mediated reactions Immediate type 1 hypersensitivity reactions affect up to 8% of children, and cows’ milk is the most common causative allergen. Most cases of milk allergy present in the first year of life.19 Reactions usually occur within minutes of milk ingestion and range in severity from acute dermatological manifestations such as urticaria and angioedema to more severe, potentially lifethreatening anaphylaxis. Successful treatment of anaphylaxis relies on early administration of adrenaline, ideally by the
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intramuscular route.20 Fatal allergic reactions are relatively rare in children and are most commonly are caused by nuts,21 though fatal reactions to milk have occurred in young children. The presence of asthma, especially when not well controlled, is a major risk factor for severe reactions.22,23 The underlying mechanism in these type 1 hypersensitivity reactions is the release of histamine and other mediators from mast cells as a result of cross-linking of surface-bound IgE by an allergenic protein. b-Lactoglobulin, casein and a-lactalbumin are the major allergens in milk.24 There is a strong structural homology between milk proteins from different mammals, and clinical cross-reactivity to most mammal milks is seen in up to 90% of patients.25–27 Diagnosis of immediate cows’ milk allergy relies on the history and on IgE tests such as the skin-prick test or measurement of serum levels of specific IgE antibody to cows’ milk. In cases of diagnostic doubt, a standardised double-blind placebo-controlled food challenge is the gold-standard investigation. Interpretation of skin-prick tests and specific IgE tests is hampered when the patient Is sensitised to cows’ milk (i.e. specific IgE to milk is present) but does not have clinical symptoms when exposed. Sampson28 reported a specific IgE level in serum of 15 kU/litre to be 95% predictive of cows’ milk allergy in a population predominantly of children with atopic dermatitis. Other studies have used the skinprick test wheal size to predict the likelihood of clinical allergy.29,30 Although such threshold values are useful in practice, it is important to understand their limitations when applied to individuals from a different population to that used in a study. Infants with immediate cows’ milk allergy have usually outgrown the allergy within 2–3 years’ follow-up.19 Regular reevaluation and allergy testing helps the clinician to decide when the child has become tolerant, so that milk can be safely reintroduced. The risk of unpredictable IgE-mediated allergies dictates that reintroduction is attempted under controlled conditions.
diarrhoea (and vomiting).37 This may result in malabsorption and failure to thrive; thus, it is more important to make a firm diagnosis. The natural history is similar to that of other forms of non-IgE-mediated milk allergy, with presentation in infancy and resolution by 1–2 years. The underlying immune mechanism is unclear; there is no association with raised milk-specific IgE, T cell responses seem to be involved.38 The differential diagnosis includes infection, and the diagnosis is usually made on a combination of endoscopic small bowel biopsy histology (the findings of which are patchy in distribution and more subtle than in other enteropathies such as coeliac disease39) and the outcome of exclusion diets. Food protein-induced enterocolitis syndrome (FPIES): is a severe, cell-mediated, gastrointestinal food hypersensitivity, typically to cows’ milk and soy, that has been recognised for decades but has received relatively little attention.40–43 FPIES represents the severe end of the spectrum of milk allergy affecting the gut only. Conditions such as milk protein-induced proctocolitis, enteropathy and eosinophilic gastoenteropathy may all present with similar, overlapping features. The degree to which these conditions can be considered as discrete immunopathogenic entities remains unclear. While FPIES may simply represent the severe end of this spectrum of allergic gastroenteropathies, there are certain features of systemic reactivity and implications for long-term management that demand that it be considered separately.44 FPIES is characterised by severe, protracted diarrhoea and vomiting, most commonly following ingestion of cows’ milk or soy-based formula (50% of infants react to both),40 though solid food allergens are occasionally implicated.45 Progression can occur to a state of dehydration and cause shock in 20% of cases.40,45–47 The combination of vomiting, lethargy and resulting acidosis in the infant often leads to a diagnosis of sepsis, and the problem recurs when the allergen is reintroduced. Failure to recognise the link with diet may lead to multiple admissions to the ICU with supposed recurrent sepsis.45 A raised WBC count with a predominance of neutrophils is also consistently found in FPIES, further blurring the clinical picture. The presence of bloody diarrhoea may lead to suspicion of infectious diarrhoea, coagulation defects or intussusception by those who fail to appreciate the significance of the temporal association with a new food. The absence of fever, presence of eosinophilic debris in the stools and negative stool cultures can help to differentiate these conditions. Some patients with FPIES present with an insidious onset of chronic diarrhoea, vomiting and failure to thrive.48 In either presentation, symptoms resolve rapidly on a diet free of allergens. Patients with FPIES classically have no specific IgE and are negative on skin-prick testing. Endoscopy is often unhelpful as infants may remain well between challenges. Atypical cases have been described with detectable IgE to the causal protein and a more prolonged course of allergy.48 The diagnosis is based on clinical criteria with a standardised oral challenge if doubt remains.49 These criteria include the onset of exclusively gastrointestinal symptoms before 9 months of age that are consistently present on further exposures.50 Removal of the offending allergen should lead to rapid and complete resolution of symptoms. There are no reports of infants developing FPIES
Non-IgE-mediated reactions CMP-induced proctocolitis: is a disease of infancy that usually presents by 2 months31 and represents the benign end of the spectrum of non-IgE-mediated allergy to milk.32 Babies usually present with visible blood mixed with mucus in the stool, but are otherwise well and thriving.33 It is more common in, but not exclusive to, breast-fed babies whose mothers are ingesting cows’ milk or soy protein.33–35 Important differential diagnoses include infection and fissures. The diagnosis is usually made on the basis of a response to the exclusion of CMP, either from the lactating mother’s diet or by substitution by extensively hydrolysed formula. Bleeding should resolve in 72 hours, though persistent bleeding may respond to an amino acid formula.35 The underlying mechanism is unclear.32 Milk-specific IgE is typically negative and biopsy reveals distal colitis with an eosinophilic infiltrate.36 Resolution occurs sooner than in IgEmediated milk allergy, and most infants are tolerant by 1–2 years of age. Milk can be reintroduced safely at home, though it is prudent to confirm that the skin-prick test or specific IgE is negative before doing this, to ensure there is no risk of an IgEmediated reaction. CMP-induced enteropathy: unlike those with CMP-induced proctocolitis, infants with enteropathy usually have protracted
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differentiation from primary reflux has been suggested on the basis of an oesophageal pH testing pattern and a b-lactoglobulin antibody response, though the former has not been substantiated by more than one center.67,68 There is recent evidence that this oesophagitis is becoming a more common presentation of infant food allergy in the developed world, and may be induced by a variety of antigens in addition to cows’ milk.65,66 Many affected infants have become sensitised while exclusively breast-fed, and a defect in oral tolerance for low doses has been postulated as the underlying cause.69,70 Oesophageal mucosal eosinophilia has been described in both suspected cow’s milk-associated65 and primary reflux oesophagitis,71 as well as in other conditions such as idiopathic eosinophilic oesophagitis.72 However, the density of the eosinophilic infiltrate has been used as a differentiator between allergic esophagitis and eosinophilic oesophagitis, with the latter defined as more than 20 eosinophils per high-power field.73 The clinical significance of eosinophils and their role in the pathogenesis of mucosal injury is poorly understood and the subject of recent debate.74 Some authors have suggested an active role for eosinophils in the inflammatory process of oesophagitis and have supported this with the observation of activation of eosinophils on electron microscopy criteria.75 In addition to dietary exclusion of cows’ milk,65,67 oral corticosteroids can induce remission of symptoms with reduced mucosal eosinophilia,67,72 suggesting a patho-aetiological role for eosinophils. In addition to eosinophils, intraepithelial T lymphocytes, known as CINC (cells with irregular nuclear contours), have also been implicated as markers of reflux esophagitis.76,77 In adults, such cells are of memory phenotype and display activation markers,78 though little is known of their paediatric equivalents. Various immunohistochemical markers have been used to examine the oesophageal mucosa, including eotaxin, a recently described eosinophil-specific chemokine,79 and markers of T cell lineage and activation. Despite the mild histological abnormality in CMP-induced oesophageal pathology, increased expression of eotaxin co-localised with activated T lymphocytes to the basal and papillary epithelium has been shown,80 distinguishing this from primary reflux esophagitis. The molecular basis of the eotaxin up-regulation is unknown. It has also been suggested that increased numbers of mucosal mast cells allow a distinction to be made between allergy-induced and reflux-induced esophagitis.81 Much work is required in this area and is ongoing.
while exclusively breast-feeding. This contrasts with IgEmediated food allergies such as acute skin reactions, and non-IgE-mediated conditions such as dietary protein-induced proctocolitis, which have been attributed to passage of food protein through the breast milk.45 The pathophysiological immune basis for FPIES is poorly understood. Mucosal biopsies from children with challengeproven FPIES show increased tumour necrosis factor-a, a proinflammatory cytokine produced from food-sensitised T lymphocytes.51,52 This may increase intestinal permeability, contributing to the influx of antigen into the submucosa.51,52 Reduced expression of transforming growth factor beta (TGF-b), a cytokine critical in oral tolerance that induces T cell suppression, promotes B cell switching to IgA production and preserves epithelial barrier function, has also been noted.53 Impaired generation within the mucosa of TGF-b producing T cells has been identified in a further cohort of children with multiple food allergies,54 suggesting an underlying primary failure to establish oral tolerance mechanisms that may relate to insufficient innate immune response to early infectious exposures.54,55 The cornerstone of management in children with FPIES is careful exclusion under the supervision of a paediatric dietitian. Reports show that, 2 years from presentation, 60% and 25% of patients lose their sensitivity to cows’ milk and soy, respectively.50,56 Confirmation of resolution requires a carefully supervised food challenge with facilities to deal with the hypotension and shock that may arise.57 Other immune-mediated reactions Allergic eosinophilic gastroenteropathies: first described by Kaijser in 1937,58 this heterogeneous group of conditions includes eosinophilic oesophagitis, eosinophilic gastroenteritis and eosinophilic gastroenterocolitis. They represent a spectrum of pathologies with overlapping symptoms, all characterised by eosinophilic inflammation in the gut. They are classified according to the site of the inflammation,59 though it is the depth and severity of the symptoms that most influence the presenting symptoms.32 These conditions are clearly associated with the atopic phenotype, but the underlying mechanism remains uncertain.60 Local production of eotaxin, a potent eosinophil chemoattractant, appears to be pivotal.61 Use of combinations of allergy tests62 to guide dietary exclusion has had some success in the treatment of these conditions and is an important consideration alongside other treatments such as corticosteroids63 and leukotriene antagonists.64 Eosinophilic oesophagitis is the most common of these conditions and is best considered in the context of the broader role of cows’ milkinduced allergic inflammation in the oesophagus.
Food-sensitive eczema: atopic eczema is a chronic inflammatory skin disorder associated with raised serum IgE, allergen sensitisation and an atopic family history.82,83 While the association between eczema and immediate food allergies is easy to demonstrate, the possible role of dietary manipulation in the treatment of chronic eczema remains controversial. Hill et al.84 demonstrated that the likelihood of concomitant IgE-mediated food allergy increased with increasingly severe infantile eczema. A number of studies have used double-blind placebo-controlled food challenge to demonstrate that food allergens, most commonly CMP, can induce delayed eczematous reactions in children.85–87 However, attempts to show that dietary exclusion can objectively influence the course of atopic eczema have remained unconvincing. Attempts at meta-analysis of studies have been hampered by differences between them, such as the age of the
CMP-induced oesophageal pathology: although it is now clear that multiple food antigens may induce oesophagitis,65,66 the most common precipitant is CMP. Standard endoscopic biopsy and histology do not reliably distinguish between primary reflux esophagitis and the emerging clinical entity of CMP-associated reflux oesophagitis. This variant of cows’ milk allergy appears to be a particularly common manifestation in infancy (up to 42% of infants with gastro-oesophageal reflux disease), with symptoms that are indistinguishable from primary gastro-oesophageal reflux disease but which settle on an exclusion diet.67 Some
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patients, the foods excluded and the scoring systems used for eczema severity. A review of 14 interventional studies suggests that dietary interventions, when guided by allergy testing, were efficacious, especially in children under 2 years of age.88 Skin-prick testing and specific IgE blood testing may be helpful in detecting food allergy in children with eczema, but around 10% of positive double-blind placebo-controlled food challenges in these children were associated with negative results for both of these tests.85 The possible role of atopy patch-testing, which elicits T cell-mediated reactions, in improving the diagnostic accuracy in children with atopic eczema is currently of considerable interest.86,89 The need for different testing modalities reflects the mixed IgE-mediated and cell-mediated mechanism that appears to underlie this condition.
12 Dahlqvist A, Hammond JD, Crane RK et al. Intestinal lactase deficiency and lactose intolerance in adults: preliminary reports. Gastroenterology 1963; 45: 488–91. 13 Johnson JD. The regional and ethnic distribution of lactose malabsorption: adaptive and genetic hypotheses. In: Paige DM, Bayless TM (eds): Lactose digestion: clinical and nutritional implications. Baltimore: Johns Hopkins University Press, 1981. p. 11–22. 14 Simoons FJ. Geographic patterns of primary adult lactose malabsorption. In: Paige DM, Bayless TM (eds): Lactose Digestion: clinical and nutritional implications. Baltimore: Johns Hopkins University Press, 1981. p. 23–48. 15 Sahi T. Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol 1994; 202: 7–20. 16 Tamm A. Management of lactose intolerance. Scand J Gastroenterol Suppl 1994; 202: 55–63. 17 Heine RG, Elsayed S, Hosking CS et al. Cow’s milk allergy in infancy. Curr Opin Allergy Clin Immunol 2002; 2: 217–25. 18 Host A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol 2002; 89(6 Suppl 1):33–7. 19 Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Allergy 1990; 45: 587–96. 20 Sampson HA. Anaphylaxis and emergency treatment. Pediatrics 2003; 111: 1601–8. 21 Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30: 1144–50. 22 Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001; 107: 191–3. 23 Sampson HA, Mendelson LM, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992; 327: 380–4. 24 Wal JM. Cow’s milk allergens. Allergy 1998; 53: 1013–22. 25 Restani P, Gaiaschi A, Plebani A et al. Cross-reactivity between milk proteins from different animal species. Clin Exp Allergy 1999; 29: 997–1004. 26 Spuergin P, Walter M, Schiltz E et al. Allergenicity of alpha-caseins from cow, sheep, and goat. Allergy 1997; 52: 293–8. 27 Bellioni-Businco B, Paganelli R, Lucenti P et al. Allergenicity Of goat’s milk in children with cow’s milk allergy. J Allergy Clin Immunol 1999; 103: 1191–4. 28 Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001; 107: 891–6. 29 Eigenmann PA, Sampson HA. Interpreting skin prick tests in the evaluation of food allergy in children. Pediatr Allergy Immunol 1998; 9: 186–91. 30 Hill DJ, Heine RG, Hosking CS. The diagnostic value of skin prick testing in children with food allergy. Pediatr Allergy Immunol 2004; 15: 435–41. 31 Odze RD, Bines J, Leichtner AM et al. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Human Pathol 1993; 24: 668–74. 32 Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics 2003; 111(6 Pt 3):1609–16. 33 Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast fed infants. J Pediatr 1982; 101: 906–10. 34 Pumberger W, Pomberger G, Geissler W. Proctocolitis in breast fed infants: a contribution to differential diagnosis of hematochesia in early childhood. Postgrad Med J 2001; 77: 252–4.
Others: as the spectrum of presentations ascribed to milk allergy increases, some areas remain contentious. Infantile colic has been shown to respond to extensively hydrolysed milk formulas in some studies,90,91 suggesting a possible role of food allergy. Infantile colic is poorly understood, and though allergy may have a role it is unlikely to be more than one of a number of important influences. Iacono et al.92 suggested a role for milk exclusion in the treatment of children with constipation that was unresponsive to conventional treatments. The response was most marked in atopic children with raised specific IgE to milk. The role of CMP as a cause of colonic dysmotility leading to ~ constipation requires further investigation.
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56 Burks AW, Casteel HB, Fiedorek SC et al. Prospective oral food challenge study of two soybean protein isolates in patients with possible milk or soy protein enterocolitis syndrome. Pediatr Allergy Immunol 1994; 5: 40–5. 57 Sicherer SH, Chehade M. Infantile food protein-induced enterocolitis syndrome. Recent Adv Paediatr 2004; 22: 135–47. 58 Kaisjer R. Allergic diseases of the gut from the point of view of the surgeon. Arch Klin Chir 1937; 188: 36–64. 59 Sampson HA, Anderson JA. Summary and recommendations: classification of gastrointestinal manifestations due to immunologic reactions to foods in infants and young children. J Pediatr Gastroenterol Nutr 2000; 30: S87–94. 60 Khan S, Orenstein SR. Eosinophilic gastroenteritis: epidemiology, diagnosis and management. Paediatr Drugs 2002; 4: 563–70. 61 Bischoff SC. Mucosal allergy: role of mast cells and eosinophil granulocytes in the gut. Baillieres Clin Gastroenterol 1996; 10: 443–59. 62 Spergel JM, Beausoleil JL, Mascarenhas M et al. The use of skin prick tests and patch tests to identify causative foods in eosinophilic esophagitis. J Allergy Clin Immunol 2002; 109: 363–8. 63 Faubion Jr. WA, Perrault J, Burgart LJ et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998; 27: 90–3. 64 Attwood SE, Lewis CJ, Bronder CS et al. Eosinophilic oesophagitis: a novel treatment using montelukast. Gut 2003; 52: 181–5. 65 Kelly KJ, Lazenby AJ, Rowe PC et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995; 109: 1503–12. 66 Hill DJ, Hosking CS. Emerging disease profiles in infants and young children with food allergy. Pediatr Allergy Immunol 1997; 8(10 Suppl): 21–6. 67 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: 822–7. 68 Cavataio F, Iacono G, Montalto G et al. Clinical and pH-metric characteristics of gastro-oesophageal reflux secondary to cows’ milk protein allergy. Arch Dis Child 1996; 75: 51–6. 69 Murch S. Diabetes and cows’ milk. Lancet 1996; 348: 1656. 70 Walker-Smith JA, Murch SH. Gastrointestinal food allergy. In: Diseases of the small intestine in childhood. 4th ed. Oxford: Isis Medical Media, 1999. p. 205–234. 71 Winter HS, Madara JL, Stafford RJ et al. Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1983; 83: 818–23. 72 Liacouras CA, Wenner WJ, Brown K et al. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998; 26: 380–5. 73 Fox VL, Nurko S, Teitelbaum JE et al. High-resolution EUS in children with eosinophilic ‘‘allergic’’ esophagitis. Gastrointest Endosc 2003; 57: 30–6. 74 Furuta GT. Eosinophils in the esophagus: acid is not the only cause. J Pediatr Gastroenterol Nutr 1998; 26: 468–71. 75 Justinich C, Ricci Jr. A, Kalafus DA et al. Activated eosinophils in esophagitis in children: a transmission electron microscopic study. J Pediatr Gastroenterol Nutr 1997; 25: 194–8. 76 Mangano M et al. Nature and significance of cells with irregular nuclear contours (CINC) in esophageal mucosa. Lab Invest 1991; 64: 38A. 77 Cucchiara S, D’Armiento F, Alfieri E et al. Intraepithelial cells with irregular nuclear contours as a marker of esophagitis in children with gastroesophageal reflux disease. Dig Dis Sci 1995; 40: 2305–11.
35 Vanderhoof JA, Murray ND, Kaufman SS et al. Intolerance to protein hydrolysate infant formulas: an underrecognised cause of gastrointestinal symptoms in infants. J Pediatr 1997; 131: 741–4. 36 Winter HS, Antonioli DA, Fukagawa N et al. Allergy-related proctocolitis in infants: diagnostic usefulness of rectal biopsy. Mod Pathol 1990; 3: 5–10. 37 Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics 2003; 111(6 Part 3):1609–16. 38 Hauer AC, Breese EJ, Walker-Smith JA et al. The frequency of cells secreting interferon-gamma and interleukin-4, -5, and -10 in the blood and duodenal mucosa of children with cow’s milk hypersensitivity. Pediatr Res 1997; 42: 629–38. 39 Walker-Smith JA. Cow milk-sensitive enteropathy: predisposing factors and treatment. J Pediatr 1992; 121(5 Part 2):S111–5. 40 Burks W. The spectrum of food hypersensitivity: Where does it end? J Pediatrics 1998; 133: 175–6. 41 Sicherer SH. Food Protein-induced enterocolitis syndrome: case presentations and management lesson. J Allergy Clin Immunol 2005; 115: 149–56. 42 Rubin M. Allergic intestinal bleeding in the newborn. Am J Med Sci 1940; 200: 385–7. 43 Gryboski J. Gastrointestinal milk allergy in infancy. Pediatrics 1967; 40: 354–62. 44 Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr 2000; 30(Suppl):S45–9. 45 Nowak-Wegrzyn A, Sampson HA, Wood RA et al. Food proteininduced enterocolitis syndrome caused by solid food proteins. Pediatrics 2003; 111: 829–35. 46 Gryboski J. Gastrointestinal milk allergy in infancy. Pediatrics 1967; 40: 354–62. 47 Powell GK. Enterocolitis in low-birth-weight infants associated with milk and soy intolerance. J Pediatrics 1976; 88: 840–4. 48 Sicherer SH. Food protein-induced enterocolitis syndrome: clinical perspectives. J Pediatr Gastroenterol Nutr 2000; 30(Suppl):S45–9. 49 Powell GK. Food protein-induced enterocolitis of infancy: differential diagnosis and management. Compr Ther 1986; 12: 28–37. 50 Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food protein-induced enterocolitis syndrome. J Pediatrics 1998; 133: 214–9. 51 Benlounes N, Candalh C, Matarazzo P et al. The time-course of milk antigen-induced TNF-a secretion differs according to the clinical symptoms in children with cow’s milk allergy. J Allergy Clin Immunol 1999; 104: 863–9. 52 Heyman M, Darmon N, Dupont C et al. Mononuclear cells from infants allergic to cow’s milk secrete tumour necrosis factor alpha, altering intestinal function. Gastroenterology 1994; 106: 1514–23. 53 Chung HL, Hwang JB, Park JJ et al. Expression of transforming growth factor b1, transforming growth factor type I and II receptors, and TNFa in the mucosa of the small intestine in infants with food proteininduced entercolitis syndrome. J Allergy Clin Immunol 2002; 109: 150–4. 54 Pe´rez-Machado MA, Ashwood P, Thomson MA et al. Reduced transforming growth factor-b1-producing T cells in the duodenal mucosa of children with food allergy. Eur J Immunol 2003; 33: 2307–15. 55 Latcham F, Merino F, Winter C et al. A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy. J Pediatr 2003; 143: 39–47.
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88 Fiocchi A, Bouygue GR, Martelli A et al. Dietary treatment of childhood atopic eczema/dermatitis syndrome (AEDS). Allergy 2004; 59(Suppl 78):78–85. 89 Niggemann B, Reibel S, Wahn U. The atopy patch test (APT)–a useful tool for the diagnosis of food allergy in children with atopic dermatitis. Allergy 2000; 55: 281–5. 90 Forsyth BW. Colic and the effect of changing formulas: a doubleblind, multiple-crossover study. J Pediatr 1989; 115: 521–6. 91 Lucassen PL, Assendelft WJ, Gubbels JW et al. Infantile colic: crying time reduction with a whey hydrolysate: a double-blind, randomised, placebo-controlled trial. Pediatrics 2000; 106: 1349–54. 92 Iacono G, Cavataio F, Montalto G et al. Intolerance of cow’s milk and chronic constipation in children. N Engl J Med 1998; 339: 1100–4.
78 Wang HH, Mangano MM, Antonioli DA. Evaluation of T-lymphocytes in esophageal mucosal biopsies. Mod Pathol 1994; 7: 55–8. 79 Garcia-Zepeda EA, Rothenberg ME, Ownbey RT et al. Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med 1996; 2: 449–56. 80 Butt A, Murch S, Ng C-L et al. Upregulated eotaxin expression and Tcell infiltration in the basal and papillary epithelium in cow’s milk associated reflux oesophagitis. Arch Dis Child 2002; 86: 124–30. 81 Justinich C et al. Mucosal mast cells distinguish allergic from gastroesophageal reflux-induced esophagitis. J Pediatr Gastroenterol Nutr 1996; 23: 342–74. 82 Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 2000; 105: 860–76. 83 Sicherer SH, Sampson HA. Food hypersensitivity and atopic dermatitis: pathophysiology, epidemiology, diagnosis, and management. J Allergy Clin Immunol 1999; 104(3 Part 2):S114–22. 84 Hill D, Hosking C. Food allergy and atopic dermatitis in infancy. Paediatr Allergy Immunol 2004; 15: 421–7. 85 Niggemann B, Reibel S, Roehr CC et al. Predictors of positive food challenge outcome in non-IgE-mediated reactions to food in children with atopic dermatitis. J Allergy Clin Immunol 2001; 108: 1053–8. 86 Isolauri E, Turjanmaa K. Combined skin prick and patch testing enhances identification of food allergy in infants with atopic dermatitis. J Allergy Clin Immunol 1996; 97(1 Part 1):9–15. 87 Breuer K, Heratizadeh A, Wulf A et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy 2004; 34: 817–24.
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Practice points Adverse reactions to milk can cause a wide spectrum of presentations particularly in infancy, from the benign to the life-threatening Diagnoses of IgE-mediated milk allergy can be supported with validated tests (skin-prick test, milk-specific IgE) There are no validated tests to support the diagnosis of nonIgE-mediated milk allergy and thus dietary exclusion and reintroduction are required Any manipulation of a child’s diet must be done under the supervision of a paediatric dietician
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Adverse reactions to cows’ milk
introduced. The first of these formulas was introduced by Baron Justus von Liebig in 1867 and contained wheat flour, cows’ milk, malt flour and potassium bicarbonate. This soon had many competitors, and the first infant milk powder appeared in 1915. Later innovations focused on humanising the formulations to mimic breast milk as closely as possible. As the safety of cows’ milk preparations has improved with modern production methods, and hence the prevalence of their ingestion has increased, there has been an increase in adverse reactions to cow’s milk. Before considering these adverse reactions, it is worth clarifying the terminology used to describe them. Terms such as ‘food allergy’, ‘food intolerance’ and ‘food hypersensitivity’ are often used interchangeably even within the same publication, yet they may represent a disparate group of conditions. Even with the help of formal classifications, the use of different systems in the USA and Europe has added to the confusion. Modern classifications have divided adverse reactions to food into those that are immune mediated (food allergy) and those that are also reproducible but are not immune mediated (food intolerance).1 By requiring the reaction to be reproducible, food aversion (a psychological phenomenon that is not reproducible under blinded conditions) is thus excluded. Up to 30% of adults report adverse food reactions when surveyed, yet most of these are not reproduced on double-blind placebo-controlled food challenge,2 illustrating the high prevalence of food aversion. The European classification divides adverse food reactions into those that are due to toxins and would affect any exposed individual if ingested in sufficient quantities (toxic reactions) and those that affect susceptible individuals only (non-toxic).3 The latter group can be divided into reactions that are mediated by the immune system (food allergy) and those that are not (food intolerance). Revision of this latter classification has replaced the term ‘food intolerance’ with ‘non-allergic food hypersensitivity’.4 Despite clear classification systems, the term ‘food intolerance’ still represents, to many practitioners and public alike, the group of allergic reactions to food that are non-IgE mediated. The common use of the term ‘cows’ milk intolerance’ to describe nonIgE-mediated immunological reactions to cow’s milk illustrates this point well.5 Non-immunological reactions to food can be further subdivided into those that are due to enzymatic deficiencies or pharmacological reactions, and those that do not fit into either of these two. This review considers the spectrum of adverse reactions to milk, both allergy and intolerance (non-allergic hypersensitivity). There is also a brief review of some of the more controversial areas where symptoms may be inappropriately linked causally with milk consumption.
Adam T Fox Mike Thomson
Abstract Cows’ milk has been drunk by humans for almost 9000 years. It is of particular importance as a substitute for human breast milk. Milk ingestion can cause a spectrum of adverse reactions in children, including both immune-mediated (food allergy) and non-immunemediated (food intolerance) reactions. Immune-mediated responses include immediate, potentially life-threatening IgE-mediated milk allergy as well as non-IgE and mixed IgE/non-IgE manifestations of disease. This review examines the different types of response that cows’ milk ingestion may elicit and considers the different underlying mechanisms. New manifestations of adverse reactions, previously considered unrelated to dietary intake, are also considered.
Keywords allergy; eczema; food allergy; gastrointestinal allergy; lactose intolerance; milk
Introduction The use of cows’ milk as a beverage probably began around 9000 years ago with the domestication of cattle. The method for making cheese from milk was known to the ancient Greeks and Romans, and the use of milk and milk products spread throughout Europe in the following centuries. Current UK consumption is around 230 kg/person/year (Food and Agriculture Organisation of the United Nations), which includes the milk used in infant formulas. Human milk substitutes existed before the modern age of formulas. When infants could not be fed by their mothers, humans adopted two methods for substitute feeding. The first was a surrogate mother (e.g. wet nurse), who would feed the child human milk. The alternative was to feed the child milk obtained from another mammal. Until the end of the 19th century, the use of a wet nurse was by far the safest of these two methods. As general sanitation measures improved during the latter part of the 19th century, and as differences in composition between human milk and that of other mammals were defined, feeding animal milk became more successful. However, few infants survived until infant formulas based on cows’ milk, with added water and carbohydrate, were
Non-immune-mediated reactions to cows’ milk: lactose intolerance
Adam T Fox MA (Hons) MSc MRCPCH is Consultant in Paediatric Allergy at the Children’s Allergy Service, Evelina Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London SE1 7EH, UK.
Most dietary disaccharides are normally hydrolyzed and absorbed in the proximal portion of the small intestine. If there are insufficiencies in the enzymes (disaccharidases) required, the osmotic load of the luminal fluid may exceed critical levels.6–8 This stimulates the right colon to propel fluid onwards and
Mike Thomson MD FRCP FRCPCH Consultant in Paediatric Gastroenterology, Centre for Paediatric Gastroenterology, Sheffield Children’s Hospital, Western Bank, Sheffield S10 2TH, UK.
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causes the passage of frequent, fluid stools. In addition, some of the unabsorbed sugar is fermented by colonic bacteria, and the gas produced by this process leads to bloating and abdominal discomfort. The symptoms worsen with increasing disaccharide intake.9,10 The most common form of disaccharidase deficiency is primary adult hypolactasia, which is commonly known as lactose intolerance.11,12 In most of the human population (particularly darker-skinned races), lactase expression is genetically programmed to decline after infancy to only 5–10% of original levels.13 This pattern mirrors that seen in other mammals, where dependence on milk occurs only during infancy. Persistence of infant lactase levels is the norm only in Northern and Central European populations and the nomadic, milk-dependent populations of the arid zones of North Africa and Arabia.14 In these populations, only around 15% of individuals show a significant decline in lactase expression. In most Asian populations, low lactase levels are found in more than 90%.15 The age of presentation with symptoms of lactose intolerance varies between ethnic groups, but is dependent on the speed of decline in lactase and the amount of lactose ingested. Classically, the onset is around the beginning of the second decade of life (at approximately 10–14 years). The most common presentation is with diarrhoea, bloating and abdominal discomfort after drinking milk. Culture-containing milks are usually better tolerated due to lower lactose levels after fermentation. Avoidance of lactose-containing products or use of commercially available enzyme supplements before ingesting lactose is an effective treatment.16 Rarely, permanent lactose intolerance results from congenital lactase deficiency, presenting as severe diarrhoea in the neonatal period. This is commonly the label misused to describe gut-related allergic hypersensitivity to cows’ milk protein (CMP) in infancy, even by medical practitioners. Intolerance of lactose may occur transiently. Lactase is commonly expressed only in mature enterocytes at the tips of the villi. Any condition that increases the enterocyte migration rate (e.g. gastroenteritis), often inducing allergy to CMP and consequent villus inflammation, leads to fewer mature enterocytes at the villus tips. These enterocytes contain less lactase and thus lactose tolerance decreases in the post-enteritis period.
Spectrum of immune-mediated reactions to cows’ milk Disorder
IgE-mediated (acute onset) Cell-mediated (delayed onset/chronic)
Immediate allergy/anaphylaxis
Other underlying mechanisms
Cows’ milk protein-induced proctocolitis Cows’ milk protein-induced enteropathy Food protein-induced enterocolitis syndrome Allergic eosinophilic gastroenteropathy Cows’ milk protein -induced refluxassociated oesophagitis Food-sensitive eczema
Table 1
Eosinophilic oesophagitis Cow's milk protein allergy-induced reflux-associated oesophagitis
Eosinophilic gastroenteritis
FPIES
Cow’s milk protein induced enteropathy Eosinophilic gastroenterocolitis
Cow’s milk protein induced proctocolitis
Immune-mediated reactions to cows’ milk CMP allergy is the commonest food allergy in childhood.17 The incidence of CMP allergy in infancy seems to be approximately 2–3% in developed countries. However, symptoms suggestive of CMP allergy may be encountered in 5–15% of infants, emphasizing the importance of controlled elimination/milk challenge procedures.18 Allergy to cows’ milk presents with a broad range of clinical symptoms and syndromes (Table 1) (Figure 1). In addition to the well-recognised immediate-type IgE-mediated allergies, a more diverse range of more delayed presentations such as eczema and gastrointestinal symptoms such as reflux, colic, enteropathy and constipation are increasingly being considered as part of the spectrum of milk allergy.17 The mechanisms underlying such presentations do not appear to be IgE mediated and are poorly understood. They may be IgG mediated or T cell mediated, and in some cases remain
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Mechanism
Figure 1 Site of pathology in milk protein induced gastrointestinal food allergy
controversial. This review outlines briefly the most common presentations of CMP allergy. IgE-mediated reactions Immediate type 1 hypersensitivity reactions affect up to 8% of children, and cows’ milk is the most common causative allergen. Most cases of milk allergy present in the first year of life.19 Reactions usually occur within minutes of milk ingestion and range in severity from acute dermatological manifestations such as urticaria and angioedema to more severe, potentially lifethreatening anaphylaxis. Successful treatment of anaphylaxis relies on early administration of adrenaline, ideally by the
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intramuscular route.20 Fatal allergic reactions are relatively rare in children and are most commonly are caused by nuts,21 though fatal reactions to milk have occurred in young children. The presence of asthma, especially when not well controlled, is a major risk factor for severe reactions.22,23 The underlying mechanism in these type 1 hypersensitivity reactions is the release of histamine and other mediators from mast cells as a result of cross-linking of surface-bound IgE by an allergenic protein. b-Lactoglobulin, casein and a-lactalbumin are the major allergens in milk.24 There is a strong structural homology between milk proteins from different mammals, and clinical cross-reactivity to most mammal milks is seen in up to 90% of patients.25–27 Diagnosis of immediate cows’ milk allergy relies on the history and on IgE tests such as the skin-prick test or measurement of serum levels of specific IgE antibody to cows’ milk. In cases of diagnostic doubt, a standardised double-blind placebo-controlled food challenge is the gold-standard investigation. Interpretation of skin-prick tests and specific IgE tests is hampered when the patient Is sensitised to cows’ milk (i.e. specific IgE to milk is present) but does not have clinical symptoms when exposed. Sampson28 reported a specific IgE level in serum of 15 kU/litre to be 95% predictive of cows’ milk allergy in a population predominantly of children with atopic dermatitis. Other studies have used the skinprick test wheal size to predict the likelihood of clinical allergy.29,30 Although such threshold values are useful in practice, it is important to understand their limitations when applied to individuals from a different population to that used in a study. Infants with immediate cows’ milk allergy have usually outgrown the allergy within 2–3 years’ follow-up.19 Regular reevaluation and allergy testing helps the clinician to decide when the child has become tolerant, so that milk can be safely reintroduced. The risk of unpredictable IgE-mediated allergies dictates that reintroduction is attempted under controlled conditions.
diarrhoea (and vomiting).37 This may result in malabsorption and failure to thrive; thus, it is more important to make a firm diagnosis. The natural history is similar to that of other forms of non-IgE-mediated milk allergy, with presentation in infancy and resolution by 1–2 years. The underlying immune mechanism is unclear; there is no association with raised milk-specific IgE, T cell responses seem to be involved.38 The differential diagnosis includes infection, and the diagnosis is usually made on a combination of endoscopic small bowel biopsy histology (the findings of which are patchy in distribution and more subtle than in other enteropathies such as coeliac disease39) and the outcome of exclusion diets. Food protein-induced enterocolitis syndrome (FPIES): is a severe, cell-mediated, gastrointestinal food hypersensitivity, typically to cows’ milk and soy, that has been recognised for decades but has received relatively little attention.40–43 FPIES represents the severe end of the spectrum of milk allergy affecting the gut only. Conditions such as milk protein-induced proctocolitis, enteropathy and eosinophilic gastoenteropathy may all present with similar, overlapping features. The degree to which these conditions can be considered as discrete immunopathogenic entities remains unclear. While FPIES may simply represent the severe end of this spectrum of allergic gastroenteropathies, there are certain features of systemic reactivity and implications for long-term management that demand that it be considered separately.44 FPIES is characterised by severe, protracted diarrhoea and vomiting, most commonly following ingestion of cows’ milk or soy-based formula (50% of infants react to both),40 though solid food allergens are occasionally implicated.45 Progression can occur to a state of dehydration and cause shock in 20% of cases.40,45–47 The combination of vomiting, lethargy and resulting acidosis in the infant often leads to a diagnosis of sepsis, and the problem recurs when the allergen is reintroduced. Failure to recognise the link with diet may lead to multiple admissions to the ICU with supposed recurrent sepsis.45 A raised WBC count with a predominance of neutrophils is also consistently found in FPIES, further blurring the clinical picture. The presence of bloody diarrhoea may lead to suspicion of infectious diarrhoea, coagulation defects or intussusception by those who fail to appreciate the significance of the temporal association with a new food. The absence of fever, presence of eosinophilic debris in the stools and negative stool cultures can help to differentiate these conditions. Some patients with FPIES present with an insidious onset of chronic diarrhoea, vomiting and failure to thrive.48 In either presentation, symptoms resolve rapidly on a diet free of allergens. Patients with FPIES classically have no specific IgE and are negative on skin-prick testing. Endoscopy is often unhelpful as infants may remain well between challenges. Atypical cases have been described with detectable IgE to the causal protein and a more prolonged course of allergy.48 The diagnosis is based on clinical criteria with a standardised oral challenge if doubt remains.49 These criteria include the onset of exclusively gastrointestinal symptoms before 9 months of age that are consistently present on further exposures.50 Removal of the offending allergen should lead to rapid and complete resolution of symptoms. There are no reports of infants developing FPIES
Non-IgE-mediated reactions CMP-induced proctocolitis: is a disease of infancy that usually presents by 2 months31 and represents the benign end of the spectrum of non-IgE-mediated allergy to milk.32 Babies usually present with visible blood mixed with mucus in the stool, but are otherwise well and thriving.33 It is more common in, but not exclusive to, breast-fed babies whose mothers are ingesting cows’ milk or soy protein.33–35 Important differential diagnoses include infection and fissures. The diagnosis is usually made on the basis of a response to the exclusion of CMP, either from the lactating mother’s diet or by substitution by extensively hydrolysed formula. Bleeding should resolve in 72 hours, though persistent bleeding may respond to an amino acid formula.35 The underlying mechanism is unclear.32 Milk-specific IgE is typically negative and biopsy reveals distal colitis with an eosinophilic infiltrate.36 Resolution occurs sooner than in IgEmediated milk allergy, and most infants are tolerant by 1–2 years of age. Milk can be reintroduced safely at home, though it is prudent to confirm that the skin-prick test or specific IgE is negative before doing this, to ensure there is no risk of an IgEmediated reaction. CMP-induced enteropathy: unlike those with CMP-induced proctocolitis, infants with enteropathy usually have protracted
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differentiation from primary reflux has been suggested on the basis of an oesophageal pH testing pattern and a b-lactoglobulin antibody response, though the former has not been substantiated by more than one center.67,68 There is recent evidence that this oesophagitis is becoming a more common presentation of infant food allergy in the developed world, and may be induced by a variety of antigens in addition to cows’ milk.65,66 Many affected infants have become sensitised while exclusively breast-fed, and a defect in oral tolerance for low doses has been postulated as the underlying cause.69,70 Oesophageal mucosal eosinophilia has been described in both suspected cow’s milk-associated65 and primary reflux oesophagitis,71 as well as in other conditions such as idiopathic eosinophilic oesophagitis.72 However, the density of the eosinophilic infiltrate has been used as a differentiator between allergic esophagitis and eosinophilic oesophagitis, with the latter defined as more than 20 eosinophils per high-power field.73 The clinical significance of eosinophils and their role in the pathogenesis of mucosal injury is poorly understood and the subject of recent debate.74 Some authors have suggested an active role for eosinophils in the inflammatory process of oesophagitis and have supported this with the observation of activation of eosinophils on electron microscopy criteria.75 In addition to dietary exclusion of cows’ milk,65,67 oral corticosteroids can induce remission of symptoms with reduced mucosal eosinophilia,67,72 suggesting a patho-aetiological role for eosinophils. In addition to eosinophils, intraepithelial T lymphocytes, known as CINC (cells with irregular nuclear contours), have also been implicated as markers of reflux esophagitis.76,77 In adults, such cells are of memory phenotype and display activation markers,78 though little is known of their paediatric equivalents. Various immunohistochemical markers have been used to examine the oesophageal mucosa, including eotaxin, a recently described eosinophil-specific chemokine,79 and markers of T cell lineage and activation. Despite the mild histological abnormality in CMP-induced oesophageal pathology, increased expression of eotaxin co-localised with activated T lymphocytes to the basal and papillary epithelium has been shown,80 distinguishing this from primary reflux esophagitis. The molecular basis of the eotaxin up-regulation is unknown. It has also been suggested that increased numbers of mucosal mast cells allow a distinction to be made between allergy-induced and reflux-induced esophagitis.81 Much work is required in this area and is ongoing.
while exclusively breast-feeding. This contrasts with IgEmediated food allergies such as acute skin reactions, and non-IgE-mediated conditions such as dietary protein-induced proctocolitis, which have been attributed to passage of food protein through the breast milk.45 The pathophysiological immune basis for FPIES is poorly understood. Mucosal biopsies from children with challengeproven FPIES show increased tumour necrosis factor-a, a proinflammatory cytokine produced from food-sensitised T lymphocytes.51,52 This may increase intestinal permeability, contributing to the influx of antigen into the submucosa.51,52 Reduced expression of transforming growth factor beta (TGF-b), a cytokine critical in oral tolerance that induces T cell suppression, promotes B cell switching to IgA production and preserves epithelial barrier function, has also been noted.53 Impaired generation within the mucosa of TGF-b producing T cells has been identified in a further cohort of children with multiple food allergies,54 suggesting an underlying primary failure to establish oral tolerance mechanisms that may relate to insufficient innate immune response to early infectious exposures.54,55 The cornerstone of management in children with FPIES is careful exclusion under the supervision of a paediatric dietitian. Reports show that, 2 years from presentation, 60% and 25% of patients lose their sensitivity to cows’ milk and soy, respectively.50,56 Confirmation of resolution requires a carefully supervised food challenge with facilities to deal with the hypotension and shock that may arise.57 Other immune-mediated reactions Allergic eosinophilic gastroenteropathies: first described by Kaijser in 1937,58 this heterogeneous group of conditions includes eosinophilic oesophagitis, eosinophilic gastroenteritis and eosinophilic gastroenterocolitis. They represent a spectrum of pathologies with overlapping symptoms, all characterised by eosinophilic inflammation in the gut. They are classified according to the site of the inflammation,59 though it is the depth and severity of the symptoms that most influence the presenting symptoms.32 These conditions are clearly associated with the atopic phenotype, but the underlying mechanism remains uncertain.60 Local production of eotaxin, a potent eosinophil chemoattractant, appears to be pivotal.61 Use of combinations of allergy tests62 to guide dietary exclusion has had some success in the treatment of these conditions and is an important consideration alongside other treatments such as corticosteroids63 and leukotriene antagonists.64 Eosinophilic oesophagitis is the most common of these conditions and is best considered in the context of the broader role of cows’ milkinduced allergic inflammation in the oesophagus.
Food-sensitive eczema: atopic eczema is a chronic inflammatory skin disorder associated with raised serum IgE, allergen sensitisation and an atopic family history.82,83 While the association between eczema and immediate food allergies is easy to demonstrate, the possible role of dietary manipulation in the treatment of chronic eczema remains controversial. Hill et al.84 demonstrated that the likelihood of concomitant IgE-mediated food allergy increased with increasingly severe infantile eczema. A number of studies have used double-blind placebo-controlled food challenge to demonstrate that food allergens, most commonly CMP, can induce delayed eczematous reactions in children.85–87 However, attempts to show that dietary exclusion can objectively influence the course of atopic eczema have remained unconvincing. Attempts at meta-analysis of studies have been hampered by differences between them, such as the age of the
CMP-induced oesophageal pathology: although it is now clear that multiple food antigens may induce oesophagitis,65,66 the most common precipitant is CMP. Standard endoscopic biopsy and histology do not reliably distinguish between primary reflux esophagitis and the emerging clinical entity of CMP-associated reflux oesophagitis. This variant of cows’ milk allergy appears to be a particularly common manifestation in infancy (up to 42% of infants with gastro-oesophageal reflux disease), with symptoms that are indistinguishable from primary gastro-oesophageal reflux disease but which settle on an exclusion diet.67 Some
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patients, the foods excluded and the scoring systems used for eczema severity. A review of 14 interventional studies suggests that dietary interventions, when guided by allergy testing, were efficacious, especially in children under 2 years of age.88 Skin-prick testing and specific IgE blood testing may be helpful in detecting food allergy in children with eczema, but around 10% of positive double-blind placebo-controlled food challenges in these children were associated with negative results for both of these tests.85 The possible role of atopy patch-testing, which elicits T cell-mediated reactions, in improving the diagnostic accuracy in children with atopic eczema is currently of considerable interest.86,89 The need for different testing modalities reflects the mixed IgE-mediated and cell-mediated mechanism that appears to underlie this condition.
12 Dahlqvist A, Hammond JD, Crane RK et al. Intestinal lactase deficiency and lactose intolerance in adults: preliminary reports. Gastroenterology 1963; 45: 488–91. 13 Johnson JD. The regional and ethnic distribution of lactose malabsorption: adaptive and genetic hypotheses. In: Paige DM, Bayless TM (eds): Lactose digestion: clinical and nutritional implications. Baltimore: Johns Hopkins University Press, 1981. p. 11–22. 14 Simoons FJ. Geographic patterns of primary adult lactose malabsorption. In: Paige DM, Bayless TM (eds): Lactose Digestion: clinical and nutritional implications. Baltimore: Johns Hopkins University Press, 1981. p. 23–48. 15 Sahi T. Genetics and epidemiology of adult-type hypolactasia. Scand J Gastroenterol 1994; 202: 7–20. 16 Tamm A. Management of lactose intolerance. Scand J Gastroenterol Suppl 1994; 202: 55–63. 17 Heine RG, Elsayed S, Hosking CS et al. Cow’s milk allergy in infancy. Curr Opin Allergy Clin Immunol 2002; 2: 217–25. 18 Host A. Frequency of cow’s milk allergy in childhood. Ann Allergy Asthma Immunol 2002; 89(6 Suppl 1):33–7. 19 Host A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Allergy 1990; 45: 587–96. 20 Sampson HA. Anaphylaxis and emergency treatment. Pediatrics 2003; 111: 1601–8. 21 Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy 2000; 30: 1144–50. 22 Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin Immunol 2001; 107: 191–3. 23 Sampson HA, Mendelson LM, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992; 327: 380–4. 24 Wal JM. Cow’s milk allergens. Allergy 1998; 53: 1013–22. 25 Restani P, Gaiaschi A, Plebani A et al. Cross-reactivity between milk proteins from different animal species. Clin Exp Allergy 1999; 29: 997–1004. 26 Spuergin P, Walter M, Schiltz E et al. Allergenicity of alpha-caseins from cow, sheep, and goat. Allergy 1997; 52: 293–8. 27 Bellioni-Businco B, Paganelli R, Lucenti P et al. Allergenicity Of goat’s milk in children with cow’s milk allergy. J Allergy Clin Immunol 1999; 103: 1191–4. 28 Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001; 107: 891–6. 29 Eigenmann PA, Sampson HA. Interpreting skin prick tests in the evaluation of food allergy in children. Pediatr Allergy Immunol 1998; 9: 186–91. 30 Hill DJ, Heine RG, Hosking CS. The diagnostic value of skin prick testing in children with food allergy. Pediatr Allergy Immunol 2004; 15: 435–41. 31 Odze RD, Bines J, Leichtner AM et al. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Human Pathol 1993; 24: 668–74. 32 Sicherer SH. Clinical aspects of gastrointestinal food allergy in childhood. Pediatrics 2003; 111(6 Pt 3):1609–16. 33 Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast fed infants. J Pediatr 1982; 101: 906–10. 34 Pumberger W, Pomberger G, Geissler W. Proctocolitis in breast fed infants: a contribution to differential diagnosis of hematochesia in early childhood. Postgrad Med J 2001; 77: 252–4.
Others: as the spectrum of presentations ascribed to milk allergy increases, some areas remain contentious. Infantile colic has been shown to respond to extensively hydrolysed milk formulas in some studies,90,91 suggesting a possible role of food allergy. Infantile colic is poorly understood, and though allergy may have a role it is unlikely to be more than one of a number of important influences. Iacono et al.92 suggested a role for milk exclusion in the treatment of children with constipation that was unresponsive to conventional treatments. The response was most marked in atopic children with raised specific IgE to milk. The role of CMP as a cause of colonic dysmotility leading to ~ constipation requires further investigation.
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Practice points Adverse reactions to milk can cause a wide spectrum of presentations particularly in infancy, from the benign to the life-threatening Diagnoses of IgE-mediated milk allergy can be supported with validated tests (skin-prick test, milk-specific IgE) There are no validated tests to support the diagnosis of nonIgE-mediated milk allergy and thus dietary exclusion and reintroduction are required Any manipulation of a child’s diet must be done under the supervision of a paediatric dietician
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